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Affinity Proteomic Profiling of Plasma, Cerebrospinal Fluid, and Brain Tissue within Multiple Sclerosis

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† Affinity Proteomics, SciLifeLab, School of Biotechnology, KTH − Royal Institute of Technology, Stockholm 171 21, Sweden

‡ Department of Neuroscience, SciLifeLab, Karolinska Institute, Stockholm 171 77, Sweden

§ Neuroimmunology Unit, Department of Clinical Neuroscience, Karolinska Institute, Tomtebodavägen 18A, Stockholm 171 77, Sweden

∥ Pathology Department, VU Medical Center, De Boelelaan 1117, Amsterdam 1081 HV, The Netherlands

*E-mail: [email protected]. Tel: +46 (0)8 5248 1482.

Cite this: J. Proteome Res. 2014, 13, 11, 4607-4619

Publication Date (Web):September 18, 2014

https://doi.org/10.1021/pr500609e

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Abstract

The brain is a vital organ and because it is well shielded from the outside environment, possibilities for noninvasive analysis are often limited. Instead, fluids taken from the spinal cord or circulatory system are preferred sources for the discovery of candidate markers within neurological diseases. In the context of multiple sclerosis (MS), we applied an affinity proteomic strategy and screened 22 plasma samples with 4595 antibodies (3450 genes) on bead arrays, then defined 375 antibodies (334 genes) for targeted analysis in a set of 172 samples and finally used 101 antibodies (43 genes) on 443 plasma as well as 573 cerebrospinal spinal fluid (CSF) samples. This revealed alteration of protein profiles in relation to MS subtypes for IRF8, IL7, METTL14, SLC30A7, and GAP43. Respective antibodies were subsequently used for immunofluorescence on human post-mortem brain tissue with MS pathology for expression and association analysis. There, antibodies for IRF8, IL7, and METTL14 stained neurons in proximity of lesions, which highlighted these candidate protein targets for further studies within MS and brain tissue. The affinity proteomic translation of profiles discovered by profiling human body fluids and tissue provides a powerful strategy to suggest additional candidates to studies of neurological disorders.

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SPECIAL ISSUE

This article is part of the Proteomics of Human Diseases: Pathogenesis, Diagnosis, Prognosis, and Treatment special issue.

Introduction

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Multiple sclerosis (MS) is the most common cause of chronic neurological disability in young adults.(1) It is a neurodegenerative and inflammatory disorder of the central nervous system (CNS), has three major subtypes, and leads to the formation of multifocal demyelinating white matter lesions and gray matter lesions.(2) Although most patients with relapsing remitting MS (RRMS) later develop secondary progressive MS (SPMS), steady progression of neurological damage without periods of remission or recovery from symptoms,(3, 4) periods of relapses, and remissions (RR-rel and RR-rem) may persist without worsening of symptoms for years. Current diagnosis of MS currently relies on a combination of several clinical investigations, such as magnetic resonance imaging of the brain and identification of oligoclonal IgG in cerebrospinal fluid (CSF).(5) However, additional indicators of disease are needed because interindividual variations in neuropathological features and clinical manifestations complicate both an early-stage diagnosis and prediction of disease progression.(6, 7)

Hereto, proteins in CNS tissue potentially hold much of the sought-after information. However, and as true for other neurological diseases, it is a challenge to access samples of brain tissue for discovery-driven approaches. To otherwise gain insights into disease-related mechanism and pathophysiology, disease-specific protein profiles can be searched for in systemic plasma or proximal CSF.(8-11) The current scarcity of so-far reported disease-specific proteins within MS(12) may be due to several reasons such as the limited number of samples and the aforementioned disease heterogeneity.

Affinity-based assays can be particularly useful to address this challenge because they allow efficient and subsequent use of binding reagents across different analysis platforms and sample materials. Affinity reagents used in the presented study were from the Human Protein Atlas (HPA),(13) which since 2005(14) has produced polyclonal antibodies against more than 80% of all human protein encoding genes and is an initiative aiming to generate affinity reagents for the proteome.(15) Besides using affinity reagents on well-established platforms such as immunohistochemistry, microarray-based assays can be used to screen hundreds of protein targets in hundreds of body fluid samples with minimal requirements on sample volume.(16)

In the presented study, we used affinity proteomic methods to discover MS related protein profiles in body fluids for subsequent tissue analysis. Starting from an initial screening, follow-up and targeted assays were performed on suspension bead arrays for multiplexed profiling of plasma and CSF of MS patients. We then chose the identified targets to study disease processes in sections from human MS brain tissues in combination with markers for astrocytes, microglia, and infiltrating macrophages.

Materials and Methods

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Samples

EDTA plasma samples utilized in the untargeted discovery stage were obtained from an in-house biobank of samples collected during routine neurological diagnostic workup at the neurology clinic of Karolinska University Hospital Stockholm, Sweden. The set of paired plasma and CSF samples utilized in the verification stage contained samples collected at three hospitals within Sweden. All patients were examined and diagnosed by a neurologist and fulfilled the McDonald criteria.(17) Patients with MS were classified as RRMS, SPMS, or primary progressive MS (PPMS), where the first subtype was subdivided further into patients during relapse (RR-rel) or remission (RR-rem). Samples from patients with a single demyelinating event, the so-called clinically isolated syndrome (CIS), were also included in the study. The control group consisted of individuals with other neurological diseases (ONDs) and ONDs with signs of inflammation (iOND). The individuals with OND had a variety of neurological signs and symptoms similar to MS, such as sensory symptoms, visual disturbance, headache, and so on, while the iOND group consisted of individuals with other inflammation-driven diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), neuropathy, or viral/bacterial infections, for example, borreliosis, meningitis, or herpes encephalitis (Table 1A–D). Study enrolment followed the recommendations of the Declaration of Helsinki and approval by the Ethics Committee of the Karolinska Institute (DNR 2009/2104-31-2). Oral and written information was given to the patients, and informed consent in writing was received before inclusion. All samples were prepared according to standard procedures and stored at −80 °C until usage.

Table 1. (A) Demographics of Plasma Samples Used for Targeted Discovery, (B) Demographics of Plasma Samples Used for Verification, (C) Demographics of CSF Specimen, and (D) Demographics of Plasma Samples Used for IRF8 Verification

(A)
			age
sample group	N	% female	median	range
OND	64	67	40	19–68
CIS-rem	13	62	33	25–60
CIS-rel	5	80	51	37–63
RR-rem	46	74	32	19–57
RR-rel	14	57	29	22–56
SPMS	20	70	52	35–68
PPMS	10	60	52	44–62
total	172
(B)
			age
sample group	N	% female	median	range
OND	101	72	41	19–68
iOND	83	72	43	18–83
CIS-rem	28	75	34	21–60
CIS-rel	11	82	37	23–63
RR-rel	147	74	39	17–70
RR-rem	38	55	38	22–60
SPMS	35	54	54	28–68
total	443
(C)
			age
sample group	N	% female	median	range
iOND	91	72	41	18–83
OND	148	74	40	19–68
CIS-rem	11	82	37	23–63
CIS-rel	31	77	33	21–60
RR-rem	42	62	40	22–68
RR-rel	193	75	38	17–70
SPMS	43	53	54	35–68
PPMS	14	64	52	35–62
total	573
(D)
			age
sample group	N	% female	median	range
CIS	17	82	37	25–50
RR-rem	17	74	37	25–50
SPMS	16	60	47	33–61
total	50

Tissue brain sections from 15 patients with MS were obtained from tissues collected at autopsy, and patient characteristics are listed in Supplementary Table 1 in the Supporting Information. The rapid autopsy regimen of The Netherlands Brain Bank in Amsterdam (coordinated by Dr. I. Huitinga) was used to acquire the samples, with the approval of the Medical Ethical Committee of the VU University Medical Center. All patients and controls had given informed consent for autopsy and use of their brain tissue for research purposes. All patient material was coded to ensure anonymity throughout tissue processing. The clinical neuropathological diagnosis for MS tissues was confirmed by Prof. P. van der Valk. Tissue samples from MS cases were obtained after ex vivo magnetic resonance imaging scanning, as previously described by De Groot et al.(18) Classification of lesion staging was based on immunohistochemical detection of cells that express major histocompatibility complex (MHC) class II/HLA-DR and the presence of proteolipid protein (PLP) to reveal areas of myelin loss.(18) A set of healthy control human brains from patients who had no infections or history of serious illness or head trauma was obtained from the Department of Immunology, Genetics and Pathology, SciLifeLab Uppsala, Stockholm.(19)

Antibodies and Bead Array Generation

The majority of the antibodies utilized in this study were generated within the Human Protein Atlas project, as previously described,(20) and additional antibodies were obtained through various commercial sources (see Supplementary Table 2 in the Supporting Information). Antibodies for the initial plasma screening were not selected based on their target protein but as they became available from the Human Protein Atlas.(21) However, in the targeted screening, the selection was made based on prior knowledge of disease relation according to literature and in-house multidisease studies including other neurodegenerative diseases (Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis, and mild cognitive impairment).

Bead arrays were created as previously described(22) with modifications that relate to normalizing the concentration of antibodies using liquid handling (EVO150, TECAN) by diluting 1.6 μg of each antibody into 100 μL of 0.05 M MES buffer (pH 4.5). All antibodies were then coupled to carboxylated, color-coded magnetic beads (MagPlex-C, Luminex) to create bead arrays of up to 384-plex. The coupling of each antibody on the beads was confirmed via R-phycoerythrin-conjugated donkey antirabbit IgG antibody (Jackson ImmunoResearch), where all antibodies revealed median fluorescence intensity (MFI) values of 15 000–19 000 AU.

Plasma Profiling

Plasma samples stored at −80 °C were thawed at 4 °C, centrifuged for 10 min at 3000 rpm, and then transferred into 96-well microtiter plates with a liquid handling system (EVO150, TECAN). Sample locations were randomized according to a plate layout design, which allowed a balanced distribution of samples across multiple plates in terms of both categorical variables and the quantitative variable of age. Samples were then labeled with biotin, as previously described(23) and transferred by liquid handling (Selma, CyBio). The 1:10 diluted and biotinylated samples were subsequently utilized without removal of excess biotin and diluted 1:50 in an assay buffer composed of 0.5% (w/v) poly(vinyl alcohol) and 0.8% (w/v) polyvinylpyrrolidone (Sigma) in 0.1% casein in PBS (PVXC) supplemented with 0.5 mg/mL nonspecific rabbit IgG (Bethyl), yielding a total sample dilution of 1:500. Diluted samples were heat-treated for 30 min at 56 °C and cooled to 20 °C for 15 min in a thermocycler (Techne, TC-PLUS), and 45 μL of heat-treated samples was added to 5 μL of the antibody suspension bead array distributed into a 384-well microtiter plate (Greiner BioOne). The incubation took place overnight on a shaker (Grant) at ambient temperature. Beads were then washed with 3 × 60 μL PBS-T (1 × PBS pH 7.4, 0.05% Tween20) using a plate washer (EL406, Biotek), followed by an incubation for 10 min with 50 μL of a stop solution containing 0.4% paraformaldehyde in PBS. Beads were washed with 1 × 60 μL of PBS-T, and 50 μL of 0.5 μg/mL R-phycoerythrin-labeled streptavidin (Invitrogen) in PBS-T was added and incubated for 20 min. Finally, beads were washed with 3 × 60 μL and measured in 60 μL of PBS-T. Measurements were performed using a FlexMap3D instrument (Luminex). For each sample and bead ID, 50 events were collected, and binding to beads was reported as MFI and used for data analysis.

CSF Profiling

Immediately after lumbar puncture, cells were removed from CSF supernatant by centrifugation at 350g, and samples were frozen at −80 °C. As previously described,(23) all CSF samples were diluted 1:2 in PBS supplemented with 0.5% BSA (Sigma) and 0.1% rabbit IgG (Bethyl) at labeling, where a 10-fold molar excess of biotin over protein amount was utilized. Before incubation with the antibody bead array, samples were diluted 1:8 in PVXC buffer, heat-treated at 56 °C for 30 min, and cooled to 20 °C for 15 min. Incubation and the following sample processing was performed according to the described plasma procedure.

Western Blot Analysis

A plasma pool from four MS patients and IRF8 overexpressing lysate (LY419485, OriGene) was diluted 1:50 and 1:100 in LDS sample buffer and sample reducing agent (both from NuPAGE Invitrogen) dissolved in Milli-Q water. Samples were heated to 95 °C for 5 min, loaded on a Bis-Tris 4–12% gel (Invitrogen) and run at constant 200 V using a XCell SureLock mini-cell electrophoresis system (Invitrogen) with MOPS SDS running buffer (Invitrogen). A Novex X-Cell II blot module (Invitrogen) was used for transferring proteins onto a 0.45 μm PVDF membrane (Invitrogen) at constant 30 V. Membranes were blocked with blocking reagents for ELISA for 2 h prior overnight incubation at 4 °C with primary antibodies (1 μg/mL). Membranes were washed three times in TBS-T (1 × TBS pH 7.5, 0.05% Tween20) and detection was enabled using HRP-labeled antirabbit, antimouse (both Dako), and antisheep antibodies (R&D) together with a chemiluminescent substrate (Immun-Star Western C Kit, Biorad).

Epitope Mapping

Epitope mapping of antibodies was performed on high-density peptide arrays as previously described,(24) where each array contained 12-mer peptides with 11-residue overlap to the next peptide, thereby covering the regions of the protein fragments used for antibody generation.

Data Analysis

Data Processing

The data analysis was performed in the statistical computing software R.(25) Data sets from the initial untargeted screening and the targeted discovery, both generated with 384-plex assays, were preprocessed in the following steps: sample outliers were detected by robust principal component analysis (rPCA) using the “rrcov” R package, and for these samples, all MFI values for the outliers were removed.(26) The refined data were subjected to probabilistic quotient normalization (PQN),(27) followed by plate normalization, which for each antibody intensity profile adjusts the mean of each plate toward the mean of all plates by the local average of other antibodies.(28) For verification of protein profiles in plasma, the data generated by the 101-plex bead array on two 384-well plates (denoted plates #1 and #2) were subjected to outlier removal and PQN normalization, as previously described. Plates #1 and #2, with a similar distribution of samples per patient group, were normalized independently and treated as two separate data sets. Out of 579 patient samples, 443 were used for statistical analysis (Table 1B) after carefully excluding samples classified as outliers (N = 13), samples from a compromised delivery (N = 118), and PPMS samples (N = 5). The data sets were further processed by a linear regression normalization of log-transformed data, where the MFI values for each antibody were adjusted by four covariates: shipment, labeling plate, age, and gender. The gender covariate was added to the intensity ≈ shipment + plate + age normalization only if it significantly (Anova P value <0.05) contributed to the model. The data set obtained for verification of IRF8 in plasma was not processed prior statistical analysis due to the small number of samples analyzed. For the data obtained from CSF analysis using the 101-plex bead array, PQN normalization was performed, and in total 28 sample outliers were removed by rPCA.

Statistical Analysis

All p values from two-group comparisons were generated by Mann–Whitney tests using log-transformed data. If stated, p values were adjusted for multiple testing by Bonferroni correction. Lasso logistic regression implemented in the “penalized” R-package(29, 30) was applied to build a multivariate classification model for two patient groups. The tuning parameter lambda for the pairwise classifier was determined by five-fold cross-validation, and the optimal lambda was chosen to have maximum cross-validated likelihood.(30) Because during cross-validation each random separation of the data into subsets gives rise to a variation of the optimal value, the cross-validations with dissimilar splits were repeated 100 times to obtain a stable parameter. The Lasso model was fitted with the mean of 100 lambdas to all data in plate #1 from the plasma verification phase. Then, the classification accuracy was assessed using the data from the separate set of samples in plate #2. The selection of contributing variables in the resulting antibody panel was performed simultaneously by Lasso. Variation in the data was assessed for plate #1 and plate #2 by the percentage of coefficients of variation (% CV), which was calculated as the average % CV across all antibody profiles in 16 replicates of a pooled sample. For correlation network analysis in plasma and in CSF, the data were log-transformed, mean-centered, and scaled before combining both plates. Correlation was calculated using Spearman rank correlation coefficients (Rho) in separate correlation matrices for the different patient groups. Rho values, both in plasma and CSF, were further visualized in correlation network diagrams(31) using Cytoscape.(32) This data set was also used for unsupervised hierarchical clustering (Euclidian distances) of SPMS and CIS samples and a direct plasma-CSF correlation for paired samples. Jalview software(33) was used for sequence alignment and tree construction of peptide sequences revealed by epitope mapping; for all peptide sequences with signals over local background >3, multiple sequence alignments were performed by ClustalO and BLOSUM62 was used for tree construction. The logos were created using WebLogo,(34) and a similarity search was performed using the NCBI BLASTP (ver. 2.2.29) algorithm and scored with PAM30 matrices.

