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Catalytic Antibodies May Contribute to Demyelination in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
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  • Michael Anthony Jensen*
    Michael Anthony Jensen
    Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
    *Email: [email protected]. Tel: 650 721 5477. Fax: 650 812 1975.
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    Orcidhttps://orcid.org/0000-0001-9230-1027
  • Miranda Lee Dafoe
    Miranda Lee Dafoe
    Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
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  • Julie Wilhelmy
    Julie Wilhelmy
    Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
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  • Layla Cervantes
    Layla Cervantes
    Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
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  • Anna N Okumu
    Anna N Okumu
    Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
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  • Lucas Kipp
    Lucas Kipp
    Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California 94304, United States
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  • Mohsen Nemat-Gorgani
    Mohsen Nemat-Gorgani
    Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
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  • Ronald Wayne Davis
    Ronald Wayne Davis
    Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
    Department of Genetics, Stanford University, Palo Alto, California 94304, United States
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Biochemistry

Cite this: Biochemistry 2024, 63, 1, 9–18
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https://doi.org/10.1021/acs.biochem.3c00433
Published November 27, 2023

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Abstract

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Here we report preliminary data demonstrating that some patients with myalgic encephalomyelitis/chronic fatiguesyndrome (ME/CFS) may have catalytic autoantibodies that cause the breakdown of myelin basic protein (MBP). We propose that these MBP-degradative antibodies are important to the pathophysiology of ME/CFS, particularly in the occurrence of white matter disease/demyelination. This is supported by magnetic resonance imagining studies that show these findings in patients with ME/CFS and could explain symptoms of nerve pain and muscle weakness. In this work, we performed a series of experiments on patient plasma samples where we isolated and characterized substrate-specific antibodies that digest MBP. We also tested glatiramer acetate (copaxone), an FDA approved immunomodulator to treat multiple sclerosis, and found that it inhibits ME/CFS antibody digestion of MBP. Furthermore, we found that aprotinin, which is a specific serine protease inhibitor, specifically prevents breakdown of MBP while the other classes of protease inhibitors had no effect. This coincides with the published literature describing catalytic antibodies as having serine protease-like activity. Postpandemic research has also provided several reports of demyelination in COVID-19. Because COVID-19 has been described as a trigger for ME/CFS, demyelination could play a bigger role in patient symptoms for those recently diagnosed with ME/CFS. Therefore, by studying proteolytic antibodies in ME/CFS, their target substrates, and inhibitors, a new mechanism of action could lead to better treatment and a possible cure for the disease.

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Introduction

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Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex, multisystem disease that is often characterized by postexertional malaise (PEM); (1,2) even minor activity can cause the patient to experience a 'crash' in physical and/or mental energy. However, symptoms experienced by these patients fall along a broad spectrum ranging from mild to severe (e.g., bedridden). Therefore, to properly diagnose the patient as having ME/CFS, a clinician refers to a checklist of conditions specific to the disease such as those outlined in the Canadian Consensus Criteria (CCC). (3) For example, the CCC considers a patient to have ME/CFS if they present with symptoms of reduced energy levels, PEM, interrupted sleep patterns, muscle pain and weakness, as well as two or more autonomic, neuroendocrine, and immune manifestations.
Since the 1980s, there has been considerable research comparing healthy controls and patients with ME/CFS where several abnormalities of the autonomic and central nervous system (CNS) have been correlated with positron emission tomography studies, revealing vast neuroinflammation. (4) Oxidative stress has also been linked to ME/CFS, (5) which may negatively impact the metabolic and immune systems, as well as contribute to increased blood–brain barrier (BBB) permeability (6) allowing the passage of larger blood components including antibodies (Abs) and other immune cells into the CNS. (7)
Autoimmunity, which has been reported in people with ME/CFS, (8) results from diminished self-tolerance where more self-antigens are seen as foreign substrates. For example, fatigue, which is correlated with PEM in ME/CFS, occurs as a major symptom in other autoimmune, mitochondrial, and infectious diseases; (9,10) therefore, PEM in ME/CFS may be the result of poor self-tolerance combined with microbial exposure involving molecular mimicry. (11−13)
Symptoms of ME/CFS also overlap with those of other autoimmune diseases, in particular, multiple sclerosis (MS). (14) MS is an inflammatory disease of the CNS primarily characterized by demyelination, which is the breakdown of the myelin sheath, leading to impaired signal transmission along the axon. (15) Here, myelin basic protein (MBP), which maintains the integrity of the myelin sheath in the healthy CNS, dissociates from the membrane during citrullination. (16) As a consequence, MBP and its fragments are then free to enter the cytoplasm, general blood supply, (17) and cerebral spinal fluid where they can trigger an autoimmune response.
Demyelination may also be a common denominator with ME/CFS where some patients experience symptoms of muscle pain and weakness as a results of diminished nerve function. (18) To strengthen this idea, there are several reports of abnormal brain magnetic resonance imagining (MRI) studies in patients with ME/CFS. (19−25) Based on images with white/gray matter hyperintensities and cerebral atrophy, Cook et al. found that ME/CFS patients had a higher level of physical impairment (motor and cognitive functions) compared to patients with normal MRI scans. (26,27) Furthermore, there is a growing body of literature on COVID-related research postpandemic (e.g., Long-COVID) that makes a strong connection to ME/CFS; (28) this suggests that COVID-19 infection may act as a precursor/trigger for ME/CFS. Demyelination in particular, which has been reported numerous times in cases of COVID-19, (29−32) may play a larger role in neurological-related symptoms in patients recently diagnosed with ME/CFS.
One contributing factor to demyelination may be catalytic Abs, also called abzymes (antibody + enzyme), that specifically target and digest MBP. (33) While abzymes (Abzs) are nearly indistinguishable from the typical Ab structure, they exhibit protease-like activity, which can be naturally or artificially induced. For example, Jencks pioneered an engineered antibody to have catalytic properties through binding to a stable transition-state analogue (TSA), (34) and then Schultz and Lerner further developed this research and became leaders in this specialty area of enzymology. (35) Catalytic Abs can also be synthesized using the TSA to perform specific functions. In one such case, Landry et al. demonstrated the production of anticocaine Ab conjugates, which exhibit cocaine benzoyl ester hydrolysis to reduce drug addiction. (36,37) Furthermore, catalytic Abs have been developed for therapeutic purposes, (38) including selective catalytic cleavage by IgM Ab of the HIV coat protein gp120. (39,40)
Naturally occurring Abzs, on the other hand, were discovered by Paul in 1989. (41) Since then, many catalytic Ab types have been identified, including those that target MBP in MS (42) and the neuropeptide vasoactive intestinal peptide in pregnant women with asthma. (43) In addition to peptides and proteins, Abzs have been shown to hydrolyze other substrates including polysaccharides, DNA, and RNA. (44,45) While a low catalytic rate and high substrate affinity have proved a challenge for chemists to design function-specific TSA Abzs, these properties have given clinical researchers the unique perspective of how certain autoimmune pathologies could result from long-term tissue damage as in the case of demyelination. One way catalytic MBP-Abs may cause damage is by directly binding to the neuronal tissue and hydrolyzing basic protein in situ; evidence supporting this has been provided by immunocytochemical studies showing that MBP-specific Abs were localized on the axon during active demyelination. (46)
In this report, we demonstrate Abs isolated from ME/CFS blood plasma appear to have proteolytic activity that targets the breakdown of MBP. Given the overlap with long COVID/MS neuropathies, catalytic MBP-Abs may contribute to symptoms of muscle weakness and nerve pain in some patients with ME/CFS, which could be the result of demyelination.

Materials and Methods

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Patient Samples

ME/CFS patient blood was collected at the Stanford Genome Technology Center (SGTC) in a Vacutainer K2 EDTA tube (BD) and then centrifuged at 1200g. The plasma was aspirated from the top layer, transferred to a 1.2 mL cryovial (Nunc) and flash frozen in liquid nitrogen and stored at −80 °C. MS samples were also provided by the Department of Neurology and Neurological Sciences at Stanford. All ME/CFS patients were diagnosed by licensed clinicians using CCC. We collected total plasma Abs from 19 ME/CFS, 19 HC, and 3 MS patients (male and female), whose ages ranged from 18 to 69 years.

Sample Preparation

Patient plasma samples stored at −80 °C were slowly thawed to room temperature (RT) and then kept at 4 °C during Ab (immunoglobulin (IgG)) collection. Total Abs were isolated by protein-A Sepharose beads, which preferentially capture human IgG1, 2, 4, and IgM/A (Thermo Fisher Scientific, Cat. 101041). Samples were collected with glycine IgG elution buffer (Thermo Fisher Scientific, Cat: 21004); 100 μL of protein-A beads was washed with 25 mM tris-HCL, pH 7.4. The beads were combined with 100 μL of plasma and 300 μL of 25 mM tris-HCL, incubated for 30 min at 4 °C (20 rotations per minute (RPM)), and then washed 5× with 25 mM tris-HCL, pH 7.4; this was followed by 2× collections with 250 μL of elution glycine IgG elution buffer (5 min at 4 °C). Samples were immediately neutralized to ∼pH 7 with 1 M tris, pH 9, followed by 2 buffer exchanges with 25 mM tris-HCL, pH 7.4. Samples were then concentrated using 0.5 mL of 50k molecular weight cutoff (MWCO) Pierce protein concentrators PES (Thermo Fisher Scientific, Cat. 88512). Finally, total Ab yield was determined for each sample with the Nanodrop OneC (Thermo Fisher Scientific) and then normalized to ∼1.5 μg/μL using 25 mM tris-HCL. Some sample aliquots were kept at 4 °C during initial testing, while backup aliquots were stored at −20 °C (in 50% glycerol).

Digest Assays

For all digest assays, 3 μg of each ME/CFS total Abs was added to 25 mM tris-HCL, pH 7.4, to a final volume of 12.5 μL. We used 1 μg of bovine brain (Thermo Fisher Scientific, Cat. 13228010, lot: 2397969) as the substrate (Note: bovine MBP is 93% homologous with human MBP, (47) and only two amino acids differ between the four immunodominant MBP-derived peptides [12–31, 82–98, 110–128 and 144–169]); (48) the encephalitogenic peptide region (86–98), however, is conserved between the two species. Bovine brain MBP has been used as a substrate for other catalytic Ab studies (49) and for inducing experimental autoimmune encephalitis (EAE) for the study of MS in humans. (50) Digest reactions were incubated in a Veriti thermal cycler (96-well) for 24 h at 37 °C and then cooled to 4 °C. Twenty-four hours was chosen as the incubation period based on previous literature studying Abz digest activity. (42) All MBP controls were treated under the same conditions as those of the Ab test samples.

High-Performance Liquid Chromatography (HPLC) Analysis, Copaxone Fractionation, and Ab Purification

Size-exclusion HPLC was used to further purify Abs after collection by protein-A Sepharose beads. The key system modules used included: Agilent 1200 Fraction collector (G1364C), Agilent 1100 HiP well plate autosampler (G1367A), Agilent 1100 diode array detector (G1315B), and Chemstation software for sample processing and chromatogram analysis. Abs were fraction-collected using the Superdex-200 Increase 10/300 GL (Cytiva, 28990944) at the flow rate of 0.7 mL/min with running buffer: 50 mM sodium dihydrogen phosphate and 150 mM sodium chloride, pH 7.4. Glatiramer acetate (GA) was also fractionated using size-exclusion chromatography with a YARRA SEC-2000 column (Phenomenex, Cat. 00H-4512-E0). Samples were processed at 1 mL/min with the running buffer: 100 mM potassium phosphate and 200 mM potassium chloride at pH 6.8, RT. For Ab fractionation, we used a protein standard mix as a reference chromatogram with samples ranging in size from 15k to 600k Da (Sigma Aldrich, Cat. 69385). In addition, we used a standard polyclonal Ab as a control (Thermo Fisher Scientific, Cat. PA1–10008) to match the chromatogram peak data with our test Ab samples.

Polyacrylamide Gel Electrophoresis (PAGE)

Postdigest/inhibition assay samples (12.5 μL) for PAGE analysis were mixed with 7.5 μL of Novex tricine SDS sample buffer (2×) (Thermo Fisher Scientific, Cat. No. LC1676) and then loaded into the wells of a Novex 16% tricine gel (Thermo Fisher Scientific, Cat. EC66952BOX); each gel was run in XCell SureLock mini cell (Invitrogen) for 45 V 30 min, 90–128 V 2 h. For gels stained with coomassie blue, we followed the manufacturer’s recommended protocol (Invitrogen, Cat. LC6025). All destained gels (24–48 h in deionized water) and fluorescence images with FITC-labeled MBP (495, 519 nm) were scanned using Go Gel Imaging System with Image Lab Touch (Bio-Rad).

MBP FITC Labeling (Copaxone Study)

Fluorescein isothiocyanate (FITC) (Thermo Fisher Scientific, Cat. F1906) was dissolved in dimethyl sulfoxide to yield 5 μg/μL; 1 μL of FITC (5 μg/μL) was added to 99 μL of MBP solution (2.5 μg/μL) plus 18.8 μL of 0.67 M borate and 31.2 μL of RNase/DNase-free ultrapure water for a total volume of 150 μL and a final pH of 8.5. The light-sensitive solution was added to a black 1.5 mL Eppendorf tube, mixed, and rotated at 20 rpm at RT for 60 min (minute). The reaction was then purified 2× using 7k MWCO Zeba protein spin desalting columns (Thermo Fisher Scientific, Cat. 89882) at 300g at RT using an Eppendorf centrifuge 5420 for 2 min to remove unincorporated FITC.

Miscellaneous Substrate Digest

To test whether Ab-substrate proteolysis was specific for MBP, we compared digest assays using the following substrates: casein (Thermo Fisher Scientific, Cat. AAJ6421422), MBP (Thermo Fisher Scientific, Cat. 13228010), α-lactalbumin (Sigma Aldrich, Cat. L5385), and lysozyme from chicken egg white (Sigma Aldrich, Cat. L6876); 1 μL (1 μg/μL) each was added to 9.5 μL 25 mM Tris-HCL (pH 7.4) and 2 μL (1.5 μg/μL) plasma Ab and incubated at 37 °C for 24 h, and 7.5 μL sample buffer was added and then run on PAGE.

Relative Activity Assays

To measure percent relative activity (dependence of the relative MBP-hydrolyzing activity of ME/CFS Abs based on their concentration), we tested Abs from various ME/CFS patients and healthy controls (HC) at 0, 0.5, 1, 1.5, and 2 μg total Ab with 1 μg MBP; 25 mM Tris-HCL (pH 7.4) was added to each for a final volume of 12.5 μL, incubated for 24 h at 37 °C, then run on 16% tricine SDS-PAGE, and stained with coomassie blue. Gels were imaged using the Go Gel Imaging System, and band intensities were analyzed using the Gel Analyzer software. Only the top bands at ∼18,400 Da were measured for disappearance relative to the control MBP substrate (no Ab addition). All assays were done in duplicate, and their results averaged.

Determination of Ab Purity after Elution from Protein-A Beads

To show purity of Ab mix after collection from protein-A Sepharose beads, we ran Ab preparations (5 μg each) on PAGE under reducing and nonreducing conditions. Here we used Novex 4–12% tris-glycine mini gels (Thermo Fisher Scientific, Cat. XP04120BOX) along with SDS-glycine running buffer and 4× glycine SDS sample buffer (Thermo Fisher Scientific, Cat. LC2672); 10× NuPAGE sample reducing agent was purchased from Invitrogen (NP0009).

Abzyme Inhibition Assays by Glatiramer Acetate (GA) and Its Fractions

GA (pharmaceutical brand name, copaxone) was purchased from Best of Chemical Sciences (molar ratio E(0.14), K(0.34), A(0.43), Y(0.09), average molecular weight (Mw) 9161 Da, Cat. 147245–92–9) and concentrated according to each assay parameter starting at 100 μM in water. Random peptides were also tested in the digest/inhibition assay to determine if GA was specific for inhibiting Abz activity. These included human YY peptide (IKPEAPGEDASPEELNRYYASLRHYLNLVTRQRY-NH2, Sigma Aldrich, Cat. P1306) at 4310 Da, human gastrin releasing peptide (VPLPAGGGTVLTKMYPRGNHWAVGHLM-NH2, Sigma Aldrich, Cat. G8022) at 2860 Da, and human influenza hemagglutinin peptide (YPYDVPDYA-NH2, Sigma Aldrich, Cat. I2149) at 1102 Da. Each was added to the assay at a 30 μM final concentration.

Affinity Purification

CNBr-activated Sepharose 4 Fast Flow (Cytiva 17-0981-01) was used to conjugate bovine brain MBP to the resin (following the manufacturer’s protocol). Total ME/CFS Ab samples were added to the column, incubated for 1 h at RT, and then washed. The supernatant (random Abs that did not bind to MBP on column) was first collected, and then Abs captured on the column were eluted with glycine buffer (pH 3.0); because low pH can potentially damage the Ab function, samples were immediately neutralized to ∼7 by adding 1 M tris-HCL pH 9, normalized to ∼1.5 μg/μL, and then stored at 4 °C for renaturation.

Protease Inhibitor Test

To determine if catalytic Abs in ME/CFS belonged to a specific class of proteases, we compared four protease inhibitors, (1) aprotinin (Sigma Aldrich, Cat. A6106), which is a serine protease inhibitor, (2) bestatin (Sigma Aldrich, Cat. B8385), which is an amino peptidase inhibitor, (3) E-64 (Sigma Aldrich, Cat. 324890), which is a cysteine protease inhibitor, and (4) pepstatin (Sigma Aldrich, Cat. 11359053001), which inhibits aspartic acid proteases; each was added at 0.1 and 0.01 μg/μL final concentration to the digest assays (3 μg of Ab and, 1 μg of MBP in, and 25 mM tris-HCL, pH 7.4) where ME/CFS patient Ab samples previously showed break down of MBP.

Results and Discussion

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Given the vast overlap in symptoms with MS (14) along with increasing reports of abnormal brain MRIs suggesting white matter disease in ME/CFS, (23) muscle weakness and nerve pain as experienced by some patients may be the result of demyelination. With numerous studies of catalytic Abs in MS and other autoimmune diseases, we decided to isolate Abs from ME/CFS plasma to determine whether they too showed proteolytic activity toward MBP.
For this study, we compared 19 ME/CFS and 19 healthy control plasma samples. Abs were also collected from MS patients for method development and as a metric for expected digestion of MBP (Figure 1, “MS”, 39–41). Here, we performed digest assays with Abs purified from plasma in addition to MBP as the target substrate (Figure 1). The level of MBP digested (disappearance of the target band “MBP” at ∼18,400 daltons) was compared to the control MBP with no Ab. Within the ME/CFS samples tested for this particular set, 47% showed to digest MBP (e.g., Figure 1, 'ME/CFS' samples 11–19), while in the healthy control group, 5% of the samples also showed digestion of MBP (e.g., Figure 1, 'HC' sample 30). Though other reports have found catalytic Abs in healthy individuals, the extent of activity is believed to be limited or below the threshold of causing pathology. (51) In addition, we suggest a few possible clinical explanations for the HC Ab digestion of MBP in this study: HC donor (1) may show digest of MBP only with in vitro conditions, but actual Abz levels, if active in vivo, were below threshold of disease (though, a clinical threshold has not been defined for catalytic Abs), (2) is at the beginning stages of demyelination, or (3) has a viral infection (asymptomatic) or was vaccinated around the time blood was collected (a recent report showed high cross-reactivity between SARS-CoV-2 and human tissue, in particular, MBP (52)). Furthermore, those ME/CFS patients whose plasma Ab samples did not breakdown MBP (Figure 1, 'ME/CFS' samples 1–10) may have symptoms unrelated to demyelination. For example, they may be experiencing symptoms more related to general malaise and fatigue as might be caused by poor energy levels due to oxidative stress and mitochondrial dysfunction. (5) More extensive demographics at the initial patient blood draw including a current list of specific symptoms, their relative severity, and whether they are acute, chronic, or relapse-remitting, would also help with the interpretation of these results.

Figure 1

Figure 1. PAGE image comparing digestion of MBP by Abs collected from 19 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), 19 healthy control (HC), and 3 multiple sclerosis (MS) patients. Numbers at the bottom are assigned to each donor sample ('C' is control (only MBP, no Ab)). Samples where Abs were further fractionated using HPLC then tested again in a separate digest assay are denoted with 'f'.

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It is interesting to note as well that the MBP digest band patterns between ME/CFS and HC/MS as shown in Figure 1 appear to be different but consistent within each group. Additional studies including sequence analysis of the digest fragments are required to determine the exact substrate cleavage sites. This information could help further validate/characterize Abz properties found in ME/CFS compared to those in healthy controls and MS patient plasma samples.
We next tested three additional substrates to determine if the breakdown of MBP was more substrate-specific or the result of random proteolysis. As shown in Figure 2A, Abs from ME/CFS_11 only digested MBP and not the other substrates tested (casein, α-lactalbumin, and lysozyme). Both casein and MBP are considered unstructured proteins because they do not contain disulfide bridges; as such, the peptide sequences of both substrates are highly exposed in an aqueous medium. Furthermore, casein is a very common substrate used for standard digest assays and is particularly susceptible to hydrolysis by trypsin (serine protease). Though we tested only three substrates that were not digested, there could be others with equal or greater Abz specificity than what was found for MBP in this study. For example, there are reports of substrate-specific Abs in ME/CFS with affinity to human insulin, collagen type IV, γ-interferon, pulmonary elastin, S100 protein, and DNA. (53) In addition to MBP, Vojdani and Kharrazian showed that several substrates were also cross-reactive to SARS-CoV-2, including alpha-myosin and actin. (52)

Figure 2

Figure 2. (A) Digest assay comparison between MBP and random substrates: (1) casein, (2) MBP, (3) α-lactalbumin, and (4) lysozyme; each set shows +/− Abs from ME/CFS_11 patient, (B) kinetics of ME/CFS_11 Abs showing correlation/percent relative activity (% RA) of MBP breakdown with increasing Ab concentration, and (C) PAGE image of ME/CFS_11 Ab with (I) nonreducing and (II) reducing conditions after protein-A purification to demonstrate Ab purity; first lane is a protein ladder. Further densitometry analysis of the digest assay (A) comparing the MBP bands +/– Ab showed the target full-length product (∼18,400 Da) for each to be 687 and 1305 (dpi), respectively. All substrates (+/– Ab) were incubated at 37 °C for 24 h.

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When we tested ME/CFS_11 for the percent relative digest activity of MBP (% RA) (Figure 2B), we found a strong correlation between catalytic activity and Ab concentration, which is expected in a typical protease kinetics assay. Additionally, Figure 2C demonstrates general ME/CFS, HC, and MS Ab purity following protein-A purification. Under nonreducing conditions, the intact Ab migrates to ∼ 150k Da on PAGE, while under reducing conditions, the same Ab is separated into heavy and light chains (∼55k and 25k Da, respectively). These results show that (1) the Ab structure is maintained during collection and (2) no other bands are visible on the gel that would suggest benon-Abz protease contamination is responsible for the breakdown of MBP during the digest assays.
To further purify the Ab samples, we help rule out help rule out possible protease involvement, we ran them through a Superdex-200 column using HPLC size-exclusion chromatography following protein-A purification. For example, in Figure 3A, six fractions were collected from patient ME/CFS_11’s total Ab plasma sample based on time points of a reference chromatogram (corresponding PAGE image above shows the post-digest assay with each fraction). Here, breakdown of MBP was observed only with the intact Ab in fraction 2 (major peak at 7.185 min). If any proteases were present, digest products would have been expected in fractions 4 or 5 (e.g., cysteine, serine, aspartyl, and aminopeptidase proteases range between 23 and 34k Da).

Figure 3

Figure 3. (A) Digest assay with ME/CFS_11 after HPLC fraction-collection of intact Ab using the Superdex-200 column. After protein-A purification, the sample was processed with HPLC and fraction-collected in six fragments (the chromatogram of Ab sample shows vertical bars separating each fraction corresponding to PAGE image of the postdigest assays above). (B) Digest assay following affinity purification of total Abs collected from ME/CFS_15 plasma sample; lane 1 shows unbound nonspecific Abs from the wash step, and lane 2 shows MBP-specific Abs captured and eluted from the resin conjugated with MBP.

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In Figure 3B, MBP was conjugated to CNBr-activated Sepharose 4B resin in a column (affinity precipitation (ppt)), which was used to capture only Abs from ME/CFS_15 plasma that had affinity for MBP. Here, we compared the wash solution (random Abs that did not bind to the resin) with the captured Abs (bound to the resin). It is clear in the PAGE image (Figure 3B, lane 1) that none of the Abs from the wash solution digested MBP. However, MBP-specific Abs from ME/CFS_15 eluted from the resin showed a significant breakdown of MBP (Figure 3B, lane 2).
While Ab binding to the MBP-conjugated resin in our study was expected to be very strong (high affinity/low Kd, which is a characteristic property of Abzs), we first attempted mild elution conditions to recover the Abs/Abz from the resin (e.g., gentle elution (pH 6.8), 1 M KCL, 1 M NaCl); however, only glycine (pH 3) was effective. Recovery yields (nonbinding, MBP-binding Abs) ranged from 4.7, 0.303 to 1.1, 0.147 μg/μL, respectively. For each digest assay, we used 3 μg of nonbinding Ab (from wash step) and 4 μL of eluted Ab and 1 μg MBP (24 h, 37 °C).
Because affinity elution is a very delicate process for standard substrate-specific Ab collection, recovery of Abs with catalytic activity is even more challenging. Abs are very sensitive to extreme pH changes, especially those with enzymatic properties, which could be irreversibly damaged. (44) Though Abs/Abzs may be renatured to some degree by dialysis/pH adjustment to ∼7, followed by refrigeration (4 °C), incubation times are sample-dependent.
Next, we tested whether glatiramer acetate (GA), which is an immunomodulator drug (pharmaceutical brand name copaxone) used to treat MS patients, (54) also inhibited catalytic Abs isolated from ME/CFS plasma that breakdown MBP. In Figure 4A, the first bar in the graph shows the MBP control at 100%; when antibodies from patient sample ME/CFS_11 were added, 68% of MBP was digested (second bar). With the addition of glatiramer acetate, a majority of the MBP remained intact (80%). We believe that peptides from the drug acted as pseudo-MBP substrates that helped block catalytic ME/CFS_11 Abs from digesting MBP. Due to the molecular weight similarities between peptides from GA and MBP and its fragments, MBP was FITC-labeled to distinguish the two during fluorescence imaging. We also processed samples with a HC sample + GA, MBP + GA, and GA only, and the results showed no change in band intensity between HC and MBP, and GA alone was not visible with fluorescence (data not shown). To further validate the specificity of GA to prevent ME/CFS Abz breakdown of MBP, we found that the drug does not inhibit the general proteolytic activity of trypsin (data not shown).

Figure 4

Figure 4. (A) Digest assay with ME/CFS_11 (Figure 1) before and after addition of whole glatiramer acetate (GA), 30 μM final; (B) GA fractionated using size-exclusion chromatography (top chromatogram with fraction demarcations (vertical lines)) corresponding to degree of inhibition in the bar graph directly below for sample ME/CFS_11; (C) comparison of four class-specific protease inhibitors on preventing ME/CFS_12 Ab digest of MBP; each inhibitor was tested at 0.1 and 0.01 μg (1.22 and 0.122 μM final, respectively); and (D) digest assay comparing inhibition by GA and three random peptides: (1) MBP only, (2) ME/CFS_12 Ab + MBP, (3) GA (30 μM), (4) peptide YY, (5) gastrin releasing peptide, and (6) influenza hemagglutinin peptide (each at 30 μM final concentration with 3 μg Ab and 1 μg MBP).