Tissue Analysis

Immunofluorescence

Multiple immunofluorescence immunohistochemistry was performed on 7 μm thick human cortex sections containing chronic and acute lesions cut from paraffin-embedded blocks on a sliding microtome and mounted onto glass slides coated with 3-aminopropyltriethoxysilane (Sigma). Sections containing human cortex cores (⌀ 2 mm) from individuals without clinical signs of neuropsychiatric disease part served as controls. All sections were stained on an automated Leica Bond RX system. Briefly, sections were deparaffinized (Bond Dewax solution AR9222), rehydrated, and treated for 40 min in an EDTA-based pH 9.0 solution (Bond Epitope Retrieval solution 2 AR9640) to unmask the antigens. Slides were then incubated in normal donkey serum for 30 min, followed by the addition of the primary antibody cocktail mix (containing IBA-1 and one HPA antibody) diluted in Bond Primary antibody diluent (AR9352) for 8 h at room temperature. Sections were washed 3 × 15 min in PBS and incubated for 90 min at room temperature with secondary antibody cocktail mix (Cy3-labelled anti-rabbit and Cy5-labelled anti-goat) diluted 1/200 in 0.2 M PB. Sections were washed 3 × 15 min in PBS and subsequently incubated for 8 h with 488-conjugated mouse anti-GFAP antibody (diluted in Bond Primary antibody diluent) at room temperature. Slides were washed 3 × 15 min in PBS and counterstained with Hoechst 33342 (diluted 1:10 000 in PBS) for 30 min at room temperature. Finally, slides were incubated for 30 min in 1% Sudan Black solution in 70% ethanol to quench autofluorescence and mounted in PVA-DABCO.

Slide Scanning Microscopy

Fluorescence microscope images were acquired on a Vslide slide scanning microscope (MetaSystems, Alltlussheim, Germany) equipped with a CoolCube 1 camera (12 bit gray scale), 10× and 20× objectives and filter sets for DAPI (EX350/50 - EM470/40), FITC (EX493/16 – EM527/30), Cy3 (EX546/10 – EM580/30), Cy3.5 (EX581/10 – EM617/40), and Cy5 (EX630/20–647/long pass). Whole microscope slides were scanned at 2.5 × , and tissue was detected based on the Hoechst 33342 signal. After generating a position map, all tissue-covered areas were scanned using 20× primary objective. Individual field of view images were stitched to generate a large four-channel fluorescence image of the entire specimen with microscopic resolution. Images obtained with Vslide were analyzed using Metaviewer (Metasystems).

Laser-Scanning Microscopy

On the basis of the generated tissue scans, areas with clear inflammatory processes and more “healthy” appearing areas were selected for further investigation. Images were acquired on a 780LSM confocal laser-scanning microscope (Zeiss). Emission spectra for each dye were limited as follows: Hoechst (420–485 nm), Cy2 (505–530 nm), Cy3 (560–610 nm), and Cy5 (640–720 nm). Coexistence was defined as immunosignals being present without physical signal separation in ≤1.0 μm optical slices at 40× (Plan-Neofluar 40 × /1.30) or 63× (Plan-Apochromat 63 × /1.40) primary magnification. Images obtained with the Zeiss confocal microscope were analyzed using the ZEN software package (Zeiss).

Results

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Here we employed an affinity proteomics approach to identify proteins related to MS by using antibodies on three different types of sample material: plasma, CSF, and brain tissue. Starting with multiplexed antibody suspension bead arrays, protein profiles were generated in three sets of plasma samples as well as in partially paired CSF samples. Lastly, the interesting antibodies were chosen to stain sections from MS brain tissues (Figure 1).

Initial Discovery Screening

Protein profiles were generated from plasma with 4595 HPA antibodies targeting 3450 unique proteins in 12 rounds of analysis on 384-plex bead arrays. Plasma from 16 MS patients (8 RRMS, 4 SPMS, 4 PPMS) and 6 nondiseased controls was analyzed, alongside 760 other serum and plasma samples within cancer, cardiovascular, and neurodegenerative diseases (data not shown). Antibodies that revealed profiles of significant differences (p < 0.05) between the 16 MS cases and 6 nondiseased controls were evaluated for further investigations. These were selected if they were (i) MS-specific in comparison with the other profiled neurodegenerative diseases or (ii) of potential relevance according to the biological processes related to a specific target. This investigation resulted in a refined list of 56 antibodies against 48 target proteins (Supplementary Table 2A in the Supporting Information), including one of the highlighted targets of the herein presented study, methyltransferase-like protein 14 (METTL14).

First Targeted Discovery Across MS Subtypes

Following the previously described initial discovery analysis based on 3450 targets, 296 additional protein targets were selected based on a thorough and inclusive literature search, including proteomic studies in blood or CSF,(35-42) a genome wide association study,(43) blood transcriptome analysis,(44) and other related works(10, 23, 41, 45-54) as well as previous results from internal neuroscience related protein profiling efforts. Subsequently, this first targeted 384-plex bead array for 334 proteins was created to profile an additional set of 172 plasma samples (Table 1). The SPMS-CIS (CIS-rel and CIS-rem combined) comparison revealed elevated protein profiles in SPMS for interleukin 7 (IL7, HPA019590; adjusted p = 0.001) and S100 calcium binding protein A8 (S100A8, HPA024372; adjusted p = 0.02). Similar differences with these two protein profiles were also found when comparing RRMS (RR-rel and RR-rem combined)-CIS (adjusted p = 0.03). An antibody targeting myotrophin (MTPN, HPA019735), showed higher intensities in the SPMS subtype compared with CIS (adjusted p = 0.01). Additional SPMS-CIS differences were revealed for interferon regulatory factor 8 (IRF8, HPA002531; p = 0.03) and serine proteinase inhibitor member 3 (SERPINA3, HPA002560; p = 0.009), when p values were not adjusted for multiple testing. For follow-up experiments, these tentative candidates as well as antibodies generated against different epitopes of the same proteins were included.

Second Targeted Analysis Across MS Subtypes

A second focused bead array was built on the above indications and by adding antibodies from a previous CSF profiling study.(23) This list was again supplemented with other internally identified targets from screening an independent MS-related serum sample cohort (data not shown). The resulting 101-plex bead array addressed 43 proteins (Supplementary Table 2B in the Supporting Information), and was used to analyze an extended set of 443 plasma samples from patients with OND, iOND, CIS, RRMS, and SPMS (Table 1B). Here assays were performed in two separate 384-well plates with %CV of 6.5 for plate #1 and 5.1 for plate #2.

In concordance with the findings above, two-group univariate comparisons revealed most significant differences between SPMS-CIS groups (Figure 2A,B, Supplementary Table 4 in the Supporting Information) and by antibodies against IL7, IRF8, METTL14, the zinc transporter solute carrier family 30 member 7 (SLC30A7), as well as the growth associated protein 43 (GAP43). For these five candidates, we observed no gender effects (p > 0.05) but an interindividual spread in MFI values within each subtype and even prior normalization (Supplementary Figure 1 in the Supporting Information). Statistically significant differences (p < 0.05) were reproducible (Supplementary Figure 2 in the Supporting Information); as an example, anti-IRF8 HPA002531 showed a high correlation (plate1: spearman Rho = 0.91; plate2: Rho = 0.89) when this antibody was utilized in a different bead array composition on the very same set of samples. These SPMS-CIS differences were further illustrated by unsupervised hierarchical clustering of plasma protein profiles for these two patient groups (Figure 2C). Models for multiparameter comparison across disease subtypes were then calculated using Lasso logistic regression and summarized in Table 2 and Supplementary Figure 3 in the Supporting Information; area under the curve (AUC) values of up to 0.80 could be achieved with antibody panels consisting of varying number of antibodies. An IRF8 contribution was found for all but the RRMS-SPMS comparison.

Table 2. Multivariate Analysisa

comparison	AUC	gene names	ENSG ID	antibodies
RRMS vs CIS	0.72	IRF8	ENSG00000140968	HPA002531
RRMS vs CIS	0.72	METTL14	ENSG00000145388	HPA038001
CIS vs SPMS	0.80	ANXA1	ENSG00000135046	HPA011271
		IL7	ENSG00000104432	HPA019590
		IRF8	ENSG00000140968	HPA002531
		METTL14	ENSG00000145388	HPA038001
		TJP2	ENSG00000119139	HPA001813
OND vs SPMS	0.78	ALPK2	ENSG00000198796	HPA029801
		ANXA1	ENSG00000135046	HPA011271
		APEX1	ENSG00000100823	HPA002564
		DNMT3B	ENSG00000088305	HPA001595
		IL7	ENSG00000104432	HPA019590
		IRF8	ENSG00000140968	HPA002531
		SLC30A7	ENSG00000162695	HPA018034
		TJP2	ENSG00000119139	HPA001813
		ZFP36L1	ENSG00000185650	HPA035423
RRMS vs SPMS	0.77	ALPK2	ENSG00000198796	HPA029801
		ANXA1	ENSG00000135046	HPA011271
		DNMT3B	ENSG00000088305	HPA001595
		IL7	ENSG00000104432	HPA019590
		SLC30A7	ENSG00000162695	HPA018034
		TJP2	ENSG00000119139	HPA001813
		ZFP36L1	ENSG00000185650	HPA035423

Lasso logistic models were fitted to plate 1 data for pair-wise classifications. The performance of each model was evaluated using the data from a separate set of individuals in plate 2. Only classifiers with AUC > 0.7 are shown. Corresponding ROC curves are shown in Supplementary Figure 4 in the Supporting Information.

Verification Analysis for IRF8

For further evaluation of differences between SPMS, CIS, and RRMS, an independent set of plasma samples was analyzed (Table 1D), where RRMS and CIS subtypes were age- and gender-matched, while diagnosis of SPMS is inherently related to older age. In contrast with previous analysis, METTL14, SLC30A7, IL7, and GAP43 did not reveal statistically significant differences (data not shown), and there was a significant difference for IRF8 (HPA002531) between genders (p = 0.02). But as shown in Figure 3, a separate analysis using the 37 female patients revealed elevated IRF8 levels for SPMS compared with CIS (p = 0.001) and RRMS (p = 0.0005).

These indications lead to focus on IRF8 as the main target of interest. Three available antibodies against IRF8 were analyzed in Western blot using a cell lysate overexpressing this regulatory factor. This revealed a single band at the predicted 50 kDa range detected by all three antibodies. When analyzing a pool of plasma samples, only HPA002531 showed a single band at a slightly lower molecular mass of ±40 kDa (Supplementary Figure 4A in the Supporting Information). In addition, epitope mapping was performed on high-density peptide arrays for HPA002531 on peptides covering the protein fragment that had been selected to generate this antibody. Two epitopes with consensus peptide sequences, PYKVYRIVPEE and MEIAEVDSVVPVNN, were found (Supplementary Figure 4B in the Supporting Information). A homology search for the first consensus sequence revealed 100% similarity to the 106–116 amino acid region of IRF8 (E value =1 × 10^–⁵), whereas the second consensus sequence showed a nonsignificant similarity of 64% to the predicted human protein GA-binding protein subunit beta-2 isoform X6 (GABPB2, E value =1.3).

Profiling of Paired CSF Samples

The targeted 101-plex bead array was then used to analyze a set of 573 CSF samples (Table 1C). As previously reported,(23) a subset of these CSF samples (n = 339) had been analyzed and revealed that levels for GAP43 and SERPINA3 were altered between MS subtypes and controls. The current analysis with 573 samples shown in Figure 2A (see Supplementary Figure 5A in the Supporting Information for analysis of the new 234 sample subset) confirmed these observations. GAP43 was detected at lower levels in SPMS compared with RRMS, OND, and iOND groups (p < 0.007). Also, antibodies against SERPINA3 confirmed pervious analysis and showed higher levels in RRMS and iOND groups (p < 0.001, Supplementary Figure 5A in the Supporting Information). For both targets, profiles obtained by paired antibodies revealed correlating intensities (Supplementary Figure 5B in the Supporting Information). Apart from GAP43, protein profiles determined in CSF did not confirm indications found in plasma (Figure 2 B). A correlation analysis between paired plasma and CSF samples did not reveal congruence in protein profiles with −0.5 < Rho < 0.5 (data not shown).

Correlation Networks Across MS Subtypes

In the second targeted analysis phase, we also studied differential correlation of protein profiles across MS subtypes in plasma and CSF to investigate the relation between the five highlighted protein profiles within each subtype. As shown for plasma in Figure 4, network analysis revealed a prominent positive correlation between SLC30A7 and GAP43 in all subtypes. Also, a higher correlation between IL7 and IRF8 profiles was found in SPMS compared with other groups. In CSF, however, a positive correlation between SLC30A7 and IL7 was observed in all subtypes. Notably, profiles for IL7 and METTL14 were most similar in SPMS, while METTL14 was concordant with IRF8 in CIS, however, discordant in relapsing RRMS. Thus, indications for subtype specific networks were shown, and intranetwork relations were found to be dependent on the type of the analyzed body fluid.

Distribution of Identified Targets in the MS Brain

Following the analysis of body fluid samples, antibodies identified for IRF8, METTL14, IL7, GAP43, SERPINA3, and SLC30A7 were applied to brain tissue sections from MS patients (Table 3 and Supplementary Table 1 in the Supporting Information). A multiplex fluorescence approach was used to investigate the expression and distribution of the MS associated proteins in the vicinity of lesions and to identify the cellular distribution of selected targets in glia cells either by expression or phagocytosis. For tissue staining, the identified antibodies were combined with antibodies for the astrocyte marker glial fibrillary acidic protein (GFAP) and the microglia marker ionized calcium adapter molecule 1 (IBA1). On the basis of GFAP immunoreactivity and Sudan Black counterstaining, single or multiple lesions could be identified. The majority of lesions were localized at the border between gray and white matter expanding into the latter (Figure 5A–D). Most plaques were active lesions characterized by large numbers of microglia cells within and surrounding the plaque (Figure 5E).

Table 3. Annotation of Candidate Expression in Brain Tissuea

location	antibody	gene name	annotation
neuronal	HPA015600	GAP43	MS: intense axon-like staining pattern
	HPA015600	GAP43	normal: N/A
	HPA019590	IL7	MS: moderate to strong expression in neurons (soma and processes) and some blood vessels
	HPA019590	IL7	normal: weak to moderate in perikarya
	HPA002531	IRF8	MS: strong staining in perikarya (including axonal processes) and blood vessels
	HPA002531	IRF8	normal: moderate staining in neuronal perikarya
	HPA038001	METTL14	MS: moderate to strong staining in neurons (mainly nuclear and some processes and some inflammatory cells)
	HPA038001	METTL14	Normal: moderate to strong expression, mostly nuclear
glial	HPA018034	SLC30A7	MS: moderate immunoreactivity in blood vessels and microglia
	HPA018034	SLC30A7	normal: N/A
	HPA024372	S100A8	MS: strong expression in macrophages and some blood vessels
	HPA024372	S100A8	normal: no expression detected
endothelial	HPA000893	SERPINA3	MS: almost exclusively expressed in blood vessels
endothelial	HPA000893	SERPINA3	normal: no expression detected

Summary of the staining pattern observed for candidate markers on normal and MS brain tissue.

All selected antibodies revealed reactivity in the MS brain. IRF8 antibody HPA002531 (Figure 5F) prominently stained the majority of neurons in the proximity of lesions but also in distal healthy appearing areas of the examined brain section. The anti-IRF8 immunoreactivity was restricted to the cytosolic compartment of neurons, and no clear coexistence of IRF8 with the glial markers GFAP and IBA-1 could be observed. For METTL14, a second antibody (HPA038002) was used and revealed a cytosolic and nuclear staining pattern in neuron-like cells (Figure 5G) from both lesion affected and more healthy appearing areas. This antibody also showed reactivity in IBA1⁺ microglia, but in these cells, METTL14 immune-reactivity was mainly nuclear. The IL7 antibody HPA019590 revealed weak to moderate staining of a few neuron-like cells in the proximity of lesions (Figure 5H) and a subset of GFAP⁺ cells in sclerotic areas (Figure 5I). Antibody HPA015600 targeting GAP43 revealed an axon-like staining pattern with highest staining intensity in the multiform layer of the cortex (Figure 5J). A clear decrease in anti-GAP43 immunoreactivity near plaques compared with less affected areas in the same sample could be observed (Figure 5K). SERPINA3 immunoreactivity was mainly found in the lumen of smaller and larger blood vessels (HPA000893, Figure 5L) and moderate immunoreactivity could be observed in IBA1⁺ microglia cells. No clear difference in staining intensity between plaques and more healthy appearing areas could be identified. Antibody HPA018034 recognizing the zinc transporter SLC30A7 revealed a weak immunoreactivity in the lumen of blood vessels and labeled IBA1⁺ microglia (Figure 5M).

These findings show that possible sources of the identified targets in blood plasma and CSF were neurons (IRF8, METTL14, IL7, and GAP43) and glia cells (IL7, METTL14) in the vicinity of lesions. This supports the hypothesis that proteins expressed in the brain can leak or be transported by macrophages into the bloodstream and can effectively be detected in plasma samples. SERPINA3 and SLC30A7 were mainly located in the lumen of blood vessels, indicating that these proteins can be involved in a peripheral component of the MS pathology.

Discussion

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In this study, we have employed an affinity proteomics approach to profile proteins in the context of MS. Starting with unbiased assays on multiplexed antibody suspension bead arrays, a large number of antibodies were utilized to identify MS-subtype-related proteins in plasma. We then built two, subsequently smaller targeted arrays for analysis of an extended study of MS sample sets using both plasma and CSF. From these investigations, antibodies targeting IRF8, IL7, SLC30A7, METTL14, and GAP43 were most indicative for disease state and progression and consequently chosen for immunofluorescence analysis of post-mortem brain tissue sections from MS patients.

Affinity proteomics is an alternative to mass spectrometry with a conceptual difference because target selection is usually conducted prior analysis. Thus, many affinity-based approaches are hypothesis-driven and generally do not incorporate large numbers of antibodies for discovery purposes. In our initial discovery screening, antibodies were included without considering any protein-disease relation, and were selected for further analysis if they revealed differential protein profiles only between the MS cases and controls and not in the sample sets belonging to other neurodegenerative diseases. This highlighted the profile for METTL14, which was subsequently confirmed to be differential between the CIS and SPMS groups. We further made use of the flexibility of the chosen bead array methodology and supplemented the first indications with targets suggested by literature. Profiling additional plasma samples as well as CSF samples led to a short list of candidate antibody targets, which we finally analyzed in rare brain tissue from diseased individuals as well as from non-MS individuals. While information about potential disease relation was available for IRF8, GAP43, SLC30A7, and IL7, little is known about the function of METTL14 and its potential relation to MS pathogenesis. As previously indicated,(55) a disease-centric selection of antibodies provides more candidates than untargeted discovery; however, they hold the potential of extending the existing knowledge.

Multiple sclerosis is widely considered to be a heterogeneous disease, indicating that further subclassification and staging might be required to better understand the differential pathophysiology. At this point, we cannot propose a novel biomarker or signature that now allows us to better classify MS, but we have shown by multivariate, as well as network analysis, that the five highlighted proteins in plasma may serve as a good basis to extend the current understanding of the disease, yet far more samples (thousands) and dedicated assays may be required to confirm that the indications we present here are valid for samples from different collections, clinics, nations, and ethnicities. It is further suggested to follow-up on or include some of the proposed candidates in coming analysis of biobanks and consider the use of multiplexed methods for multiparallel determination of MS-related proteins. An intrinsic challenge will remain in finding markers for this disease because individuals diagnosed with SPMS are generally older than those suffering from other subtypes of MS. In part, this means that associations found for a subtype may also be driven by age, gender, or other variables than disease and need to be taken into account during the statistical evaluation.

We have recently developed assays for CSF analysis on the bead array platform, which we utilized for protein profiling(23) as well as for autoantibody profiling.(56) In the presented work, basically no correlation of protein levels between paired plasma and CSF samples could be shown, which might be related to where (organ proximity) and when (related to event) the sample had been taken. For the studied MS subtypes, correlation networks based on the highlighted proteins were different in plasma compared with CSF. Such discrepancy may though be explained by the complexity of the samples as well as changes in target abundance and resulting analytical sensitivity. We found GAP43 to reveal statistically significant differences for both plasma and CSF. However, when comparing gene expression of all selected targets (Supplementary Table 5 in the Supporting Information) in different organs and tissue types,(57) GAP43 has 25 times higher expression in the brain compared with all other analyzed tissues. Interestingly, all other targets suggested as potential markers in plasma but not in CSF were highly expressed in multiple peripheral organs and tissue types. Even though the presence of target proteins in brain was confirmed, this suggests that a majority of target proteins detected in body fluids could originate from other tissues or appear as a consequence of an immune response. An alternative explanation for absence of targets detected in plasma but not in CSF might come from the direct interaction of (juxtavascular) microglia with the bloodstream, as found for METTL14, SERPINA3, and SLC30A7 in IBA1+ microglia (Figure 5G,L,M).

There is still a great need for noninvasive tools to diagnose neurological disorders and monitor disease progression and efficiency of therapeutic intervention. Physiological readouts, neuroimaging, and analysis of CSF and plasma are the only acceptable diagnostic tools available to neurologists. Technological advances now enable us to use small sample quantities to detect target proteins at concentrations as low as in the range of high pg/mL in multiplex, thus making it possible to detect proteins expressed by brain cells in CSF or plasma. As indicated in this study, the challenging aspect of such an approach is to understand the relations between altered protein levels in systemic or proximal body fluids and the ongoing pathological processes in the brain. Future approaches might benefit from focusing on genes highly expressed or enriched in certain (diseased) areas of the brain or as compared with peripheral organs. As shown for GAP43 and degeneration of neurons, proteins present within these neurons can be detectable in CSF and plasma, and it would be interesting to see if other cell-type-specific proteins could also be detected in both body fluids.

Among the candidates and besides the aforementioned GAP43, we obtained most supportive evidence for antibody-based detection of IRF8. It is a transcription factor with a known function in interferon signaling, response to infection, and for the development of microphages and other myeloid lineages.(58, 59) Alleles in the vicinity of the IRF8 gene have been associated with MS susceptibility,(60, 61) suggesting that disease susceptibility is potentially linked to the regulation of IRF8 transcription. Moreover, a very recent study in mouse models and neuroinflammation showed that IRF8^–/– mice were resistant to experimental autoimmune encephalomyelitis and that expression of IRF8 in antigen-presenting cells facilitated disease onset and progression.(62) We, for instance, found that profiles from IL7 and IRF8 were similar in SPMS plasma but not in CSF, and the antibody reactivity in tissue was located to the majority of neurons close to lesions. Still, more insights need to be obtained to further define the role of IRF8 in disease development, but our study shows that using affinity proteomics tools across different samples types and analytical assays may contribute to that aim. Regarding IL7, we recently obtained elevated levels in plasma from the IL7 antibody HPA019590 when studying childhood malaria,(55) and as shown elsewhere, levels of IL7 were increased in relation to RRMS.(63) Less is known about METTL14, which was newly linked to methylation of nuclear RNA,(64) as well as about the zinc transporter SLC30A7.

In summary, integrative affinity proteomic approaches were used for analysis of plasma, CSF and brain tissue to identify candidate proteins, in particular, IRF8, for further investigations. We demonstrated the broad-scale applicability of antibodies across different samples types and platforms and indicate that the use of multiplexed affinity-proteomics methods holds a promise for identification of proteins, which can be investigated further for an improved understanding of molecular mechanism of neurological diseases such as MS. Further studies across different biobanks are now needed to determine the contribution of our findings to a better understanding of the MS and its subtypes.

Supporting Information

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S-Table 1: Demographics of brain tissue samples. S-Table 2A: Antibodies suggested by discovery screening. S-Table 2B: Antibodies used for second, focused 101-plex bead array. S-Table 3: Antibody performance in plasma and CSF. S-Table 4: Antibodies used for analysis of brain tissue. S-Table 5: RNA expression levels (FPKM) related to candidate proteins. S-Figure 1: Protein profiles prior normalization. S-Figure 2: Experimental reproducibility of candidate profiles. S-Figure 3: ROC curves from multivariate analysis. S-Figure 4: Western blot and epitope mapping of IRF8. S-Figure 5: Candidate profiles in CSF. S-Figure 6: Hierarchical clustering of SPMS and CIS in CSF. This material is available free of charge via the Internet at http://pubs.acs.org.

pdf
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⊥Author Contributions

S.B. and B.A.

contributed equally.

The authors declare no competing financial interest.

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Acknowledgment

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We thank the whole group of Biobank Profiling-Affinity Proteomics at SciLifeLab Stockholm and the entire staff of the Human Protein Atlas for their efforts in generating the antibodies. We also thank the clinical teams and biobank staff who helped with sample collection. We thank Hjalmar Brismar and Hans Blom at SciLifeLab for providing access to microscopes. This work was supported by grants from the Swedish Research Council, the Swedish Brain Foundation, the AFA Foundation, as well as SciLifeLab and the Knut and Alice Wallenberg Foundation.

Abbreviations

AUC	area under curve
CIS	clinically isolated syndrome
CSF	cerebrospinal fluid
CV	coefficient of variation
GAP43	growth associated protein 43
GFAP	glial fibrillary acidic protein
HPA	Human Protein Atlas
IBA1	ionized calcium adapter molecule 1
IL7	interleukin 7
IRF8	interferon regulatory factor 8
METTL14	methyltransferase-like protein 14
MFI	median fluorescence intensity
MS	multiple sclerosis
OND	other neurological diseases
iOND	OND with signs of inflammation
PCA	principal component analysis
PPMS	primary progressive MS
PrEST	protein epitope signature tag
PQN	probabilistic quotient normalization
ROC	receiver operating characteristics
RRMS	relapsing remitting MS
SLC30A7	zinc transporter solute carrier family 30 member 7
SPMS	secondary progressive MS