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GA, which is a complex mixture of peptides (∼1036) that share physical properties with the MBP structure, (55) has three proposed mechanisms of action against neuroinflammation in vivo. Peptides from GA may (1) directly compete with fragments of MBP at the junction between the antigen presenting cell’s major histocompatible complex II and the T-cell receptor; this in turn down-regulates T-cell activation and polyclonal expansion of MBP-specific Abs, (56) (2) act as a competitive ligand, which inhibits MBP from binding to the αMβ2 integrin, (57) and (3) compete with Abzs in proximity to intact axonal MBP. (46) It is worth noting here as well, though the BBB is highly substrate-selective with a small number of sequence-specific peptide transporters, (58) systemic inflammation, as in MS and ME/CFS, may cause increased BBB permeability allowing leakage of GA; animal studies monitoring radio-labeled peptides of GA after injection showed some fragments actually reached the CNS. (59) Furthermore, Nevinsky et al., demonstrated proteolytic activity of MBP-Abs collected from MS plasma and cerebral spinal fluid (CSF) was also inhibited by GA in vitro. (44)
Next, we fractionated GA into four equal subsets (25% each of the peptide mix) based on HPLC size-exclusion chromatography. We used ME/CFS_11 in a separate digest assay (Figure 4B), which was shown to break down 70% of the MBP substrate (second bar); and when total GA was included, none of the substrate was digested. However, when we added the individual fractions to separate digest assays, fractions 3 and 4 (lower Mw peptides < 9161 Da) were not as potent as fractions 1 and 2 (higher Mw > 9161 Da) in preventing digestion of MBP. As a control, we tested three random peptides with varying Mws (peptide YY, 4310 Da; gastrin releasing peptide, 2860 Da; and influenza hemagglutinin peptide, 1102 Da) and found none had any inhibitory effect (Figure 4D). These results also coincide with those in Figure 4B where the lower Mw peptides appeared to have less potency in protecting MBP from being digested. However, a more extensive study of GA and its fractions might help determine if higher molecular weight peptides in general prevent breakdown of MBP in patients with ME/CFS. We also note here that 30 μM GA in our digest assays (24 h at 37 °C) is significantly more than what is initially administered by injection to a patient (e.g., 20 or 40 mg GA/dose); typically, injections are given every 3 days for an indefinite period of time, and often it can take between 6 and 9 months before the patient reports whether any symptoms have been alleviated. (60) From our preliminary results exploring inhibitory effects of GA on the Abz activity, this superdose of the drug in vitro may represent to some degree the cumulative effect of long-term treatment of GA in vivo. Nevertheless, a more extensive look at the pharmacokinetics of GA as an inhibitor to Abz activity is recommended.
We also tested whether catalytic Abs in ME/CFS (i.e., ME/CFS_12) that digested MBP were of a particular class of protease (i.e., serine, cysteine, aspartic acid, or amino peptidase). In Figure 4C, aprotinin (serine protease inhibitor) showed the greatest potency at 0.1 μg (1.22 μM, 100% inhibition) and 0.01 μg (0.122 μM, 74% inhibition), while the other 3 inhibitors averaged 16% inhibition at the same concentrations each. These results coincide with other published results describing catalytic Abs/Abzs as being serine protease-like. (61)
In many autoimmune disorders, particularly MS, it has been suggested that abzymes may contribute to direct tissue damage. (51) Further evidence for this has been provided by immunocytochemical studies showing MBP-specific Abs are localized to the axon during active demyelination. (46) Effects of the Abz breakdown of MBP at the neuron, which can take months for disease symptoms to manifest, may be explained by the extremely slow turnover rate of the catalytic Ab. For example, one report showed the catalytic rate of an Abz (4 kcat (S1–)) to be >10-fold slower than trypsin (48–55 (kcat (S1–)). (61) Low Abz kcat may be explained by high-affinity binding (low Kd) through the Ab FAB (fragment antigen binding) region and/or increased spacing between the three amino acids that make up a catalytic triad of traditional serine proteases, which includes serine, histidine, and aspartic acid. (62) It has also been proposed that only two amino acids in the catalytic site, histidine and serine, are involved in peptide hydrolysis. (61) Furthermore, the kcat of Abzs isolated from cerebral spinal fluid (CSF) of MS patients was found to be significantly higher compared to plasma (0.0067 and 0.000123 S1–, respectively). (63) Also, binding capacity and degree of catalysis may be contingent on other factors such as the ratio of Abz to Ab in the total Ab population and the conformation/ modification(s) of the substrate.
While natural Abz production in vivo may be the result of random mutation in the Ab FAB region, (63) there are many factors that could influence the configuration of MBP in both the healthy and disease states, which can also elicit Abz development. Truscott and Friedrich mentioned that long-lived proteins, in particular MBP, go through posttranslational modifications (PTM) in human adults. (64) For example, in the cerebellum, three primary covalent modifications were found: (1) deamidation of asparagine and glutamine, (2) isomerization of aspartic acid, which leads to protein cross-linking and aggregation, and (3) deimination of arginine to citrulline, which is irreversibly catalyzed by the epigenetically controlled peptidylarginine deiminase (PAD); (65) this is an especially important modification because citrulline, which has zero charge and is not a natural component of the MBP sequence, causes profound changes to the protein structure. Without the positive charge of arginine to keep it anchored to the phospholipid bilayer in the major dense line of the myelin sheath, MBP becomes unfolded in the cytoplasm making it a prime target for immunogenic attack. (66,67) Moreover, anticitrullinated protein autoantibodies have been found to be highly specific in several autoimmune diseases, including rheumatoid arthritis, where inhibition of PAD shows therapeutic potential. (65,68)
Patients with ME/CFS may also present with fluctuations in severity of the disease akin to MS where symptoms rise and fall through cycles of relapse and remission. (69) Onset or exacerbation of ME/CFS symptoms may be triggered as well by factors including (1) infection (28) (viral and bacterial), (70) (2) diet, (3) hormonal changes, (71) (4) age, (5) environment, (72) and (6) drug induction. (73,74) Molecular mimicry has also been proposed to induce autoimmunity in ME/CFS where viruses present infectious material such as peptides that have similar residue sequences as the host antigen(s); these foreign agents, which may cause an autoimmune response, include, for example, herpes 6, Epstein-Bar, and corona virus 229E. (11−13)

Conclusions

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As this research contributes only one small piece to a much larger, intricate composition of ME/CFS, we have presented evidence that autoantibodies with enzymatic properties (abzymes) may cause demyelination in some patients diagnosed with ME/CFS; and given the broad spectrum of overlapping pathologies with MS and other autoimmune diseases including long COVID, demyelination should be considered a possibility in ME/CFS as well, especially for patients experiencing nerve pain and muscle weakness.
Moving forward with this research, we believe that there are additional steps and considerations worth noting. For example, the MBP substrate used to test proteolytic Ab hydrolysis should closely simulate in vivo conditions; to accomplish this, certain modifications to the substrate could be made in vitro (e.g., methylation/citrullination) or the target substrate can be extracted/isolated from diseased tissue obtained through an ME/CFS patient biobank. (75)
It is possible too that ME/CFS patient symptoms may be relapsing-remitting as in MS. Therefore, a study should be conducted to examine the catalytic activity of a patient’s plasma Abs over time. In addition to MRI data, this may be a useful diagnostic tool for tracking disease severity with corresponding levels of proteolysis. Also, we have not tested CSF, which may have a higher concentration/more active catalytic Abs (>kcat), as has been shown for MS patient samples in previous reports. (42) Further assessment of the CSF Abz content compared with peripheral blood may help generate a more complete profile of the ME/CFS patient’s demographics, which could prove to be an accurate metric in identifying and characterizing disease symptoms and severity.
Finally, there is currently no diagnostic tool or assay that definitively states whether a patient has ME/CFS or is likely to contract the disease; however, there are metrics available that look for commonalities among patients, for example, the use of nanoelectronics in blood-based diagnostics. (76) Catalytic Abs have also been used in clinical settings to monitor autoimmune disease progression. For example, Kalinina et al. found that the degree of cardiac myosin (CM) hydrolysis in autoimmune myocarditis (AM) was strongly correlated not only with anti-CM autoantibody serum levels but also with AM disease manifestations and symptom severity. (77) In addition to MBP, (78,79) there are many substrate-specific Abs (antiprotein and anti-DNA) that have been previously identified, (53) which could be of clinical significance if they too cause tissue damage. Therefore, we propose an assay for MBP hydrolysis by catalytic Abs in ME/CFS patients may provide information to better diagnose and treat patients in the early stages of demyelination.

Author Information

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  • Corresponding Author
  • Authors
    • Miranda Lee Dafoe - Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
    • Julie Wilhelmy - Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
    • Layla Cervantes - Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
    • Anna N Okumu - Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
    • Lucas Kipp - Department of Neurology and Neurological Sciences, Stanford University, Palo Alto, California 94304, United States
    • Mohsen Nemat-Gorgani - Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States
    • Ronald Wayne Davis - Stanford Genome Technology Center, Department of Biochemistry, Stanford University, Palo Alto, California 94304, United States;  Department of Genetics, Stanford University, Palo Alto, California 94304, United States
  • Notes
    The authors declare no competing financial interest.

Acknowledgments

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First and foremost, we would like to thank all the patients who generously donated to this project. We would also like to thank Whitney Dafoe for raising funds to purchase an HPLC unit for sample processing and analysis performed in this research. We also wish to thank Anna Tomczak, Viktoriya Bourakova, and Drs. Yamuna Joseph, Jeffrey Dunn, and May Han at Stanford’s Department of Neurology and Neurological Sciences for providing MS samples to establish proof of concept in our study of catalytic Abs in ME/CFS. We also would like to thank Angela Chu (SGTC) for reviewing this manuscript and providing comments/edits, as well as discussions regarding our catalytic Ab work. We also would like to thank Dr. Bela Chheda for providing patient samples and Linda Tannenbaum and the Open Medicine Foundation for their support. Finally, the work presented here was also made possible by the generous support of the Khosla Family gift fund.

References

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    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)-6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic anal. was conducted by pulsed stable isotope labeling by amino acids in cell culture anal. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metab., dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidn. of fatty acid, amino acid, and glucose metab., including pyruvate dehydrogenase, were strongly inhibited. Adoptive transfer of U2-OS cell supernatants after reactivation of HHV6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the assocd. antiviral state in the A549 cell assay. In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metab.
  12. 12
    Ruiz-Pablos, M.; Paiva, B.; Montero-Mateo, R.; Garcia, N.; Zabaleta, A. Epstein-Barr Virus and the Origin of myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front Immunol 2021, 12, 656797  DOI: 10.3389/fimmu.2021.656797
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    Epstein-Barr virus and the origin of myalgic encephalomyelitis or chronic fatigue syndrome
    Ruiz-Pablos, Manuel; Paiva, Bruno; Montero-Mateo, Rosario; Garcia, Nicolas; Zabaleta, Aintzane
    Frontiers in Immunology (2021), 12 (), 656797CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
    A review. Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approx. 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiol. of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-assocd. autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiol. generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.
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    Talbot, P. J.; Paquette, J. S.; Ciurli, C.; Antel, J. P.; Ouellet, F. Myelin basic protein and human coronavirus 229E cross-reactive T cells in multiple sclerosis. Ann. Neurol. 1996, 39, 233– 240,  DOI: 10.1002/ana.410390213
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    Myelin basic protein and human coronavirus 229E cross-reactive T cells in multiple sclerosis
    Talbot P J; Paquette J S; Ciurli C; Antel J P; Ouellet F
    Annals of neurology (1996), 39 (2), 233-40 ISSN:0364-5134.
    Multiple sclerosis (MS) is an inflammatory demyelinating neurological disease in which autoreactive T lymphocytes sensitized to myelin components of the central nervous system are postulated to contribute to pathogenesis. The possible relevance of molecular mimicry between a human coronavirus and the myelin basic protein component of myelin in the generation of this autoimmune reaction was evaluated. Myelin basic protein- and virus-reactive T-cell lines were established from 16 MS patients and 14 healthy donors and shown to be mostly CD4+. In contrast to healthy donors, several T-cell lines isolated from MS patients showed cross-reactivity between myelin and coronavirus antigens. Overall, 29% of T-cell lines from MS patients (10 donors) but only 1.3% of T-cell lines from normal control subjects (2 donors) showed an HLA-DR-restricted cross-reactive pattern of antigen activation after in vitro selection with either myelin basic protein or human coronavirus strain 229E antigens. Moreover, reciprocal reactivities were only observed in MS patients (4 donors). This establishes molecular mimicry between a common viral pathogen, such as this human coronavirus, and myelin as a possible immunopathological mechanism in MS and is consistent with the possible involvement of more than one infectious pathogen as an environmental trigger of disease.
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    Morris, G.; Maes, M. myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Med. 2013, 11, 205,  DOI: 10.1186/1741-7015-11-205
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    Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics
    Morris Gerwyn; Maes Michael
    BMC medicine (2013), 11 (), 205 ISSN:.
    BACKGROUND: 'Encephalomyelitis disseminata' (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS. DISCUSSION: There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels. SUMMARY: This review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.
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    Dobson, R.; Giovannoni, G. Multiple sclerosis - a review. Eur J Neurol 2019, 26, 27– 40,  DOI: 10.1111/ene.13819
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    Multiple sclerosis - a review
    Dobson R; Dobson R; Giovannoni G; Giovannoni G
    European journal of neurology (2019), 26 (1), 27-40 ISSN:.
    Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene-environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.
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    Moscarello, M. A.; Mastronardi, F. G.; Wood, D. D. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem. Res. 2007, 32, 251– 256,  DOI: 10.1007/s11064-006-9144-5
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    The Role of Citrullinated Proteins Suggests a Novel Mechanism in the Pathogenesis of Multiple Sclerosis
    Moscarello, Mario A.; Mastronardi, Fabrizio G.; Wood, D. Denise
    Neurochemical Research (2007), 32 (2), 251-256CODEN: NEREDZ; ISSN:0364-3190. (Springer)
    The pathogenesis of MS is unknown. In our studies, we have demonstrated an important role for citrullinated myelin basic protein (MBP). The accompanying loss of pos. charge compromises the ability of MBP to interact with the lipid bilayer. The conversion of arginine to citrulline in brain is carried out by an enzyme peptidyl arginine deiminase (PAD) 2. The amt. of PAD 2 in brain was increased in MS normal-appearing white matter. The mechanism responsible for this increase involved hypomethylation of the promoter region in the PAD 2 gene in MS, but no change (compared to normal) was found in thymus tissue DNA from the same MS patients. In addn., no change was obsd. in other neurol. diseases, including Alzheimer's, Parkinson's, and Huntington's. We propose that citrullinated MBP, resulting from elevated levels of PAD 2 represents an important biochem. pathway in the pathogenesis of MS.
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    Smith, R.; Chepisheva, M.; Cronin, T.; Seemungal, B. M. Chapter 16 - Diagnostic Approaches Techniques in Concussion/Mild Traumatic Brain Injury: Where are we?, In Neurosensory Disorders in Mild Traumatic Brain Injury (Hoffer, M. E., Balaban, C. D., Eds.); Academic Press: 2019, 247- 277.
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    Inglese, M. Multiple sclerosis: new insights and trends. AJNR Am. J. Neuroradiol. 2006, 27, 954– 957
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    Multiple sclerosis: new insights and trends
    Inglese M
    AJNR. American journal of neuroradiology (2006), 27 (5), 954-7 ISSN:0195-6108.
    There is no expanded citation for this reference.
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    Lange, G.; DeLuca, J.; Maldjian, J. A.; Lee, H.; Tiersky, L. A.; Natelson, B. H. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci 1999, 171, 3– 7,  DOI: 10.1016/S0022-510X(99)00243-9
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    Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome
    Lange G; DeLuca J; Maldjian J A; Lee H; Tiersky L A; Natelson B H
    Journal of the neurological sciences (1999), 171 (1), 3-7 ISSN:0022-510X.
    Presence of MRI brain abnormalities in patients with Chronic Fatigue Syndrome (CFS) was determined and the profile of MRI abnormalities was compared between 39 CFS patients, 18 with (CFS-Psych) and 21 without (CFS-No Psych) a DSM-III-R Axis I psychiatric diagnosis since illness onset, and 19 healthy, sedentary controls (HC). Two neuroradiologists, blind to group membership, separately read the MR films using a detailed protocol for rating and categorizing abnormal signal changes. When findings were incongruent, the two neuroradiologists met to try to reach consensus, otherwise a third neuroradiologist evaluated the MR images and served as a tie-breaker. The CFS-No Psych group showed a significantly larger number of brain abnormalities on T2 weighted images than the CFS-Psych and HC groups. Cerebral changes in the CFS-No Psych group consisted mostly of small, punctate, subcortical white matter hyperintensities, found predominantly in the frontal lobes. No significant difference was found when both CFS groups were combined and compared to the HC group. The use of stratification techniques is an important strategy in understanding the pathophysiology of CFS. This frontal lobe pathology could explain the more severe cognitive impairment previously reported in this subset of CFS patients.
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    Chen, R.; Liang, F. X.; Moriya, J.; Yamakawa, J.; Sumino, H.; Kanda, T.; Takahashi, T. Chronic fatigue syndrome and the central nervous system. J Int Med Res 2008, 36, 867– 874,  DOI: 10.1177/147323000803600501
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    Chronic fatigue syndrome and the central nervous system
    Chen, R.; Liang, F. X.; Moriya, J.; Yamakawa, J.; Sumino, H.; Kanda, T.; Takahashi, T.
    Journal of International Medical Research (2008), 36 (5), 867-874CODEN: JIMRBV; ISSN:0300-0605. (Field House Publishing LLP)
    A review. An increasing amt. of neuroimaging evidence supports the hypothesis that chronic fatigue syndrome patients have structural or functional abnormalities within the brain. Moreover, some neurotrophic factors, neurotransmitters and cytokines have also been evaluated in order to elucidate the mechanism of abnormal neuropsychic findings in chronic fatigue syndrome. In this review, we suggest that the focal point of chronic fatigue syndrome research should be transferred to the central nervous system.
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    Barnden, L. R.; Shan, Z. Y.; Staines, D. R.; Marshall-Gradisnik, S.; Finegan, K.; Ireland, T.; Bhuta, S. Intra brainstem connectivity is impaired in chronic fatigue syndrome. Neuroimage Clin 2019, 24, 102045  DOI: 10.1016/j.nicl.2019.102045
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    Intra brainstem connectivity is impaired in chronic fatigue syndrome
    Barnden Leighton R; Staines Donald R; Marshall-Gradisnik Sonya; Shan Zack Y; Finegan Kevin; Ireland Timothy; Bhuta Sandeep
    NeuroImage. Clinical (2019), 24 (), 102045 ISSN:.
    In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.
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    Kimura, Y.; Sato, N.; Ota, M.; Shigemoto, Y.; Morimoto, E.; Enokizono, M.; Matsuda, H.; Shin, I.; Amano, K.; Ono, H.; Sato, W.; Yamamura, T. Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging. J Magn Reson Imaging 2019, 49, 818– 824,  DOI: 10.1002/jmri.26247
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    Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging
    Kimura Yukio; Sato Noriko; Shigemoto Yoko; Morimoto Emiko; Enokizono Mikako; Ota Miho; Ota Miho; Matsuda Hiroshi; Shin Isu; Amano Keiko; Ono Hirohiko; Sato Wakiro; Yamamura Takashi
    Journal of magnetic resonance imaging : JMRI (2019), 49 (3), 818-824 ISSN:.
    BACKGROUND: Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) metrics provide more specific information regarding pathological changes than diffusion tensor imaging (DTI). PURPOSE: To detect microstructural abnormalities in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) patients by using DKI and NODDI metrics. STUDY TYPE: Prospective. POPULATION: Twenty ME/CFS patients and 23 healthy controls were recruited. FIELD STRENGTH/SEQUENCE: Three-b value DWI (b-values = 0, 1000, and 2000 sec/mm(2) ) and 3D T1 -weighted images were at 3.0T. ASSESSMENT: Mean kurtosis (MK), neurite density index (NDI), orientation dispersion index (ODI), fractional anisotropy (FA), and mean diffusivity (MD) were calculated. STATISTICAL TESTING: The two-sample t-test analysis in SPM12 software was used to compare the differences between ME/CFS and control groups. RESULTS: In the ME/CFS patients, we observed significant FA decreases in the genu of the corpus callosum and the anterior limb of the right internal capsule (P < 0.05), but no significant difference in MD (P = 0.164); there were also significant MK decreases in the right frontal area, anterior cingulate gyrus, superior longitudinal fasciculus (SLF), and left parietal area (P < 0.05). Significant NDI decreases were observed in the right posterior cingulate gyrus, SLF, and left frontal area of the ME/CFS patients (P < 0.05). Significant ODI decreases were seen in the bilateral occipital areas, right superior temporal gyrus, the anterior limb of internal capsule, and the posterior cingulate gyrus (P < 0.05), and significant ODI increases were revealed in the bilateral occipital and right temporal areas (P < 0.05). DATA CONCLUSION: Right SLF abnormalities may be a diagnostic marker for ME/CFS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:818-824.
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    Shan, Z. Y.; Barnden, L. R.; Kwiatek, R. A.; Bhuta, S.; Hermens, D. F.; Lagopoulos, J. Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review. J. Transl. Med. 2020, 18, 335,  DOI: 10.1186/s12967-020-02506-6
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    Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review
    Shan Zack Y; Kwiatek Richard A; Hermens Daniel F; Lagopoulos Jim; Shan Zack Y; Barnden Leighton R; Bhuta Sandeep
    Journal of translational medicine (2020), 18 (1), 335 ISSN:.
    BACKGROUND: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible. METHOD: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported. RESULTS: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies. CONCLUSION: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.
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    Shan, Z. Y.; Kwiatek, R.; Burnet, R.; Del Fante, P.; Staines, D. R.; Marshall-Gradisnik, S. M.; Barnden, L. R. Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study. J Magn Reson Imaging 2016, 44, 1301– 1311,  DOI: 10.1002/jmri.25283
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    Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study
    Shan Zack Y; Staines Donald R; Marshall-Gradisnik Sonya M; Barnden Leighton R; Kwiatek Richard; Burnet Richard; Del Fante Peter
    Journal of magnetic resonance imaging : JMRI (2016), 44 (5), 1301-1311 ISSN:.
    PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311.
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    Puri, B. K.; Jakeman, P. M.; Agour, M.; Gunatilake, K. D.; Fernando, K. A.; Gurusinghe, A. I.; Treasaden, I. H.; Waldman, A. D.; Gishen, P. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. Br J Radiol 2012, 85, e270– 273,  DOI: 10.1259/bjr/93889091
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    Cook, D. B.; Lange, G.; DeLuca, J.; Natelson, B. H. Relationship of brain MRI abnormalities and physical functional status in chronic fatigue syndrome. Int J Neurosci 2001, 107, 1– 6,  DOI: 10.3109/00207450109149754
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    Relationship of brain MRI abnormalities and physical functional status in chronic fatigue syndrome
    Cook D B; Lange G; DeLuca J; Natelson B H
    The International journal of neuroscience (2001), 107 (1-2), 1-6 ISSN:0020-7454.
    Chronic Fatigue Syndrome (CFS) is an unexplained illness that is characterized by severe fatigue. Some have suggested that CFS is a "functional somatic syndrome" in which symptoms of fatigue are inappropriately attributed to a serious illness. However, brain magnetic resonance imaging (MRI) data suggest that there may be an organic abnormality associated with CFS. To understand further the significance of brain MRI abnormalities, we examined the relationship between MRI identified brain abnormalities and self-reported physical functional status in 48 subjects with CFS who underwent brain MR imaging and completed the Medical Outcomes Study SF-36. Brain MR images were examined for the presence of abnormalities based on 5 general categories previously shown to be sensitive to differentiating CFS patients from healthy controls. There were significant negative relationships between the presence of brain abnormalities and both the physical functioning (PF) (rho=-.31, p=.03), and physical component summary PCS (rho=-.32, p=.03) subscales of the SF-36. CFS patients with MRI identified brain abnormalities scored significantly lower on both PF (t(1,46) =2.3, p=.026) and the PCS (t(1,41) =2.4, p=.02) than CFS subjects without an identified brain abnormality. When adjusted for age differences only the PF analysis remained significant. However, the effect sizes for both analyses were large indicating meaningful differences in perceived functional status between the groups. These results demonstrate that the presence of brain abnormalities in CFS are significantly related to subjective reports of physical function and that CFS subjects with MRI brain abnormalities report being more physically impaired than those patients without brain abnormalities.
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    Sbardella, E.; Petsas, N.; Tona, F.; Prosperini, L.; Raz, E.; Pace, G.; Pozzilli, C.; Pantano, P. Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients. PLoS One 2013, 8, e63250  DOI: 10.1371/journal.pone.0063250
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    Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients
    Sbardella, Emilia; Petsas, Nikolaos; Tona, Francesca; Prosperini, Luca; Raz, Eytan; Pace, Gianvito; Pozzilli, Carlo; Pantano, Patrizia
    PLoS One (2013), 8 (5), e63250CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    Background: Multiple sclerosis (MS) is characterized by demyelinating and degenerative processes within the central nervous system. Unlike conventional MRI, new advanced imaging techniques improve pathol. specificity and better highlight the relationship between anatomical damage and clin. impairment. Objective: To investigate the relationship between clin. disability and both gray (GM) and white matter (WM) regional damage in MS patients. Methods: Thirty-six relapsing remitting-MS patients and 25 sex- and age-matched controls were enrolled. All patients were clin. evaluated by the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite (MSFC) scale, which includes the 9-hole peg test (9HPT), the timed 25-ft walking test (T25FW) and the paced auditory serial addn. test (PASAT). All subjects were imaged by a 3.0 T scanner: dual-echo fast spin-echo, 3DT1-weighted and diffusion-tensor imaging (DTI) sequences were acquired. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were run for regional GM and WM assessment, resp. T2 lesion vols. were also calcd., by using a semi-automated technique. Results: Brain volumetric assessment of GM and DTI measures revealed significant differences between patients and controls. In patients, different measures of WM damage correlated each-other (p<0.0001), whereas none of them correlated with GM vol. In patients, focal GM atrophy and widespread WM damage significantly correlated with clin. measures. In particular, VBM anal. revealed a significant correlation (p<0.05) between GM vol. and 9HPT in cerebellum and between GM vol. and PASAT in orbito-frontal cortex. TBSS showed significant correlations between DTI metrics with 9HPT and PASAT scores in many WM bundles (p<0.05), including corpus callosum, internal capsule, posterior thalamic radiations, cerebral peduncles. Conclusions: Selective GM atrophy and widespread WM tracts damage are assocd. with functional impairment of upper-limb motion and cognition. The combined anal. of volumetric and DTI data may help to better understand structural alterations underlying phys. and cognitive dysfunction in MS.
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    Komaroff, A. L.; Lipkin, W. I. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Front. Med. (Lausanne) 2023, 10, 1187163  DOI: 10.3389/fmed.2023.1187163
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    ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature
    Komaroff Anthony L; Lipkin W Ian
    Frontiers in medicine (2023), 10 (), 1187163 ISSN:2296-858X.
    Some patients remain unwell for months after "recovering" from acute COVID-19. They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function and that can leave some people housebound and disabled. The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as to persisting illnesses that can follow a wide variety of other infectious agents and following major traumatic injury. Together, these illnesses are projected to cost the U.S. trillions of dollars. In this review, we first compare the symptoms of ME/CFS and Long COVID, noting the considerable similarities and the few differences. We then compare in extensive detail the underlying pathophysiology of these two conditions, focusing on abnormalities of the central and autonomic nervous system, lungs, heart, vasculature, immune system, gut microbiome, energy metabolism and redox balance. This comparison highlights how strong the evidence is for each abnormality, in each illness, and helps to set priorities for future investigation. The review provides a current road map to the extensive literature on the underlying biology of both illnesses.
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    Khodanovich, M. Y.; Kamaeva, D. A.; Naumova, A. V. Role of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19. Int J Mol Sci 2022, 23, 11291,  DOI: 10.3390/ijms231911291
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    Shabani, Z. Demyelination as a result of an immune response in patients with COVID-19. Acta Neurol Belg 2021, 121, 859– 866,  DOI: 10.1007/s13760-021-01691-5
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    Demyelination as a result of an immune response in patients with COVID-19
    Shabani Zahra
    Acta neurologica Belgica (2021), 121 (4), 859-866 ISSN:.
    The coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), that already appeared as a global pandemic. Presentation of the disease often includes upper respiratory symptoms like dry cough, dyspnea, chest pain, and rhinorrhea that can develop to respiratory failure, needing intubation. Furthermore, the occurrence of acute and subacute neurological manifestations such as stroke, encephalitis, headache, and seizures are frequently stated in patients with COVID-19. One of the reported neurological complications of severe COVID-19 is the demolition of the myelin sheath. Indeed, the complex immunological dysfunction provides a substrate for the development of demyelination. Nevertheless, few published reports in the literature describe demyelination in subjects with COVID-19. In this short narrative review, we discuss probable pathological mechanisms that may trigger demyelination in patients with SARS-CoV-2 infection and summarize the clinical evidence, confirming SARS-CoV-2 condition as a risk factor for the destruction of myelin.
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    Khair, A. M.; Nikam, R.; Husain, S.; Ortiz, M.; Kaur, G. Para and Post-COVID-19 CNS Acute Demyelinating Disorders in Children: A Case Series on Expanding the Spectrum of Clinical and Radiological Characteristics. Cureus 2022, 14, e23405  DOI: 10.7759/cureus.23405
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    Kara, S.; Candelore, T.; Youssef, P.; Nedd, K. Evidence of Post-COVID-19 Transverse Myelitis Demyelination. Cureus 2021, 13, e19087  DOI: 10.7759/cureus.19087
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    Shokat, K. M.; Schultz, P. G. Catalytic antibodies. Annu. Rev. Immunol. 1990, 8, 335– 363,  DOI: 10.1146/annurev.iy.08.040190.002003
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    Catalytic antibodies
    Shokat, K. M.; Schultz, P. G.
    Annual Review of Immunology (1990), 8 (), 335-63CODEN: ARIMDU; ISSN:0732-0582.
    A review with 89 refs. on the generation, design, and activity of catalytic antibodies.
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    Jencks, W. P. Catalysis in Chemistry and Enzymology; Dover: New York, NY, 1969, 836.
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    Schultz, P; Lerner, R. A. Antibody catalysis of difficult chemical transformations. Acc. Chem. Res. 1993, 26, 391– 395,  DOI: 10.1021/ar00032a001
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    Antibody catalysis of difficult chemical transformations
    Schultz, Peter G.; Lerner, Richard A.
    Accounts of Chemical Research (1993), 26 (8), 391-5CODEN: ACHRE4; ISSN:0001-4842.
    A review, with 28 refs., on antibody catalysis. Topics include disfavored chem. reactions, control of regio- and enantioselectivity of reactions, control of ortho transfers, and transesterification reactions.
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    Landry, D. W.; Zhao, K.; Yang, G. X.; Glickman, M.; Georgiadis, T. M. Antibody-catalyzed degradation of cocaine. Science 1993, 259, 1899– 1901,  DOI: 10.1126/science.8456315
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    Antibody-catalyzed degradation of cocaine
    Landry, Donald W.; Zhao, Kang; Yang, Ginger X. Q.; Glickman, Michael; Georgiadis, Taxiarchis M.
    Science (Washington, DC, United States) (1993), 259 (5103), 1899-901CODEN: SCIEAS; ISSN:0036-8075.
    Immunization with a phosphonate monoester transition-state analog of cocaine provided monoclonal antibodies capable of catalyzing the hydrolysis of the cocaine benzoyl ester group. An assay for the degrdn. of radiolabeled cocaine identified active enzymes. Benzoyl esterolysis yields ecgonine Me ester and benzoic acid, fragments devoid of cocaine's stimulant activity. Passive immunization with such an artificial enzyme could provide a treatment for dependence by blunting reinforcement.
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    Landry, D. W.; Yang, G. X. Anti-cocaine catalytic antibodies--a novel approach to the problem of addiction. J Addict Dis 1997, 16, 1– 17,  DOI: 10.1300/J069v16n03_01
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    Anti-cocaine catalytic antibodies--a novel approach to the problem of addiction
    Landry D W; Yang G X
    Journal of addictive diseases (1997), 16 (3), 1-17 ISSN:1055-0887.
    Cocaine reinforces its self-administration in relation to the magnitude of and rate of rise to the peak serum concentration of the drug. Catalytic antibodies are artificial enzymes which could reduce serum cocaine concentrations, deprive the abuser of cocaine's reinforcing effect and thus favor extinction of the addiction. Catalytic antibodies are elicited by immunization with a stable analog of a transition-state for a chemical reaction. Through our new method for synthesizing phosphonate monoesters, we constructed several phosphonate-based transition-state analogs of cocaine hydrolysis. Using these analogs, monoclonal antibodies were elicited and, thus far, nine anti-analog antibodies with hydrolytic activity against cocaine have been identified, cloned and studied. The activity of one of these antibodies, 15A10, is sufficient to commence preclinical studies.
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    Mahendra, A.; Sharma, M.; Rao, D. N.; Peyron, I.; Planchais, C.; Dimitrov, J. D.; Kaveri, S. V.; Lacroix-Desmazes, S. Antibody-mediated catalysis: induction and therapeutic relevance. Autoimmun Rev 2013, 12, 648– 652,  DOI: 10.1016/j.autrev.2012.10.009
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    Antibody-mediated catalysis: Induction and therapeutic relevance
    Mahendra, Ankit; Sharma, Meenu; Rao, Desirazu N.; Peyron, Ivan; Planchais, Cyril; Dimitrov, Jordan D.; Kaveri, Srini V.; Lacroix-Desmazes, Sebastien
    Autoimmunity Reviews (2013), 12 (6), 648-652CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)
    A review. Abzymes are Igs endowed with enzymic activities. The catalytic activity of an abzyme resides in the variable domain of the antibody, which is constituted by the close spatial arrangement of amino acid residues involved in catalysis. The origin of abzymes is conferred by the innate diversity of the Ig gene repertoire. Under deregulated immune conditions, as in autoimmune diseases, the generation of abzymes to self-antigens could be deleterious. Tech. advancement in the ability to generate monoclonal antibodies has been exploited in the generation of abzymes with defined specificities and activities. Therapeutic applications of abzymes are being investigated with the generation of monoclonal abzymes against several pathogenesis-assocd. antigens. Here, we review the different contexts in which abzymes are generated, and we discuss the relevance of monoclonal abzymes for the treatment of human diseases.
  39. 39
    Paul, S.; Karle, S.; Planque, S.; Taguchi, H.; Salas, M.; Nishiyama, Y.; Handy, B.; Hunter, R.; Edmundson, A.; Hanson, C. Naturally occurring proteolytic antibodies: selective immunoglobulin M-catalyzed hydrolysis of HIV gp120. J. Biol. Chem. 2004, 279, 39611– 39619,  DOI: 10.1074/jbc.M406719200
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    Naturally Occurring Proteolytic Antibodies: Selective immunoglobulin M-catalyzed hydrolysis of HIV gp120
    Paul, Sudhir; Karle, Sangeeta; Planque, Stephanie; Taguchi, Hiroaki; Salas, Maria; Nishiyama, Yasuhiro; Handy, Beverly; Hunter, Robert; Edmundson, Allen; Hanson, Carl
    Journal of Biological Chemistry (2004), 279 (38), 39611-39619CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
    We report the selective catalytic cleavage of the HIV coat protein gp120, a B cell superantigen, by IgM antibodies (Abs) from uninfected humans and mice that had not been previously exposed to gp120. The rate of IgM-catalyzed gp120 cleavage was greater than of other polypeptide substrates, including the bacterial superantigen protein A. The kinetic parameters of gp120 cleavage varied over a broad range depending on the source of the IgMs, and turnover nos. as great as 2.1/min were obsd., suggesting that different Abs possess distinct gp120 recognition properties. IgG Abs failed to cleave gp120 detectably. The Fab fragment of a monoclonal IgM cleaved gp120, suggesting that the catalytic activity belongs to the antibody combining site. The electrophoretic profile of gp120 incubated with a monoclonal human IgM suggested hydrolysis at several sites. One of the cleavage sites was identified as the Lys432-Ala433 peptide bond, located within the region thought to be the Ab-recognizable superantigenic determinant. A covalently reactive peptide analog (CRA) corresponding to gp120 residues 421-431 with a C-terminal amidino phosphonate diester mimetic of the Lys432-Ala433 bond was employed to probe IgM nucleophilic reactivity. The peptidyl CRA inhibited the IgM-catalyzed cleavage of gp120 and formed covalent IgM adducts at levels exceeding a control hapten CRA devoid of the peptide sequence. These observations suggest that IgMs can selectively cleave gp120 by a nucleophilic mechanism and raise the possibility of their role as defense enzymes.
  40. 40
    Planque, S.; Nishiyama, Y.; Taguchi, H.; Salas, M.; Hanson, C.; Paul, S. Catalytic antibodies to HIV: physiological role and potential clinical utility. Autoimmun Rev 2008, 7, 473– 479,  DOI: 10.1016/j.autrev.2008.04.002
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    Catalytic antibodies to HIV: physiological role and potential clinical utility
    Planque, Stephanie; Nishiyama, Yasuhiro; Taguchi, Hiroaki; Salas, Maria; Hanson, Carl; Paul, Sudhir
    Autoimmunity Reviews (2008), 7 (6), 473-479CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)
    A review. Igs in uninfected humans recognize residues 421-433 located in the B cell superantigenic site (SAg) of the HIV envelope protein gp120 and catalyze its hydrolysis by a serine protease-like mechanism. The catalytic activity is encoded by germline Ig variable (V) region genes, and is expressed at robust levels by IgMs and IgAs but poorly by IgGs. Mucosal IgAs are highly catalytic and neutralize HIV, suggesting that they constitute a first line of defense against HIV. Lupus patients produce the Igs at enhanced levels. Homol. of the 421-433 region with an endogenous retroviral sequence and a bacterial protein may provide clues about the antigen driving anti-SAg synthesis in lupus patients and uninfected subjects. The potency and breadth of HIV neutralization revives hopes of clin. application of catalytic anti-421-433 Igs as immunotherapeutic and topical microbicide reagents. Adaptive improvement of anti-SAg catalytic Igs in HIV infected subjects is not customary. Further study of the properties of the naturally occurring anti-SAg catalytic Igs should provide valuable guidance in designing a prophylactic vaccine that amplifies protective catalytic immunity to HIV.
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    Paul, S.; Volle, D. J.; Beach, C. M.; Johnson, D. R.; Powell, M. J.; Massey, R. J. Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science 1989, 244, 1158– 1162,  DOI: 10.1126/science.2727702
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    Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody
    Paul, Sudhir; Volle, Deanna J.; Beach, Carol M.; Johnson, Donald R.; Powell, Michael J.; Massey, Richard J.
    Science (Washington, DC, United States) (1989), 244 (4909), 1158-62CODEN: SCIEAS; ISSN:0036-8075.
    VIP labeled with 125I, [Tyr10-125I]VIP, can be hydrolyzed by IgG purified from a human subject, as judged by trichloroacetic acid pptn. and reversed-phase HPLC. The hydrolytic activity was pptd. by antibody to human IgG, it was bound by immobilized protein G, and showed a mol. mass close to 150 kilodaltons by gel filtration chromatog., properties similar to those of authentic IgG. The Fab fragment, prepd. from IgG by papain treatment, retained the VIP hydrolytic activity of the IgG. Peptide fragments produced by treatment of VIP with the antibody fraction were purified by reversed-phase HPLC and identified by fast atom bombardment-mass spectrometry and peptide sequencing. The scissile bond in VIP deduced from these expts. was Gln16-Met17. The antibody concn. (73.4 fmol per mg of IgG) and the Kd (0.4 nM) were computed from anal. of VIP binding under conditions that did not result in peptide hydrolysis. Anal. of the antibody-mediated VIP hydrolysis at varying concns. of substrate suggested conformity with Michaelis-Menten kinetics (Km). The values for Km (37.9 × 10-9M) and the turnover no. kcat (15.6 min-1) suggested relatively tight VIP binding and a moderate catalytic efficiency of the antibody.
  42. 42
    Ponomarenko, N. A.; Durova, O. M.; Vorobiev, I. I.; Belogurov, A. A., Jr.; Kurkova, I. N.; Petrenko, A. G.; Telegin, G. B.; Suchkov, S. V.; Kiselev, S. L.; Lagarkova, M. A.; Govorun, V. M.; Serebryakova, M. V.; Avalle, B.; Tornatore, P.; Karavanov, A.; Morse, H. C., 3rd; Thomas, D.; Friboulet, A.; Gabibov, A. G. Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen. Proc Natl Acad Sci U S A 2006, 103, 281– 286,  DOI: 10.1073/pnas.0509849103
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    Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen
    Ponomarenko, Natalia A.; Durova, Oxana M.; Vorobiev, Ivan I.; Belogurov, Alexey A., Jr.; Kurkova, Inna N.; Petrenko, Alexander G.; Telegin, Georgy B.; Suchkov, Sergey V.; Kiselev, Sergey L.; Lagarkova, Maria A.; Govorun, Vadim M.; Serebryakova, Marina V.; Avalle, Berangere; Tornatore, Pete; Karavanov, Alexander; Morse, Herbert C., III; Thomas, Daniel; Friboulet, Alain; Gabibov, Alexander G.
    Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (2), 281-286CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
    Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes "an antibody enzyme" (abzyme) contribution to the site-specific degrdn. of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced exptl. allergic encephalomyelitis. Chromatog. and zymog. data demonstrated that the proteolytic activity of this prepn. was exclusively assocd. with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage detd. by mass spectrometry were localized within immuno-dominant regions of MBP. The abzymes could also cleave recombinant substrates contg. encephalitogenic MBP85-101 peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibody-mediated degrdn. of MBP suggests a mechanistic explanation of the slow development of neurodegeneration assocd. with MS.
  43. 43
    Olopade, C. O.; Yu, J.; Abubaker, J.; Mensah, E.; Paul, S. Catalytic hydrolysis of VIP in pregnant women with asthma. J Asthma 2006, 43, 429– 432,  DOI: 10.1080/02770900600710730
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    Catalytic hydrolysis of VIP in pregnant women with asthma
    Olopade, Christopher O.; Yu, John; Abubaker, Jawed; Mensah, Edward; Paul, Sudhir
    Journal of Asthma (2006), 43 (6), 429-432CODEN: JOUADU; ISSN:0277-0903. (Taylor & Francis, Inc.)
    The neuropeptide vasoactive intestinal peptide (VIP) is one of the physiol. mediators of non-adrenergic, non-cholinergic smooth muscle relaxation of the airway and an important modulator of innate and adaptive immune responses. VIP catalytic autoantibodies are increased in asthma and serum VIP level is decreased during acute exacerbation of asthma. The effect of pregnancy on asthma is variable and depends in part on the severity of pre-existing asthma, along with other physiol. and pathophysiol. changes. We hypothesized that hydrolysis of VIP by circulating catalytic VIP antibodies will be increased in pregnancy in patients with asthma. To det. the level of catalytic autoantibodies to VIP in pregnant asthmatics compared to non-pregnant asthmatics and control pregnant women without asthma. We prospectively enrolled eight pregnant asthmatics (age, 26.5 ± 2.6 years; mean ± SEM), nine pregnant women without asthma (32.0 ± 3.0 years), seven non-pregnant women with asthma (25.0 ± 1.9 years), and seven non-pregnant women without asthma (34.4 ± 2 years) into the study. VIP hydrolysis was performed in all subjects. IgG autoantibodies that catalyze the hydrolysis of vasoactive intestinal peptide (VIP) were present at greater levels in the blood of pregnant women with asthma (7.6 ± 1.1 pM VIP/6 h) compared to pregnant women without asthma (4.0 ± 0.5; p < 0.001), non-pregnant asthmatics (4.9 ± 0.9; p < 0.05) or non-pregnant women without asthma (1.9 ± 0.7; p < 0.05). An increase in the VIP hydrolyzing activity of IgG is independently assocd. with asthma and pregnancy. The autoantibodies hold the potential of affecting the pathophysiol. of the airways in pregnant asthmatics.
  44. 44
    Nevinsky, G. A.; Buneva, V. N. Human catalytic RNA- and DNA-hydrolyzing antibodies. J Immunol Methods 2002, 269, 235– 249,  DOI: 10.1016/S0022-1759(02)00234-X
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    Human catalytic RNA- and DNA-hydrolyzing antibodies
    Nevinsky, Georgy A.; Buneva, Valentina N.
    Journal of Immunological Methods (2002), 269 (1-2), 235-249CODEN: JIMMBG; ISSN:0022-1759. (Elsevier Science B.V.)
    A review. In patients with autoimmune diseases, anti-idiotypic antibodies directed to nucleoprotein complexes, DNA, and enzymes that participate in nucleic acid metab. may be induced spontaneously by primary antigens and can have characteristics of the primary antigen, including catalytic activity. The first natural catalytic antibody, now termed abzyme, which hydrolyzes intestinal vasoactive peptide, was discovered by Paul et al. [Science 244 (1989) 1158]. Subsequently, other abzymes able to hydrolyze proteins, DNA, RNA, or polysaccharides have been found in the sera of patients with autoimmune and also viral pathologies. Further, we have discovered in the milk of healthy human mothers antibodies that catalyze the hydrolysis of RNA, DNA, nucleotides, and the phosphorylation of lipids and proteins. The phenomenon of catalysis by autoantibodies is extremely interesting and can potentially be applied to many different objectives including new types of efficient catalysts, evaluation of the functional roles of abzymes in innate and adaptive immunity, and understanding of certain aspects of self-tolerance and of the destructive responses in autoimmune diseases. In this review, we collate methods for purifying and characterizing natural abzymes esp. those catalyzing DNA and RNA hydrolysis. We also describe new methods that we have developed to provide rigorous criteria that catalytic activity is an intrinsic property of some antibodies. Some major current themes are discussed as well as potential applications of abzymes in scientific, medical, and biotechnol. fields.
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    Nevinsky, G. A.; Buneva, V. N. Natural catalytic antibodies in norm, autoimmune, viral, and bacterial diseases. ScientificWorldJournal 2010, 10, 1203– 1233,  DOI: 10.1100/tsw.2010.98
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    Natural catalytic antibodies in norm, autoimmune, viral, and bacterial diseases
    Nevinsky Georgy A; Buneva Valentina N
    TheScientificWorldJournal (2010), 10 (), 1203-33 ISSN:.
    In human patients with autoimmune, viral, and bacterial diseases, the generation of antibodies (Abs) to foreign antigens and/or autoantibodies to self-antigens usually occurs. Some Abs with different catalytic activities (abzymes, Abzs) may be induced spontaneously by primary antigens and can have characteristics of the primary antigen, including the catalytic activity of idiotypic and/or anti-idiotypic Abs. Healthy humans usually do not develop Abzs or their activities are low, often on the borderline of sensitivity of the detection methods. Detection of Abzs was shown to be the earliest indicator of development of different autoimmune diseases (ADs). At the early stages of ADs, the repertoire of Abzs is usually relatively narrow, but it greatly expands with the progress of the disease, leading to the generation of catalytically diverse Abzs with different activities and functions. Some Abzs are cytotoxic and can play an important negative role in the pathogenesis of ADs, while positive roles have been proposed for other Abzs. Abzs with some low activities can temporarily be present in the blood of patients in the course of viral and bacterial diseases, but their activity increases significantly if these infections stimulate development of ADs. A significant increase in the relative Abz activities associated with a specific reorganization of the immune system, including changes in the differentiation and proliferation of bone marrow hematopoietic stem cells and lymphocyte proliferation in different organs. Different mechanisms of Abz production can be proposed for healthy externally immunized and for autoimmune mammals during the development of pathology.