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Proteomics (2014), 14 (4-5), 467-480CODEN: PROTC7; ISSN:1615-9853. (Wiley-VCH Verlag GmbH & Co. KGaA)
A review. Multiple sclerosis, which is the most common cause of chronic neurol. disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid anal., which requires an invasive collection. Addnl., the mol. mechanisms of the disease are not completely elucidated, esp. those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and mol. mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biol. samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its exptl. model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets.
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Comabella, M.; Montalban, X. Body fluid biomarkers in multiple sclerosis Lancet Neurol 2014, 13 (1) 113– 126
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Body fluid biomarkers in multiple sclerosis
Comabella Manuel; Montalban Xavier
The Lancet. Neurology (2014), 13 (1), 113-26 ISSN:.
Biomarkers can be thought of as multifaceted indicators of healthy status or of pathological disorders. The study of multiple sclerosis can benefit from the use of biomarkers because of the disease's inherent heterogeneity. Biomarkers in multiple sclerosis might assist with diagnosis, prediction of disease course, or identification of response outcome to treatments. Despite the need for biomarkers and extensive research to identify them, validation and clinical application of biomarkers is still an unmet need in multiple sclerosis, and large gaps remain between exploratory biomarkers proposed in many studies, validated biomarkers, and biomarkers that are integrated into routine clinical practice.
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Uhlen, M. Towards a knowledge-based Human Protein Atlas Nat. Biotechnol. 2010, 28 (12) 1248– 1250
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Towards a knowledge-based Human Protein Atlas
Uhlen, Mathias; Oksvold, Per; Fagerberg, Linn; Lundberg, Emma; Jonasson, Kalle; Forsberg, Mattias; Zwahlen, Martin; Kampf, Caroline; Wester, Kenneth; Hober, Sophia; Wernerus, Henrik; Bjoerling, Lisa; Ponten, Fredrik
Nature Biotechnology (2010), 28 (12), 1248-1250CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
There is no expanded citation for this reference.
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14
Uhlen, M. A human protein atlas for normal and cancer tissues based on antibody proteomics Mol. Cell. Proteomics 2005, 4 (12) 1920– 1932
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A human protein atlas for normal and cancer tissues based on antibody proteomics
Uhlen, Mathias; Bjoerling, Erik; Agaton, Charlotta; Szigyarto, Cristina Al-Khalili; Amini, Bahram; Andersen, Elisabet; Andersson, Ann-Catrin; Angelidou, Pia; Asplund, Anna; Asplund, Caroline; Berglund, Lisa; Bergstroem, Kristina; Brumer, Harry; Cerjan, Dijana; Ekstroem, Marica; Elobeid, Adila; Eriksson, Cecilia; Fagerberg, Linn; Falk, Ronny; Fall, Jenny; Forsberg, Mattias; Bjoerklund, Marcus Gry; Gumbel, Kristoffer; Halimi, Asif; Hallin, Inga; Hamsten, Carl; Hansson, Marianne; Hedhammar, My; Hercules, Goerel; Kampf, Caroline; Larsson, Karin; Lindskog, Mats; Lodewyckx, Wald; Lund, Jan; Lundeberg, Joakim; Magnusson, Kristina; Malm, Erik; Nilsson, Peter; Oedling, Jenny; Oksvold, Per; Olsson, Ingmarie; Oester, Emma; Ottosson, Jenny; Paavilainen, Linda; Persson, Anja; Rimini, Rebecca; Rockberg, Johan; Runeson, Marcus; Sivertsson, Aasa; Skoellermo, Anna; Steen, Johanna; Stenvall, Maria; Sterky, Fredrik; Stroemberg, Sara; Sundberg, Maarten; Tegel, Hanna; Tourle, Samuel; Wahlund, Eva; Walden, Annelie; Wan, Jinghong; Wernerus, Henrik; Westberg, Joakim; Wester, Kenneth; Wrethagen, Ulla; Xu, Lan Lan; Hober, Sophia; Ponten, Fredrik
Molecular and Cellular Proteomics (2005), 4 (12), 1920-1932CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology)
Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database contg., in the first version, ∼400,000 high resoln. images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this anal. to the majority of all human proteins thus providing a valuable tool for medical and biol. research.
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Stoevesandt, O.; Taussig, M. J. Affinity proteomics: the role of specific binding reagents in human proteome analysis Expert Rev. Proteomics 2012, 9 (4) 401– 414
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Affinity proteomics: the role of specific binding reagents in human proteome analysis
Stoevesandt, Oda; Taussig, Michael J.
Expert Review of Proteomics (2012), 9 (4), 401-414CODEN: ERPXA3; ISSN:1478-9450. (Expert Reviews Ltd.)
A review. Affinity proteomics is the field of proteome anal. based on the use of antibodies and other binding reagents as protein-specific detection probes. In this review, the particular strengths of affinity methods for detn. of protein localization, functional characterization, biomarker discovery and intracellular applications, and their resulting impact in basic and clin. research are highlighted. An addnl. focus is on the requirements for systematic binder generation and current large-scale binder projects, including bioinformatic frameworks for epitope selection and for documentation of available binding reagents and their performance. In addn. to current affinity proteomics methods and applications, including arrays of proteins, binders, lysates and tissues, approaches coupling mass spectrometry-based proteomics and affinity proteomics are reviewed.
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Ayoglu, B. Systematic antibody and antigen-based proteomic profiling with microarrays Expert Rev. Mol. Diagn. 2011, 11 (2) 219– 234
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Systematic antibody and antigen-based proteomic profiling with microarrays
Ayoglu, Burcu; Haeggmark, Anna; Neiman, Maja; Igel, Ulrika; Uhlen, Mathias; Schwenk, Jochen M.; Nilsson, Peter
Expert Review of Molecular Diagnostics (2011), 11 (2), 219-234CODEN: ERMDCW; ISSN:1473-7159. (Expert Reviews Ltd.)
Current approaches within affinity-based proteomics are driven both by the accessibility and availability of antigens and capture reagents, and by suitable multiplexed technologies onto which these are implemented. By combining planar microarrays and other multiparallel systems with sets of reagents, possibilities to discover new and unpredicted protein--disease assocns., either via directed hypothesis-driven or via undirected hypothesis-generating target selection, can be created. In the following stages, the discoveries made during these screening phases have to be verified for potential clin. relevance based on both tech. and biol. aspects. The use of affinity tools throughout discovery and verification has the potential to streamline the introduction of new markers, as transition into clin. required assay formats appears straightforward. In this article, we summarize some of the current building blocks within array- and affinity-based proteomic profiling with a focus on body fluids, by giving a perspective on how current and upcoming developments in this bioscience could enable a path of pursuit for biomarker discovery.
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17
McDonald, W. I. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis Ann. Neurol. 2001, 50 (1) 121– 127
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Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis
McDonald W I; Compston A; Edan G; Goodkin D; Hartung H P; Lublin F D; McFarland H F; Paty D W; Polman C H; Reingold S C; Sandberg-Wollheim M; Sibley W; Thompson A; van den Noort S; Weinshenker B Y; Wolinsky J S
Annals of neurology (2001), 50 (1), 121-7 ISSN:0364-5134.
The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."
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18
De Groot, C. J. Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions Brain 2001, 124 (Pt 8) 1635– 1645
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Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions
De Groot C J; Bergers E; Kamphorst W; Ravid R; Polman C H; Barkhof F; van der Valk P
Brain : a journal of neurology (2001), 124 (Pt 8), 1635-45 ISSN:0006-8950.
Macroscopic sampling of multiple sclerosis lesions in the brain tends to find chronic lesions. For a better understanding of the dynamics of the multiple sclerosis disease process, research into new and developing lesions is of great interest. As MRI in vivo effectively demonstrates lesions in multiple sclerosis patients, we have applied it to unfixed post-mortem brain slices to identify abnormalities, in order to obtain a higher yield of active lesions. The Netherlands Brain Bank organized the rapid autopsy of 29 multiple sclerosis patients. The brain was cut in 1 cm coronal slices. One or two slices were subjected to T(1)- and T(2)-weighted MRI, and then cut at the plane of the MRI scan into 5 mm thick opposing sections. Areas of interest were identified based on the MRI findings and excised. One half was fixed in 10% formalin and paraffin-embedded, and the corresponding area in the adjacent half was snap-frozen in liquid nitrogen. In total, 136 out of 174 brain tissue samples could be matched with the abnormalities seen on T(2)-weighted MRIs. The stage of lesional development was determined (immuno) histochemically. For 54 MRI-detectable samples, it was recorded whether they were macroscopically detectable, i.e. visible and/or palpable. Histopathological analysis revealed that 48% of the hyperintense areas seen on T(2)-weighted images represented active lesions, including lesions localized in the normal appearing white matter, without apparent loss of myelin but nevertheless showing a variable degree of oedema, small clusters of microglial cells with enhanced major histocompatibility complex class II antigen, CD45 and CD68 antigen expression and a variable number of perivascular lymphocytes around small blood vessels [designated as (p)reactive lesions]. From the macroscopically not-visible/not-palpable MRI-detected abnormalities, 58% were (p)reactive lesions and 21% contained active demyelinating lesions. In contrast, visible and/or palpable brain tissue samples mainly contained chronic inactive lesions. We conclude that MRI-guided sampling of brain tissue increases the yield of active multiple sclerosis lesions, including active demyelinating and (p)reactive lesions.
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19
Kampf, C. Production of tissue microarrays, immunohistochemistry staining and digitalization within the human protein atlas J. Vis. Exp. 2012, 63) 3620
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Nilsson, P. Towards a human proteome atlas: high-throughput generation of mono-specific antibodies for tissue profiling Proteomics 2005, 5 (17) 4327– 4337
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Towards a human proteome atlas: High-throughput generation of mono-specific antibodies for tissue profiling
Nilsson, Peter; Paavilainen, Linda; Larsson, Karin; Oedling, Jenny; Sundberg, Maarten; Andersson, Ann-Catrin; Kampf, Caroline; Persson, Anja; Al-Khalili Szigyarto, Cristina; Ottosson, Jenny; Bjoerling, Erik; Hober, Sophia; Wernerus, Henrik; Wester, Kenneth; Ponten, Fredrik; Uhlen, Mathias
Proteomics (2005), 5 (17), 4327-4337CODEN: PROTC7; ISSN:1615-9853. (Wiley-VCH Verlag GmbH & Co. KGaA)
A great need exists for the systematic generation of specific antibodies to explore the human proteome. Here, the authors show that antibodies specific to human proteins can be generated in a high-throughput manner involving stringent affinity purifn. using recombinant protein epitope signature tags (PrESTs) as immunogens and affinity-ligands. The specificity of the generated affinity reagents, here called mono-specific antibodies (msAb), were validated with a novel protein microarray assay. The success rate for 464 antibodies generated towards human proteins was more than 90% as judged by the protein array assay. The antibodies were used for parallel profiling of patient biopsies using tissue microarrays generated from 48 human tissues. Comparative anal. with well-characterized monoclonal antibodies showed identical or similar specificity and expression patterns. The results suggest that a comprehensive atlas contg. extensive protein expression and subcellular localization data of the human proteome can be generated in an efficient manner with mono-specific antibodies.
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21
Sjoberg, R. Validation of affinity reagents using antigen microarrays New Biotechnol. 2012, 29 (5) 555– 563
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Validation of affinity reagents using antigen microarrays
Sjoberg Ronald; Sundberg Marten; Gundberg Anna; Sivertsson Asa; Schwenk Jochen M; Uhlen Mathias; Nilsson Peter
New biotechnology (2012), 29 (5), 555-63 ISSN:.
There is a need for standardised validation of affinity reagents to determine their binding selectivity and specificity. This is of particular importance for systematic efforts that aim to cover the human proteome with different types of binding reagents. One such international program is the SH2-consortium, which was formed to generate a complete set of renewable affinity reagents to the SH2-domain containing human proteins. Here, we describe a microarray strategy to validate various affinity reagents, such as recombinant single-chain antibodies, mouse monoclonal antibodies and antigen-purified polyclonal antibodies using a highly multiplexed approach. An SH2-specific antigen microarray was designed and generated, containing more than 6000 spots displayed by 14 identical subarrays each with 406 antigens, where 105 of them represented SH2-domain containing proteins. Approximately 400 different affinity reagents of various types were analysed on these antigen microarrays carrying antigens of different types. The microarrays revealed not only very detailed specificity profiles for all the binders, but also showed that overlapping target sequences of spotted antigens were detected by off-target interactions. The presented study illustrates the feasibility of using antigen microarrays for integrative, high-throughput validation of various types of binders and antigens.
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Drobin, K.; Nilsson, P.; Schwenk, J. M. Highly multiplexed antibody suspension bead arrays for plasma protein profiling Methods Mol. Biol. 2013, 1023, 137– 145
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Highly multiplexed antibody suspension bead arrays for plasma protein profiling
Drobin, Kimi; Nilsson, Peter; Schwenk, Jochen M.
Methods in Molecular Biology (New York, NY, United States) (2013), 1023 (Low Molecular Weight Proteome), 137-145CODEN: MMBIED; ISSN:1064-3745. (Springer)
Alongside the increasing availability of affinity reagents, antibody microarrays have become a powerful tool to screen for target proteins in complex samples. Applying directly labeled samples onto arrays instead of using sandwich assays offers an approach to facilitate a systematic, high-throughput, and flexible exploration of protein profiles in body fluids such as serum or plasma. As an alternative to planar arrays, a system based on color-coded beads for the creation of antibody arrays in suspension has become available to offer a microtiter plate-based option for screening larger no. of samples with variable sets of capture reagents. A procedure was established for analyzing biotinylated samples without the necessity to remove excess labeling substance. We have shown that this assay system allows detecting proteins down into lower pico-molar and higher pg/mL levels with dynamic ranges over three orders of magnitude. Presently, this workflow enables the profiling of 384 samples for up to 384 proteins per assay.
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Haggmark, A. Antibody-based profiling of cerebrospinal fluid within multiple sclerosis Proteomics 2013, 13 (15) 2256– 2267
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Antibody-based profiling of cerebrospinal fluid within multiple sclerosis
Haggmark Anna; Bystrom Sanna; Ayoglu Burcu; Qundos Ulrika; Uhlen Mathias; Khademi Mohsen; Olsson Tomas; Schwenk Jochen M; Nilsson Peter
Proteomics (2013), 13 (15), 2256-67 ISSN:.
Antibody suspension bead arrays have proven to enable multiplexed and high-throughput protein profiling in unfractionated plasma and serum samples through a direct labeling approach. We here describe the development and application of an assay for protein profiling of cerebrospinal fluid (CSF). While setting up the assay, systematic intensity differences between sample groups were observed that reflected inherent sample specific total protein amounts. Supplementing the labeling reaction with BSA and IgG diminished these differences without impairing the apparent sensitivity of the assay. We also assessed the effects of heat treatment on the analysis of CSF proteins and applied the assay to profile 43 selected proteins by 101 antibodies in 339 CSF samples from a multiple sclerosis (MS) cohort. Two proteins, GAP43 and SERPINA3 were found to have a discriminating potential with altered intensity levels between sample groups. GAP43 was detected at significantly lower levels in secondary progressive MS compared to early stages of MS and the control group of other neurological diseases. SERPINA3 instead was detected at higher levels in all MS patients compared to controls. The developed assay procedure now offers new possibilities for broad-scale protein profiling of CSF within neurological disorders.
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Forsstrom, B. Proteome-wide epitope mapping of antibodies using ultra-dense peptide arrays Mol. Cell. Proteomics 2014, 13, 1585– 1597
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Proteome-wide epitope mapping of antibodies using ultra-dense peptide arrays
Forsstrom Bjorn; Nilsson Peter; Axnas Barbara Bislawska; Hu Francis Jingxin; Hudson Elton P; Rockberg Johan; Stengele Klaus-Peter; Buhler Jochen; Albert Thomas J; Richmond Todd A; Uhlen Mathias
Molecular & cellular proteomics : MCP (2014), 13 (6), 1585-97 ISSN:.
Antibodies are of importance for the field of proteomics, both as reagents for imaging cells, tissues, and organs and as capturing agents for affinity enrichment in mass-spectrometry-based techniques. It is important to gain basic insights regarding the binding sites (epitopes) of antibodies and potential cross-reactivity to nontarget proteins. Knowledge about an antibody's linear epitopes is also useful in, for instance, developing assays involving the capture of peptides obtained from trypsin cleavage of samples prior to mass spectrometry analysis. Here, we describe, for the first time, the design and use of peptide arrays covering all human proteins for the analysis of antibody specificity, based on parallel in situ photolithic synthesis of a total of 2.1 million overlapping peptides. This has allowed analysis of on- and off-target binding of both monoclonal and polyclonal antibodies, complemented with precise mapping of epitopes based on full amino acid substitution scans. The analysis suggests that linear epitopes are relatively short, confined to five to seven residues, resulting in apparent off-target binding to peptides corresponding to a large number of unrelated human proteins. However, subsequent analysis using recombinant proteins suggests that these linear epitopes have a strict conformational component, thus giving us new insights regarding how antibodies bind to their antigens.
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Dieterle, F. Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in ¹H NMR metabonomics Anal. Chem. 2006, 78 (13) 4281– 4290
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Probabilistic Quotient Normalization as Robust Method to Account for Dilution of Complex Biological Mixtures. Application in 1H NMR Metabonomics
Dieterle, Frank; Ross, Alfred; Schlotterbeck, Goetz; Senn, Hans
Analytical Chemistry (2006), 78 (13), 4281-4290CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