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    Genain, C. P.; Cannella, B.; Hauser, S. L.; Raine, C. S. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999, 5, 170– 175,  DOI: 10.1038/5532
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    Identification of autoantibodies associated with myelin damage in multiple sclerosis
    Genain, Claude P.; Cannella, Barbara; Hauser, Stephen L.; Raine, Cedric S.
    Nature Medicine (New York) (1999), 5 (2), 170-175CODEN: NAMEFI; ISSN:1078-8956. (Nature America)
    The mol. mechanisms underlying myelin sheath destruction in multiple sclerosis lesions remain unresolved. With immunogold-labeled peptides of myelin antigens and high-resoln. microscopy, techniques that can detect antigen-specific antibodies in situ, we have identified autoantibodies specific for the central nervous system myelin antigen myelin/oligodendrocyte glycoprotein. These autoantibodies were specifically bound to disintegrating myelin around axons in lesions of acute multiple sclerosis and the marmoset model of allergic encephalomyelitis. These findings represent direct evidence that autoantibodies against a specific myelin protein mediate target membrane damage in central nervous system demyelinating disease.
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    Eylar, E. H. Amino acid sequence of the basic protein of the myelin membrane. Proc Natl Acad Sci U S A 1970, 67, 1425– 1431,  DOI: 10.1073/pnas.67.3.1425
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    Amino acid sequence of the basic protein of the myelin membrane
    Eylar, Edwin H.
    Proceedings of the National Academy of Sciences of the United States of America (1970), 67 (3), 1425-31CODEN: PNASA6; ISSN:0027-8424.
    The amino acid sequences of the encephalitogenic basic protein, Al, from bovine and human myelin are similar, differing by only 11 residues. The sequence reveals that while basic residues are spread randomly over most of the polypeptide chain, several regions (8-10 residues) exist that are nonpolar in character. The bovine protein has 170 residues with mol. wt. 18,400. The human protein, which has an addnl. His-Gly sequence, contains 172 residues. The major encephalitogenic determinant (tryptophan region) of the bovine protein differs from the human only by a lysine to arginine substitution. The structural features of the A1 protein are discussed, with special reference to its role in stabilization of the myelin membrane, and its relation to multiple sclerosis.
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    Ponomarenko, N. A.; Durova, O. M.; Vorobiev, I. I.; Belogurov, A. A.; Telegin, G. B.; Suchkov, S. V.; Misikov, V. K.; Morse, H. C., 3rd; Gabibov, A. G. Catalytic activity of autoantibodies toward myelin basic protein correlates with the scores on the multiple sclerosis expanded disability status scale. Immunol. Lett. 2006, 103, 45– 50,  DOI: 10.1016/j.imlet.2005.10.006
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    Catalytic activity of autoantibodies toward myelin basic protein correlates with the scores on the multiple sclerosis expanded disability status scale
    Ponomarenko, Natalia A.; Durova, Oxana M.; Vorobiev, Ivan I.; Belogurov, Alexey A.; Telegin, Georgy B.; Suchkov, Sergey V.; Misikov, Victor K.; Morse, Herbert C.; Gabibov, Alexander G.
    Immunology Letters (2006), 103 (1), 45-50CODEN: IMLED6; ISSN:0165-2478. (Elsevier B.V.)
    Autoantibodies toward myelin basic protein (MBP) evidently emerge in sera and cerebrospinal fluid of the patients with multiple sclerosis (MS), as well as in a MS rodent model, i.e., exptl. autoimmune encephalomyelitis (EAE). The studies of the last two decades have unveiled somewhat controversial data on the diagnostic applicability of anti-MBP autoantibodies as a disease' marker. Here, we present the results of new functional anal. of the anti-MBP autoantibodies isolated from MS (in patients) and EAE (in mice) sera, based on their proteolytic activity against the targeted autoantigen. The activity was shown to be the intrinsic property of the IgG mol. No activity was found in the sera-derived antibody fraction of healthy donors and control mice. Sera of 24 patients with clin. proven MS at different stages of the disease, and 20 healthy controls were screened for the anti-MBP antibody-mediated proteolytic activity. The activity correlated with the scores on the MS expanded disability status scale (EDSS) (r2 = 0.85, P < 0.001). Thus, the anti-MBP autoantibody-mediated proteolysis may be regarded as an addnl. marker of the disease progression.
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    Eylar, E. H.; Salk, J.; Beveridge, G. C.; Brown, L. V. Experimental allergic encephalomyelitis. An encephalitogenic basic protein from bovine myelin. Arch. Biochem. Biophys. 1969, 132, 34– 48,  DOI: 10.1016/0003-9861(69)90336-1
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    Experimental allergic encephalomyelitis. An encephalitogenic basic protein from bovine myelin
    Eylar, Edwin H.; Salk, Jonas; Beveridge, George C.; Brown, Lenora V.
    Archives of Biochemistry and Biophysics (1969), 132 (1), 34-48CODEN: ABBIA4; ISSN:0003-9861.
    A homogeneous encephalitogenic protein was prepd. in high yield (35-40%) from bovine spinal cord and myelin. This protein, referred to as A1 protein, is susceptible to proteolysis in situ at pH 6-7; this effect is arrested by prompt freezing of tissue upon removal from the animal. The purification procedure consists of (1) defatting with CHCl3-MeOH (2:1), (2) acid extn. at pH 1.7, (3) pptn. of contaminating protein and dialysis at pH 7, (4) DEAE-cellulose chromatog., and (5) gel filtration. CM-cellulose or Cellex-P chromatog. was also used for final purification in place of gel filtration. The DEAE eluate contained the basic protein fraction of which the A1 protein comprised 80-95%. The data suggest that the A1 protein is very likely the only encephalitogenic basic protein of native myelin, constituting ∼30% of the total myelin protein. It was obtained in homogeneous form as demonstrated by a single sharp band on polyacrylamide gel electrophoresis at pH 4.5 and 8.6, and by immunoelectrophoresis and immunodouble diffusion. As little as 0.1 μg. induced histol. lesions in the central nervous system and 10-100 μg. induced clin. disease in 80-100% of guinea pigs. In addn. to its encephalitogenic activity the A1 protein induces in rabbits and guinea pigs the formation of pptg. antibody which was detected by immunodouble diffusion and assayed in a passive hemagglutination test. Antibody-combining activity of the A1 protein was also demonstrated by immunodouble diffusion and was measured by a passive hemagglutination-inhibition test. The delayed hypersensitive response developed in guinea pigs after injection of 20 μg. of the A1 protein and was demonstrated using 5 μg. as skin test antigen. The pos. skin test and histol. lesions characterizing exptl. allergic encephalomyelitis both appeared 4-5 days after sensitization and developed simultaneously. The principal findings here reported, on the in situ proteolysis of the encephalitogenic basic protein, provide a partial explanation for the reports from different labs. of encephalitogens possessing widely differing properties.
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    Hedegaard, C. J.; Chen, N.; Sellebjerg, F.; Sorensen, P. S.; Leslie, R. G.; Bendtzen, K.; Nielsen, C. H. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP. Immunology 2009, 128, e451– 461,  DOI: 10.1111/j.1365-2567.2008.02999.x
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    Gonzalez-Gronow, M; Pizzo, S. V. Relevance of Catalytic Autoantibodies to Myelin Basic Protein (MBP) in Autoimmune Disorders. J Neurol Neuromedicine 2018, 3 (4), 75– 78,  DOI: 10.29245/2572.942X/2018/4.1199
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    Vojdani, A.; Kharrazian, D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol 2020, 217, 108480  DOI: 10.1016/j.clim.2020.108480
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    Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases
    Vojdani, Aristo; Kharrazian, Datis
    Clinical Immunology (Amsterdam, Netherlands) (2020), 217 (), 108480CODEN: CLIIFY; ISSN:1521-6616. (Elsevier B.V.)
    Since the outbreak of COVID-19 caused by SARS-CoV-2, we tested 5 different blood specimens that were confirmed pos. for SARS-CoV-2 IgG and IgM antibodies. The measurements were for anti-nuclear antibody (ANA), anti-extractable nuclear antigen (ENA), anti-double-stranded DNA (dsDNA),actin antibody, mitochondrial antibody,rheumatoid factor(RF), and C1q immunecomplexes. We were surprised to find out that 3 of the 5 specimens had significant elevations in ANA, ENA,actin and mitochondrial antibodies,but not against sDNA or RF. This prompted us to investigate patterns of cross-reactivity between SARS-CoV-2 and autoimmune target proteins.
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    Danilenko, O. V.; Gavrilova, N. Y.; Churilov, L. P. Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology. Pathophysiology 2022, 29, 187– 199,  DOI: 10.3390/pathophysiology29020016
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    Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology
    Danilenko Olga V; Churilov Leonid P; Gavrilova Natalia Y; Gavrilova Natalia Y; Gavrilova Natalia Y; Churilov Leonid P
    Pathophysiology : the official journal of the International Society for Pathophysiology (2022), 29 (2), 187-199 ISSN:.
    Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease. Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or "healthy but tired" (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999). In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed. An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.
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    Lalive, P. H.; Neuhaus, O.; Benkhoucha, M.; Burger, D.; Hohlfeld, R.; Zamvil, S. S.; Weber, M. S. Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 2011, 25, 401– 414,  DOI: 10.2165/11588120-000000000-00000
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    Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action
    Lalive, Patrice H.; Neuhaus, Oliver; Benkhoucha, Mahdia; Burger, Danielle; Hohlfeld, Reinhard; Zamvil, Scott S.; Weber, Martin S.
    CNS Drugs (2011), 25 (5), 401-414CODEN: CNDREF; ISSN:1172-7047. (Adis Data Information BV)
    A review. Glatiramer acetate is a synthetic, random copolymer widely used as a first-line agent for the treatment of relapsing-remitting multiple sclerosis (MS). While earlier studies primarily attributed its clin. effect to a shift in the cytokine secretion of CD4+ T helper (Th) cells, growing evidence in MS and its animal model, exptl. autoimmune encephalomyelitis (EAE), suggests that glatiramer acetate treatment is assocd. with a broader immunomodulatory effect on cells of both the innate and adaptive immune system. To date, glatiramer acetate-mediated modulation of antigen-presenting cells (APC) such as monocytes and dendritic cells, CD4+ Th cells, CD8+ T cells, Foxp3+ regulatory T cells and antibody prodn. by plasma cells have been reported; in addn., most recent investigations indicate that glatiramer acetate treatment may also promote regulatory B-cell properties. Exptl. evidence suggests that, among these diverse effects, a fostering interplay between anti-inflammatory T-cell populations and regulatory type II APC may be the central axis in glatiramer acetate-mediated immune modulation of CNS autoimmune disease. Besides altering inflammatory processes, glatiramer acetate could exert direct neuroprotective and/or neuroregenerative properties, which could be of relevance for the treatment of MS, but even more so for primarily neurodegenerative disorders, such as Alzheimer's or Parkinson's disease. In this review, we provide a comprehensive and crit. overview of established and recent findings aiming to elucidate the complex mechanism of action of glatiramer acetate.
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    Ziemssen, T.; Schrempf, W. Glatiramer acetate: mechanisms of action in multiple sclerosis. Int Rev Neurobiol 2007, 79, 537– 570,  DOI: 10.1016/S0074-7742(07)79024-4
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    Glatiramer acetate: mechanisms of action in multiple sclerosis
    Ziemssen, Tjalf; Schrempf, Wiebke
    International Review of Neurobiology (2007), 79 (Neurobiology of Multiple Sclerosis), 537-570CODEN: IRNEAE; ISSN:0074-7742. (Elsevier)
    A review. Glatiramer acetate (GA), formerly known as copolymer 1, is a mixt. of synthetic polypeptides composed of four amino acids resembling the myelin basic protein (MSP). GA has been shown to be highly effective in preventing and suppressing exptl. autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Therefore, it was tested in several clin. studies and so approved for the immunomodulatory treatment of relapsing-type MS. In contrast to other immunomodulatory MS therapies, GA has a distinct mechanism of action: GA demonstrates an initial strong promiscuous binding to to major histocompatibility complex mols. and consequent competition with various (myelin) antigens for their presentation to T cells. In addn., antigen-based therapy generating a GA-specific immune response seems to be the prerequisite for GA therapy. GA treatment induces an in vivo change of the frequency, cytokine secretion pattern and the effector function of GA-specific CD4+ and CD8+ T cells, probably by affecting the properties of antigen-presenting cells such as monocytes and dendritic cells. As demonstrated extensively in animal expts., GA-specific, mostly, T helper 2 cells migrate to the brain and lead to in situ bystander suppression of the inflammatory process in the brain. Furthermore, GA-specific cells in the brain express neurotrophic factors like the brain-derived neurotrophic factor (BDNF) in addn. to anti-inflammatory T helper 2-like cytokines. This might help tip the balance in favor of more beneficial influences because there is a complex interplay between detrimental and beneficial factors and mediators in the inflammatory milieu of MS lesions.
  56. 56
    Johnson, K. P. Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: an update. Expert Opin Drug Metab Toxicol 2010, 6, 643– 660,  DOI: 10.1517/17425251003752715
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    Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: an update
    Johnson, Kenneth P.
    Expert Opinion on Drug Metabolism & Toxicology (2010), 6 (5), 643-660CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)
    A review. Importance of the field: MS is a chronic progressive inflammatory and neurodegenerative disease assocd. with autoimmune dysregulation. Glatiramer acetate (GA), a complex polypeptides mixt. and first member of the glatiramoid class, is a first-line therapy for relapsing MS. New glatiramoids are under development.Areas covered in this review: Studies from a PubMed search with terms glatiramer' and glatiramoid' were evaluated, focussing on studies conducted between 2007 and 2010.What the reader will gain: We review newly discovered GA effects on innate and acquired immunity and results of recent clin. studies. GA delays conversion from a clin. isolated syndrome to definite MS and has clin. benefits comparable to those of IFN-β drugs, but is more cost-effective and improves quality of life. Preclin. studies of protiramer, a higher mol. mass glatiramoid, showed unexpected toxicity in animals, resulting in discontinuation of drug development.Take home messages: GA is a cost-effective, safe and efficacious MS treatment with pleiotropic immunomodulation activity, is best prescribed early and may safely enhance outcomes when used with other immunomodulators. Protiramer experience indicates the potential for unexpected toxicity assocd. with new glatiramoids. The safety, efficacy and immunogenicity of new glatiramoids must be evaluated thoroughly.
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    Stapulionis, R.; Pinto Oliveira, C. L.; Gjelstrup, M. C.; Pedersen, J. S.; Hokland, M. E.; Hoffmann, S. V.; Poulsen, K.; Jacobsen, C.; Vorup-Jensen, T. Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ21. The Journal of Immunology 2008, 180, 3946– 3956,  DOI: 10.4049/jimmunol.180.6.3946
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    Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2
    Stapulionis, Romualdas; Pinto Oliveira, Cristiano Luis; Gjelstrup, Mikkel Carstensen; Pedersen, Jan Skov; Hokland, Marianne Elisabet; Hoffmann, Soren Vronning; Poulsen, Knud; Jacobsen, Christian; Vorup-Jensen, Thomas
    Journal of Immunology (2008), 180 (6), 3946-3956CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
    Multiple sclerosis (MS) is an inflammatory disease where phagocytic cells infiltrate the nerve tissue and act as terminal agents in destruction of the myelin sheath. However, the mechanism that triggers the ability of these cells to recognize myelin remains obscure. The authors show that myelin basic protein (MBP), a major autoantigen in MS, is a potent and specific ligand for the integrin αMβ2 (Mac-1, CD11b/CD18) expressed mainly on phagocytic cells. MBP undergoes a dramatic conformational change when liberated from the lipid-rich environment of the myelin sheath. The MS drug glatiramer acetate mimics the conformationally labile regions of MBP, interacts in the unfolded state strongly with αMβ2, and inhibits the MBP binding to αMβ2. This study reveals a link between MBP, glatiramer acetate, and the αMβ2 integrin, and suggests a new model for MS pathogenesis based on the recognition of unfolded MBP by the αMβ2 integrin.
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    Banks, W. A. Peptides and the blood-brain barrier. Peptides 2015, 72, 16– 19,  DOI: 10.1016/j.peptides.2015.03.010
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    Peptides and the blood-brain barrier
    Banks, William A.
    Peptides (New York, NY, United States) (2015), 72 (), 16-19CODEN: PPTDD5; ISSN:0196-9781. (Elsevier)
    The demonstration that peptides and regulatory proteins can cross the blood-brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first to propose that peptides could cross the BBB, the first to show that an endogenous peptide did so, and the first to describe a saturable transport system at the BBB for peptides. His work shows that in crossing the BBB, peptides and regulatory proteins act as informational mols., informing the brain of peripheral events. Brain-to-blood passage helps to control levels of peptides with the brain and can deliver information in the brain-to-blood direction. He showed that the transporters for peptides and proteins are not static, but respond to developmental and physiol. changes and are affected by disease states. As such, the BBB is adaptive to the needs of the CNS, but when that adaptation goes awry, the BBB can be a cause of disease. The mechanisms by which peptides and proteins cross the BBB offer opportunities for drug delivery of these substances or their analogs to the brain in the treatment of diseases of the central nervous system.
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    Prod’homme, T.; Zamvil, S. S. The Evolving Mechanisms of Action of Glatiramer Acetate. Cold Spring Harb. Perspect. Med. 2019, 9, 29249,  DOI: 10.1101/cshperspect.a029249
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    The evolving mechanisms of action of glatiramer acetate
    Prod'homme, Thomas; Zamvil, Scott S.
    Cold Spring Harbor Perspectives in Medicine (2019), 9 (2), a029249CODEN: CSHPFV; ISSN:2157-1422. (Cold Spring Harbor Laboratory Press)
    Glatiramer acetate (GA) is a synthetic amino acid copolymer that is approved for treatment of relapsing remitting multiple sclerosis (RRMS) and clin. isolated syndrome (CIS). GA reduces multiple sclerosis (MS) disease activity and has shown comparable efficacy with high-dose interferon-β. The mechanism of action (MOA) of GA has long been an enigma. Originally, it was recognized that GA treatment promoted expansion of GA-reactive T-helper 2 and regulatory T cells, and induced the release of neurotrophic factors. However, GA treatment influences both innate and adaptive immune compartments, and it is now recognized that antigen-presenting cells (APCs) are the initial cellular targets for GA. The anti-inflammatory (M2) APCs induced following treatment with GA are responsible for the induction of anti-inflammatory T cells that contribute to its therapeutic benefit. Here, we review studies that have shaped our current understanding of the MOA of GA.
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    Caporro, M.; Disanto, G.; Gobbi, C.; Zecca, C. Two decades of subcutaneous Glatiramer acetate injection: current role of the standard dose, and new high-dose low-frequency Glatiramer acetate in relapsing-remitting multiple sclerosis treatment. Patient Prefer Adherence 2014, 8, 1123– 1134,  DOI: 10.2147/PPA.S68698
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    Two decades of subcutaneous glatiramer acetate injection: current role of the standard dose, and new high-dose low-frequency glatiramer acetate in relapsing-remitting multiple sclerosis treatment
    Caporro Matteo; Disanto Giulio; Gobbi Claudio; Zecca Chiara
    Patient preference and adherence (2014), 8 (), 1123-34 ISSN:1177-889X.
    Glatiramer acetate, a synthetic amino acid polymer analog of myelin basic protein, is one of the first approved drugs for the treatment of relapsing-remitting multiple sclerosis. Several clinical trials have shown consistent and sustained efficacy of glatiramer acetate 20 mg subcutaneously daily in reducing relapses and new demyelinating lesions on magnetic resonance imaging in patients with relapsing-remitting multiple sclerosis, as well as comparable efficacy to high-dose interferon beta. Some preclinical and clinical data suggest a neuroprotective role for glatiramer acetate in multiple sclerosis. Glatiramer acetate is associated with a relatively favorable side-effect profile, and importantly this was confirmed also during long-term use. Glatiramer acetate is the only multiple sclerosis treatment compound that has gained the US Food and Drug Administration pregnancy category B. All these data support its current use as a first-line treatment option for patients with clinical isolated syndrome or relapsing-remitting multiple sclerosis. More recent data have shown that high-dose glatiramer acetate (ie, 40 mg) given three times weekly is effective, safe, and well tolerated in the treatment of relapsing-remitting multiple sclerosis, prompting the approval of this dosage in the US in early 2014. This high-dose, lower-frequency glatiramer acetate might represent a new, more convenient regimen of administration, and this might enhance patients' adherence to the treatment, crucial for optimal disease control.
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    Zhou, G. W.; Guo, J.; Huang, W.; Fletterick, R. J.; Scanlan, T. S. Crystal structure of a catalytic antibody with a serine protease active site. Science 1994, 265, 1059– 1064,  DOI: 10.1126/science.8066444
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    Crystal structure of a catalytic antibody with a serine protease active site
    Zhou, G. Wayne; Guo, Jincan; Huang, Wei; Fletterick, Robert J.; Scanlan, Thomas S.
    Science (Washington, D. C.) (1994), 265 (5175), 1059-1064CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
    The three-dimensional structure of an unusually active hydrolytic antibody with a phosphonate transition state analog (hapten) bound to the active site has been solved to 2.5 Å resoln. The antibody (17E8) catalyzes the hydrolysis of norleucine and methionine Ph esters and is selective for amino acid esters that have the natural α-carbon L configuration. A plot of the pH-dependence of the antibody-catalyzed reaction is bell-shaped with an actively max. at pH 9.5; expts. on mechanism lend support to the formation of a covalent acyl-antibody intermediate. The structural and kinetic data are complementary and support a hydrolytic mechanism for the antibody that is remarkably similar to that of the serine proteases. The antibody active site contains a Ser-His dyad structure proximal to the phosphorous atom of the bound hapten that resembles two of the three components of the Ser-His-Asp catalytic triad of serine proteases. The antibody active site also contains a Lys residue to stabilize oxyanion formation, and a hydrophobic binding pocket for specific substrate recognition of norleucine and methionine side chains. The structure identifies active site residues that mediate catalysis and suggests specific mutations that may improve the catalytic efficiency of the antibody. This high resoln. structure of a catalytic antibody-hapten complex shows that antibodies can converge on active site structures that have arisen through natural enzyme evolution.
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    Dimitrov, J. D.; Lacroix-Desmazes, S. Noncanonical Functions of Antibodies. Trends Immunol 2020, 41, 379– 393,  DOI: 10.1016/j.it.2020.03.006
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    Noncanonical Functions of Antibodies
    Dimitrov, Jordan D.; Lacroix-Desmazes, Sebastien
    Trends in Immunology (2020), 41 (5), 379-393CODEN: TIRMAE; ISSN:1471-4906. (Elsevier Ltd.)
    A review. The typical functions of antibodies are based on linking the process of antigen recognition with initiation of innate immune reactions. With the introduction of modern research technologies and the use of sophisticated model systems, recent years have witnessed the discovery of a no. of noncanonical functions of antibodies. These functions encompass either untypical strategies for neutralization of pathogens or exertion of activities that are characteristic for other proteins (cytokines, chaperones, or enzymes). Here, we provide an overview of the noncanonical functions of antibodies and discuss their mechanisms and implications in immune regulation and defense. A better comprehension of these functions will enrich our knowledge of the adaptive immune response and shall inspire the development of novel therapeutics.
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    Doronin, V. B.; Parkhomenko, T. A.; Castellazzi, M.; Padroni, M.; Pastore, M.; Buneva, V. N.; Granieri, E.; Nevinsky, G. A. Comparison of antibodies hydrolyzing myelin basic protein from the cerebrospinal fluid and serum of patients with multiple sclerosis. PLoS One 2014, 9, e107807  DOI: 10.1371/journal.pone.0107807
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    Comparison of antibodies hydrolyzing myelin basic protein from the cerebrospinal fluid and serum of patients with multiple sclerosis
    Doronin, Visilii B.; Parkhomenko, Taisiya A.; Castellazzi, Massimiliano; Padroni, Marina; Pastore, Michela; Buneva, Valentina N.; Granieri, Enrico; Nevinsky, Georgy A.
    PLoS One (2014), 9 (9), e107807/1-e107807/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
    It was found that antibodies (Abs) against myelin basic protein (MBP) are the major components of the antibody response in multiple sclerosis (MS) patients. We have recently shown that IgGs from sera of MS patients are active in the hydrolysis of MBP. However, in literature there are no available data concerning possible MBP-hydrolyzing Abs in cerebrospinal fluid (CSF) of MS patients. We have shown that the av. content of IgGs in their sera is about 195-fold higher than that in their CSF. Here we have compared, for the first time, the av. content of lambda- and kappa-IgGs as well as IgGs of four different subclasses (IgG1-IgG4) in CSF and sera of MS patients. The av. relative content of lambda-IgGs and kappa -IgGs in the case of CSFs (8.0 and 92.0%) and sera (12.3 and 87.7%) are comparable, while IgG1, IgG2, IgG3, and IgG4: CSF - 40.4, 49.0, 8.2, and 2.5% of total IgGs, resp. and the sera - 53.6, 36.0, 5.6, and 4.8%, decreased in different order. Electrophoretically and immunol. homogeneous IgGs were obtained by sequential affinity chromatog. of the CSF proteins on protein G-Sepharose and FPLC gel filtration. We present first evidence showing that IgGs from CSF efficiently hydrolyze MBP and that their av. specific catalytic activity is unpredictably ∼54-fold higher than that of Abs from sera of the same MS patients. Some possible reasons of these findings are discussed. We suggest that anti-MBP abzymes of CSF may promote important neuropathol. mechanisms in this chronic inflammatory disorder and in MS pathogenesis development.
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    Truscott, R. J. W.; Friedrich, M. G. Can the Fact That Myelin Proteins Are Old and Break down Explain the Origin of Multiple Sclerosis in Some People?. J. Clin. Med. 2018, 7, 7090281  DOI: 10.3390/jcm7090281
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    Abdel-Magid, A. F. Great Therapeutic Potential of Peptidylarginine deiminase 4 (PAD4) Inhibitors: Treatment of Rheumatoid Arthritis, Epigenetic Tools, Regulation of Pluripotency in Stem Cells, and More. ACS Med Chem Lett 2017, 8, 19– 21,  DOI: 10.1021/acsmedchemlett.6b00515
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    Great Therapeutic Potential of Peptidylarginine Deiminase 4 (PAD4) Inhibitors: Treatment of Rheumatoid Arthritis, Epigenetic Tools, Regulation of Pluripotency in Stem Cells, and More
    Abdel-Magid Ahmed F
    ACS medicinal chemistry letters (2017), 8 (1), 19-21 ISSN:1948-5875.
    There is no expanded citation for this reference.
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    Ciesielski, O.; Biesiekierska, M.; Panthu, B.; Soszynski, M.; Pirola, L.; Balcerczyk, A. citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives. Cell. Mol. Life Sci. 2022, 79, 94,  DOI: 10.1007/s00018-022-04126-3
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    Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives
    Ciesielski, Oskar; Biesiekierska, Marta; Panthu, Baptiste; Soszynski, Miroslaw; Pirola, Luciano; Balcerczyk, Aneta
    Cellular and Molecular Life Sciences (2022), 79 (2), 94CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)
    A review. Numerous post-translational modifications (PTMs) govern the collective metab. of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalyzed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metab. and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochem. nature of arginine citrullination, the enzymic machinery behind it and also provide information on the pathol. consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clin. trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.
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    Kolarz, B.; Ciesla, M.; Dryglewska, M.; Majdan, M. Peptidyl Arginine deiminase Type 4 Gene Promoter Hypo-Methylation in Rheumatoid Arthritis. J. Clin. Med. 2020, 9, 72049,  DOI: 10.3390/jcm9072049
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    Aliko, A.; Kaminska, M.; Falkowski, K.; Bielecka, E.; Benedyk-Machaczka, M.; Malicki, S.; Koziel, J.; Wong, A.; Bryzek, D.; Kantyka, T.; Mydel, P Discovery of Novel Potential Reversible Peptidyl Arginine deiminase Inhibitor. Int. J. Mol. Sci. 2019, 20, 92174,  DOI: 10.3390/ijms20092174
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    Filippi, M.; Bar-Or, A.; Piehl, F.; Preziosa, P.; Solari, A.; Vukusic, S.; Rocca, M. A. Multiple sclerosis. Nat. Rev. Dis. Primers 2018, 4, 43,  DOI: 10.1038/s41572-018-0041-4
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    Multiple sclerosis
    Filippi Massimo; Preziosa Paolo; Rocca Maria A; Filippi Massimo; Preziosa Paolo; Rocca Maria A; Bar-Or Amit; Piehl Fredrik; Piehl Fredrik; Piehl Fredrik; Solari Alessandra; Vukusic Sandra
    Nature reviews. Disease primers (2018), 4 (1), 43 ISSN:.
    Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing-remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers.
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    Gross, C. M.; Baumgartner, A.; Rauer, S.; Stich, O. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology 2012, 79, 2006– 2007,  DOI: 10.1212/WNL.0b013e3182735d24
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    Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod
    Gross Claus Michael; Baumgartner Annette; Rauer Sebastian; Stich Oliver
    Neurology (2012), 79 (19), 2006-7 ISSN:.
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    Ysrraelit, M. C.; Correale, J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology 2019, 156, 9– 22,  DOI: 10.1111/imm.13004
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    Impact of sex hormones on immune function and multiple sclerosis development
    Ysrraelit, Maria C.; Correale, Jorge
    Immunology (2019), 156 (1), 9-22CODEN: IMMUAM; ISSN:0019-2805. (Wiley-Blackwell)
    Summary : Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting young people and leading to demyelination and neurodegeneration. The disease is clearly more common in women, in whom incidence has been rising. Gender differences include: earlier disease onset and more frequent relapses in women; and faster progression and worse outcomes in men. Hormone-related physiol. conditions in women such as puberty, pregnancy, puerperium, and menopause also exert significant influence both on disease prevalence as well as on outcomes. Hormonal and/or genetic factors are therefore believed to be involved in regulating the course of disease. In this review, we discuss clin. evidence for the impact of sex hormones (estrogens, progesterone, prolactin, and testosterone) on MS and attempt to elucidate the hormonal and immunol. mechanisms potentially underlying these changes. We also review current knowledge on the relationship between sex hormones and resident CNS cells and provide new insights in the context of MS. Understanding these mol. mechanisms may contribute to the development of new and safer treatments for both men and women.
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    Roux, J.; Bard, D.; Le Pabic, E.; Segala, C.; Reis, J.; Ongagna, J. C.; de Seze, J.; Leray, E. Air pollution by particulate matter PM10 may trigger multiple sclerosis relapses. Environ Res 2017, 156, 404– 410,  DOI: 10.1016/j.envres.2017.03.049
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    Air pollution by particulate matter PM10 may trigger multiple sclerosis relapses
    Roux, Jonathan; Bard, Denis; Le Pabic, Estelle; Segala, Claire; Reis, Jacques; Ongagna, Jean-Claude; de Seze, Jerome; Leray, Emmanuelle
    Environmental Research (2017), 156 (), 404-410CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
    Seasonal variation of relapses in multiple sclerosis (MS) suggests that season-dependent factors, such as ambient air pollution, may trigger them. However, only few studies have considered possible role of air pollutants as relapse's risk factor. We investigated the effect of particulate matter of aerodynamic diam. smaller than 10μm (PM10) on MS relapses. In total, 536 relapsing MS patients from Strasbourg city (France) were included, accounting for 2052 relapses over 2000-2009 period. A case-crossover design was used with cases defined as the days of relapse and controls being selected in the same patient at plus and minus 35 days. Different lags from 0 to 30 days were considered. Conditional logistic regressions, adjusted on meteorol. parameters, school and public holidays, were used and exposure was considered first as a quant. variable and second, as a binary variable. The natural logarithm of the av. PM10 concn. lagged from 1 to 3 days before relapse onset was significantly assocd. with relapse risk (OR =1.40 [95% confidence interval 1.08-1.81]) in cold season. Consistent results were obsd. when considering PM10 as a binary variable, even if not significant. With an appropriate study design and robust ascertainment of neurol. events and exposure, the present study highlights the effect of PM10 on the risk of relapse in MS patients, probably through oxidative stress mechanisms.
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    Dedeoglu, F. Drug-induced autoimmunity. Curr Opin Rheumatol 2009, 21, 547– 551,  DOI: 10.1097/BOR.0b013e32832f13db
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    Drug-induced autoimmunity
    Dedeoglu, Fatma
    Current Opinion in Rheumatology (2009), 21 (5), 547-551CODEN: CORHES; ISSN:1040-8711. (Lippincott Williams & Wilkins)
    Purpose of review: This review aims to draw attention to the increased spectrum of the features of drug-induced autoimmunity (DIA), including both clin. and autoantibody profiles in addn. to the potential chronicity of the syndrome. Recent findings: In recent years, not only has the no. of medications causing DIA increased but the spectrum of the features has broadened as well. With the use of newer medications, esp. biologics, mostly directed towards immune system manipulation, the range of signs and symptoms of DIA as well as the patterns of autoantibody profiles have widened. Rashes and visceral involvement have started to be reported more often, esp. with tumor necrosis factor antagonists. In addn., autoantibodies such as antidouble-stranded DNA, which are usually seen with idiopathic systemic lupus erythematosus, are appearing in place of the antihistone antibodies, typically found in drug-induced lupus. Finally, some medications have been implicated in causing the very same entity, which they may be used to treat. It is clear that progress in the field of pharmacogenetics and pharmacogenomics will help further our understanding of these and other adverse effects of medications. Summary: Even though DIA has been known for many years, the underlying mechanisms remain unclear. However, with recently described new and unexpected features, novel hypotheses have been proposed, thus opening doors to further research in understanding these mechanisms.
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    Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease characterized by unexplained incapacitating fatigue, accompanied by variable multi-systemic symptoms. ME/CFS causes a significant personal and public health burden, and urgently requires the coordination of research efforts to investigate its etiology and pathophysiology and to develop and validate sensitive and specific biomarkers to confirm diagnosis. This narrative paper describes how people with ME/CFS, together with a multidisciplinary team of researchers, have established the UK ME/CFS Biobank (UKMEB), a unique research infrastructure specifically designed to expedite biomedical research into ME/CFS. We describe the journey that led to its conceptualization and operation, and how the resource has served as a model disease-specific biobank, aggregating human biospecimens alongside comprehensive health information on participants. The UKMEB currently has data and samples from 600 donors including people with ME/CFS and a comparison group with multiple sclerosis and healthy controls. A longitudinal sub-cohort has been established of participants having follow-up assessments at multiple time-points. As an open resource for quality and ethical research into ME/CFS, biological samples and data have not only been analyzed within our research team but have also been shared with researchers across Europe, America and the Middle East. We continue to encourage researchers from academic and commercial sectors to access the UKMEB. Major steps have been taken and challenges remain; these include sustainability and expansion, and harmonization of processes to facilitate integration with other bioresources and databanks internationally.
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  1. Krista S. P. Clarke, Caroline C. Kingdon, Michael Pycraft Hughes, Eliana Mattos Lacerda, Rebecca Lewis, Emily J. Kruchek, Robert A. Dorey, Fatima H. Labeed. The search for a blood-based biomarker for Myalgic Encephalomyelitis/ Chronic Fatigue Syndrome (ME/CFS): from biochemistry to electrophysiology. Journal of Translational Medicine 2025, 23 (1) https://doi.org/10.1186/s12967-025-06146-6
  2. Amolak Singh Bansal, Katharine A. Seton, Jonathan C. W. Brooks, Simon R. Carding. Cognitive Dysfunction in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome—Aetiology and Potential Treatments. International Journal of Molecular Sciences 2025, 26 (5) , 1896. https://doi.org/10.3390/ijms26051896
  3. Yunhang Cui, Xuchen Zhou, Sainan Li, Jingfei Chen, Mingming Qin, Liaoyuan An, Yefei Wang, Lishan Yao. Enhancing the Thermostability and solubility of a single-domain catalytic antibody. Protein Engineering, Design and Selection 2025, 38 https://doi.org/10.1093/protein/gzaf002
  4. Yujing Sun, Zhenhua Zhang, Qincheng Qiao, Ying Zou, Lina Wang, Tixiao Wang, Bo Lou, Guosheng Li, Miao Xu, Yanxiang Wang, Zhenhong Zhang, Xinguo Hou, Li Chen, Ruxing Zhao. Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing. Journal of Translational Medicine 2024, 22 (1) https://doi.org/10.1186/s12967-024-05710-w
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  • Abstract