For the anal. of the spectra of complex biofluids, preprocessing methods play a crucial role in rendering the subsequent data analyses more robust and accurate. Normalization is a preprocessing method, which accounts for different dilns. of samples by scaling the spectra to the same virtual overall concn. In the field of 1H NMR metabonomics integral normalization, which scales spectra to the same total integral, is the de facto std. In this work, it is shown that integral normalization is a suboptimal method for normalizing spectra from metabonomic studies. Esp. strong metabonomic changes, evident as massive amts. of single metabolites in samples, significantly hamper the integral normalization resulting in incorrectly scaled spectra. The probabilistic quotient normalization is introduced in this work. This method is based on the calcn. of a most probable diln. factor by looking at the distribution of the quotients of the amplitudes of a test spectrum by those of a ref. spectrum. Simulated spectra, spectra of urine samples from a metabonomic study with cyclosporin-A as the active compd., and spectra of more than 4000 samples of control animals demonstrate that the probabilistic quotient normalization is by far more robust and more accurate than the widespread integral normalization and vector length normalization.
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Hong, M.-G., Multi-Dimensional Normalization of Plate Effects in the Application of Affnity Proteomics for Plasma Profiling, unpublished.
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L1 penalized estimation in the Cox proportional hazards model
Goeman Jelle J
Biometrical journal. Biometrische Zeitschrift (2010), 52 (1), 70-84 ISSN:.
This article presents a novel algorithm that efficiently computes L(1) penalized (lasso) estimates of parameters in high-dimensional models. The lasso has the property that it simultaneously performs variable selection and shrinkage, which makes it very useful for finding interpretable prediction rules in high-dimensional data. The new algorithm is based on a combination of gradient ascent optimization with the Newton-Raphson algorithm. It is described for a general likelihood function and can be applied in generalized linear models and other models with an L(1) penalty. The algorithm is demonstrated in the Cox proportional hazards model, predicting survival of breast cancer patients using gene expression data, and its performance is compared with competing approaches. An R package, penalized, that implements the method, is available on CRAN.
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Tibshirani, R. Regression shrinkage and selection via the Lasso Journal of the Royal Statistical Society Series B-Methodological 1996, 58 (1) 267– 288
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Britschgi, M. Modeling of pathological traits in Alzheimer’s disease based on systemic extracellular signaling proteome Mol. Cell. Proteomics 2011, 10 (10) M111 008862
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Smoot, M. E. Cytoscape 2.8: new features for data integration and network visualization Bioinformatics 2011, 27 (3) 431– 432
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Cytoscape 2.8: new features for data integration and network visualization
Smoot, Michael E.; Ono, Keiichiro; Ruscheinski, Johannes; Wang, Peng-Liang; Ideker, Trey
Bioinformatics (2011), 27 (3), 431-432CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
Summary: Cytoscape is a popular bioinformatics package for biol. network visualization and data integration. Version 2.8 introduces two powerful new features-Custom Node Graphics and Attribute Equations-which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities. Custom Node Graphics allow an image to be projected onto a node, including images generated dynamically or at remote locations. Attribute Equations provide Cytoscape with spreadsheet-like functionality in which the value of an attribute is computed dynamically as a function of other attributes and network properties. Availability and implementation: Cytoscape is a desktop Java application released under the Library Gnu Public License (LGPL). Binary install bundles and source code for Cytoscape 2.8 are available for download from http://cytoscape.org. Contact: [email protected]
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Waterhouse, A. M. Jalview Version 2--a multiple sequence alignment editor and analysis workbench Bioinformatics 2009, 25 (9) 1189– 1191
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Jalview Version 2-a multiple sequence alignment editor and analysis workbench
Waterhouse, Andrew M.; Procter, James B.; Martin, David M. A.; Clamp, Michele; Barton, Geoffrey J.
Bioinformatics (2009), 25 (9), 1189-1191CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
Summary: Jalview Version 2 is a system for interactive WYSIWYG editing, anal. and annotation of multiple sequence alignments. Core features include keyboard and mouse-based editing, multiple views and alignment overviews, and linked structure display with Jmol. Jalview 2 is available in two forms: a lightwt. Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server. Availability: The Jalview 2 Desktop application and JalviewLite applet are made freely available under the GPL, and can be downloaded from www.jalview.org.
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34
WebLogo: A sequence logo generator
Crooks, Gavin E.; Hon, Gary; Chandonia, John-Marc; Brenner, Steven E.
Genome Research (2004), 14 (6), 1188-1190CODEN: GEREFS; ISSN:1088-9051. (Cold Spring Harbor Laboratory Press)
WebLogo generates sequence logos, graphical representations of the patterns within a multiple sequence alignment. Sequence logos provide a richer and more precise description of sequence similarity than consensus sequences and can rapidly reveal significant features of the alignment otherwise difficult to perceive. Each logo consists of stacks of letters, one stack for each position in the sequence. The overall height of each stack indicates the sequence conservation at that position (measured in bits), whereas the height of symbols within the stack reflects the relative frequency of the corresponding amino or nucleic acid at that position. WebLogo has been enhanced recently with addnl. features and options, to provide a convenient and highly configurable sequence logo generator. A command line interface and the complete, open WebLogo source code are available for local installation and customization.
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Suk, K. Combined analysis of the glia secretome and the CSF proteome: neuroinflammation and novel biomarkers Expert Rev. Proteomics 2010, 7 (2) 263– 274
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35
Combined analysis of the glia secretome and the CSF proteome: neuroinflammation and novel biomarkers
Suk, Kyoungho
Expert Review of Proteomics (2010), 7 (2), 263-274CODEN: ERPXA3; ISSN:1478-9450. (Expert Reviews Ltd.)
A review. Glial cells in the CNS are likely to communicate with other glial cells and neurons through secreted proteins. Glia-derived proteins also participate in neuroinflammation, which is a major component of neurodegenerative disease. Cerebrospinal fluid (CSF) is the biol. fluid that best reflects the physiol. or pathol. conditions of the CNS. Proteins secreted from glial cells are often detected in the CSF. One of the major cellular sources of the highly abundant CSF proteins is glia. Combined anal. of secreted proteins of glial cells and CSF proteins of patients with inflammatory CNS disorders can provide new knowledge to the field of glia biol. and neuron-glia interaction. The comparative anal. of the glia secretome and the CSF proteome would also facilitate the targeted proteomics-based discovery of new biomarkers for brain disease. Omics and systems biol. approaches to glia and neuroinflammation will be a focus of future investigation and will enable an integrative understanding of inflammatory CNS disorders, such as neurodegenerative disease.
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Stoop, M. P. Proteomics comparison of cerebrospinal fluid of relapsing remitting and primary progressive multiple sclerosis PLoS One 2010, 5 (8) e12442
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There is no corresponding record for this reference.
37
Sakurai, T. Identification of antibodies as biological markers in serum from multiple sclerosis patients by immunoproteomic approach J. Neuroimmunol. 2011, 233 (1–2) 175– 180
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Identification of antibodies as biological markers in serum from multiple sclerosis patients by immunoproteomic approach
Sakurai, Takeo; Kimura, Akio; Yamada, Megumi; Koumura, Akihiro; Hayashi, Yu-Ichi; Tanaka, Yuji; Hozumi, Isao; Inuzuka, Takashi
Journal of Neuroimmunology (2011), 233 (1-2), 175-180CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)
The authors identified the antibody against mitochondrial heat shock protein 70 (mtHSP70) in serum from multiple sclerosis (MS) patients by proteomics-based anal. The prevalence of the anti-mtHSP70 antibody is significantly higher in serum from MS patients than in serum from Parkinson disease patients, multiple cerebral infarction patients, infectious meningoencephalitis patients, and healthy controls (HCs) (68% sensitivity; 74% specificity). The authors studied the clin. features and magnetic resonance imaging findings of MS patients with the anti-mtHSP70 antibody. As a result, there were no significant differences between the anti-mtHSP70-antibody-pos. and -neg. MS patients. Addnl., in the authors' comprehensive anal. of the prevalence of both the anti-mtHSP70 antibody and the anti-phosphoglycerate mutase 1 (PGAM1) antibody, which was previously reported by the authors to also show a higher prevalence in serum from MS patients, the positivity rates of both these antibodies were significantly higher in serum from MS patients than in serum from patients with other neurol. diseases and from HCs; moreover, the specificity of this combination assay was higher than that of the assay of only one antibody (57% sensitivity; 93% specificity). Results of the authors' study suggest that not only the anti-PGAM1 antibody but also the anti-mtHSP70 antibody is good diagnostic markers of MS and the combination of both these antibodies is useful for a more specific diagnosis of MS.
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Ottervald, J. Multiple sclerosis: Identification and clinical evaluation of novel CSF biomarkers J. Proteomics 2010, 73 (6) 1117– 1132
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38
Multiple sclerosis: Identification and clinical evaluation of novel CSF biomarkers
Ottervald, Jan; Franzen, Bo; Nilsson, Kerstin; Andersson, Lars I.; Khademi, Mohsen; Eriksson, Bodil; Kjellstroem, Sven; Marko-Varga, Gyoergy; Vegvari, Akos; Harris, Robert A.; Laurell, Thomas; Miliotis, Tasso; Matusevicius, Darius; Salter, Hugh; Ferm, Mats; Olsson, Tomas
Journal of Proteomics (2010), 73 (6), 1117-1132CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)
Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that results in damage to myelin sheaths and axons in the central nervous system and which preferentially affects young adults. We performed a proteomics-based biomarker discovery study in which cerebrospinal fluid (CSF) from MS and control individuals was analyzed (n = 112). Ten candidate biomarkers were selected for evaluation by quant. immunoassay using an independent cohort of MS and control subjects (n = 209). In relapsing-remitting MS (RRMS) patients there were significant increases in the CSF levels of alpha-1 antichymotrypsin (A1AC), alpha-1 macroglobulin (A2MG) and fibulin 1 as compared to control subjects. In secondary progressive MS (SPMS) four addnl. proteins (contactin 1, fetuin A, vitamin D binding protein and angiotensinogen (ANGT)) were increased as compared to control subjects. In particular, ANGT was increased 3-fold in SPMS, indicating a potential as biomarker of disease progression in MS. In PPMS, A1AC and A2MG exhibit significantly higher CSF levels than controls, with a trend of increase for ANGT. Classification models based on the biomarker panel could identify 70% of the RRMS and 80% of the SPMS patients correctly. Further evaluation was conducted in a pilot study of CSF from RRMS patients (n = 36), before and after treatment with natalizumab.
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Noben, J. P. Lumbar cerebrospinal fluid proteome in multiple sclerosis: characterization by ultrafiltration, liquid chromatography, and mass spectrometry J. Proteome Res. 2006, 5 (7) 1647– 1657
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Lumbar Cerebrospinal Fluid Proteome in Multiple Sclerosis: Characterization by Ultrafiltration, Liquid Chromatography, and Mass Spectrometry
Noben, Jean-Paul; Dumont, Debora; Kwasnikowska, Natalia; Verhaert, Peter; Somers, Veerle; Hupperts, Raymond; Stinissen, Piet; Robben, Johan
Journal of Proteome Research (2006), 5 (7), 1647-1657CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
Neurol. diseases, including multiple sclerosis (M.S.), often provoke changes in the functioning of the endothelial and epithelial brain barriers and give rise to disease-assocd. alterations of the cerebrospinal fluid (CSF) proteome. In the present study, pooled and ultrafiltered CSF of M.S. and non-M.S. patients was digested with trypsin and analyzed by off-line strong cation-exchange chromatog. (SCX) coupled to online reversed-phase LC-ESI-MS/MS. In an alternative approach, the trypsin-treated subproteomes were analyzed directly by LC-ESI-MS/MS and gas-phase fractionation in the mass spectrometer. Taken together, both proteomic approaches in combination with a three-step evaluation process including the search engines Sequest and Mascot, and the validation software Scaffold, resulted in the identification of 148 proteins. Sixty proteins were identified in CSF for the first time by mass spectrometry. For validation purposes, the concn. of cystatin A was detd. in individual CSF and serum samples of M.S. and non-M.S. patients using ELISA.
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40
Hammack, B. N. Proteomic analysis of multiple sclerosis cerebrospinal fluid Mult. Scler. 2004, 10 (3) 245– 260
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40
Proteomic analysis of multiple sclerosis cerebrospinal fluid
Hammack, B. N.; Fung, K. Y. C.; Hunsucker, S. W.; Duncan, M. W.; Burgoon, M. P.; Owens, G. P.; Gilden, D. H.
Multiple Sclerosis (2004), 10 (3), 245-260CODEN: MUSCFZ; ISSN:1352-4585. (Arnold, Hodder Headline)
Two-dimensional gel electrophoresis and peptide mass fingerprinting were used to identify proteins in cerebrospinal fluid (CSF) pooled from three patients with multiple sclerosis (MS) and in CSF pooled from three patients with non-MS inflammatory central nervous system (CNS) disorders. Resoln. of CSF proteins on three pH gradients (3-10, 4-7 and 6-11) enabled identification of a total of 430 spots in the MS CSF proteome that represented 61 distinct proteins. The gels contg. MS CSF revealed 103 protein spots that were not seen on control gels. All but four of these 103 spots were proteins known to be present in normal human CSF. The four exceptions were: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signaling glycoprotein), and autotaxin t (a phosphodiesterase). It remains unknown whether these four proteins are related to the cause and pathogenesis of MS.
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Alexander, J. S. Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b Mult. Scler. 2010, 16 (7) 801– 809
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41
Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-β1b
Alexander, J. S.; Harris, M. K.; Wells, S. R.; Mills, G.; Chalamidas, K.; Ganta, V. C.; McGee, J.; Jennings, M. H.; Gonzalez-Toledo, E.; Minagar, A.
Multiple Sclerosis (2010), 16 (7), 801-809CODEN: MUSCFZ; ISSN:1352-4585. (Sage Publications Ltd.)
Background: Interferon-β1b (IFN-β1b), an effective treatment for multiple sclerosis (MS), lessens disease severity in MS patients. However, the mechanisms of its immunoregulatory and anti-inflammatory effects in MS remain only partially understood. Matrix metalloproteinases (MMP) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are involved in blood brain barrier disruption and formation of MS lesions. Th1/Th17 cytokines e.g. interleukins IL-12p40, IL-17, and IL-23, are assocd. with MS disease activity and are significant players in pathogenesis of MS. Objective: During a 1-yr prospective study, we serially measured serum MMP-8, MMP-9, TIMP-1, IL-12p40, IL-17, and IL-23 in 24 patients with relapsing-remitting MS. We compared the results to clin. course and to brain magnetic resonance imaging. IFN-β1b decreased serum MMP-8 and MMP-9 (not TIMP-1). Results: The sustained treatment with IFN-β1b attenuated the pro-inflammatory environment by significantly reducing the serum IL-12p40, IL-23, and showed a trend for decreasing IL-17. Decreased serum MMP-8, MMP-9, IL-12 and IL-23 levels were correlated with a decrease in the no. of contrast-enhanced T2-weighted lesions. Conclusion: Early treatment of MS with IFN-β1b may stabilize clin. disease by attenuating levels of inflammatory cytokines and MMPs. Serial measurement of inflammatory mediators may serve as sensitive markers to gauge therapeutic responses to IFN-β1b during the first year of treatment.
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42
Sawcer, S. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis Nature 2011, 476 (7359) 214– 219
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42
Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C. A.; Patsopoulos, Nikolaos A.; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Booth, David R.; Potter, Simon C.; Goris, An; Band, Gavin; Bang Oturai, Annette; Strange, Amy; Saarela, Janna; Bellenguez, Celine; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D'Afonso, Sandra; Blackburn, Hannah; Boneschi, Filippo Martinelli; Liddle, Jennifer; Harbo, Hanne F.; Perez, Marc L.; Spurkland, Anne; Waller, Matthew J.; Mycko, Marcin P.; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T.; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J.; Barcellos, Lisa F.; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E.; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P.; Brassat, David; Broadley, Simon A.; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M.; Cavalla, Paola; Celius, Elisabeth G.; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Francoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B.; Cozen, Wendy; Cree, Bruce A. C.; Cross, Anne H.; Cusi, Daniele; Daly, Mark J.; Davis, Emma; de Bakker, Paul I. W.; Debouverie, Marc; D'Hoghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Benedicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F. A.; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N.; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G.; Kilpatrick, Trevor J.; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S.; Leone, Maurizio A.; Leppae, Virpi; Liljedahl, Ulrika; Lima Bomfim, Izaura; Lincoln, Robin R.; Link, Jenny; Liu, Jianjun; Lorentzen, Aslaug R.; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L.; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L.; Ramsay, Patricia P.; Reunanen, Mauri; Reynolds, Richard; Rioux, John D.; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P.; Rueckert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A.; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J.; Sellebjerg, Finn; Selmaj, Krzysztof W.; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M. A.; Smestad, Cathrine; Sorensen, Per Soelberg; Sondergaard, Helle Bach; Stankovich, Jim; Strange, Richard C.; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvaenen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M.; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A.; Tronczynska, Ewa; Casas, Juan P.; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S.; Wang, Kai; Mathew, Christopher G.; Wason, James; Palmer, Colin N. A.; Wichmann, H.-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C.; Yaouanq, Jacqueline; Viswanathan, Ananth C.; Zhang, Haitao; Wood, Nicholas W.; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J.; De Jager, Philip L.; Peltonen, Leena; Stewart, Graeme J.; Hafler, David A.; Hauser, Stephen L.; McVean, Gil; Donnelly, Peter; Compston, Alastair