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    Figure 1

    Figure 1. PAGE image comparing digestion of MBP by Abs collected from 19 myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), 19 healthy control (HC), and 3 multiple sclerosis (MS) patients. Numbers at the bottom are assigned to each donor sample ('C' is control (only MBP, no Ab)). Samples where Abs were further fractionated using HPLC then tested again in a separate digest assay are denoted with 'f'.

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    Figure 2

    Figure 2. (A) Digest assay comparison between MBP and random substrates: (1) casein, (2) MBP, (3) α-lactalbumin, and (4) lysozyme; each set shows +/− Abs from ME/CFS_11 patient, (B) kinetics of ME/CFS_11 Abs showing correlation/percent relative activity (% RA) of MBP breakdown with increasing Ab concentration, and (C) PAGE image of ME/CFS_11 Ab with (I) nonreducing and (II) reducing conditions after protein-A purification to demonstrate Ab purity; first lane is a protein ladder. Further densitometry analysis of the digest assay (A) comparing the MBP bands +/– Ab showed the target full-length product (∼18,400 Da) for each to be 687 and 1305 (dpi), respectively. All substrates (+/– Ab) were incubated at 37 °C for 24 h.

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    Figure 3

    Figure 3. (A) Digest assay with ME/CFS_11 after HPLC fraction-collection of intact Ab using the Superdex-200 column. After protein-A purification, the sample was processed with HPLC and fraction-collected in six fragments (the chromatogram of Ab sample shows vertical bars separating each fraction corresponding to PAGE image of the postdigest assays above). (B) Digest assay following affinity purification of total Abs collected from ME/CFS_15 plasma sample; lane 1 shows unbound nonspecific Abs from the wash step, and lane 2 shows MBP-specific Abs captured and eluted from the resin conjugated with MBP.

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    Figure 4

    Figure 4. (A) Digest assay with ME/CFS_11 (Figure 1) before and after addition of whole glatiramer acetate (GA), 30 μM final; (B) GA fractionated using size-exclusion chromatography (top chromatogram with fraction demarcations (vertical lines)) corresponding to degree of inhibition in the bar graph directly below for sample ME/CFS_11; (C) comparison of four class-specific protease inhibitors on preventing ME/CFS_12 Ab digest of MBP; each inhibitor was tested at 0.1 and 0.01 μg (1.22 and 0.122 μM final, respectively); and (D) digest assay comparing inhibition by GA and three random peptides: (1) MBP only, (2) ME/CFS_12 Ab + MBP, (3) GA (30 μM), (4) peptide YY, (5) gastrin releasing peptide, and (6) influenza hemagglutinin peptide (each at 30 μM final concentration with 3 μg Ab and 1 μg MBP).