Nature (London, United Kingdom) (2011), 476 (7359), 214-219CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurol. disturbance followed by progressive accumulation of disability. Epidemiol. studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide assocn. studies (GWAS) have enabled more than 20 addnl. risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the anal. of sample sizes that are beyond the nos. currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested assocns. and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunol. relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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Gandhi, K. S. The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis Hum. Mol. Genet. 2010, 19 (11) 2134– 2143
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The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
Gandhi, Kaushal S.; McKay, Fiona C.; Cox, Mathew; Riveros, Carlos; Armstrong, Nicola; Heard, Robert N.; Vucic, Steve; Williams, David W.; Stankovich, Jim; Brown, Matthew; Danoy, Patrick; Stewart, Graeme J.; Broadley, Simon; Moscato, Pablo; Lechner-Scott, Jeannette; Scott, Rodney J.; Booth, David R.; Griffiths, Lyn; Slee, Mark; Browning, Sharon; Browning, Brian L.; Kilpatrick, Trevor; Rubio, Justin; Perreau, Victoria; Butzkeuven, Helmut; Tanner, Mary; Wiley, Jim; Foote, Simon; Stankovich, Jim; Taylor, Bruce; Kermode, Allan; Carroll, Bill; Bahlo, Melanie
Human Molecular Genetics (2010), 19 (11), 2134-2143CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300,000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10-12) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not assocd. with clin. course or disability. The ANZgene genome wide assocn. screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory mol., CD40; the other a region on chromosome 12q13-14. The CD40 haplotype assocd. with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequil. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10-14). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
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Zeis, T. Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection Brain 2008, 131 (Pt 1) 288– 303
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Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection
Zeis Thomas; Graumann Ursula; Reynolds Richard; Schaeren-Wiemers Nicole
Brain : a journal of neurology (2008), 131 (Pt 1), 288-303 ISSN:.
Multiple sclerosis is a chronic inflammatory disease of the CNS. Although progressive axonal injury and diffuse inflammatory damage has been shown in the chronic phase of the disease, little is known about the molecular mechanisms underlying these pathological processes. In order to identify these mechanisms, we have studied the gene expression profile in non-lesion containing tissue, the so-called normal-appearing white matter (NAWM). We performed differential gene expression analysis and quantitative RT-PCR on subcortical white matter from 11 multiple sclerosis and 8 control cases. Differentially expressed genes were further analysed in detail by in situ hybridization and immunofluorescence studies. We show that genes known to be involved in anti-inflammatory and protective mechanisms such as STAT6, JAK1, IL-4R, IL-10, Chromogranin C and Hif-1alpha are consistently upregulated in the multiple sclerosis NAWM. On the other hand, genes involved in pro-inflammatory mechanisms, such as STAT4, IL-1beta and MCSF, were also upregulated but less regularly. Immunofluorescence colocalization analysis revealed expression of STAT6, JAK1, IL-4R and IL-13R mainly in oligodendrocytes, whereas STAT4 expression was detected predominantly in microglia. In line with these data, in situ hybridization analysis showed an increased expression in multiple sclerosis NAWM of HIF-1alpha in oligodendrocytes and HLA-DRalpha in microglia cells. The consistency of the expression levels of STAT6, JAK1, JAK3 and IL-4R between the multiple sclerosis cases suggests an overall activation of the STAT6-signalling pathway in oligodendrocytes, whereas the expression of STAT4 and HLA-DRalpha indicates the activation of pro-inflammatory pathways in microglia. The upregulation of genes involved in anti-inflammatory mechanisms driven by oligodendrocytes may protect the CNS environment and thus limit lesion formation, whereas the activation of pro-inflammatory mechanisms in microglia may favour disease progression. Altogether, our data suggests an endogenous inflammatory reaction throughout the whole white matter of multiple sclerosis brain, in which oligodendrocytes actively participate. This reaction might further influence and to some extent facilitate lesion formation.
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Valdo, P. Enhanced expression of NGF receptors in multiple sclerosis lesions J. Neurol., Neurosurg. Psychiatry 2002, 61 (1) 91– 98
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There is no corresponding record for this reference.
46
Thangarajh, M. Increased levels of APRIL (a proliferation-inducing ligand) mRNA in multiple sclerosis J. Neuroimmunol. 2005, 167 (1–2) 210– 214
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Increased levels of APRIL (A Proliferation-Inducing Ligand) mRNA in multiple sclerosis
Thangarajh, Mathula; Masterman, Thomas; Rot, Uros; Duvefelt, Kristina; Brynedal, Boel; Karrenbauer, Virginija Danylaite; Hillert, Jan
Journal of Neuroimmunology (2005), 167 (1-2), 210-214CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)
B cells play an indispensable, yet indeterminate, role in the pathogenesis of multiple sclerosis (MS). We measured mRNA of APRIL-a promotor of B-cell survival-in peripheral blood and quantified protein levels in plasma and cerebrospinal fluid in MS patients and controls. APRIL mRNA levels in monocytes and T cells were significantly higher in MS patients than in controls. Levels of sol. APRIL in plasma were higher in patients with chronic progressive MS than in patients with relapsing-remitting MS, albeit not significantly. MS may thus be assocd. with increased transcription in peripheral blood of factors promoting B-cell survival, including APRIL.
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Tanaka, M. Anti-aquaporin 4 antibody in Japanese multiple sclerosis: the presence of optic spinal multiple sclerosis without long spinal cord lesions and anti-aquaporin 4 antibody J. Neurol., Neurosurg. Psychiatry 2007, 78 (9) 990– 992
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47
Anti-aquaporin 4 antibody in Japanese multiple sclerosis: the presence of optic spinal multiple sclerosis without long spinal cord lesions and anti-aquaporin 4 antibody
Tanaka Masami; Tanaka Keiko; Komori Mika; Saida Takahiko
Journal of neurology, neurosurgery, and psychiatry (2007), 78 (9), 990-2 ISSN:.
BACKGROUND: Anti-aquaporin 4 (AQP4) antibodies were found in patients with neuromyelitis optica (NMO) and Japanese optic-spinal multiple sclerosis (OSMS). OBJECTIVE: To review the clinical features and investigate anti-AQP4 antibodies of Japanese patients with multiple sclerosis (MS), with or without long spinal cord lesions (LCL). METHODS: Anti-AQP4 antibodies were examined in the sera of 128 consecutive Japanese patients by the immunofluorescence method using AQP4 transfected cells. RESULTS: The 45 LCL-MS patients included 28 with a long spinal cord lesion extending contiguously over three vertebral segments on sagittal T2 weighted images (long T2 lesion) and 17 with segmental cord atrophy extending more than three vertebral segments. We identified 25 patients with anti-AQP4 antibody with LCL and anti-AQP4 antibody. Anti-AQP4 antibody was found in 12/17 (70.6%) LCL-MS patients with segmental cord atrophy, and in 13/28 (46.4%) LCL-MS patients without segmental long cord atrophy (p = 0.135, Fisher's exact test). Seropositive MS patients with LCL had more relapses than seronegative patients (p = 0.0004, Mann-Whitney U test). 9 patients with OSMS were negative for anti-AQP4 antibody who did not show LCL. CONCLUSION: These results suggest that an anti-AQP4 antibody is found not only in MS patients with long T2 lesions but also in patients with segmental cord atrophy extending more than three vertebral segments. It is a marker of LCL-MS showing frequent exacerbations. Japanese OSMS cases comprised those that were identical to NMO cases and those that were more closely related to classic MS.
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Solomon, B. D. Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (5) 2040– 2045
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Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis
Solomon, Benjamin D.; Mueller, Cynthia; Chae, Wook-Jin; Alabanza, Leah M.; Bynoe, Margaret S.
Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (5), 2040-2045, S2040/1-S2040/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
Neuropilin-1 (Nrp1) is a cell surface mol. originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T (Treg) cells. In this study, we provide evidence for a central role of Nrp1 in the regulation of CD4 T-cell immune responses in exptl. autoimmune encephalitis (EAE). EAE serves as an animal model for the central nervous system (CNS) inflammatory disorder multiple sclerosis (MS). EAE is mediated primarily by CD4+ T cells that migrate to the CNS and mount an inflammatory attack against myelin components, resulting in CNS pathol. Using a tissue-specific deletion system, we obsd. that the lack of Nrp1 on CD4+ T cells results in increased EAE severity. These conditional knockout mice exhibit preferential TH-17 lineage commitment and decreased Treg-cell functionality. Conversely, CD4+ T cells expressing Nrp1 suppress effector T-cell proliferation and cytokine prodn. both in vivo and in vitro independent of Treg cells. Nrp1-mediated suppression can be inhibited by TGF-β blockade but not by IL-10 blockade. These results suggest that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses, leading to diseases like EAE and potentially MS.
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Reder, A. T. MxA: a biomarker for predicting multiple sclerosis disease activity Neurology 2010, 75 (14) 1222– 1223
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MxA: a biomarker for predicting multiple sclerosis disease activity
Reder Anthony T
Neurology (2010), 75 (14), 1222-3 ISSN:.
There is no expanded citation for this reference.
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Ramanathan, M. In vivo gene expression revealed by cDNA arrays: the pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects J. Neuroimmunol. 2001, 116 (2) 213– 219
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50
In vivo gene expression revealed by cDNA arrays: the pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects
Ramanathan, M.; Weinstock-Guttman, B.; Nguyen, L. T.; Badgett, D.; Miller, C.; Patrick, K.; Brownscheidle, C.; Jacobs, L.
Journal of Neuroimmunology (2001), 116 (2), 213-219CODEN: JNRIDW; ISSN:0165-5728. (Elsevier Science B.V.)
Objectives: To use DNA arrays to identify differences in gene expression assocd. with relapsing-remitting (RR) MS. Methods: Total RNA was isolated from monocyte depleted peripheral blood mononuclear cells of 15 RR MS patients and 15 age- and sex-matched controls. The RNA was reverse transcribed to radiolabeled cDNA and the resultant cDNA was used to probe a DNA array contg. over 4000 named human genes. The binding of radiolabeled cDNA to the probes on the array was measured by phosphorimager. Results: Of >4000 genes tested, only 34 were significantly different in RR-MS patients from controls. Of these, 25 were significantly increased and 9 significantly decreased in the RR MS patients. Twelve of these genes have inflammatory and/or immunol. functions that could be relevant to the MS disease process. The potentially relevant genes that were elevated (15% to 28%) were P protein, LCK, cAMP responsive element modulator, IL-7 receptor, matrix metalloproteinase-19, M130 antigen, and peptidyl-prolyl isomerase. Those that were significantly decreased (15% to 35%) were SAS transmembrane 4 superfamily protein, STRL22 (C-C chemokine receptor 6), AFX protein, DNA fragmentation factor-45 and Ig gamma 3 (Gm marker). Conclusions: The RR-MS disease effect was relatively restricted and most of the mRNAs tested were not different from the normal controls. However, there were significant differences identified in the expression of a subset of mRNAs, including 13 with inflammatory/immune functions that could be relevant to MS. The systematic use of DNA arrays can provide insight into the dynamic cellular pathways involved in MS pathogenesis and its phenotypic heterogeneity.
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51
Mc Guire, C. Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination J. Immunol. 2010, 185 (12) 7646– 7653
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51
Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination
Mc Guire Conor; Volckaert Thomas; Wolke Uta; Sze Mozes; de Rycke Riet; Waisman Ari; Prinz Marco; Beyaert Rudi; Pasparakis Manolis; van Loo Geert
Journal of immunology (Baltimore, Md. : 1950) (2010), 185 (12), 7646-53 ISSN:.
Apoptosis of oligodendrocytes (ODCs), the myelin-producing glial cells in the CNS, plays a central role in demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To investigate the mechanism behind ODC apoptosis in EAE, we made use of conditional knockout mice lacking the adaptor protein FADD specifically in ODCs (FADD(ODC-KO)). FADD mediates apoptosis by coupling death receptors with downstream caspase activation. In line with this, ODCs from FADD(ODC-KO) mice were completely resistant to death receptor-induced apoptosis in vitro. In the EAE model, FADD(ODC-KO) mice followed an ameliorated clinical disease course in comparison with control littermates. Lymphocyte and macrophage infiltration into the spinal cord parenchyma was significantly reduced, as was the extent of demyelination and proinflammatory gene expression. Collectively, our data show that FADD is critical for ODC apoptosis and the development of autoimmune demyelinating disease.
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Lindsey, J. W.; Agarwal, S. K.; Tan, F. K. Gene expression changes in multiple sclerosis relapse suggest activation of T and non-T cells Mol. Med. 2011, 17 (1–2) 95– 102
[ Crossref], [ PubMed], [ CAS], Google Scholar
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Gene expression changes in multiple sclerosis relapse suggest activation of T and non-T cells
Lindsey, J. William; Agarwal, Sandeep K.; Tan, Filemon K.
Molecular Medicine (Manhasset, NY, United States) (2011), 17 (1-2), 95-102CODEN: MOMEF3; ISSN:1076-1551. (Feinstein Institute for Medical Research)
A defining feature of multiple sclerosis (MS) is the occurrence of clin. relapses sepd. by periods of clin. stability. Better understanding of the events underlying clin. relapse might suggest new approaches to treatment. The objective of this study was to measure changes in the expression of RNA in the blood during relapse. We used microarrays to measure mRNA expression in paired samples from 14 MS patients during clin. relapse and while stable. Seventy-one transcripts changed expression at the P < 0.001 significance level. The most notable finding was decreased expression of transcripts with regulatory function, expressed primarily in non-T cells. These decreased transcripts included the interleukin-1 receptor antagonist, which had a corresponding decrease in the protein concn. in serum. Transcripts with increased expression were expressed primarily in T cells. Pathways anal. suggested involvement of the cytokine network, coagulation and complement cascades, IL-10 signaling and NF-κB signaling. We conclude that there are alterations of mRNA expression in both T cells and non-T cells during MS relapse.
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Harris, V. K. Bri2–23 is a potential cerebrospinal fluid biomarker in multiple sclerosis Neurobiol. Dis. 2010, 40 (1) 331– 339
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53
Bri2-23 is a potential cerebrospinal fluid biomarker in multiple sclerosis
Harris, Violaine K.; Diamanduros, Andrew; Good, Pamela; Zakin, Elina; Chalivendra, Varun; Sadiq, Saud A.
Neurobiology of Disease (2010), 40 (1), 331-339CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)
To identify potential multiple sclerosis (MS)-specific biomarkers, we used a proteomic approach to screen cerebrospinal fluid (CSF) from 40 MS patients and 13 controls. We identified seven proteins (Beta-2-microglobulin, Bri2-23, Fetuin-A, Kallikrein-6, Plasminogen, RNase-1, and Transferrin) that had significantly altered levels in MS compared to controls. Clin. subgroup anal. revealed that decreased CSF levels of Bri2-23, a peptide cleaved from Bri2, were significantly assocd. with patients having cerebellar dysfunction and cognition impairment. Furthermore, expression levels of Bri2 were specifically decreased in the cerebellum compared to other areas of same brain in MS but not in controls, suggesting that decreased cerebellar Bri2 expression may play a role in cerebellar dysfunction. The assocn. with cognition impairment is also of interest because Bri2 is linked to the amyloid processing pathway in the brain. CSF levels of Bri2-23 may serve as a biomarker of these functions in MS and merits further investigation.
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Alcina, A. The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis Genes Immun. 2010, 11 (5) 439– 445
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54
The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis
Alcina, A.; Vandenbroeck, K.; Otaegui, D.; Saiz, A.; Gonzalez, J. R.; Fernandez, O.; Cavanillas, M. L.; Cenit, M. C.; Arroyo, R.; Alloza, I.; Garcia-Barcina, M.; Antigueedad, A.; Leyva, L.; Izquierdo, G.; Lucas, M.; Fedetz, M.; Pinto-Medel, M. J.; Olascoaga, J.; Blanco, Y.; Comabella, M.; Montalban, X.; Urcelay, E.; Matesanz, F.
Genes and Immunity (2010), 11 (5), 439-445CODEN: GEIMA2; ISSN:1466-4879. (Nature Publishing Group)
Genome-wide assocn. studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously assocd. with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be assocd. with MS: rs1678542 in KIF5A (P=0.001, odds ratio (OR)=1.13, 95% confidence interval (CI)=1.05-1.23); rs3184504 in SH2B3 (P=0.00001, OR=1.19, 95% CI=1.10-1.27) and rs763361 in CD226 (P=0.00007, OR=1.16, 95%CI=1.08-1.25). These variants have previously been assocd. with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has addnl. been assocd. with systemic lupus erythematosus. Our results, in addn. to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders.
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Bachmann, J. Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria PLoS Pathog. 2014, 10 (4) e1004038
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Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria
Bachmann, Julie; Burte, Florence; Pramana, Setia; Conte, Ianina; Brown, Biobele J.; Orimadegun, Adebola E.; Ajetunmobi, Wasiu A.; Afolabi, Nathaniel K.; Akinkunmi, Francis; Omokhodion, Samuel; Akinbami, Felix O.; Shokunbi, Wuraola A.; Kampf, Caroline; Pawitan, Yudi; Uhlen, Mathias; Sodeinde, Olugbemiro; Schwenk, Jochen M.; Wahlgren, Mats; Fernandez-Reyes, Delmiro; Nilsson, Peter
PLoS Pathogens (2014), 10 (4), e1004038/1-e1004038/12, 12 pp.CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiol. of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metab. in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.
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Ayoglu, B. Autoantibody profiling in multiple sclerosis using arrays of human protein fragments Mol. Cell. Proteomics 2013, 12 (9) 2657– 2672
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Autoantibody Profiling in Multiple Sclerosis Using Arrays of Human Protein Fragments
Ayoglu, Burcu; Haeggmark, Anna; Khademi, Mohsen; Olsson, Tomas; Uhlen, Mathias; Schwenk, Jochen M.; Nilsson, Peter
Molecular & Cellular Proteomics (2013), 12 (9), 2657-2672CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