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      A review. B cells represent a relatively minor cell population within both the healthy and diseased central nervous system (CNS), yet they can have profound effects. This is emphasized in multiple sclerosis, in which B cell-depleting therapies are arguably the most efficacious treatment for the condition. In this Review, we discuss how B cells enter and persist in the CNS and how, in many neurol. conditions, B cells conc. within CNS barriers but are rarely found in the parenchyma. We highlight how B cells can contribute to CNS pathol. through antibody secretion, antigen presentation and secretion of neurotoxic mols., using examples from CNS tumors, CNS infections and autoimmune conditions such as neuromyelitis optica and, in particular, multiple sclerosis. Overall, understanding common and divergent principles of B cell accumulation and their effects within the CNS could offer new insights into treating these devastating neurol. conditions.
    8. 8
      Sotzny, F.; Blanco, J.; Capelli, E.; Castro-Marrero, J.; Steiner, S.; Murovska, M.; Scheibenbogen, C. European Network on, ME/CFS (EUROMENE) myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease. Autoimmun. Rev. 2018, 17, 601– 609,  DOI: 10.1016/j.autrev.2018.01.009
      8
      Myalgic Encephalomyelitis/Chronic Fatigue Syndrome - Evidence for an autoimmune disease
      Sotzny, Franziska; Blanco, Julia; Capelli, Enrica; Castro-Marrero, Jesus; Steiner, Sophie; Murovska, Modra; Scheibenbogen, Carmen
      Autoimmunity Reviews (2018), 17 (6), 601-609CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)
      A review. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a frequent and severe chronic disease drastically impairing life quality. The underlying pathomechanism is incompletely understood yet but there is convincing evidence that in at least a subset of patients ME/CFS has an autoimmune etiol. In this review, we will discuss current autoimmune aspects for ME/CFS. Immune dysregulation in ME/CFS has been frequently described including changes in cytokine profiles and Ig levels, T- and B-cell phenotype and a decrease of natural killer cell cytotoxicity. Moreover, autoantibodies against various antigens including neurotransmitter receptors have been recently identified in ME/CFS individuals by several groups. Consistently, clin. trials from Norway have shown that B-cell depletion with rituximab results in clin. benefits in about half of ME/CFS patients. Furthermore, recent studies have provided evidence for severe metabolic disturbances presumably mediated by serum autoantibodies in ME/CFS. Therefore, further efforts are required to delineate the role of autoantibodies in the onset and pathomechanisms of ME/CFS in order to better understand and properly treat this disease.
    9. 9
      Blomberg, J.; Gottfries, C. G.; Elfaitouri, A.; Rizwan, M.; Rosen, A. Infection Elicited Autoimmunity and myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Explanatory Model. Front. Immunol. 2018, 9, 229,  DOI: 10.3389/fimmu.2018.00229
      9
      Infection elicited autoimmunity and myalgic encephalomyelitis/chronic fatigue syndrome: an explanatory model
      Blomberg, Jonas; Gottfries, Carl-Gerhard; Elfaitouri, Amal; Rizwan, Muhammad; Rosen, Anders
      Frontiers in Immunology (2018), 9 (), 229/1-229/20CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
      Myalgic encephalomyelitis (ME) often also called chronic fatigue syndrome (ME/CFS) is a common, debilitating, disease of unknown origin. Although a subject of controversy and a considerable scientific literature, we think that a solid understanding of ME/CFS pathogenesis is emerging. In this study, we compiled recent findings and placed them in the context of the clin. picture and natural history of the disease. A pattern emerged, giving rise to an explanatory model. ME/CFS often starts after or during an infection. A logical explanation is that the infection initiates an autoreactive process, which affects several functions, including brain and energy metab. According to our model for ME/CFS pathogenesis, patients with a genetic predisposition and dysbiosis experience a gradual development of B cell clones prone to autoreactivity. Under normal circumstances these B cell offsprings would have led to tolerance. Subsequent exogenous microbial exposition (triggering) can lead to comorbidities such as fibromyalgia, thyroid disorder, and orthostatic hypotension. A decisive infectious trigger may then lead to immunization against autoantigens involved in aerobic energy prodn. and/or hormone receptors and ion channel proteins, producing postexertional malaise and ME/CFS, affecting both muscle and brain. In principle, cloning and sequencing of Ig variable domains could reveal the evolution of pathogenic clones. Although evidence consistent with the model accumulated in recent years, there are several missing links in it. Hopefully, the hypothesis generates testable propositions that can augment the understanding of the pathogenesis of ME/CFS.
    10. 10
      Wirth, K.; Scheibenbogen, C. A Unifying Hypothesis of the Pathophysiology of myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ss2-adrenergic receptors. Autoimmun Rev 2020, 19, 102527  DOI: 10.1016/j.autrev.2020.102527
      10
      A Unifying Hypothesis of the Pathophysiology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Recognitions from the finding of autoantibodies against ss2-adrenergic receptors
      Wirth, Klaus; Scheibenbogen, Carmen
      Autoimmunity Reviews (2020), 19 (6), 102527CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)
      A review. Myalgic Encephalomyelitis or Chronic Fatigue Syndrome (CFS/ME) is a complex and severely disabling disease with a prevalence of 0.3% and no approved treatment and therefore a very high medical need. Following an infectious onset patients suffer from severe central and muscle fatigue, chronic pain, cognitive impairment, and immune and autonomic dysfunction. Although the etiol. of CFS/ME is not solved yet, there is numerous evidence for an autoantibody mediated dysregulation of the immune and autonomic nervous system. We found elevated ss2 adrenergic receptor (ss2AdR) and M3 acetylcholine receptor antibodies in a subset of CFS/ME patients. As both ss2AdR and M3 acetylcholine receptor are important vasodilators, we would expect their functional disturbance to result in vasoconstriction and hypoxemia. An impaired circulation and oxygen supply could result in many symptoms of ME/CFS. There are consistent reports of vascular dysfunction in ME/CFS. Muscular and cerebral hypoperfusion has been shown in ME/CFS in various studies and correlated with fatigue. Metabolic changes in ME/CFS are also in line with a concept of hypoxia and ischemia. Here we try to develop a unifying working concept for the complex pathomechanism of ME/CFS based on the presence of dysfunctional autoantibodies against ss2AdR and M3 acetylcholine receptor and extrapolate it to the pathophysiol. of ME/CFS without an autoimmune pathogenesis.
    11. 11
      Schreiner, P.; Harrer, T.; Scheibenbogen, C.; Lamer, S.; Schlosser, A.; Naviaux, R. K.; Prusty, B. K. Human Herpesvirus-6 Reactivation, Mitochondrial Fragmentation, and the Coordination of Antiviral and Metabolic Phenotypes in myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Immunohorizons 2020, 4, 201– 215,  DOI: 10.4049/immunohorizons.2000006
      11
      Human herpesvirus-6 reactivation, mitochondrial fragmentation, and the coordination of antiviral and metabolic phenotypes in myalgic encephalomyelitis/chronic fatigue syndrome
      Schreiner, Philipp; Harrer, Thomas; Scheibenbogen, Carmen; Lamer, Stephanie; Schlosser, Andreas; Naviaux, Robert K.; Prusty, Bhupesh K.
      ImmunoHorizons (2020), 4 (4), 201-215CODEN: IMMUGS; ISSN:2573-7732. (American Association of Immunologists)
      Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifactorial disorder with many possible triggers. Human herpesvirus (HHV)-6 and HHV-7 are two infectious triggers for which evidence has been growing. To understand possible causative role of HHV-6 in ME/CFS, metabolic and antiviral phenotypes of U2-OS cells were studied with and without chromosomally integrated HHV-6 and with or without virus reactivation using the histone deacetylase inhibitor trichostatin-A. Proteomic anal. was conducted by pulsed stable isotope labeling by amino acids in cell culture anal. Antiviral properties that were induced by HHV-6 transactivation were studied in virus-naive A549 cells challenged by infection with influenza-A (H1N1) or HSV-1. Mitochondria were fragmented and 1-carbon metab., dUTPase, and thymidylate synthase were strongly induced by HHV-6 reactivation, whereas superoxide dismutase 2 and proteins required for mitochondrial oxidn. of fatty acid, amino acid, and glucose metab., including pyruvate dehydrogenase, were strongly inhibited. Adoptive transfer of U2-OS cell supernatants after reactivation of HHV6A led to an antiviral state in A549 cells that prevented superinfection with influenza-A and HSV-1. Adoptive transfer of serum from 10 patients with ME/CFS produced a similar fragmentation of mitochondria and the assocd. antiviral state in the A549 cell assay. In conclusion, HHV-6 reactivation in ME/CFS patients activates a multisystem, proinflammatory, cell danger response that protects against certain RNA and DNA virus infections but comes at the cost of mitochondrial fragmentation and severely compromised energy metab.
    12. 12
      Ruiz-Pablos, M.; Paiva, B.; Montero-Mateo, R.; Garcia, N.; Zabaleta, A. Epstein-Barr Virus and the Origin of myalgic Encephalomyelitis or Chronic Fatigue Syndrome. Front Immunol 2021, 12, 656797  DOI: 10.3389/fimmu.2021.656797
      12
      Epstein-Barr virus and the origin of myalgic encephalomyelitis or chronic fatigue syndrome
      Ruiz-Pablos, Manuel; Paiva, Bruno; Montero-Mateo, Rosario; Garcia, Nicolas; Zabaleta, Aintzane
      Frontiers in Immunology (2021), 12 (), 656797CODEN: FIRMCW; ISSN:1664-3224. (Frontiers Media S.A.)
      A review. Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS) affects approx. 1% of the general population. It is a chronic, disabling, multi-system disease for which there is no effective treatment. Here, we summarized the current knowledge about the pathogenesis of ME/CFS and revisit the immunopathobiol. of Epstein-Barr virus (EBV) infection. Given the similarities between EBV-assocd. autoimmune diseases and cancer in terms of poor T cell surveillance of cells with EBV latency, expanded EBV-infected cells in peripheral blood and increased antibodies against EBV, we hypothesize that there could be a common etiol. generated by cells with EBV latency that escape immune surveillance. Albeit inconclusive, multiple studies in patients with ME/CFS have suggested an altered cellular immunity and augmented Th2 response that could result from mechanisms of evasion to some pathogens such as EBV, which has been identified as a risk factor in a subset of ME/CFS patients. Namely, cells with latency may evade the immune system in individuals with genetic predisposition to develop ME/CFS and in consequence, there could be poor CD4 T cell immunity to mitogens and other specific antigens, as it has been described in some individuals. Ultimately, we hypothesize that within ME/CFS there is a subgroup of patients with DRB1 and DQB1 alleles that could confer greater susceptibility to EBV, where immune evasion mechanisms generated by cells with latency induce immunodeficiency. Accordingly, we propose new endeavors to investigate if anti-EBV therapies could be effective in selected ME/CFS patients.
    13. 13
      Talbot, P. J.; Paquette, J. S.; Ciurli, C.; Antel, J. P.; Ouellet, F. Myelin basic protein and human coronavirus 229E cross-reactive T cells in multiple sclerosis. Ann. Neurol. 1996, 39, 233– 240,  DOI: 10.1002/ana.410390213
      13
      Myelin basic protein and human coronavirus 229E cross-reactive T cells in multiple sclerosis
      Talbot P J; Paquette J S; Ciurli C; Antel J P; Ouellet F
      Annals of neurology (1996), 39 (2), 233-40 ISSN:0364-5134.
      Multiple sclerosis (MS) is an inflammatory demyelinating neurological disease in which autoreactive T lymphocytes sensitized to myelin components of the central nervous system are postulated to contribute to pathogenesis. The possible relevance of molecular mimicry between a human coronavirus and the myelin basic protein component of myelin in the generation of this autoimmune reaction was evaluated. Myelin basic protein- and virus-reactive T-cell lines were established from 16 MS patients and 14 healthy donors and shown to be mostly CD4+. In contrast to healthy donors, several T-cell lines isolated from MS patients showed cross-reactivity between myelin and coronavirus antigens. Overall, 29% of T-cell lines from MS patients (10 donors) but only 1.3% of T-cell lines from normal control subjects (2 donors) showed an HLA-DR-restricted cross-reactive pattern of antigen activation after in vitro selection with either myelin basic protein or human coronavirus strain 229E antigens. Moreover, reciprocal reactivities were only observed in MS patients (4 donors). This establishes molecular mimicry between a common viral pathogen, such as this human coronavirus, and myelin as a possible immunopathological mechanism in MS and is consistent with the possible involvement of more than one infectious pathogen as an environmental trigger of disease.
    14. 14
      Morris, G.; Maes, M. myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics. BMC Med. 2013, 11, 205,  DOI: 10.1186/1741-7015-11-205
      14
      Myalgic encephalomyelitis/chronic fatigue syndrome and encephalomyelitis disseminata/multiple sclerosis show remarkable levels of similarity in phenomenology and neuroimmune characteristics
      Morris Gerwyn; Maes Michael
      BMC medicine (2013), 11 (), 205 ISSN:.
      BACKGROUND: 'Encephalomyelitis disseminata' (multiple sclerosis) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) are both classified as diseases of the central nervous system by the World Health Organization. This review aims to compare the phenomenological and neuroimmune characteristics of MS with those of ME/CFS. DISCUSSION: There are remarkable phenomenological and neuroimmune overlaps between both disorders. Patients with ME/CFS and MS both experience severe levels of disabling fatigue and a worsening of symptoms following exercise and resort to energy conservation strategies in an attempt to meet the energy demands of day-to-day living. Debilitating autonomic symptoms, diminished cardiac responses to exercise, orthostatic intolerance and postural hypotension are experienced by patients with both illnesses. Both disorders show a relapsing-remitting or progressive course, while infections and psychosocial stress play a large part in worsening of fatigue symptoms. Activated immunoinflammatory, oxidative and nitrosative (O+NS) pathways and autoimmunity occur in both illnesses. The consequences of O+NS damage to self-epitopes is evidenced by the almost bewildering and almost identical array of autoantibodies formed against damaged epitopes seen in both illnesses. Mitochondrial dysfunctions, including lowered levels of ATP, decreased phosphocreatine synthesis and impaired oxidative phosphorylation, are heavily involved in the pathophysiology of both MS and ME/CFS. The findings produced by neuroimaging techniques are quite similar in both illnesses and show decreased cerebral blood flow, atrophy, gray matter reduction, white matter hyperintensities, increased cerebral lactate and choline signaling and lowered acetyl-aspartate levels. SUMMARY: This review shows that there are neuroimmune similarities between MS and ME/CFS. This further substantiates the view that ME/CFS is a neuroimmune illness and that patients with MS are immunologically primed to develop symptoms of ME/CFS.
    15. 15
      Dobson, R.; Giovannoni, G. Multiple sclerosis - a review. Eur J Neurol 2019, 26, 27– 40,  DOI: 10.1111/ene.13819
      15
      Multiple sclerosis - a review
      Dobson R; Dobson R; Giovannoni G; Giovannoni G
      European journal of neurology (2019), 26 (1), 27-40 ISSN:.
      Multiple sclerosis (MS) is the commonest non-traumatic disabling disease to affect young adults. The incidence of MS is increasing worldwide, together with the socioeconomic impact of the disease. The underlying cause of MS and mechanisms behind this increase remain opaque, although complex gene-environment interactions almost certainly play a significant role. The epidemiology of MS indicates that low serum levels of vitamin D, smoking, childhood obesity and infection with the Epstein-Barr virus are likely to play a role in disease development. Changes in diagnostic methods and criteria mean that people with MS can be diagnosed increasingly early in their disease trajectory. Alongside this, treatments for MS have increased exponentially in number, efficacy and risk. There is now the possibility of a diagnosis of 'pre-symptomatic MS' being made; as a result potentially preventive strategies could be studied. In this comprehensive review, MS epidemiology, potential aetiological factors and pathology are discussed, before moving on to clinical aspects of MS diagnosis and management.
    16. 16
      Moscarello, M. A.; Mastronardi, F. G.; Wood, D. D. The role of citrullinated proteins suggests a novel mechanism in the pathogenesis of multiple sclerosis. Neurochem. Res. 2007, 32, 251– 256,  DOI: 10.1007/s11064-006-9144-5
      16
      The Role of Citrullinated Proteins Suggests a Novel Mechanism in the Pathogenesis of Multiple Sclerosis
      Moscarello, Mario A.; Mastronardi, Fabrizio G.; Wood, D. Denise
      Neurochemical Research (2007), 32 (2), 251-256CODEN: NEREDZ; ISSN:0364-3190. (Springer)
      The pathogenesis of MS is unknown. In our studies, we have demonstrated an important role for citrullinated myelin basic protein (MBP). The accompanying loss of pos. charge compromises the ability of MBP to interact with the lipid bilayer. The conversion of arginine to citrulline in brain is carried out by an enzyme peptidyl arginine deiminase (PAD) 2. The amt. of PAD 2 in brain was increased in MS normal-appearing white matter. The mechanism responsible for this increase involved hypomethylation of the promoter region in the PAD 2 gene in MS, but no change (compared to normal) was found in thymus tissue DNA from the same MS patients. In addn., no change was obsd. in other neurol. diseases, including Alzheimer's, Parkinson's, and Huntington's. We propose that citrullinated MBP, resulting from elevated levels of PAD 2 represents an important biochem. pathway in the pathogenesis of MS.
    17. 17
      Smith, R.; Chepisheva, M.; Cronin, T.; Seemungal, B. M. Chapter 16 - Diagnostic Approaches Techniques in Concussion/Mild Traumatic Brain Injury: Where are we?, In Neurosensory Disorders in Mild Traumatic Brain Injury (Hoffer, M. E., Balaban, C. D., Eds.); Academic Press: 2019, 247- 277.
      There is no corresponding record for this reference.
    18. 18
      Inglese, M. Multiple sclerosis: new insights and trends. AJNR Am. J. Neuroradiol. 2006, 27, 954– 957
      18
      Multiple sclerosis: new insights and trends
      Inglese M
      AJNR. American journal of neuroradiology (2006), 27 (5), 954-7 ISSN:0195-6108.
      There is no expanded citation for this reference.
    19. 19
      Lange, G.; DeLuca, J.; Maldjian, J. A.; Lee, H.; Tiersky, L. A.; Natelson, B. H. Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome. J Neurol Sci 1999, 171, 3– 7,  DOI: 10.1016/S0022-510X(99)00243-9
      19
      Brain MRI abnormalities exist in a subset of patients with chronic fatigue syndrome
      Lange G; DeLuca J; Maldjian J A; Lee H; Tiersky L A; Natelson B H
      Journal of the neurological sciences (1999), 171 (1), 3-7 ISSN:0022-510X.
      Presence of MRI brain abnormalities in patients with Chronic Fatigue Syndrome (CFS) was determined and the profile of MRI abnormalities was compared between 39 CFS patients, 18 with (CFS-Psych) and 21 without (CFS-No Psych) a DSM-III-R Axis I psychiatric diagnosis since illness onset, and 19 healthy, sedentary controls (HC). Two neuroradiologists, blind to group membership, separately read the MR films using a detailed protocol for rating and categorizing abnormal signal changes. When findings were incongruent, the two neuroradiologists met to try to reach consensus, otherwise a third neuroradiologist evaluated the MR images and served as a tie-breaker. The CFS-No Psych group showed a significantly larger number of brain abnormalities on T2 weighted images than the CFS-Psych and HC groups. Cerebral changes in the CFS-No Psych group consisted mostly of small, punctate, subcortical white matter hyperintensities, found predominantly in the frontal lobes. No significant difference was found when both CFS groups were combined and compared to the HC group. The use of stratification techniques is an important strategy in understanding the pathophysiology of CFS. This frontal lobe pathology could explain the more severe cognitive impairment previously reported in this subset of CFS patients.
    20. 20
      Chen, R.; Liang, F. X.; Moriya, J.; Yamakawa, J.; Sumino, H.; Kanda, T.; Takahashi, T. Chronic fatigue syndrome and the central nervous system. J Int Med Res 2008, 36, 867– 874,  DOI: 10.1177/147323000803600501
      20
      Chronic fatigue syndrome and the central nervous system
      Chen, R.; Liang, F. X.; Moriya, J.; Yamakawa, J.; Sumino, H.; Kanda, T.; Takahashi, T.
      Journal of International Medical Research (2008), 36 (5), 867-874CODEN: JIMRBV; ISSN:0300-0605. (Field House Publishing LLP)
      A review. An increasing amt. of neuroimaging evidence supports the hypothesis that chronic fatigue syndrome patients have structural or functional abnormalities within the brain. Moreover, some neurotrophic factors, neurotransmitters and cytokines have also been evaluated in order to elucidate the mechanism of abnormal neuropsychic findings in chronic fatigue syndrome. In this review, we suggest that the focal point of chronic fatigue syndrome research should be transferred to the central nervous system.
    21. 21
      Barnden, L. R.; Shan, Z. Y.; Staines, D. R.; Marshall-Gradisnik, S.; Finegan, K.; Ireland, T.; Bhuta, S. Intra brainstem connectivity is impaired in chronic fatigue syndrome. Neuroimage Clin 2019, 24, 102045  DOI: 10.1016/j.nicl.2019.102045
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      Intra brainstem connectivity is impaired in chronic fatigue syndrome
      Barnden Leighton R; Staines Donald R; Marshall-Gradisnik Sonya; Shan Zack Y; Finegan Kevin; Ireland Timothy; Bhuta Sandeep
      NeuroImage. Clinical (2019), 24 (), 102045 ISSN:.
      In myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), abnormal MRI correlations with symptom severity and autonomic measures have suggested impaired nerve signal conduction within the brainstem. Here we analyse fMRI correlations to directly test connectivity within and from the brainstem. Resting and task functional MRI (fMRI) were acquired for 45 ME/CFS (Fukuda criteria) and 27 healthy controls (HC). We selected limited brainstem reticular activation system (RAS) regions-of-interest (ROIs) based on previous structural MRI findings in a different ME/CFS cohort (bilateral rostral medulla and midbrain cuneiform nucleus), the dorsal Raphe nucleus, and two subcortical ROIs (hippocampus subiculum and thalamus intralaminar nucleus) reported to have rich brainstem connections. When HC and ME/CFS were analysed separately, significant correlations were detected for both groups during both rest and task, with stronger correlations during task than rest. In ME/CFS, connections were absent between medulla and midbrain nuclei, although hippocampal connections with these nuclei were enhanced. When corresponding correlations from HC and ME/CFS were compared, ME/CFS connectivity deficits were detected within the brainstem between the medulla and cuneiform nucleus and between the brainstem and hippocampus and intralaminar thalamus, but only during task. In CFS/ME, weaker connectivity between some RAS nuclei was associated with increased symptom severity. RAS neuron oscillatory signals facilitate coherence in thalamo-cortical oscillations. Brainstem RAS connectivity deficits can explain autonomic changes and diminish cortical oscillatory coherence which can impair attention, memory, cognitive function, sleep quality and muscle tone, all symptoms of ME/CFS.
    22. 22
      Kimura, Y.; Sato, N.; Ota, M.; Shigemoto, Y.; Morimoto, E.; Enokizono, M.; Matsuda, H.; Shin, I.; Amano, K.; Ono, H.; Sato, W.; Yamamura, T. Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging. J Magn Reson Imaging 2019, 49, 818– 824,  DOI: 10.1002/jmri.26247
      22
      Brain abnormalities in myalgic encephalomyelitis/chronic fatigue syndrome: Evaluation by diffusional kurtosis imaging and neurite orientation dispersion and density imaging
      Kimura Yukio; Sato Noriko; Shigemoto Yoko; Morimoto Emiko; Enokizono Mikako; Ota Miho; Ota Miho; Matsuda Hiroshi; Shin Isu; Amano Keiko; Ono Hirohiko; Sato Wakiro; Yamamura Takashi
      Journal of magnetic resonance imaging : JMRI (2019), 49 (3), 818-824 ISSN:.
      BACKGROUND: Diffusional kurtosis imaging (DKI) and neurite orientation dispersion and density imaging (NODDI) metrics provide more specific information regarding pathological changes than diffusion tensor imaging (DTI). PURPOSE: To detect microstructural abnormalities in myalgic encephalomyelitis (ME) / chronic fatigue syndrome (CFS) patients by using DKI and NODDI metrics. STUDY TYPE: Prospective. POPULATION: Twenty ME/CFS patients and 23 healthy controls were recruited. FIELD STRENGTH/SEQUENCE: Three-b value DWI (b-values = 0, 1000, and 2000 sec/mm(2) ) and 3D T1 -weighted images were at 3.0T. ASSESSMENT: Mean kurtosis (MK), neurite density index (NDI), orientation dispersion index (ODI), fractional anisotropy (FA), and mean diffusivity (MD) were calculated. STATISTICAL TESTING: The two-sample t-test analysis in SPM12 software was used to compare the differences between ME/CFS and control groups. RESULTS: In the ME/CFS patients, we observed significant FA decreases in the genu of the corpus callosum and the anterior limb of the right internal capsule (P < 0.05), but no significant difference in MD (P = 0.164); there were also significant MK decreases in the right frontal area, anterior cingulate gyrus, superior longitudinal fasciculus (SLF), and left parietal area (P < 0.05). Significant NDI decreases were observed in the right posterior cingulate gyrus, SLF, and left frontal area of the ME/CFS patients (P < 0.05). Significant ODI decreases were seen in the bilateral occipital areas, right superior temporal gyrus, the anterior limb of internal capsule, and the posterior cingulate gyrus (P < 0.05), and significant ODI increases were revealed in the bilateral occipital and right temporal areas (P < 0.05). DATA CONCLUSION: Right SLF abnormalities may be a diagnostic marker for ME/CFS. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 2 J. Magn. Reson. Imaging 2019;49:818-824.
    23. 23
      Shan, Z. Y.; Barnden, L. R.; Kwiatek, R. A.; Bhuta, S.; Hermens, D. F.; Lagopoulos, J. Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review. J. Transl. Med. 2020, 18, 335,  DOI: 10.1186/s12967-020-02506-6
      23
      Neuroimaging characteristics of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): a systematic review
      Shan Zack Y; Kwiatek Richard A; Hermens Daniel F; Lagopoulos Jim; Shan Zack Y; Barnden Leighton R; Bhuta Sandeep
      Journal of translational medicine (2020), 18 (1), 335 ISSN:.
      BACKGROUND: Since the 1990s, neuroimaging has been utilised to study Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), a debilitating illness with unknown aetiology. While brain abnormalities in ME/CFS have been identified, relatively little is known regarding which specific abnormalities are consistently observed across research groups and to what extent the observed abnormalities are reproducible. METHOD: To identify consistent and inconsistent neuroimaging observations in ME/CFS, this retrospective and systematic review searched for studies in which neuroimaging was used to investigate brain abnormalities in ME/CFS in Ovid MEDLINE, PubMed (NCBI), and Scopus from January 1988 to July 2018. A qualitative synthesis of observations was performed to identify brain abnormalities that were consistently and inconsistently reported. RESULTS: 63 full-text articles were included in the synthesis of results from 291 identified papers. Additional brain area recruitment for cognitive tasks and abnormalities in the brain stem are frequent observations in 11 and 9 studies using different modalities from different research teams respectively. Also, sluggish blood oxygenation level-dependent (BOLD) signal responses to tasks, reduced serotonin transporters, and regional hypometabolism are consistent observations by more than two research teams. Single observations include abnormal brain tissue properties, regional metabolic abnormalities, and association of brain measures with ME/CFS symptoms. Reduced resting cerebral blood flow and volumetric brain changes are inconsistent observations across different studies. CONCLUSION: Neuroimaging studies of ME/CFS have frequently observed additional brain area recruitment during cognitive tasks and abnormalities in the brain stem. The frequent observation of additional brain area recruitment and consistent observation of sluggish fMRI signal response suggest abnormal neurovascular coupling in ME/CFS.
    24. 24
      Shan, Z. Y.; Kwiatek, R.; Burnet, R.; Del Fante, P.; Staines, D. R.; Marshall-Gradisnik, S. M.; Barnden, L. R. Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study. J Magn Reson Imaging 2016, 44, 1301– 1311,  DOI: 10.1002/jmri.25283
      24
      Progressive brain changes in patients with chronic fatigue syndrome: A longitudinal MRI study
      Shan Zack Y; Staines Donald R; Marshall-Gradisnik Sonya M; Barnden Leighton R; Kwiatek Richard; Burnet Richard; Del Fante Peter
      Journal of magnetic resonance imaging : JMRI (2016), 44 (5), 1301-1311 ISSN:.
      PURPOSE: To examine progressive brain changes associated with chronic fatigue syndrome (CFS). MATERIALS AND METHODS: We investigated progressive brain changes with longitudinal MRI in 15 CFS and 10 normal controls (NCs) scanned twice 6 years apart on the same 1.5 Tesla (T) scanner. MR images yielded gray matter (GM) volumes, white matter (WM) volumes, and T1- and T2-weighted signal intensities (T1w and T2w). Each participant was characterized with Bell disability scores, and somatic and neurological symptom scores. We tested for differences in longitudinal changes between CFS and NC groups, inter group differences between pooled CFS and pooled NC populations, and correlations between MRI and symptom scores using voxel based morphometry. The analysis methodologies were first optimized using simulated atrophy. RESULTS: We found a significant decrease in WM volumes in the left inferior fronto-occipital fasciculus (IFOF) in CFS while in NCs it was unchanged (family wise error adjusted cluster level P value, PFWE < 0.05). This longitudinal finding was consolidated by the group comparisons which detected significantly decreased regional WM volumes in adjacent regions (PFWE < 0.05) and decreased GM and blood volumes in contralateral regions (PFWE < 0.05). Moreover, the regional GM and WM volumes and T2w in those areas showed significant correlations with CFS symptom scores (PFWE < 0.05). CONCLUSION: The results suggested that CFS is associated with IFOF WM deficits which continue to deteriorate at an abnormal rate. J. Magn. Reson. Imaging 2016;44:1301-1311.
    25. 25
      Puri, B. K.; Jakeman, P. M.; Agour, M.; Gunatilake, K. D.; Fernando, K. A.; Gurusinghe, A. I.; Treasaden, I. H.; Waldman, A. D.; Gishen, P. Regional grey and white matter volumetric changes in myalgic encephalomyelitis (chronic fatigue syndrome): a voxel-based morphometry 3 T MRI study. Br J Radiol 2012, 85, e270– 273,  DOI: 10.1259/bjr/93889091
      There is no corresponding record for this reference.
    26. 26
      Cook, D. B.; Lange, G.; DeLuca, J.; Natelson, B. H. Relationship of brain MRI abnormalities and physical functional status in chronic fatigue syndrome. Int J Neurosci 2001, 107, 1– 6,  DOI: 10.3109/00207450109149754
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      Relationship of brain MRI abnormalities and physical functional status in chronic fatigue syndrome
      Cook D B; Lange G; DeLuca J; Natelson B H
      The International journal of neuroscience (2001), 107 (1-2), 1-6 ISSN:0020-7454.
      Chronic Fatigue Syndrome (CFS) is an unexplained illness that is characterized by severe fatigue. Some have suggested that CFS is a "functional somatic syndrome" in which symptoms of fatigue are inappropriately attributed to a serious illness. However, brain magnetic resonance imaging (MRI) data suggest that there may be an organic abnormality associated with CFS. To understand further the significance of brain MRI abnormalities, we examined the relationship between MRI identified brain abnormalities and self-reported physical functional status in 48 subjects with CFS who underwent brain MR imaging and completed the Medical Outcomes Study SF-36. Brain MR images were examined for the presence of abnormalities based on 5 general categories previously shown to be sensitive to differentiating CFS patients from healthy controls. There were significant negative relationships between the presence of brain abnormalities and both the physical functioning (PF) (rho=-.31, p=.03), and physical component summary PCS (rho=-.32, p=.03) subscales of the SF-36. CFS patients with MRI identified brain abnormalities scored significantly lower on both PF (t(1,46) =2.3, p=.026) and the PCS (t(1,41) =2.4, p=.02) than CFS subjects without an identified brain abnormality. When adjusted for age differences only the PF analysis remained significant. However, the effect sizes for both analyses were large indicating meaningful differences in perceived functional status between the groups. These results demonstrate that the presence of brain abnormalities in CFS are significantly related to subjective reports of physical function and that CFS subjects with MRI brain abnormalities report being more physically impaired than those patients without brain abnormalities.
    27. 27
      Sbardella, E.; Petsas, N.; Tona, F.; Prosperini, L.; Raz, E.; Pace, G.; Pozzilli, C.; Pantano, P. Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients. PLoS One 2013, 8, e63250  DOI: 10.1371/journal.pone.0063250
      27
      Assessing the correlation between grey and white matter damage with motor and cognitive impairment in multiple sclerosis patients
      Sbardella, Emilia; Petsas, Nikolaos; Tona, Francesca; Prosperini, Luca; Raz, Eytan; Pace, Gianvito; Pozzilli, Carlo; Pantano, Patrizia
      PLoS One (2013), 8 (5), e63250CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      Background: Multiple sclerosis (MS) is characterized by demyelinating and degenerative processes within the central nervous system. Unlike conventional MRI, new advanced imaging techniques improve pathol. specificity and better highlight the relationship between anatomical damage and clin. impairment. Objective: To investigate the relationship between clin. disability and both gray (GM) and white matter (WM) regional damage in MS patients. Methods: Thirty-six relapsing remitting-MS patients and 25 sex- and age-matched controls were enrolled. All patients were clin. evaluated by the Expanded Disability Status Scale and the Multiple Sclerosis Functional Composite (MSFC) scale, which includes the 9-hole peg test (9HPT), the timed 25-ft walking test (T25FW) and the paced auditory serial addn. test (PASAT). All subjects were imaged by a 3.0 T scanner: dual-echo fast spin-echo, 3DT1-weighted and diffusion-tensor imaging (DTI) sequences were acquired. Voxel-based morphometry (VBM) and tract-based spatial statistics (TBSS) analyses were run for regional GM and WM assessment, resp. T2 lesion vols. were also calcd., by using a semi-automated technique. Results: Brain volumetric assessment of GM and DTI measures revealed significant differences between patients and controls. In patients, different measures of WM damage correlated each-other (p<0.0001), whereas none of them correlated with GM vol. In patients, focal GM atrophy and widespread WM damage significantly correlated with clin. measures. In particular, VBM anal. revealed a significant correlation (p<0.05) between GM vol. and 9HPT in cerebellum and between GM vol. and PASAT in orbito-frontal cortex. TBSS showed significant correlations between DTI metrics with 9HPT and PASAT scores in many WM bundles (p<0.05), including corpus callosum, internal capsule, posterior thalamic radiations, cerebral peduncles. Conclusions: Selective GM atrophy and widespread WM tracts damage are assocd. with functional impairment of upper-limb motion and cognition. The combined anal. of volumetric and DTI data may help to better understand structural alterations underlying phys. and cognitive dysfunction in MS.
    28. 28
      Komaroff, A. L.; Lipkin, W. I. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Front. Med. (Lausanne) 2023, 10, 1187163  DOI: 10.3389/fmed.2023.1187163
      28
      ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature
      Komaroff Anthony L; Lipkin W Ian
      Frontiers in medicine (2023), 10 (), 1187163 ISSN:2296-858X.
      Some patients remain unwell for months after "recovering" from acute COVID-19. They develop persistent fatigue, cognitive problems, headaches, disrupted sleep, myalgias and arthralgias, post-exertional malaise, orthostatic intolerance and other symptoms that greatly interfere with their ability to function and that can leave some people housebound and disabled. The illness (Long COVID) is similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) as well as to persisting illnesses that can follow a wide variety of other infectious agents and following major traumatic injury. Together, these illnesses are projected to cost the U.S. trillions of dollars. In this review, we first compare the symptoms of ME/CFS and Long COVID, noting the considerable similarities and the few differences. We then compare in extensive detail the underlying pathophysiology of these two conditions, focusing on abnormalities of the central and autonomic nervous system, lungs, heart, vasculature, immune system, gut microbiome, energy metabolism and redox balance. This comparison highlights how strong the evidence is for each abnormality, in each illness, and helps to set priorities for future investigation. The review provides a current road map to the extensive literature on the underlying biology of both illnesses.
    29. 29
      Khodanovich, M. Y.; Kamaeva, D. A.; Naumova, A. V. Role of Demyelination in the Persistence of Neurological and Mental Impairments after COVID-19. Int J Mol Sci 2022, 23, 11291,  DOI: 10.3390/ijms231911291
      There is no corresponding record for this reference.
    30. 30
      Shabani, Z. Demyelination as a result of an immune response in patients with COVID-19. Acta Neurol Belg 2021, 121, 859– 866,  DOI: 10.1007/s13760-021-01691-5
      30
      Demyelination as a result of an immune response in patients with COVID-19
      Shabani Zahra
      Acta neurologica Belgica (2021), 121 (4), 859-866 ISSN:.
      The coronavirus disease of 2019 (COVID-19) is caused by the severe acute respiratory syndrome coronavirus-2 (SARS CoV-2), that already appeared as a global pandemic. Presentation of the disease often includes upper respiratory symptoms like dry cough, dyspnea, chest pain, and rhinorrhea that can develop to respiratory failure, needing intubation. Furthermore, the occurrence of acute and subacute neurological manifestations such as stroke, encephalitis, headache, and seizures are frequently stated in patients with COVID-19. One of the reported neurological complications of severe COVID-19 is the demolition of the myelin sheath. Indeed, the complex immunological dysfunction provides a substrate for the development of demyelination. Nevertheless, few published reports in the literature describe demyelination in subjects with COVID-19. In this short narrative review, we discuss probable pathological mechanisms that may trigger demyelination in patients with SARS-CoV-2 infection and summarize the clinical evidence, confirming SARS-CoV-2 condition as a risk factor for the destruction of myelin.
    31. 31
      Khair, A. M.; Nikam, R.; Husain, S.; Ortiz, M.; Kaur, G. Para and Post-COVID-19 CNS Acute Demyelinating Disorders in Children: A Case Series on Expanding the Spectrum of Clinical and Radiological Characteristics. Cureus 2022, 14, e23405  DOI: 10.7759/cureus.23405
      There is no corresponding record for this reference.
    32. 32
      Kara, S.; Candelore, T.; Youssef, P.; Nedd, K. Evidence of Post-COVID-19 Transverse Myelitis Demyelination. Cureus 2021, 13, e19087  DOI: 10.7759/cureus.19087
      There is no corresponding record for this reference.
    33. 33
      Shokat, K. M.; Schultz, P. G. Catalytic antibodies. Annu. Rev. Immunol. 1990, 8, 335– 363,  DOI: 10.1146/annurev.iy.08.040190.002003
      33
      Catalytic antibodies
      Shokat, K. M.; Schultz, P. G.
      Annual Review of Immunology (1990), 8 (), 335-63CODEN: ARIMDU; ISSN:0732-0582.
      A review with 89 refs. on the generation, design, and activity of catalytic antibodies.
    34. 34
      Jencks, W. P. Catalysis in Chemistry and Enzymology; Dover: New York, NY, 1969, 836.
      There is no corresponding record for this reference.
    35. 35
      Schultz, P; Lerner, R. A. Antibody catalysis of difficult chemical transformations. Acc. Chem. Res. 1993, 26, 391– 395,  DOI: 10.1021/ar00032a001
      35
      Antibody catalysis of difficult chemical transformations
      Schultz, Peter G.; Lerner, Richard A.
      Accounts of Chemical Research (1993), 26 (8), 391-5CODEN: ACHRE4; ISSN:0001-4842.
      A review, with 28 refs., on antibody catalysis. Topics include disfavored chem. reactions, control of regio- and enantioselectivity of reactions, control of ortho transfers, and transesterification reactions.
    36. 36
      Landry, D. W.; Zhao, K.; Yang, G. X.; Glickman, M.; Georgiadis, T. M. Antibody-catalyzed degradation of cocaine. Science 1993, 259, 1899– 1901,  DOI: 10.1126/science.8456315
      36
      Antibody-catalyzed degradation of cocaine
      Landry, Donald W.; Zhao, Kang; Yang, Ginger X. Q.; Glickman, Michael; Georgiadis, Taxiarchis M.
      Science (Washington, DC, United States) (1993), 259 (5103), 1899-901CODEN: SCIEAS; ISSN:0036-8075.
      Immunization with a phosphonate monoester transition-state analog of cocaine provided monoclonal antibodies capable of catalyzing the hydrolysis of the cocaine benzoyl ester group. An assay for the degrdn. of radiolabeled cocaine identified active enzymes. Benzoyl esterolysis yields ecgonine Me ester and benzoic acid, fragments devoid of cocaine's stimulant activity. Passive immunization with such an artificial enzyme could provide a treatment for dependence by blunting reinforcement.
    37. 37
      Landry, D. W.; Yang, G. X. Anti-cocaine catalytic antibodies--a novel approach to the problem of addiction. J Addict Dis 1997, 16, 1– 17,  DOI: 10.1300/J069v16n03_01
      37
      Anti-cocaine catalytic antibodies--a novel approach to the problem of addiction
      Landry D W; Yang G X
      Journal of addictive diseases (1997), 16 (3), 1-17 ISSN:1055-0887.
      Cocaine reinforces its self-administration in relation to the magnitude of and rate of rise to the peak serum concentration of the drug. Catalytic antibodies are artificial enzymes which could reduce serum cocaine concentrations, deprive the abuser of cocaine's reinforcing effect and thus favor extinction of the addiction. Catalytic antibodies are elicited by immunization with a stable analog of a transition-state for a chemical reaction. Through our new method for synthesizing phosphonate monoesters, we constructed several phosphonate-based transition-state analogs of cocaine hydrolysis. Using these analogs, monoclonal antibodies were elicited and, thus far, nine anti-analog antibodies with hydrolytic activity against cocaine have been identified, cloned and studied. The activity of one of these antibodies, 15A10, is sufficient to commence preclinical studies.
    38. 38
      Mahendra, A.; Sharma, M.; Rao, D. N.; Peyron, I.; Planchais, C.; Dimitrov, J. D.; Kaveri, S. V.; Lacroix-Desmazes, S. Antibody-mediated catalysis: induction and therapeutic relevance. Autoimmun Rev 2013, 12, 648– 652,  DOI: 10.1016/j.autrev.2012.10.009
      38
      Antibody-mediated catalysis: Induction and therapeutic relevance
      Mahendra, Ankit; Sharma, Meenu; Rao, Desirazu N.; Peyron, Ivan; Planchais, Cyril; Dimitrov, Jordan D.; Kaveri, Srini V.; Lacroix-Desmazes, Sebastien
      Autoimmunity Reviews (2013), 12 (6), 648-652CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)
      A review. Abzymes are Igs endowed with enzymic activities. The catalytic activity of an abzyme resides in the variable domain of the antibody, which is constituted by the close spatial arrangement of amino acid residues involved in catalysis. The origin of abzymes is conferred by the innate diversity of the Ig gene repertoire. Under deregulated immune conditions, as in autoimmune diseases, the generation of abzymes to self-antigens could be deleterious. Tech. advancement in the ability to generate monoclonal antibodies has been exploited in the generation of abzymes with defined specificities and activities. Therapeutic applications of abzymes are being investigated with the generation of monoclonal abzymes against several pathogenesis-assocd. antigens. Here, we review the different contexts in which abzymes are generated, and we discuss the relevance of monoclonal abzymes for the treatment of human diseases.
    39. 39
      Paul, S.; Karle, S.; Planque, S.; Taguchi, H.; Salas, M.; Nishiyama, Y.; Handy, B.; Hunter, R.; Edmundson, A.; Hanson, C. Naturally occurring proteolytic antibodies: selective immunoglobulin M-catalyzed hydrolysis of HIV gp120. J. Biol. Chem. 2004, 279, 39611– 39619,  DOI: 10.1074/jbc.M406719200
      39
      Naturally Occurring Proteolytic Antibodies: Selective immunoglobulin M-catalyzed hydrolysis of HIV gp120
      Paul, Sudhir; Karle, Sangeeta; Planque, Stephanie; Taguchi, Hiroaki; Salas, Maria; Nishiyama, Yasuhiro; Handy, Beverly; Hunter, Robert; Edmundson, Allen; Hanson, Carl
      Journal of Biological Chemistry (2004), 279 (38), 39611-39619CODEN: JBCHA3; ISSN:0021-9258. (American Society for Biochemistry and Molecular Biology)
      We report the selective catalytic cleavage of the HIV coat protein gp120, a B cell superantigen, by IgM antibodies (Abs) from uninfected humans and mice that had not been previously exposed to gp120. The rate of IgM-catalyzed gp120 cleavage was greater than of other polypeptide substrates, including the bacterial superantigen protein A. The kinetic parameters of gp120 cleavage varied over a broad range depending on the source of the IgMs, and turnover nos. as great as 2.1/min were obsd., suggesting that different Abs possess distinct gp120 recognition properties. IgG Abs failed to cleave gp120 detectably. The Fab fragment of a monoclonal IgM cleaved gp120, suggesting that the catalytic activity belongs to the antibody combining site. The electrophoretic profile of gp120 incubated with a monoclonal human IgM suggested hydrolysis at several sites. One of the cleavage sites was identified as the Lys432-Ala433 peptide bond, located within the region thought to be the Ab-recognizable superantigenic determinant. A covalently reactive peptide analog (CRA) corresponding to gp120 residues 421-431 with a C-terminal amidino phosphonate diester mimetic of the Lys432-Ala433 bond was employed to probe IgM nucleophilic reactivity. The peptidyl CRA inhibited the IgM-catalyzed cleavage of gp120 and formed covalent IgM adducts at levels exceeding a control hapten CRA devoid of the peptide sequence. These observations suggest that IgMs can selectively cleave gp120 by a nucleophilic mechanism and raise the possibility of their role as defense enzymes.
    40. 40
      Planque, S.; Nishiyama, Y.; Taguchi, H.; Salas, M.; Hanson, C.; Paul, S. Catalytic antibodies to HIV: physiological role and potential clinical utility. Autoimmun Rev 2008, 7, 473– 479,  DOI: 10.1016/j.autrev.2008.04.002
      40
      Catalytic antibodies to HIV: physiological role and potential clinical utility
      Planque, Stephanie; Nishiyama, Yasuhiro; Taguchi, Hiroaki; Salas, Maria; Hanson, Carl; Paul, Sudhir
      Autoimmunity Reviews (2008), 7 (6), 473-479CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)
      A review. Igs in uninfected humans recognize residues 421-433 located in the B cell superantigenic site (SAg) of the HIV envelope protein gp120 and catalyze its hydrolysis by a serine protease-like mechanism. The catalytic activity is encoded by germline Ig variable (V) region genes, and is expressed at robust levels by IgMs and IgAs but poorly by IgGs. Mucosal IgAs are highly catalytic and neutralize HIV, suggesting that they constitute a first line of defense against HIV. Lupus patients produce the Igs at enhanced levels. Homol. of the 421-433 region with an endogenous retroviral sequence and a bacterial protein may provide clues about the antigen driving anti-SAg synthesis in lupus patients and uninfected subjects. The potency and breadth of HIV neutralization revives hopes of clin. application of catalytic anti-421-433 Igs as immunotherapeutic and topical microbicide reagents. Adaptive improvement of anti-SAg catalytic Igs in HIV infected subjects is not customary. Further study of the properties of the naturally occurring anti-SAg catalytic Igs should provide valuable guidance in designing a prophylactic vaccine that amplifies protective catalytic immunity to HIV.
    41. 41
      Paul, S.; Volle, D. J.; Beach, C. M.; Johnson, D. R.; Powell, M. J.; Massey, R. J. Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science 1989, 244, 1158– 1162,  DOI: 10.1126/science.2727702
      41
      Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody
      Paul, Sudhir; Volle, Deanna J.; Beach, Carol M.; Johnson, Donald R.; Powell, Michael J.; Massey, Richard J.
      Science (Washington, DC, United States) (1989), 244 (4909), 1158-62CODEN: SCIEAS; ISSN:0036-8075.
      VIP labeled with 125I, [Tyr10-125I]VIP, can be hydrolyzed by IgG purified from a human subject, as judged by trichloroacetic acid pptn. and reversed-phase HPLC. The hydrolytic activity was pptd. by antibody to human IgG, it was bound by immobilized protein G, and showed a mol. mass close to 150 kilodaltons by gel filtration chromatog., properties similar to those of authentic IgG. The Fab fragment, prepd. from IgG by papain treatment, retained the VIP hydrolytic activity of the IgG. Peptide fragments produced by treatment of VIP with the antibody fraction were purified by reversed-phase HPLC and identified by fast atom bombardment-mass spectrometry and peptide sequencing. The scissile bond in VIP deduced from these expts. was Gln16-Met17. The antibody concn. (73.4 fmol per mg of IgG) and the Kd (0.4 nM) were computed from anal. of VIP binding under conditions that did not result in peptide hydrolysis. Anal. of the antibody-mediated VIP hydrolysis at varying concns. of substrate suggested conformity with Michaelis-Menten kinetics (Km). The values for Km (37.9 × 10-9M) and the turnover no. kcat (15.6 min-1) suggested relatively tight VIP binding and a moderate catalytic efficiency of the antibody.
    42. 42
      Ponomarenko, N. A.; Durova, O. M.; Vorobiev, I. I.; Belogurov, A. A., Jr.; Kurkova, I. N.; Petrenko, A. G.; Telegin, G. B.; Suchkov, S. V.; Kiselev, S. L.; Lagarkova, M. A.; Govorun, V. M.; Serebryakova, M. V.; Avalle, B.; Tornatore, P.; Karavanov, A.; Morse, H. C., 3rd; Thomas, D.; Friboulet, A.; Gabibov, A. G. Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen. Proc Natl Acad Sci U S A 2006, 103, 281– 286,  DOI: 10.1073/pnas.0509849103
      42
      Autoantibodies to myelin basic protein catalyze site-specific degradation of their antigen
      Ponomarenko, Natalia A.; Durova, Oxana M.; Vorobiev, Ivan I.; Belogurov, Alexey A., Jr.; Kurkova, Inna N.; Petrenko, Alexander G.; Telegin, Georgy B.; Suchkov, Sergey V.; Kiselev, Sergey L.; Lagarkova, Maria A.; Govorun, Vadim M.; Serebryakova, Marina V.; Avalle, Berangere; Tornatore, Pete; Karavanov, Alexander; Morse, Herbert C., III; Thomas, Daniel; Friboulet, Alain; Gabibov, Alexander G.
      Proceedings of the National Academy of Sciences of the United States of America (2006), 103 (2), 281-286CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      Autoantibody-mediated tissue destruction is among the main features of organ-specific autoimmunity. This report describes "an antibody enzyme" (abzyme) contribution to the site-specific degrdn. of a neural antigen. We detected proteolytic activity toward myelin basic protein (MBP) in the fraction of antibodies purified from the sera of humans with multiple sclerosis (MS) and mice with induced exptl. allergic encephalomyelitis. Chromatog. and zymog. data demonstrated that the proteolytic activity of this prepn. was exclusively assocd. with the antibodies. No activity was found in the IgG fraction of healthy donors. The human and murine abzymes efficiently cleaved MBP but not other protein substrates tested. The sites of MBP cleavage detd. by mass spectrometry were localized within immuno-dominant regions of MBP. The abzymes could also cleave recombinant substrates contg. encephalitogenic MBP85-101 peptide. An established MS therapeutic Copaxone appeared to be a specific abzyme inhibitor. Thus, the discovered epitope-specific antibody-mediated degrdn. of MBP suggests a mechanistic explanation of the slow development of neurodegeneration assocd. with MS.
    43. 43
      Olopade, C. O.; Yu, J.; Abubaker, J.; Mensah, E.; Paul, S. Catalytic hydrolysis of VIP in pregnant women with asthma. J Asthma 2006, 43, 429– 432,  DOI: 10.1080/02770900600710730
      43
      Catalytic hydrolysis of VIP in pregnant women with asthma
      Olopade, Christopher O.; Yu, John; Abubaker, Jawed; Mensah, Edward; Paul, Sudhir
      Journal of Asthma (2006), 43 (6), 429-432CODEN: JOUADU; ISSN:0277-0903. (Taylor & Francis, Inc.)
      The neuropeptide vasoactive intestinal peptide (VIP) is one of the physiol. mediators of non-adrenergic, non-cholinergic smooth muscle relaxation of the airway and an important modulator of innate and adaptive immune responses. VIP catalytic autoantibodies are increased in asthma and serum VIP level is decreased during acute exacerbation of asthma. The effect of pregnancy on asthma is variable and depends in part on the severity of pre-existing asthma, along with other physiol. and pathophysiol. changes. We hypothesized that hydrolysis of VIP by circulating catalytic VIP antibodies will be increased in pregnancy in patients with asthma. To det. the level of catalytic autoantibodies to VIP in pregnant asthmatics compared to non-pregnant asthmatics and control pregnant women without asthma. We prospectively enrolled eight pregnant asthmatics (age, 26.5 ± 2.6 years; mean ± SEM), nine pregnant women without asthma (32.0 ± 3.0 years), seven non-pregnant women with asthma (25.0 ± 1.9 years), and seven non-pregnant women without asthma (34.4 ± 2 years) into the study. VIP hydrolysis was performed in all subjects. IgG autoantibodies that catalyze the hydrolysis of vasoactive intestinal peptide (VIP) were present at greater levels in the blood of pregnant women with asthma (7.6 ± 1.1 pM VIP/6 h) compared to pregnant women without asthma (4.0 ± 0.5; p < 0.001), non-pregnant asthmatics (4.9 ± 0.9; p < 0.05) or non-pregnant women without asthma (1.9 ± 0.7; p < 0.05). An increase in the VIP hydrolyzing activity of IgG is independently assocd. with asthma and pregnancy. The autoantibodies hold the potential of affecting the pathophysiol. of the airways in pregnant asthmatics.
    44. 44
      Nevinsky, G. A.; Buneva, V. N. Human catalytic RNA- and DNA-hydrolyzing antibodies. J Immunol Methods 2002, 269, 235– 249,  DOI: 10.1016/S0022-1759(02)00234-X
      44
      Human catalytic RNA- and DNA-hydrolyzing antibodies
      Nevinsky, Georgy A.; Buneva, Valentina N.
      Journal of Immunological Methods (2002), 269 (1-2), 235-249CODEN: JIMMBG; ISSN:0022-1759. (Elsevier Science B.V.)
      A review. In patients with autoimmune diseases, anti-idiotypic antibodies directed to nucleoprotein complexes, DNA, and enzymes that participate in nucleic acid metab. may be induced spontaneously by primary antigens and can have characteristics of the primary antigen, including catalytic activity. The first natural catalytic antibody, now termed abzyme, which hydrolyzes intestinal vasoactive peptide, was discovered by Paul et al. [Science 244 (1989) 1158]. Subsequently, other abzymes able to hydrolyze proteins, DNA, RNA, or polysaccharides have been found in the sera of patients with autoimmune and also viral pathologies. Further, we have discovered in the milk of healthy human mothers antibodies that catalyze the hydrolysis of RNA, DNA, nucleotides, and the phosphorylation of lipids and proteins. The phenomenon of catalysis by autoantibodies is extremely interesting and can potentially be applied to many different objectives including new types of efficient catalysts, evaluation of the functional roles of abzymes in innate and adaptive immunity, and understanding of certain aspects of self-tolerance and of the destructive responses in autoimmune diseases. In this review, we collate methods for purifying and characterizing natural abzymes esp. those catalyzing DNA and RNA hydrolysis. We also describe new methods that we have developed to provide rigorous criteria that catalytic activity is an intrinsic property of some antibodies. Some major current themes are discussed as well as potential applications of abzymes in scientific, medical, and biotechnol. fields.
    45. 45
      Nevinsky, G. A.; Buneva, V. N. Natural catalytic antibodies in norm, autoimmune, viral, and bacterial diseases. ScientificWorldJournal 2010, 10, 1203– 1233,  DOI: 10.1100/tsw.2010.98
      45
      Natural catalytic antibodies in norm, autoimmune, viral, and bacterial diseases
      Nevinsky Georgy A; Buneva Valentina N
      TheScientificWorldJournal (2010), 10 (), 1203-33 ISSN:.
      In human patients with autoimmune, viral, and bacterial diseases, the generation of antibodies (Abs) to foreign antigens and/or autoantibodies to self-antigens usually occurs. Some Abs with different catalytic activities (abzymes, Abzs) may be induced spontaneously by primary antigens and can have characteristics of the primary antigen, including the catalytic activity of idiotypic and/or anti-idiotypic Abs. Healthy humans usually do not develop Abzs or their activities are low, often on the borderline of sensitivity of the detection methods. Detection of Abzs was shown to be the earliest indicator of development of different autoimmune diseases (ADs). At the early stages of ADs, the repertoire of Abzs is usually relatively narrow, but it greatly expands with the progress of the disease, leading to the generation of catalytically diverse Abzs with different activities and functions. Some Abzs are cytotoxic and can play an important negative role in the pathogenesis of ADs, while positive roles have been proposed for other Abzs. Abzs with some low activities can temporarily be present in the blood of patients in the course of viral and bacterial diseases, but their activity increases significantly if these infections stimulate development of ADs. A significant increase in the relative Abz activities associated with a specific reorganization of the immune system, including changes in the differentiation and proliferation of bone marrow hematopoietic stem cells and lymphocyte proliferation in different organs. Different mechanisms of Abz production can be proposed for healthy externally immunized and for autoimmune mammals during the development of pathology.
    46. 46
      Genain, C. P.; Cannella, B.; Hauser, S. L.; Raine, C. S. Identification of autoantibodies associated with myelin damage in multiple sclerosis. Nat Med 1999, 5, 170– 175,  DOI: 10.1038/5532
      46
      Identification of autoantibodies associated with myelin damage in multiple sclerosis
      Genain, Claude P.; Cannella, Barbara; Hauser, Stephen L.; Raine, Cedric S.
      Nature Medicine (New York) (1999), 5 (2), 170-175CODEN: NAMEFI; ISSN:1078-8956. (Nature America)
      The mol. mechanisms underlying myelin sheath destruction in multiple sclerosis lesions remain unresolved. With immunogold-labeled peptides of myelin antigens and high-resoln. microscopy, techniques that can detect antigen-specific antibodies in situ, we have identified autoantibodies specific for the central nervous system myelin antigen myelin/oligodendrocyte glycoprotein. These autoantibodies were specifically bound to disintegrating myelin around axons in lesions of acute multiple sclerosis and the marmoset model of allergic encephalomyelitis. These findings represent direct evidence that autoantibodies against a specific myelin protein mediate target membrane damage in central nervous system demyelinating disease.
    47. 47
      Eylar, E. H. Amino acid sequence of the basic protein of the myelin membrane. Proc Natl Acad Sci U S A 1970, 67, 1425– 1431,  DOI: 10.1073/pnas.67.3.1425
      47
      Amino acid sequence of the basic protein of the myelin membrane
      Eylar, Edwin H.
      Proceedings of the National Academy of Sciences of the United States of America (1970), 67 (3), 1425-31CODEN: PNASA6; ISSN:0027-8424.
      The amino acid sequences of the encephalitogenic basic protein, Al, from bovine and human myelin are similar, differing by only 11 residues. The sequence reveals that while basic residues are spread randomly over most of the polypeptide chain, several regions (8-10 residues) exist that are nonpolar in character. The bovine protein has 170 residues with mol. wt. 18,400. The human protein, which has an addnl. His-Gly sequence, contains 172 residues. The major encephalitogenic determinant (tryptophan region) of the bovine protein differs from the human only by a lysine to arginine substitution. The structural features of the A1 protein are discussed, with special reference to its role in stabilization of the myelin membrane, and its relation to multiple sclerosis.
    48. 48
      Ponomarenko, N. A.; Durova, O. M.; Vorobiev, I. I.; Belogurov, A. A.; Telegin, G. B.; Suchkov, S. V.; Misikov, V. K.; Morse, H. C., 3rd; Gabibov, A. G. Catalytic activity of autoantibodies toward myelin basic protein correlates with the scores on the multiple sclerosis expanded disability status scale. Immunol. Lett. 2006, 103, 45– 50,  DOI: 10.1016/j.imlet.2005.10.006
      48
      Catalytic activity of autoantibodies toward myelin basic protein correlates with the scores on the multiple sclerosis expanded disability status scale
      Ponomarenko, Natalia A.; Durova, Oxana M.; Vorobiev, Ivan I.; Belogurov, Alexey A.; Telegin, Georgy B.; Suchkov, Sergey V.; Misikov, Victor K.; Morse, Herbert C.; Gabibov, Alexander G.
      Immunology Letters (2006), 103 (1), 45-50CODEN: IMLED6; ISSN:0165-2478. (Elsevier B.V.)
      Autoantibodies toward myelin basic protein (MBP) evidently emerge in sera and cerebrospinal fluid of the patients with multiple sclerosis (MS), as well as in a MS rodent model, i.e., exptl. autoimmune encephalomyelitis (EAE). The studies of the last two decades have unveiled somewhat controversial data on the diagnostic applicability of anti-MBP autoantibodies as a disease' marker. Here, we present the results of new functional anal. of the anti-MBP autoantibodies isolated from MS (in patients) and EAE (in mice) sera, based on their proteolytic activity against the targeted autoantigen. The activity was shown to be the intrinsic property of the IgG mol. No activity was found in the sera-derived antibody fraction of healthy donors and control mice. Sera of 24 patients with clin. proven MS at different stages of the disease, and 20 healthy controls were screened for the anti-MBP antibody-mediated proteolytic activity. The activity correlated with the scores on the MS expanded disability status scale (EDSS) (r2 = 0.85, P < 0.001). Thus, the anti-MBP autoantibody-mediated proteolysis may be regarded as an addnl. marker of the disease progression.
    49. 49
      Eylar, E. H.; Salk, J.; Beveridge, G. C.; Brown, L. V. Experimental allergic encephalomyelitis. An encephalitogenic basic protein from bovine myelin. Arch. Biochem. Biophys. 1969, 132, 34– 48,  DOI: 10.1016/0003-9861(69)90336-1
      49
      Experimental allergic encephalomyelitis. An encephalitogenic basic protein from bovine myelin
      Eylar, Edwin H.; Salk, Jonas; Beveridge, George C.; Brown, Lenora V.
      Archives of Biochemistry and Biophysics (1969), 132 (1), 34-48CODEN: ABBIA4; ISSN:0003-9861.
      A homogeneous encephalitogenic protein was prepd. in high yield (35-40%) from bovine spinal cord and myelin. This protein, referred to as A1 protein, is susceptible to proteolysis in situ at pH 6-7; this effect is arrested by prompt freezing of tissue upon removal from the animal. The purification procedure consists of (1) defatting with CHCl3-MeOH (2:1), (2) acid extn. at pH 1.7, (3) pptn. of contaminating protein and dialysis at pH 7, (4) DEAE-cellulose chromatog., and (5) gel filtration. CM-cellulose or Cellex-P chromatog. was also used for final purification in place of gel filtration. The DEAE eluate contained the basic protein fraction of which the A1 protein comprised 80-95%. The data suggest that the A1 protein is very likely the only encephalitogenic basic protein of native myelin, constituting ∼30% of the total myelin protein. It was obtained in homogeneous form as demonstrated by a single sharp band on polyacrylamide gel electrophoresis at pH 4.5 and 8.6, and by immunoelectrophoresis and immunodouble diffusion. As little as 0.1 μg. induced histol. lesions in the central nervous system and 10-100 μg. induced clin. disease in 80-100% of guinea pigs. In addn. to its encephalitogenic activity the A1 protein induces in rabbits and guinea pigs the formation of pptg. antibody which was detected by immunodouble diffusion and assayed in a passive hemagglutination test. Antibody-combining activity of the A1 protein was also demonstrated by immunodouble diffusion and was measured by a passive hemagglutination-inhibition test. The delayed hypersensitive response developed in guinea pigs after injection of 20 μg. of the A1 protein and was demonstrated using 5 μg. as skin test antigen. The pos. skin test and histol. lesions characterizing exptl. allergic encephalomyelitis both appeared 4-5 days after sensitization and developed simultaneously. The principal findings here reported, on the in situ proteolysis of the encephalitogenic basic protein, provide a partial explanation for the reports from different labs. of encephalitogens possessing widely differing properties.
    50. 50
      Hedegaard, C. J.; Chen, N.; Sellebjerg, F.; Sorensen, P. S.; Leslie, R. G.; Bendtzen, K.; Nielsen, C. H. Autoantibodies to myelin basic protein (MBP) in healthy individuals and in patients with multiple sclerosis: a role in regulating cytokine responses to MBP. Immunology 2009, 128, e451– 461,  DOI: 10.1111/j.1365-2567.2008.02999.x
      There is no corresponding record for this reference.
    51. 51
      Gonzalez-Gronow, M; Pizzo, S. V. Relevance of Catalytic Autoantibodies to Myelin Basic Protein (MBP) in Autoimmune Disorders. J Neurol Neuromedicine 2018, 3 (4), 75– 78,  DOI: 10.29245/2572.942X/2018/4.1199
      There is no corresponding record for this reference.
    52. 52
      Vojdani, A.; Kharrazian, D. Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases. Clin Immunol 2020, 217, 108480  DOI: 10.1016/j.clim.2020.108480
      52
      Potential antigenic cross-reactivity between SARS-CoV-2 and human tissue with a possible link to an increase in autoimmune diseases
      Vojdani, Aristo; Kharrazian, Datis
      Clinical Immunology (Amsterdam, Netherlands) (2020), 217 (), 108480CODEN: CLIIFY; ISSN:1521-6616. (Elsevier B.V.)
      Since the outbreak of COVID-19 caused by SARS-CoV-2, we tested 5 different blood specimens that were confirmed pos. for SARS-CoV-2 IgG and IgM antibodies. The measurements were for anti-nuclear antibody (ANA), anti-extractable nuclear antigen (ENA), anti-double-stranded DNA (dsDNA),actin antibody, mitochondrial antibody,rheumatoid factor(RF), and C1q immunecomplexes. We were surprised to find out that 3 of the 5 specimens had significant elevations in ANA, ENA,actin and mitochondrial antibodies,but not against sDNA or RF. This prompted us to investigate patterns of cross-reactivity between SARS-CoV-2 and autoimmune target proteins.
    53. 53
      Danilenko, O. V.; Gavrilova, N. Y.; Churilov, L. P. Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology. Pathophysiology 2022, 29, 187– 199,  DOI: 10.3390/pathophysiology29020016
      53
      Chronic Fatigue Exhibits Heterogeneous Autoimmunity Characteristics Which Reflect Etiology
      Danilenko Olga V; Churilov Leonid P; Gavrilova Natalia Y; Gavrilova Natalia Y; Gavrilova Natalia Y; Churilov Leonid P
      Pathophysiology : the official journal of the International Society for Pathophysiology (2022), 29 (2), 187-199 ISSN:.
      Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) is considered to be associated with post-viral complications and mental stress, but the role of autoimmunity also remains promising. A comparison of autoimmune profiles in chronic fatigue of different origin may bring insights on the pathogenesis of this disease. Thirty-three patients with CFS/ME were divided into three subgroups. The first group included Herpesviridae carriers (group V), the second group included stress-related causes of chronic fatigue (distress, group D), and the third group included idiopathic CFS/ME (group I). Were evaluated thirty-six neural and visceral autoantigens with the ELISA ELI-test (Biomarker, Russia) and compared to 20 healthy donors, either without any fatigue (group H), or "healthy but tired" (group HTd) with episodes of fatigue related to job burnout not fitting the CFS/ME criteria. β2-glycoprotein-I autoantibodies were increased in CFS/ME patients, but not in healthy participants, that alludes the link between CFS/ME and antiphospholipid syndrome (APS) earlier suspected by Berg et al. (1999). In CFS/ME patients, an increase in levels of autoantibodies towards the non-specific components of tissue debris (double-stranded DNA, collagen) was shown. Both CFS and HTd subgroups had elevated level of autoantibodies against serotonin receptors, glial fibrillary acidic protein and protein S100. Only group V showed an elevation in the autoantibodies towards voltage-gated calcium channels, and only group D had elevated levels of dopamine-, glutamate- and GABA-receptor autoantibodies, as well as NF200-protein autoantibodies. Therefore, increased autoimmune reactions to the multiple neural antigens and to adrenal medullar antigen, but not to other tissue-specific somatic ones were revealed. An increase in autoantibody levels towards some neural and non-tissue-specific antigens strongly correlated with a CFS/ME diagnosis. Autoimmune reactions were described in all subtypes of the clinically significant chronic fatigue. Visceral complaints in CFS/ME patients may be secondary to the neuroendocrine involvement and autoimmune dysautonomia. CFS may be closely interrelated with antiphospholipid syndrome, that requires further study.
    54. 54
      Lalive, P. H.; Neuhaus, O.; Benkhoucha, M.; Burger, D.; Hohlfeld, R.; Zamvil, S. S.; Weber, M. S. Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action. CNS Drugs 2011, 25, 401– 414,  DOI: 10.2165/11588120-000000000-00000
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      Glatiramer acetate in the treatment of multiple sclerosis: emerging concepts regarding its mechanism of action
      Lalive, Patrice H.; Neuhaus, Oliver; Benkhoucha, Mahdia; Burger, Danielle; Hohlfeld, Reinhard; Zamvil, Scott S.; Weber, Martin S.
      CNS Drugs (2011), 25 (5), 401-414CODEN: CNDREF; ISSN:1172-7047. (Adis Data Information BV)
      A review. Glatiramer acetate is a synthetic, random copolymer widely used as a first-line agent for the treatment of relapsing-remitting multiple sclerosis (MS). While earlier studies primarily attributed its clin. effect to a shift in the cytokine secretion of CD4+ T helper (Th) cells, growing evidence in MS and its animal model, exptl. autoimmune encephalomyelitis (EAE), suggests that glatiramer acetate treatment is assocd. with a broader immunomodulatory effect on cells of both the innate and adaptive immune system. To date, glatiramer acetate-mediated modulation of antigen-presenting cells (APC) such as monocytes and dendritic cells, CD4+ Th cells, CD8+ T cells, Foxp3+ regulatory T cells and antibody prodn. by plasma cells have been reported; in addn., most recent investigations indicate that glatiramer acetate treatment may also promote regulatory B-cell properties. Exptl. evidence suggests that, among these diverse effects, a fostering interplay between anti-inflammatory T-cell populations and regulatory type II APC may be the central axis in glatiramer acetate-mediated immune modulation of CNS autoimmune disease. Besides altering inflammatory processes, glatiramer acetate could exert direct neuroprotective and/or neuroregenerative properties, which could be of relevance for the treatment of MS, but even more so for primarily neurodegenerative disorders, such as Alzheimer's or Parkinson's disease. In this review, we provide a comprehensive and crit. overview of established and recent findings aiming to elucidate the complex mechanism of action of glatiramer acetate.
    55. 55
      Ziemssen, T.; Schrempf, W. Glatiramer acetate: mechanisms of action in multiple sclerosis. Int Rev Neurobiol 2007, 79, 537– 570,  DOI: 10.1016/S0074-7742(07)79024-4
      55
      Glatiramer acetate: mechanisms of action in multiple sclerosis
      Ziemssen, Tjalf; Schrempf, Wiebke
      International Review of Neurobiology (2007), 79 (Neurobiology of Multiple Sclerosis), 537-570CODEN: IRNEAE; ISSN:0074-7742. (Elsevier)
      A review. Glatiramer acetate (GA), formerly known as copolymer 1, is a mixt. of synthetic polypeptides composed of four amino acids resembling the myelin basic protein (MSP). GA has been shown to be highly effective in preventing and suppressing exptl. autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS). Therefore, it was tested in several clin. studies and so approved for the immunomodulatory treatment of relapsing-type MS. In contrast to other immunomodulatory MS therapies, GA has a distinct mechanism of action: GA demonstrates an initial strong promiscuous binding to to major histocompatibility complex mols. and consequent competition with various (myelin) antigens for their presentation to T cells. In addn., antigen-based therapy generating a GA-specific immune response seems to be the prerequisite for GA therapy. GA treatment induces an in vivo change of the frequency, cytokine secretion pattern and the effector function of GA-specific CD4+ and CD8+ T cells, probably by affecting the properties of antigen-presenting cells such as monocytes and dendritic cells. As demonstrated extensively in animal expts., GA-specific, mostly, T helper 2 cells migrate to the brain and lead to in situ bystander suppression of the inflammatory process in the brain. Furthermore, GA-specific cells in the brain express neurotrophic factors like the brain-derived neurotrophic factor (BDNF) in addn. to anti-inflammatory T helper 2-like cytokines. This might help tip the balance in favor of more beneficial influences because there is a complex interplay between detrimental and beneficial factors and mediators in the inflammatory milieu of MS lesions.