Profiling the autoantibody repertoire with large antigen collections is emerging as a powerful tool for the identification of biomarkers for autoimmune diseases. Here, a systematic and undirected approach was taken to screen for profiles of IgG in human plasma from 90 individuals with multiple sclerosis related diagnoses. Reactivity pattern of 11,520 protein fragments (representing ∼38% of all human protein encoding genes) were generated on planar protein microarrays built within the Human Protein Atlas. For more than 2,000 antigens IgG reactivity was obsd., among which 64% were found only in single individuals. We used reactivity distributions among multiple sclerosis subgroups to select 384 antigens, which were then re-evaluated on planar microarrays, corroborated with suspension bead arrays in a larger cohort (n = 376) and confirmed for specificity in inhibition assays. Among the heterogeneous pattern within and across multiple sclerosis subtypes, differences in recognition frequencies were found for 51 antigens, which were enriched for proteins of transcriptional regulation. In conclusion, using protein fragments and complementary high-throughput protein array platforms facilitated an alternative route to discovery and verification of potentially disease-assocd. autoimmunity signatures, that are now proposed as addnl. antigens for large-scale validation studies across multiple sclerosis biobanks.
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Fagerberg, L. Analysis of the human tissue-specific expression by genome-wide integration of transcriptomics and antibody-based proteomics Mol. Cell. Proteomics 2014, 13 (2) 397– 406
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Analysis of the Human Tissue-specific Expression by Genome-wide Integration of Transcriptomics and Antibody-based Proteomics
Fagerberg, Linn; Hallstroem, Bjoern M.; Oksvold, Per; Kampf, Caroline; Djureinovic, Dijana; Odeberg, Jacob; Habuka, Masato; Tahmasebpoor, Simin; Danielsson, Angelika; Edlund, Karolina; Asplund, Anna; Sjoestedt, Evelina; Lundberg, Emma; Al-Khalili Szigyarto, Cristina; Skogs, Marie; Takanen, Jenny Ottosson; Berling, Holger; Tegel, Hanna; Mulder, Jan; Nilsson, Peter; Schwenk, Jochen M.; Lindskog, Cecilia; Danielsson, Frida; Mardinoglu, Adil; Sivertsson, Aasa; von Feilitzen, Kalle; Forsberg, Mattias; Zwahlen, Martin; Olsson, IngMarie; Navani, Sanjay; Huss, Mikael; Nielsen, Jens; Ponten, Fredrik; Uhlen, Mathias
Molecular & Cellular Proteomics (2014), 13 (2), 397-406CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biol. and disease. Here, we used a quant. transcriptomics anal. (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this anal. with antibody-based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to ∼80% of the human protein-coding genes with access to the primary data for both the RNA and the protein anal. on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the mol. constituents of the human body.
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Tamura, T. The IRF family transcription factors in immunity and oncogenesis Annu. Rev. Immunol. 2008, 26, 535– 584
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The IRF family transcription factors in immunity and oncogenesis
Tamura, Tomohiko; Yanai, Hideyuki; Savitsky, David; Taniguchi, Tadatsugu
Annual Review of Immunology (2008), 26 (), 535-584CODEN: ARIMDU; ISSN:0732-0582. (Annual Reviews Inc.)
A review. The interferon regulatory factor (IRF) family, consisting of nine members in mammals, was identified in the late 1980s in the context of research into the type I interferon system. Subsequent studies over the past two decades have revealed the versatile and crit. functions performed by this transcription factor family. Indeed, many IRF members play central roles in the cellular differentiation of hematopoietic cells and in the regulation of gene expression in response to pathogen-derived danger signals. In particular, the advances made in understanding the immunobiol. of Toll-like and other pattern-recognition receptors have recently generated new momentum for the study of IRFs. Moreover, the role of several IRF family members in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.
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Wang, H.; Morse, H. C., 3rd. IRF8 regulates myeloid and B lymphoid lineage diversification Immunol. Res. 2009, 43 (1–3) 109– 117
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59
IRF8 regulates myeloid and B lymphoid lineage diversification
Wang, Hongsheng; Morse, Herbert C., III
Immunologic Research (2009), 43 (1-3), 109-117CODEN: IMRSEB; ISSN:0257-277X. (Springer)
A review. Interferon regulatory factor 8 (IRF8) is a member of the IRF family of transcription factors whose members play crit. roles in interferon (IFN) signaling pathways governing the establishment of innate immune responses by myeloid and dendritic cells. IRF8 is also expressed in lymphoid cells and recent studies have documented its involvement in B cell lineage specification, Ig light chain gene rearrangement, the distribution of mature B cells into the marginal zone and follicular B cell compartment, and the transcriptional regulation of crit. elements of the germinal center reaction. Here we review the contributions of IRF8 to B cell development from hematopoietic stem cells in the bone marrow and its place in the hierarchical regulatory network governing specification and commitment to the B cell fate.
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International Multiple Sclerosis Genetics Consortium. The genetic association of variants in CD6, TNFRSF1A and IRF8 to multiple sclerosis: a multicenter case-control study PLoS One 2011, 6 (4) e18813
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There is no corresponding record for this reference.
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De Jager, P. L. Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci Nat. Genet. 2009, 41 (7) 776– 782
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Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci
De Jager, Philip L.; Jia, Xiaoming; Wang, Joanne; de Bakker, Paul I. W.; Ottoboni, Linda; Aggarwal, Neelum T.; Piccio, Laura; Raychaudhuri, Soumya; Tran, Dong; Aubin, Cristin; Briskin, Rebeccah; Romano, Susan; Baranzini, Sergio E.; McCauley, Jacob L.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Gibson, Rachel A.; Naeglin, Yvonne; Uitdehaag, Bernard; Matthews, Paul M.; Kappos, Ludwig; Polman, Chris; McArdle, Wendy L.; Strachan, David P.; Evans, Denis; Cross, Anne H.; Daly, Mark J.; Compston, Alastair; Sawcer, Stephen J.; Weiner, Howard L.; Hauser, Stephen L.; Hafler, David A.; Oksenberg, Jorge R.
Nature Genetics (2009), 41 (7), 776-782CODEN: NGENEC; ISSN:1061-4036. (Nature Publishing Group)
We report the results of a meta-anal. of genome-wide assocn. scans for multiple sclerosis (MS) susceptibility that includes 2624 subjects with MS and 7220 control subjects. Replication in an independent set of 2215 subjects with MS and 2116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10-11), IRF8 (P = 3.73 × 10-9) and CD6 (P = 3.79 × 10-9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is assocd. with higher mRNA expression of interferon-response pathway genes in subjects with MS.
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Yoshida, Y. The transcription factor IRF8 activates integrin-mediated TGF-beta signaling and promotes neuroinflammation Immunity 2014, 40 (2) 187– 198
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The Transcription Factor IRF8 Activates Integrin-Mediated TGF-β Signaling and Promotes Neuroinflammation
Yoshida, Yuko; Yoshimi, Ryusuke; Yoshii, Hiroaki; Kim, Daniel; Dey, Anup; Xiong, Huabao; Munasinghe, Jeeva; Yazawa, Itaru; O'Donovan, Michael J.; Maximova, Olga A.; Sharma, Suveena; Zhu, Jinfang; Wang, Hongsheng; Morse, Herbert C.; Ozato, Keiko
Immunity (2014), 40 (2), 187-198CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)
Recent epidemiol. studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in exptl. autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8-/- mice are resistant to EAE. Furthermore, expression of IRF8 in antigen-presenting cells (APCs, such as macrophages, dendritic cells, and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced αvβ8 integrin expression in APCs and activated TGF-β signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL-12) and IL-23 prodn., but inhibiting IL-27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS.
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Romme Christensen, J. Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis J. Neuroinflammation 2012, 9, 215
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Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis
Romme Christensen Jeppe; Bornsen Lars; Hesse Dan; Krakauer Martin; Sorensen Per Soelberg; Sondergaard Helle Bach; Sellebjerg Finn
Journal of neuroinflammation (2012), 9 (), 215 ISSN:.
BACKGROUND: Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce. METHODS: We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND). RESULTS: RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression. CONCLUSIONS: Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.
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A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation
Liu, Jianzhao; Yue, Yanan; Han, Dali; Wang, Xiao; Fu, Ye; Zhang, Liang; Jia, Guifang; Yu, Miao; Lu, Zhike; Deng, Xin; Dai, Qing; Chen, Weizhong; He, Chuan
Nature Chemical Biology (2014), 10 (2), 93-95CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
N6-methyladenosine (m6A) is the most prevalent and reversible internal modification in mammalian messenger and noncoding RNAs. We report here that human methyltransferase-like 14 (METTL14) catalyzes m6A RNA methylation. Together with METTL3, the only previously known m6A methyltransferase, these two proteins form a stable heterodimer core complex of METTL3-METTL14 that functions in cellular m6A deposition on mammalian nuclear RNAs. WTAP, a mammalian splicing factor, can interact with this complex and affect this methylation.
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Abstract
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Figure 1
Figure 1. Study overview. Over initial screening and targeted discovery analysis, protein profiles were generated in plasma from more than 170 000 immunoassays on antibody suspension bead arrays. In the screening phase, 3450 unique proteins targeted by 4595 antibodies were profiled for untargeted discovery in 22 plasma samples from MS cases and nondiseased controls. 384 antibodies toward 334 proteins, including 48 proteins that had been selected from the initial screening, were then used for a targeted discovery in plasma from a total of 172 different individuals diagnosed with MS, CIS, or OND. To confirm initial findings, we evaluated 43 protein targets in additional sample material on a 101-plex focused bead array. A set of 443 plasma samples–out of which 124 had been included in the prior stage–and 573 CSF samples were analyzed. These body fluid profiling efforts resulted in candidate targets that were subsequently evaluated by immunofluorescence analysis of post-mortem brain tissue sections from MS patients. One of these candidate antibodies, anti-IRF8, was further verified in an independent set of 50 plasma samples and characterized by Western blot analysis and epitope mapping.
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Figure 2
Figure 2. Candidate protein profiles in plasma and CSF. (A) Antibodies targeting IRF8, IL7, METTL14, SLC30A7, and GAP43 revealed differential levels in plasma from 443 individuals (left panel). For the same antibodies, corresponding plots are shown for 573 CSF individuals (right panel), with 418 individuals overlapping between plasma and CSF. Data shown are both normalized and scaled. For visualization purposes, outliers are not shown. (B) Overview of two-group comparisons performed between the main MS subtypes, for each of the five proteins and on both plasma and CSF. (C) Unsupervised hierarchical cluster analysis for CIS and SPMS plasma using the five antibodies resulted in two main clusters, each being enriched for either of the two subtypes. No gender-related enrichment was observed, and by definition, SPMS patients were older than those of CIS. The corresponding plot for CSF can be found as Supplementary Figure 5 in the Supporting Information.
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Figure 3
Figure 3. Analysis of IRF8 in an independent set of plasma samples. Signal intensities from HPA002531 (IRF8) in 50 plasma samples (CIS, RRMS (RR-rem), and SPMS). Although the signal intensities differed between males and females (left), a comparison only within the 37 female individuals revealed statistically significant and elevated signal intensities in SPMS samples compared with RRMS and CIS samples.
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Figure 4
Figure 4. Correlation networks of candidate profiles in plasma and CSF. Network diagrams were generated to summarize correlation relationships between the five highlighted proteins for subtypes of MS and OND and both plasma (left panel) and CSF (right panel). For all combinations of these five proteins, Spearman’s rank correlation coefficient was calculated between MFI values for any given two proteins within each sample group and sample type, and the correlations were visualized in the network diagrams. The strength and direction of correlation coefficients were visualized with different line widths and colors. The network diagrams demonstrate considerable differences in correlation relations across these five proteins within plasma and CSF. Note, for example, the strong positive correlation between SLC30A7 and GAP43 exclusively unveiled in plasma samples of all sample groups. Furthermore, two correlation relations were uniquely revealed for the SPMS subgroup: the positive correlations between IL7 and IRF8 in plasma and IL7 and METTL14 in CSF.
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Figure 5
Figure 5. Expression of candidate proteins in human MS brain tissue. Selected antibodies were applied to three to four cortical brain sections containing a single or multiple lesions. (A–D) Schematic drawing of the specimens illustrating gray (blue color) and white matter (light gray color) structures and identified lesion sites (red color). (E) All specimens were stained with antibodies against the astrocyte marker GFAP and microglia marker IBA1 in combination with antibodies directed against the selected targets. Panel E shows the distribution of GFAP and IBA-1 immunoreactivity at the border of a plaque. The presence of numerous IBA1-immunoreactive microglia indicates that this is an active lesion (E₁). (F) IRF8-immunoreactivity could only be detected in neuron-like cells throughout the examined brain sections including the gray matter near lesions. (G) Neuron-like mainly nuclear staining pattern was observed for METTL14. In addition, a nuclear staining in microglia (open arrowheads in G) could also be identified. (H) IL7-immunoreactivity was limited to sparsely distributed neuron-like cells and (I) GFAP⁺ astrocytes in MS affected areas. (J) Differences in GAP43-immunoreactivity within a single section could be observed. In areas lacking signs of sclerosis, GAP43-immunoreactivity revealed a network of fibers with strongest intensity in the deeper cortical layers. (K) In lesion sites characterized by the strong activation of astrocytes and expression of GFAP, the amount of GAP43 immunoreactivity fibers was markedly reduced. (L,M) Immunohistochemistry for SERPINA3 (L) and SLC30A7 (M) revealed labeling of IBA1⁺ microglia for both (open arrowheads in L and M) while immunoreactivity could also be detected in the lumen of brain capillaries (arrows in L and M). Scale bars: 1 cm (A–D), 100 μm (E), 20 μm (E₁,J–M), 10 μm (F–I).
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  Multiple Sclerosis (MS) is the most common demyelinating disease of the central nervous system. Although the etiology and the pathogenesis of MS has been extensively investigated, no single pathway, reliable biomarker, diagnostic test, or specific treatment have yet been identified for all MS patients. One of the reasons behind this failure is likely to be the wide heterogeneity observed within the MS population. The clinical course of MS is highly variable and includes several subcategories and variants. Moreover, apart from the well-established association with the HLA-class II DRB1*15:01 allele, other genetic variants have been shown to vary significantly across different populations and individuals. Finally both pathological and immunological studies suggest that different pathways may be active in different MS patients. We conclude that these "MS subtypes" should still be considered as part of the same disease but hypothesize that spatiotemporal effects of genetic and environmental agents differentially influence MS course. These considerations are extremely relevant, as outcome prediction and personalised medicine represent the central aim of modern research.
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7. 7
  Lucchinetti, C. Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination Ann. Neurol. 2000, 47 (6) 707– 717
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  Heterogeneity of multiple sclerosis lesions: implications for the pathogenesis of demyelination
  Lucchinetti C; Bruck W; Parisi J; Scheithauer B; Rodriguez M; Lassmann H
  Annals of neurology (2000), 47 (6), 707-17 ISSN:0364-5134.
  Multiple sclerosis (MS) is a disease with profound heterogeneity in clinical course, neuroradiological appearance of the lesions, involvement of susceptibility gene loci, and response to therapy. These features are supported by experimental evidence, which demonstrates that fundamentally different processes, such as autoimmunity or virus infection, may induce MS-like inflammatory demyelinating plaques and suggest that MS may be a disease with heterogeneous pathogenetic mechanisms. From a large pathology sample of MS, collected in three international centers, we selected 51 biopsies and 32 autopsies that contained actively demyelinating lesions defined by stringent criteria. The pathology of the lesions was analyzed using a broad spectrum of immunological and neurobiological markers. Four fundamentally different patterns of demyelination were found, defined on the basis of myelin protein loss, the geography and extension of plaques, the patterns of oligodendrocyte destruction, and the immunopathological evidence of complement activation. Two patterns (I and II) showed close similarities to T-cell-mediated or T-cell plus antibody-mediated autoimmune encephalomyelitis, respectively. The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity. At a given time point of the disease--as reflected in autopsy cases--the patterns of demyelination were heterogeneous between patients, but were homogenous within multiple active lesions from the same patient. This pathogenetic heterogeneity of plaques from different MS patients may have fundamental implications for the diagnosis and therapy of this disease.
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8. 8
  Kroksveen, A. C. Proteomics of human cerebrospinal fluid: discovery and verification of biomarker candidates in neurodegenerative diseases using quantitative proteomics J. Proteomics 2011, 74 (4) 371– 388
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  Proteomics of human cerebrospinal fluid: Discovery and verification of biomarker candidates in neurodegenerative diseases using quantitative proteomics
  Kroksveen, A. C.; Opsahl, J. A.; Aye, T. T.; Ulvik, R. J.; Berven, F. S.
  Journal of Proteomics (2011), 74 (4), 371-388CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)
  A review. There is an urgent need for novel biomarkers that can be used to improve the diagnosis, predict the disease progression, improve our understanding of the pathol. or serve as therapeutic targets for neurodegenerative diseases. Cerebrospinal fluid (CSF) is in direct contact with the CNS and reflects the biochem. state of the CNS under different physiol. and pathol. settings. Because of this, CSF is regarded as an excellent source for identifying biomarkers for neurol. diseases and other diseases affecting the CNS. Quant. proteomics and sophisticated computational software applied to analyze the protein content of CSF has been fronted as an attractive approach to find novel biomarkers for neurol. diseases. This review will focus on some of the potential pitfalls in biomarker studies using CSF, summarize the status of the field of CSF proteomics in general, and discuss some of the most promising proteomics biomarker study approaches. A brief status of the biomarker discovery efforts in multiple sclerosis, Alzheimer's disease, and Parkinson's disease is also given.