    56. 56
      Johnson, K. P. Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: an update. Expert Opin Drug Metab Toxicol 2010, 6, 643– 660,  DOI: 10.1517/17425251003752715
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      Glatiramer acetate and the glatiramoid class of immunomodulator drugs in multiple sclerosis: an update
      Johnson, Kenneth P.
      Expert Opinion on Drug Metabolism & Toxicology (2010), 6 (5), 643-660CODEN: EODMAP; ISSN:1742-5255. (Informa Healthcare)
      A review. Importance of the field: MS is a chronic progressive inflammatory and neurodegenerative disease assocd. with autoimmune dysregulation. Glatiramer acetate (GA), a complex polypeptides mixt. and first member of the glatiramoid class, is a first-line therapy for relapsing MS. New glatiramoids are under development.Areas covered in this review: Studies from a PubMed search with terms glatiramer' and glatiramoid' were evaluated, focussing on studies conducted between 2007 and 2010.What the reader will gain: We review newly discovered GA effects on innate and acquired immunity and results of recent clin. studies. GA delays conversion from a clin. isolated syndrome to definite MS and has clin. benefits comparable to those of IFN-β drugs, but is more cost-effective and improves quality of life. Preclin. studies of protiramer, a higher mol. mass glatiramoid, showed unexpected toxicity in animals, resulting in discontinuation of drug development.Take home messages: GA is a cost-effective, safe and efficacious MS treatment with pleiotropic immunomodulation activity, is best prescribed early and may safely enhance outcomes when used with other immunomodulators. Protiramer experience indicates the potential for unexpected toxicity assocd. with new glatiramoids. The safety, efficacy and immunogenicity of new glatiramoids must be evaluated thoroughly.
    57. 57
      Stapulionis, R.; Pinto Oliveira, C. L.; Gjelstrup, M. C.; Pedersen, J. S.; Hokland, M. E.; Hoffmann, S. V.; Poulsen, K.; Jacobsen, C.; Vorup-Jensen, T. Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ21. The Journal of Immunology 2008, 180, 3946– 3956,  DOI: 10.4049/jimmunol.180.6.3946
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      Structural Insight into the Function of Myelin Basic Protein as a Ligand for Integrin αMβ2
      Stapulionis, Romualdas; Pinto Oliveira, Cristiano Luis; Gjelstrup, Mikkel Carstensen; Pedersen, Jan Skov; Hokland, Marianne Elisabet; Hoffmann, Soren Vronning; Poulsen, Knud; Jacobsen, Christian; Vorup-Jensen, Thomas
      Journal of Immunology (2008), 180 (6), 3946-3956CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
      Multiple sclerosis (MS) is an inflammatory disease where phagocytic cells infiltrate the nerve tissue and act as terminal agents in destruction of the myelin sheath. However, the mechanism that triggers the ability of these cells to recognize myelin remains obscure. The authors show that myelin basic protein (MBP), a major autoantigen in MS, is a potent and specific ligand for the integrin αMβ2 (Mac-1, CD11b/CD18) expressed mainly on phagocytic cells. MBP undergoes a dramatic conformational change when liberated from the lipid-rich environment of the myelin sheath. The MS drug glatiramer acetate mimics the conformationally labile regions of MBP, interacts in the unfolded state strongly with αMβ2, and inhibits the MBP binding to αMβ2. This study reveals a link between MBP, glatiramer acetate, and the αMβ2 integrin, and suggests a new model for MS pathogenesis based on the recognition of unfolded MBP by the αMβ2 integrin.
    58. 58
      Banks, W. A. Peptides and the blood-brain barrier. Peptides 2015, 72, 16– 19,  DOI: 10.1016/j.peptides.2015.03.010
      58
      Peptides and the blood-brain barrier
      Banks, William A.
      Peptides (New York, NY, United States) (2015), 72 (), 16-19CODEN: PPTDD5; ISSN:0196-9781. (Elsevier)
      The demonstration that peptides and regulatory proteins can cross the blood-brain barrier (BBB) is one of the major contributions of Dr. Abba J. Kastin. He was the first to propose that peptides could cross the BBB, the first to show that an endogenous peptide did so, and the first to describe a saturable transport system at the BBB for peptides. His work shows that in crossing the BBB, peptides and regulatory proteins act as informational mols., informing the brain of peripheral events. Brain-to-blood passage helps to control levels of peptides with the brain and can deliver information in the brain-to-blood direction. He showed that the transporters for peptides and proteins are not static, but respond to developmental and physiol. changes and are affected by disease states. As such, the BBB is adaptive to the needs of the CNS, but when that adaptation goes awry, the BBB can be a cause of disease. The mechanisms by which peptides and proteins cross the BBB offer opportunities for drug delivery of these substances or their analogs to the brain in the treatment of diseases of the central nervous system.
    59. 59
      Prod’homme, T.; Zamvil, S. S. The Evolving Mechanisms of Action of Glatiramer Acetate. Cold Spring Harb. Perspect. Med. 2019, 9, 29249,  DOI: 10.1101/cshperspect.a029249
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      The evolving mechanisms of action of glatiramer acetate
      Prod'homme, Thomas; Zamvil, Scott S.
      Cold Spring Harbor Perspectives in Medicine (2019), 9 (2), a029249CODEN: CSHPFV; ISSN:2157-1422. (Cold Spring Harbor Laboratory Press)
      Glatiramer acetate (GA) is a synthetic amino acid copolymer that is approved for treatment of relapsing remitting multiple sclerosis (RRMS) and clin. isolated syndrome (CIS). GA reduces multiple sclerosis (MS) disease activity and has shown comparable efficacy with high-dose interferon-β. The mechanism of action (MOA) of GA has long been an enigma. Originally, it was recognized that GA treatment promoted expansion of GA-reactive T-helper 2 and regulatory T cells, and induced the release of neurotrophic factors. However, GA treatment influences both innate and adaptive immune compartments, and it is now recognized that antigen-presenting cells (APCs) are the initial cellular targets for GA. The anti-inflammatory (M2) APCs induced following treatment with GA are responsible for the induction of anti-inflammatory T cells that contribute to its therapeutic benefit. Here, we review studies that have shaped our current understanding of the MOA of GA.
    60. 60
      Caporro, M.; Disanto, G.; Gobbi, C.; Zecca, C. Two decades of subcutaneous Glatiramer acetate injection: current role of the standard dose, and new high-dose low-frequency Glatiramer acetate in relapsing-remitting multiple sclerosis treatment. Patient Prefer Adherence 2014, 8, 1123– 1134,  DOI: 10.2147/PPA.S68698
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      Two decades of subcutaneous glatiramer acetate injection: current role of the standard dose, and new high-dose low-frequency glatiramer acetate in relapsing-remitting multiple sclerosis treatment
      Caporro Matteo; Disanto Giulio; Gobbi Claudio; Zecca Chiara
      Patient preference and adherence (2014), 8 (), 1123-34 ISSN:1177-889X.
      Glatiramer acetate, a synthetic amino acid polymer analog of myelin basic protein, is one of the first approved drugs for the treatment of relapsing-remitting multiple sclerosis. Several clinical trials have shown consistent and sustained efficacy of glatiramer acetate 20 mg subcutaneously daily in reducing relapses and new demyelinating lesions on magnetic resonance imaging in patients with relapsing-remitting multiple sclerosis, as well as comparable efficacy to high-dose interferon beta. Some preclinical and clinical data suggest a neuroprotective role for glatiramer acetate in multiple sclerosis. Glatiramer acetate is associated with a relatively favorable side-effect profile, and importantly this was confirmed also during long-term use. Glatiramer acetate is the only multiple sclerosis treatment compound that has gained the US Food and Drug Administration pregnancy category B. All these data support its current use as a first-line treatment option for patients with clinical isolated syndrome or relapsing-remitting multiple sclerosis. More recent data have shown that high-dose glatiramer acetate (ie, 40 mg) given three times weekly is effective, safe, and well tolerated in the treatment of relapsing-remitting multiple sclerosis, prompting the approval of this dosage in the US in early 2014. This high-dose, lower-frequency glatiramer acetate might represent a new, more convenient regimen of administration, and this might enhance patients' adherence to the treatment, crucial for optimal disease control.
    61. 61
      Zhou, G. W.; Guo, J.; Huang, W.; Fletterick, R. J.; Scanlan, T. S. Crystal structure of a catalytic antibody with a serine protease active site. Science 1994, 265, 1059– 1064,  DOI: 10.1126/science.8066444
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      Crystal structure of a catalytic antibody with a serine protease active site
      Zhou, G. Wayne; Guo, Jincan; Huang, Wei; Fletterick, Robert J.; Scanlan, Thomas S.
      Science (Washington, D. C.) (1994), 265 (5175), 1059-1064CODEN: SCIEAS; ISSN:0036-8075. (American Association for the Advancement of Science)
      The three-dimensional structure of an unusually active hydrolytic antibody with a phosphonate transition state analog (hapten) bound to the active site has been solved to 2.5 Å resoln. The antibody (17E8) catalyzes the hydrolysis of norleucine and methionine Ph esters and is selective for amino acid esters that have the natural α-carbon L configuration. A plot of the pH-dependence of the antibody-catalyzed reaction is bell-shaped with an actively max. at pH 9.5; expts. on mechanism lend support to the formation of a covalent acyl-antibody intermediate. The structural and kinetic data are complementary and support a hydrolytic mechanism for the antibody that is remarkably similar to that of the serine proteases. The antibody active site contains a Ser-His dyad structure proximal to the phosphorous atom of the bound hapten that resembles two of the three components of the Ser-His-Asp catalytic triad of serine proteases. The antibody active site also contains a Lys residue to stabilize oxyanion formation, and a hydrophobic binding pocket for specific substrate recognition of norleucine and methionine side chains. The structure identifies active site residues that mediate catalysis and suggests specific mutations that may improve the catalytic efficiency of the antibody. This high resoln. structure of a catalytic antibody-hapten complex shows that antibodies can converge on active site structures that have arisen through natural enzyme evolution.
    62. 62
      Dimitrov, J. D.; Lacroix-Desmazes, S. Noncanonical Functions of Antibodies. Trends Immunol 2020, 41, 379– 393,  DOI: 10.1016/j.it.2020.03.006
      62
      Noncanonical Functions of Antibodies
      Dimitrov, Jordan D.; Lacroix-Desmazes, Sebastien
      Trends in Immunology (2020), 41 (5), 379-393CODEN: TIRMAE; ISSN:1471-4906. (Elsevier Ltd.)
      A review. The typical functions of antibodies are based on linking the process of antigen recognition with initiation of innate immune reactions. With the introduction of modern research technologies and the use of sophisticated model systems, recent years have witnessed the discovery of a no. of noncanonical functions of antibodies. These functions encompass either untypical strategies for neutralization of pathogens or exertion of activities that are characteristic for other proteins (cytokines, chaperones, or enzymes). Here, we provide an overview of the noncanonical functions of antibodies and discuss their mechanisms and implications in immune regulation and defense. A better comprehension of these functions will enrich our knowledge of the adaptive immune response and shall inspire the development of novel therapeutics.
    63. 63
      Doronin, V. B.; Parkhomenko, T. A.; Castellazzi, M.; Padroni, M.; Pastore, M.; Buneva, V. N.; Granieri, E.; Nevinsky, G. A. Comparison of antibodies hydrolyzing myelin basic protein from the cerebrospinal fluid and serum of patients with multiple sclerosis. PLoS One 2014, 9, e107807  DOI: 10.1371/journal.pone.0107807
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      Comparison of antibodies hydrolyzing myelin basic protein from the cerebrospinal fluid and serum of patients with multiple sclerosis
      Doronin, Visilii B.; Parkhomenko, Taisiya A.; Castellazzi, Massimiliano; Padroni, Marina; Pastore, Michela; Buneva, Valentina N.; Granieri, Enrico; Nevinsky, Georgy A.
      PLoS One (2014), 9 (9), e107807/1-e107807/12, 12 pp.CODEN: POLNCL; ISSN:1932-6203. (Public Library of Science)
      It was found that antibodies (Abs) against myelin basic protein (MBP) are the major components of the antibody response in multiple sclerosis (MS) patients. We have recently shown that IgGs from sera of MS patients are active in the hydrolysis of MBP. However, in literature there are no available data concerning possible MBP-hydrolyzing Abs in cerebrospinal fluid (CSF) of MS patients. We have shown that the av. content of IgGs in their sera is about 195-fold higher than that in their CSF. Here we have compared, for the first time, the av. content of lambda- and kappa-IgGs as well as IgGs of four different subclasses (IgG1-IgG4) in CSF and sera of MS patients. The av. relative content of lambda-IgGs and kappa -IgGs in the case of CSFs (8.0 and 92.0%) and sera (12.3 and 87.7%) are comparable, while IgG1, IgG2, IgG3, and IgG4: CSF - 40.4, 49.0, 8.2, and 2.5% of total IgGs, resp. and the sera - 53.6, 36.0, 5.6, and 4.8%, decreased in different order. Electrophoretically and immunol. homogeneous IgGs were obtained by sequential affinity chromatog. of the CSF proteins on protein G-Sepharose and FPLC gel filtration. We present first evidence showing that IgGs from CSF efficiently hydrolyze MBP and that their av. specific catalytic activity is unpredictably ∼54-fold higher than that of Abs from sera of the same MS patients. Some possible reasons of these findings are discussed. We suggest that anti-MBP abzymes of CSF may promote important neuropathol. mechanisms in this chronic inflammatory disorder and in MS pathogenesis development.
    64. 64
      Truscott, R. J. W.; Friedrich, M. G. Can the Fact That Myelin Proteins Are Old and Break down Explain the Origin of Multiple Sclerosis in Some People?. J. Clin. Med. 2018, 7, 7090281  DOI: 10.3390/jcm7090281
      There is no corresponding record for this reference.
    65. 65
      Abdel-Magid, A. F. Great Therapeutic Potential of Peptidylarginine deiminase 4 (PAD4) Inhibitors: Treatment of Rheumatoid Arthritis, Epigenetic Tools, Regulation of Pluripotency in Stem Cells, and More. ACS Med Chem Lett 2017, 8, 19– 21,  DOI: 10.1021/acsmedchemlett.6b00515
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      Great Therapeutic Potential of Peptidylarginine Deiminase 4 (PAD4) Inhibitors: Treatment of Rheumatoid Arthritis, Epigenetic Tools, Regulation of Pluripotency in Stem Cells, and More
      Abdel-Magid Ahmed F
      ACS medicinal chemistry letters (2017), 8 (1), 19-21 ISSN:1948-5875.
      There is no expanded citation for this reference.
    66. 66
      Ciesielski, O.; Biesiekierska, M.; Panthu, B.; Soszynski, M.; Pirola, L.; Balcerczyk, A. citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives. Cell. Mol. Life Sci. 2022, 79, 94,  DOI: 10.1007/s00018-022-04126-3
      66
      Citrullination in the pathology of inflammatory and autoimmune disorders: recent advances and future perspectives
      Ciesielski, Oskar; Biesiekierska, Marta; Panthu, Baptiste; Soszynski, Miroslaw; Pirola, Luciano; Balcerczyk, Aneta
      Cellular and Molecular Life Sciences (2022), 79 (2), 94CODEN: CMLSFI; ISSN:1420-682X. (Birkhaeuser Basel)
      A review. Numerous post-translational modifications (PTMs) govern the collective metab. of a cell through altering the structure and functions of proteins. The action of the most prevalent PTMs, encompassing phosphorylation, methylation, acylations, ubiquitination and glycosylation is well documented. A less explored protein PTM, conversion of peptidylarginine to citrulline, is the subject of this review. The process of citrullination is catalyzed by peptidylarginine deiminases (PADs), a family of conserved enzymes expressed in a variety of human tissues. Accumulating evidence suggest that citrullination plays a significant role in regulating cellular metab. and gene expression by affecting a multitude of pathways and modulating the chromatin status. Here, we will discuss the biochem. nature of arginine citrullination, the enzymic machinery behind it and also provide information on the pathol. consequences of citrullination in the development of inflammatory diseases (rheumatoid arthritis, multiple sclerosis, psoriasis, systemic lupus erythematosus, periodontitis and COVID-19), cancer and thromboembolism. Finally, developments on inhibitors against protein citrullination and recent clin. trials providing a promising therapeutic approach to inflammatory disease by targeting citrullination are discussed.
    67. 67
      Kolarz, B.; Ciesla, M.; Dryglewska, M.; Majdan, M. Peptidyl Arginine deiminase Type 4 Gene Promoter Hypo-Methylation in Rheumatoid Arthritis. J. Clin. Med. 2020, 9, 72049,  DOI: 10.3390/jcm9072049
      There is no corresponding record for this reference.
    68. 68
      Aliko, A.; Kaminska, M.; Falkowski, K.; Bielecka, E.; Benedyk-Machaczka, M.; Malicki, S.; Koziel, J.; Wong, A.; Bryzek, D.; Kantyka, T.; Mydel, P Discovery of Novel Potential Reversible Peptidyl Arginine deiminase Inhibitor. Int. J. Mol. Sci. 2019, 20, 92174,  DOI: 10.3390/ijms20092174
      There is no corresponding record for this reference.
    69. 69
      Filippi, M.; Bar-Or, A.; Piehl, F.; Preziosa, P.; Solari, A.; Vukusic, S.; Rocca, M. A. Multiple sclerosis. Nat. Rev. Dis. Primers 2018, 4, 43,  DOI: 10.1038/s41572-018-0041-4
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      Multiple sclerosis
      Filippi Massimo; Preziosa Paolo; Rocca Maria A; Filippi Massimo; Preziosa Paolo; Rocca Maria A; Bar-Or Amit; Piehl Fredrik; Piehl Fredrik; Piehl Fredrik; Solari Alessandra; Vukusic Sandra
      Nature reviews. Disease primers (2018), 4 (1), 43 ISSN:.
      Multiple sclerosis (MS) is the most common chronic inflammatory, demyelinating and neurodegenerative disease of the central nervous system in young adults. This disorder is a heterogeneous, multifactorial, immune-mediated disease that is influenced by both genetic and environmental factors. In most patients, reversible episodes of neurological dysfunction lasting several days or weeks characterize the initial stages of the disease (that is, clinically isolated syndrome and relapsing-remitting MS). Over time, irreversible clinical and cognitive deficits develop. A minority of patients have a progressive disease course from the onset. The pathological hallmark of MS is the formation of demyelinating lesions in the brain and spinal cord, which can be associated with neuro-axonal damage. Focal lesions are thought to be caused by the infiltration of immune cells, including T cells, B cells and myeloid cells, into the central nervous system parenchyma, with associated injury. MS is associated with a substantial burden on society owing to the high cost of the available treatments and poorer employment prospects and job retention for patients and their caregivers.
    70. 70
      Gross, C. M.; Baumgartner, A.; Rauer, S.; Stich, O. Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod. Neurology 2012, 79, 2006– 2007,  DOI: 10.1212/WNL.0b013e3182735d24
      70
      Multiple sclerosis rebound following herpes zoster infection and suspension of fingolimod
      Gross Claus Michael; Baumgartner Annette; Rauer Sebastian; Stich Oliver
      Neurology (2012), 79 (19), 2006-7 ISSN:.
      There is no expanded citation for this reference.
    71. 71
      Ysrraelit, M. C.; Correale, J. Impact of sex hormones on immune function and multiple sclerosis development. Immunology 2019, 156, 9– 22,  DOI: 10.1111/imm.13004
      71
      Impact of sex hormones on immune function and multiple sclerosis development
      Ysrraelit, Maria C.; Correale, Jorge
      Immunology (2019), 156 (1), 9-22CODEN: IMMUAM; ISSN:0019-2805. (Wiley-Blackwell)
      Summary : Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS) affecting young people and leading to demyelination and neurodegeneration. The disease is clearly more common in women, in whom incidence has been rising. Gender differences include: earlier disease onset and more frequent relapses in women; and faster progression and worse outcomes in men. Hormone-related physiol. conditions in women such as puberty, pregnancy, puerperium, and menopause also exert significant influence both on disease prevalence as well as on outcomes. Hormonal and/or genetic factors are therefore believed to be involved in regulating the course of disease. In this review, we discuss clin. evidence for the impact of sex hormones (estrogens, progesterone, prolactin, and testosterone) on MS and attempt to elucidate the hormonal and immunol. mechanisms potentially underlying these changes. We also review current knowledge on the relationship between sex hormones and resident CNS cells and provide new insights in the context of MS. Understanding these mol. mechanisms may contribute to the development of new and safer treatments for both men and women.
    72. 72
      Roux, J.; Bard, D.; Le Pabic, E.; Segala, C.; Reis, J.; Ongagna, J. C.; de Seze, J.; Leray, E. Air pollution by particulate matter PM10 may trigger multiple sclerosis relapses. Environ Res 2017, 156, 404– 410,  DOI: 10.1016/j.envres.2017.03.049
      72
      Air pollution by particulate matter PM10 may trigger multiple sclerosis relapses
      Roux, Jonathan; Bard, Denis; Le Pabic, Estelle; Segala, Claire; Reis, Jacques; Ongagna, Jean-Claude; de Seze, Jerome; Leray, Emmanuelle
      Environmental Research (2017), 156 (), 404-410CODEN: ENVRAL; ISSN:0013-9351. (Elsevier)
      Seasonal variation of relapses in multiple sclerosis (MS) suggests that season-dependent factors, such as ambient air pollution, may trigger them. However, only few studies have considered possible role of air pollutants as relapse's risk factor. We investigated the effect of particulate matter of aerodynamic diam. smaller than 10μm (PM10) on MS relapses. In total, 536 relapsing MS patients from Strasbourg city (France) were included, accounting for 2052 relapses over 2000-2009 period. A case-crossover design was used with cases defined as the days of relapse and controls being selected in the same patient at plus and minus 35 days. Different lags from 0 to 30 days were considered. Conditional logistic regressions, adjusted on meteorol. parameters, school and public holidays, were used and exposure was considered first as a quant. variable and second, as a binary variable. The natural logarithm of the av. PM10 concn. lagged from 1 to 3 days before relapse onset was significantly assocd. with relapse risk (OR =1.40 [95% confidence interval 1.08-1.81]) in cold season. Consistent results were obsd. when considering PM10 as a binary variable, even if not significant. With an appropriate study design and robust ascertainment of neurol. events and exposure, the present study highlights the effect of PM10 on the risk of relapse in MS patients, probably through oxidative stress mechanisms.
    73. 73
      Dedeoglu, F. Drug-induced autoimmunity. Curr Opin Rheumatol 2009, 21, 547– 551,  DOI: 10.1097/BOR.0b013e32832f13db
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      Drug-induced autoimmunity
      Dedeoglu, Fatma
      Current Opinion in Rheumatology (2009), 21 (5), 547-551CODEN: CORHES; ISSN:1040-8711. (Lippincott Williams & Wilkins)
      Purpose of review: This review aims to draw attention to the increased spectrum of the features of drug-induced autoimmunity (DIA), including both clin. and autoantibody profiles in addn. to the potential chronicity of the syndrome. Recent findings: In recent years, not only has the no. of medications causing DIA increased but the spectrum of the features has broadened as well. With the use of newer medications, esp. biologics, mostly directed towards immune system manipulation, the range of signs and symptoms of DIA as well as the patterns of autoantibody profiles have widened. Rashes and visceral involvement have started to be reported more often, esp. with tumor necrosis factor antagonists. In addn., autoantibodies such as antidouble-stranded DNA, which are usually seen with idiopathic systemic lupus erythematosus, are appearing in place of the antihistone antibodies, typically found in drug-induced lupus. Finally, some medications have been implicated in causing the very same entity, which they may be used to treat. It is clear that progress in the field of pharmacogenetics and pharmacogenomics will help further our understanding of these and other adverse effects of medications. Summary: Even though DIA has been known for many years, the underlying mechanisms remain unclear. However, with recently described new and unexpected features, novel hypotheses have been proposed, thus opening doors to further research in understanding these mechanisms.
    74. 74
      Niklas, K.; Niklas, A. A.; Majewski, D.; Puszczewicz, M. Rheumatic diseases induced by drugs and environmental factors: the state-of-the-art - part one. Reumatologia 2016, 54, 122– 127,  DOI: 10.5114/reum.2016.61212
      74
      Rheumatic diseases induced by drugs and environmental factors: the state-of-the-art - part one
      Niklas Karolina; Majewski Dominik; Puszczewicz Mariusz; Niklas Arkadiusz A
      Reumatologia (2016), 54 (3), 122-7 ISSN:0034-6233.
      The majority of rheumatic diseases belong to the group of autoimmune diseases and are associated with autoantibody production. Their etiology is not fully understood. Certain medications and environmental factors may have an influence on the occurrence of rheumatic diseases. Establishing a cause-effect relationship between a certain factor and disease induction is not always simple. It is important to administer the drug continuously or monitor exposure to a given factor in the period preceding the onset of symptoms. The lack of previously diagnosed autoimmune disease, or finally the lack of symptoms within a few weeks/months after discontinuation of the drug/cessation of exposure, is also important. The most frequently mentioned rheumatic diseases caused by drugs and environmental factors include systemic lupus erythematosus, scleroderma, systemic vasculitis, polymyositis, dermatomyositis, and Sjogren's syndrome. The objective of this study is to summarize current knowledge on rheumatic diseases induced by drugs and environmental factors.
    75. 75
      Lacerda, E. M.; Mudie, K.; Kingdon, C. C.; Butterworth, J. D.; O’Boyle, S.; Nacul, L. The UK ME/CFS biobank: A Disease-Specific biobank for Advancing Clinical Research Into myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Front. Neurol. 2018, 9, 1026,  DOI: 10.3389/fneur.2018.01026
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      The UK ME/CFS Biobank: A Disease-Specific Biobank for Advancing Clinical Research Into Myalgic Encephalomyelitis/Chronic Fatigue Syndrome
      Lacerda Eliana M; Mudie Kathleen; Kingdon Caroline C; Butterworth Jack D; O'Boyle Shennae; Nacul Luis
      Frontiers in neurology (2018), 9 (), 1026 ISSN:1664-2295.
      Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disabling disease characterized by unexplained incapacitating fatigue, accompanied by variable multi-systemic symptoms. ME/CFS causes a significant personal and public health burden, and urgently requires the coordination of research efforts to investigate its etiology and pathophysiology and to develop and validate sensitive and specific biomarkers to confirm diagnosis. This narrative paper describes how people with ME/CFS, together with a multidisciplinary team of researchers, have established the UK ME/CFS Biobank (UKMEB), a unique research infrastructure specifically designed to expedite biomedical research into ME/CFS. We describe the journey that led to its conceptualization and operation, and how the resource has served as a model disease-specific biobank, aggregating human biospecimens alongside comprehensive health information on participants. The UKMEB currently has data and samples from 600 donors including people with ME/CFS and a comparison group with multiple sclerosis and healthy controls. A longitudinal sub-cohort has been established of participants having follow-up assessments at multiple time-points. As an open resource for quality and ethical research into ME/CFS, biological samples and data have not only been analyzed within our research team but have also been shared with researchers across Europe, America and the Middle East. We continue to encourage researchers from academic and commercial sectors to access the UKMEB. Major steps have been taken and challenges remain; these include sustainability and expansion, and harmonization of processes to facilitate integration with other bioresources and databanks internationally.
    76. 76
      Esfandyarpour, R.; Kashi, A.; Nemat-Gorgani, M.; Wilhelmy, J.; Davis, R. W. A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Proc Natl Acad Sci U S A 2019, 116, 10250– 10257,  DOI: 10.1073/pnas.1901274116
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      A nanoelectronics-blood-based diagnostic biomarker for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)
      Esfandyarpour, R.; Kashi, A.; Nemat-Gorgani, M.; Wilhelmy, J.; Davis, R. W.
      Proceedings of the National Academy of Sciences of the United States of America (2019), 116 (21), 10250-10257CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
      There is not currently a well-established, if any, biol. test to diagnose myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The mol. aberrations obsd. in numerous studies of ME/CFS blood cells offer the opportunity to develop a diagnostic assay from blood samples. Here we developed a nanoelectronics assay designed as an ultrasensitive assay capable of directly measuring biomol. interactions in real time, at low cost, and in a multiplex format. To pursue the goal of developing a reliable biomarker for ME/CFS and to demonstrate the utility of our platform for point-of-care diagnostics, we validated the array by testing patients with moderate to severe ME/CFS patients and healthy controls. The ME/CFS samples' response to the hyperosmotic stressor obsd. as a unique characteristic of the impedance pattern and dramatically different from the response obsd. among the control samples. We believe the obsd. robust impedance modulation difference of the samples in response to hyperosmotic stress can potentially provide us with a unique indicator of ME/CFS. Moreover, using supervised machine learning algorithms, we developed a classifier for ME/CFS patients capable of identifying new patients, required for a robust diagnostic tool.
    77. 77
      Kalinina, E. V.; Ponomarenko, N. A.; Durova, O. M.; Paleev, F. N.; Vorob’ev, I. I.; Kekenadze, N. N.; Shogenov, Z. S.; Zemtsova, M. E.; Gnuchev, N. V.; Gabibov, A. G. Catalytic autoantibodies in autoimmune myocarditis: clinical and pathogenetic implications. Ter. Arkh. 2005, 77, 65– 70
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      Catalytic autoantibodies in autoimmune myocarditis: clinical and pathogenetic implications
      Kalinina E V; Ponomarenko N A; Durova O M; Paleev F N; Vorob'ev I I; Kekenadze N N; Shogenov Z S; Zemtsova M E; Gnuchev N V; Gabibov A G
      Terapevticheskii arkhiv (2005), 77 (9), 65-70 ISSN:0040-3660.
      AIM: To evaluate pathogenetic and clinical significance of autoantibodies (AAB) with catalytic activity in the serum of patients with autoimmune myocarditis (AM). MATERIAL AND METHODS: The study was made on the sera from 99 patients with AM of different course: malignant, benign, myocardiosclerosis (MCS). In addition to standard immunological parameters, the study was made of serum levels of anticardiomyosine-antiCM (protabzymes) and anti-DNA (DNA-abzymes) of AAB. After obtaining anti-CM and anti-DNA IgG-AT, we determined non-specific and specific proteolytic activity of anti-CM. RESULTS: Maximal specific activity of protabzymes was seen in 73% patients with malignant AM, it correlated with blood levels of anti-CM AAB, DNA-abzymes activity was very high in 45% patients. In MCS proteolytic activity of autoAT was absent in 61% patients. In benign AM occurrence of protabzymes was confirmed in 35% cases. Elevated DNA-hydrolyzing activity of DNA-abzymes occurred in 13% cases. The activity had no significant correlation with serum titers of AB. In MCS proteolytic activity of AAB was absent in 61% cases, but high activity of anti-CM AAB was in 28%. The activity of DNA-abzymes in 44% ranged considerably which, in seropositive cases, detected significant correlation with serum titers of DNA-binding autoAT. CONCLUSION: Evaluation of catalytic activity of AAB may be considered as a criterial test assessing the stage, clinical variants and severity of AM. It also permits formulation of the disease prognosis and its possible outcomes.
    78. 78
      Belogurov, A. A., Jr.; Kurkova, I. N.; Friboulet, A.; Thomas, D.; Misikov, V. K.; Zakharova, M. Y.; Suchkov, S. V.; Kotov, S. V.; Alehin, A. I.; Avalle, B.; Souslova, E. A.; Morse, H. C., 3rd; Gabibov, A. G.; Ponomarenko, N. A. Recognition and degradation of myelin basic protein peptides by serum autoantibodies: novel biomarker for multiple sclerosis. J Immunol 2008, 180, 1258– 1267,  DOI: 10.4049/jimmunol.180.2.1258
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      Recognition and Degradation of Myelin Basic Protein Peptides by Serum Autoantibodies: Novel Biomarker for Multiple Sclerosis
      Belogurov, Alexey A., Jr.; Kurkova, Inna N.; Friboulet, Alain; Thomas, Daniel; Misikov, Viktor K.; Zakharova, Maria Yu.; Suchkov, Sergey V.; Kotov, Sergey V.; Alehin, Alexander I.; Avalle, Berangere; Souslova, Ekaterina A.; Morse, Herbert C., III; Gabibov, Alexander G.; Ponomarenko, Natalia A.
      Journal of Immunology (2008), 180 (2), 1258-1267CODEN: JOIMA3; ISSN:0022-1767. (American Association of Immunologists)
      The pathol. role of autoantibodies in autoimmune disease is widely accepted. Recently, the authors reported that anti-myelin basic protein (MBP) serum Abs from multiple sclerosis (MS) patients exhibit proteolytic activity toward the autoantigen. The aim of this study is to det. MBP epitopes specific for the autoantibodies in MS and compare these data with those from other neuronal disorders (OND), leading to the generation of new diagnostic and prognostic criteria. The authors constructed a MBP-derived recombinant "epitope library" covering the entire mol. The authors used ELISA and PAGE/surface-enhanced laser desorption/ionization mass spectroscopy assays to define the epitope binding/cleaving activities of autoantibodies isolated from the sera of 26 MS patients, 22 OND patients, and 11 healthy individuals. The levels of autoantibodies to MBP fragments 48-70 and 85-170 as well as to whole MBP and myelin oligodendrocyte glycoprotein mols. were significantly higher in the sera of MS patients than in those of healthy donors. In contrast, selective reactivity to the two MBP fragments 43-68 and 146-170 distinguished the OND and MS patients. Patients with MS (77% of progressive and 85% of relapsing-remitting) but only 9% of patients with OND and no healthy donors were pos. for catalysis, showing pronounced epitope specificity to the encephalitogenic MBP peptide 81-103. This peptide retained its substrate properties when flanked with two fluorescent proteins, providing a novel fluorescent resonance energy transfer approach for MS studies. Thus, anti-MBP autoantibody-mediated, epitope-specific binding and cleavage may be regarded as a specific characteristic of MS compared with OND and healthy donors and may serve as an addnl. biomarker of disease progression.
    79. 79
      Gabibov, A. G.; Ponomarenko, N. A.; Tretyak, E. B.; Paltsev, M. A.; Suchkov, S. V. Catalytic autoantibodies in clinical autoimmunity and modern medicine. Autoimmun Rev 2006, 5, 324– 330,  DOI: 10.1016/j.autrev.2006.01.004
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      Catalytic autoantibodies in clinical autoimmunity and modern medicine
      Gabibov, Alexander G.; Ponomarenko, Natalya A.; Tretyak, Eugenia B.; Paltsev, Mikhail A.; Suchkov, Sergey V.
      Autoimmunity Reviews (2006), 5 (5), 324-330CODEN: ARUEBU; ISSN:1568-9972. (Elsevier B.V.)
      A review. Abzymes (catalytic autoantibodies) belong to an absolutely new group of physiol. active substances with dual characteristics: they represent a pool of canonical autoantibodies and possess catalytic activity. Among them, proteolytic and DNA-hydrolyzing autoantibodies are of special value. Abzymes are an important pathogenic factor in the progression of clin. autoimmunity syndrome. The presence of autoantibodies against various autoantigens is accompanied by their high catalytic potential. The increase in this activity correlates with serum levels of the autoantibodies, clin. manifestations of autoimmune disorders, disease severity and the rate of progressing disability. Abzymes are crucial for immune homeostasis regulation. They can be of practical value in the development of modern immunodiagnostic tools and schedules of immunotherapy.