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  Tumani, H. Cerebrospinal fluid biomarkers in multiple sclerosis Neurobiol. Dis. 2009, 35 (2) 117– 127
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  Cerebrospinal fluid biomarkers in multiple sclerosis
  Tumani, Hayrettin; Hartung, Hans-Peter; Hemmer, Bernhard; Teunissen, Charlotte; Deisenhammer, Florian; Giovannoni, Gavin; Zettl, Uwe K.
  Neurobiology of Disease (2009), 35 (2), 117-127CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)
  A review. In patients with multiple sclerosis (MS) intensive efforts are directed at identifying biomarkers in bodily fluids related to underlying disease mechanisms, disease activity and progression, and therapeutic response. Besides MR imaging parameters cerebrospinal fluid (CSF) biomarkers provide important and specific information since changes in the CSF compn. may reflect disease mechanisms inherent to MS. The different cellular and protein-anal. methods of the CSF and the recommended std. of the diagnostic CSF profile in MS are described. A brief update on possible CSF biomarkers that might reflect key pathol. processes of MS such as inflammation, demyelination, neuroaxonal loss, gliosis and regeneration is provided.
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  Bielekova, B.; Martin, R. Development of biomarkers in multiple sclerosis Brain 2004, 127 (Pt 7) 1463– 1478
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  Development of biomarkers in multiple sclerosis
  Bielekova Bibiana; Martin Roland
  Brain : a journal of neurology (2004), 127 (Pt 7), 1463-78 ISSN:0006-8950.
  Multiple sclerosis is a complex disease, as several pathophysiological processes (including inflammation, demyelination, axonal damage and repair mechanisms) participate in the disease process. Furthermore, as new pathological evidence reveals, these processes are not uniformly represented across patient populations but can selectively predominate in individual patients, thus contributing to the heterogeneity in phenotypic expression of the disease, its prognosis and response to therapies. While the armamentarium of available therapies for multiple sclerosis broadens, little is known about factors that predict treatment response in individual patients to a specific drug. More importantly, we are beginning to understand that, analogous to cancer therapy, the successful therapeutic strategy in multiple sclerosis might ultimately involve the combination of different therapeutics targeting several dominant pathophysiological processes. The development of these process-specific therapies will be impossible without the use of biomarkers that reflect the targeted process, can select patient population in which the targeted process is prevailing and can aid during the more rapid screening of therapeutic agents in the early phase of their development. This review summarizes the general concepts of biomarkers and their potential use as surrogate endpoints and tailors these concepts to specific applications in multiple sclerosis research.
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  Farias, A. S. Ten years of proteomics in multiple sclerosis Proteomics 2014, 14 (4–5) 467– 480
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  Ten years of proteomics in multiple sclerosis
  Farias, Alessandro S.; Pradella, Fernando; Schmitt, Andrea; Santos, Leonilda M. B.; Martins-de-Souza, Daniel
  Proteomics (2014), 14 (4-5), 467-480CODEN: PROTC7; ISSN:1615-9853. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A review. Multiple sclerosis, which is the most common cause of chronic neurol. disability in young adults, is an inflammatory, demyelinating, and neurodegenerative disease of the CNS, which leads to the formation of multiple foci of demyelinated lesions in the white matter. The diagnosis is based currently on magnetic resonance image and evidence of dissemination in time and space. However, this could be facilitated if biomarkers were available to rule out other disorders with similar symptoms as well as to avoid cerebrospinal fluid anal., which requires an invasive collection. Addnl., the mol. mechanisms of the disease are not completely elucidated, esp. those related to the neurodegenerative aspects of the disease. The identification of biomarker candidates and mol. mechanisms of multiple sclerosis may be approached by proteomics. In the last 10 years, proteomic techniques have been applied in different biol. samples (CNS tissue, cerebrospinal fluid, and blood) from multiple sclerosis patients and in its exptl. model. In this review, we summarize these data, presenting their value to the current knowledge of the disease mechanisms, as well as their importance in identifying biomarkers or treatment targets.
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  Comabella, M.; Montalban, X. Body fluid biomarkers in multiple sclerosis Lancet Neurol 2014, 13 (1) 113– 126
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  Body fluid biomarkers in multiple sclerosis
  Comabella Manuel; Montalban Xavier
  The Lancet. Neurology (2014), 13 (1), 113-26 ISSN:.
  Biomarkers can be thought of as multifaceted indicators of healthy status or of pathological disorders. The study of multiple sclerosis can benefit from the use of biomarkers because of the disease's inherent heterogeneity. Biomarkers in multiple sclerosis might assist with diagnosis, prediction of disease course, or identification of response outcome to treatments. Despite the need for biomarkers and extensive research to identify them, validation and clinical application of biomarkers is still an unmet need in multiple sclerosis, and large gaps remain between exploratory biomarkers proposed in many studies, validated biomarkers, and biomarkers that are integrated into routine clinical practice.
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  Uhlen, M. Towards a knowledge-based Human Protein Atlas Nat. Biotechnol. 2010, 28 (12) 1248– 1250
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  Towards a knowledge-based Human Protein Atlas
  Uhlen, Mathias; Oksvold, Per; Fagerberg, Linn; Lundberg, Emma; Jonasson, Kalle; Forsberg, Mattias; Zwahlen, Martin; Kampf, Caroline; Wester, Kenneth; Hober, Sophia; Wernerus, Henrik; Bjoerling, Lisa; Ponten, Fredrik
  Nature Biotechnology (2010), 28 (12), 1248-1250CODEN: NABIF9; ISSN:1087-0156. (Nature Publishing Group)
  There is no expanded citation for this reference.
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  Uhlen, M. A human protein atlas for normal and cancer tissues based on antibody proteomics Mol. Cell. Proteomics 2005, 4 (12) 1920– 1932
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  A human protein atlas for normal and cancer tissues based on antibody proteomics
  Uhlen, Mathias; Bjoerling, Erik; Agaton, Charlotta; Szigyarto, Cristina Al-Khalili; Amini, Bahram; Andersen, Elisabet; Andersson, Ann-Catrin; Angelidou, Pia; Asplund, Anna; Asplund, Caroline; Berglund, Lisa; Bergstroem, Kristina; Brumer, Harry; Cerjan, Dijana; Ekstroem, Marica; Elobeid, Adila; Eriksson, Cecilia; Fagerberg, Linn; Falk, Ronny; Fall, Jenny; Forsberg, Mattias; Bjoerklund, Marcus Gry; Gumbel, Kristoffer; Halimi, Asif; Hallin, Inga; Hamsten, Carl; Hansson, Marianne; Hedhammar, My; Hercules, Goerel; Kampf, Caroline; Larsson, Karin; Lindskog, Mats; Lodewyckx, Wald; Lund, Jan; Lundeberg, Joakim; Magnusson, Kristina; Malm, Erik; Nilsson, Peter; Oedling, Jenny; Oksvold, Per; Olsson, Ingmarie; Oester, Emma; Ottosson, Jenny; Paavilainen, Linda; Persson, Anja; Rimini, Rebecca; Rockberg, Johan; Runeson, Marcus; Sivertsson, Aasa; Skoellermo, Anna; Steen, Johanna; Stenvall, Maria; Sterky, Fredrik; Stroemberg, Sara; Sundberg, Maarten; Tegel, Hanna; Tourle, Samuel; Wahlund, Eva; Walden, Annelie; Wan, Jinghong; Wernerus, Henrik; Westberg, Joakim; Wester, Kenneth; Wrethagen, Ulla; Xu, Lan Lan; Hober, Sophia; Ponten, Fredrik
  Molecular and Cellular Proteomics (2005), 4 (12), 1920-1932CODEN: MCPOBS; ISSN:1535-9476. (American Society for Biochemistry and Molecular Biology)
  Antibody-based proteomics provides a powerful approach for the functional study of the human proteome involving the systematic generation of protein-specific affinity reagents. We used this strategy to construct a comprehensive, antibody-based protein atlas for expression and localization profiles in 48 normal human tissues and 20 different cancers. Here we report a new publicly available database contg., in the first version, ∼400,000 high resoln. images corresponding to more than 700 antibodies toward human proteins. Each image has been annotated by a certified pathologist to provide a knowledge base for functional studies and to allow queries about protein profiles in normal and disease tissues. Our results suggest it should be possible to extend this anal. to the majority of all human proteins thus providing a valuable tool for medical and biol. research.
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15. 15
  Stoevesandt, O.; Taussig, M. J. Affinity proteomics: the role of specific binding reagents in human proteome analysis Expert Rev. Proteomics 2012, 9 (4) 401– 414
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  Affinity proteomics: the role of specific binding reagents in human proteome analysis
  Stoevesandt, Oda; Taussig, Michael J.
  Expert Review of Proteomics (2012), 9 (4), 401-414CODEN: ERPXA3; ISSN:1478-9450. (Expert Reviews Ltd.)
  A review. Affinity proteomics is the field of proteome anal. based on the use of antibodies and other binding reagents as protein-specific detection probes. In this review, the particular strengths of affinity methods for detn. of protein localization, functional characterization, biomarker discovery and intracellular applications, and their resulting impact in basic and clin. research are highlighted. An addnl. focus is on the requirements for systematic binder generation and current large-scale binder projects, including bioinformatic frameworks for epitope selection and for documentation of available binding reagents and their performance. In addn. to current affinity proteomics methods and applications, including arrays of proteins, binders, lysates and tissues, approaches coupling mass spectrometry-based proteomics and affinity proteomics are reviewed.
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  Ayoglu, B. Systematic antibody and antigen-based proteomic profiling with microarrays Expert Rev. Mol. Diagn. 2011, 11 (2) 219– 234
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  Systematic antibody and antigen-based proteomic profiling with microarrays
  Ayoglu, Burcu; Haeggmark, Anna; Neiman, Maja; Igel, Ulrika; Uhlen, Mathias; Schwenk, Jochen M.; Nilsson, Peter
  Expert Review of Molecular Diagnostics (2011), 11 (2), 219-234CODEN: ERMDCW; ISSN:1473-7159. (Expert Reviews Ltd.)
  Current approaches within affinity-based proteomics are driven both by the accessibility and availability of antigens and capture reagents, and by suitable multiplexed technologies onto which these are implemented. By combining planar microarrays and other multiparallel systems with sets of reagents, possibilities to discover new and unpredicted protein--disease assocns., either via directed hypothesis-driven or via undirected hypothesis-generating target selection, can be created. In the following stages, the discoveries made during these screening phases have to be verified for potential clin. relevance based on both tech. and biol. aspects. The use of affinity tools throughout discovery and verification has the potential to streamline the introduction of new markers, as transition into clin. required assay formats appears straightforward. In this article, we summarize some of the current building blocks within array- and affinity-based proteomic profiling with a focus on body fluids, by giving a perspective on how current and upcoming developments in this bioscience could enable a path of pursuit for biomarker discovery.
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  McDonald, W. I. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis Ann. Neurol. 2001, 50 (1) 121– 127
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  Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis
  McDonald W I; Compston A; Edan G; Goodkin D; Hartung H P; Lublin F D; McFarland H F; Paty D W; Polman C H; Reingold S C; Sandberg-Wollheim M; Sibley W; Thompson A; van den Noort S; Weinshenker B Y; Wolinsky J S
  Annals of neurology (2001), 50 (1), 121-7 ISSN:0364-5134.
  The International Panel on MS Diagnosis presents revised diagnostic criteria for multiple sclerosis (MS). The focus remains on the objective demonstration of dissemination of lesions in both time and space. Magnetic resonance imaging is integrated with dinical and other paraclinical diagnostic methods. The revised criteria facilitate the diagnosis of MS in patients with a variety of presentations, including "monosymptomatic" disease suggestive of MS, disease with a typical relapsing-remitting course, and disease with insidious progression, without clear attacks and remissions. Previously used terms such as "clinically definite" and "probable MS" are no longer recommended. The outcome of a diagnostic evaluation is either MS, "possible MS" (for those at risk for MS, but for whom diagnostic evaluation is equivocal), or "not MS."
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18. 18
  De Groot, C. J. Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions Brain 2001, 124 (Pt 8) 1635– 1645
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  Post-mortem MRI-guided sampling of multiple sclerosis brain lesions: increased yield of active demyelinating and (p)reactive lesions
  De Groot C J; Bergers E; Kamphorst W; Ravid R; Polman C H; Barkhof F; van der Valk P
  Brain : a journal of neurology (2001), 124 (Pt 8), 1635-45 ISSN:0006-8950.
  Macroscopic sampling of multiple sclerosis lesions in the brain tends to find chronic lesions. For a better understanding of the dynamics of the multiple sclerosis disease process, research into new and developing lesions is of great interest. As MRI in vivo effectively demonstrates lesions in multiple sclerosis patients, we have applied it to unfixed post-mortem brain slices to identify abnormalities, in order to obtain a higher yield of active lesions. The Netherlands Brain Bank organized the rapid autopsy of 29 multiple sclerosis patients. The brain was cut in 1 cm coronal slices. One or two slices were subjected to T(1)- and T(2)-weighted MRI, and then cut at the plane of the MRI scan into 5 mm thick opposing sections. Areas of interest were identified based on the MRI findings and excised. One half was fixed in 10% formalin and paraffin-embedded, and the corresponding area in the adjacent half was snap-frozen in liquid nitrogen. In total, 136 out of 174 brain tissue samples could be matched with the abnormalities seen on T(2)-weighted MRIs. The stage of lesional development was determined (immuno) histochemically. For 54 MRI-detectable samples, it was recorded whether they were macroscopically detectable, i.e. visible and/or palpable. Histopathological analysis revealed that 48% of the hyperintense areas seen on T(2)-weighted images represented active lesions, including lesions localized in the normal appearing white matter, without apparent loss of myelin but nevertheless showing a variable degree of oedema, small clusters of microglial cells with enhanced major histocompatibility complex class II antigen, CD45 and CD68 antigen expression and a variable number of perivascular lymphocytes around small blood vessels [designated as (p)reactive lesions]. From the macroscopically not-visible/not-palpable MRI-detected abnormalities, 58% were (p)reactive lesions and 21% contained active demyelinating lesions. In contrast, visible and/or palpable brain tissue samples mainly contained chronic inactive lesions. We conclude that MRI-guided sampling of brain tissue increases the yield of active multiple sclerosis lesions, including active demyelinating and (p)reactive lesions.
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  Kampf, C. Production of tissue microarrays, immunohistochemistry staining and digitalization within the human protein atlas J. Vis. Exp. 2012, 63) 3620
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  Nilsson, P. Towards a human proteome atlas: high-throughput generation of mono-specific antibodies for tissue profiling Proteomics 2005, 5 (17) 4327– 4337
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  Towards a human proteome atlas: High-throughput generation of mono-specific antibodies for tissue profiling
  Nilsson, Peter; Paavilainen, Linda; Larsson, Karin; Oedling, Jenny; Sundberg, Maarten; Andersson, Ann-Catrin; Kampf, Caroline; Persson, Anja; Al-Khalili Szigyarto, Cristina; Ottosson, Jenny; Bjoerling, Erik; Hober, Sophia; Wernerus, Henrik; Wester, Kenneth; Ponten, Fredrik; Uhlen, Mathias
  Proteomics (2005), 5 (17), 4327-4337CODEN: PROTC7; ISSN:1615-9853. (Wiley-VCH Verlag GmbH & Co. KGaA)
  A great need exists for the systematic generation of specific antibodies to explore the human proteome. Here, the authors show that antibodies specific to human proteins can be generated in a high-throughput manner involving stringent affinity purifn. using recombinant protein epitope signature tags (PrESTs) as immunogens and affinity-ligands. The specificity of the generated affinity reagents, here called mono-specific antibodies (msAb), were validated with a novel protein microarray assay. The success rate for 464 antibodies generated towards human proteins was more than 90% as judged by the protein array assay. The antibodies were used for parallel profiling of patient biopsies using tissue microarrays generated from 48 human tissues. Comparative anal. with well-characterized monoclonal antibodies showed identical or similar specificity and expression patterns. The results suggest that a comprehensive atlas contg. extensive protein expression and subcellular localization data of the human proteome can be generated in an efficient manner with mono-specific antibodies.
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  Sjoberg, R. Validation of affinity reagents using antigen microarrays New Biotechnol. 2012, 29 (5) 555– 563
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  Validation of affinity reagents using antigen microarrays
  Sjoberg Ronald; Sundberg Marten; Gundberg Anna; Sivertsson Asa; Schwenk Jochen M; Uhlen Mathias; Nilsson Peter
  New biotechnology (2012), 29 (5), 555-63 ISSN:.
  There is a need for standardised validation of affinity reagents to determine their binding selectivity and specificity. This is of particular importance for systematic efforts that aim to cover the human proteome with different types of binding reagents. One such international program is the SH2-consortium, which was formed to generate a complete set of renewable affinity reagents to the SH2-domain containing human proteins. Here, we describe a microarray strategy to validate various affinity reagents, such as recombinant single-chain antibodies, mouse monoclonal antibodies and antigen-purified polyclonal antibodies using a highly multiplexed approach. An SH2-specific antigen microarray was designed and generated, containing more than 6000 spots displayed by 14 identical subarrays each with 406 antigens, where 105 of them represented SH2-domain containing proteins. Approximately 400 different affinity reagents of various types were analysed on these antigen microarrays carrying antigens of different types. The microarrays revealed not only very detailed specificity profiles for all the binders, but also showed that overlapping target sequences of spotted antigens were detected by off-target interactions. The presented study illustrates the feasibility of using antigen microarrays for integrative, high-throughput validation of various types of binders and antigens.
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22. 22
  Drobin, K.; Nilsson, P.; Schwenk, J. M. Highly multiplexed antibody suspension bead arrays for plasma protein profiling Methods Mol. Biol. 2013, 1023, 137– 145
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  Highly multiplexed antibody suspension bead arrays for plasma protein profiling
  Drobin, Kimi; Nilsson, Peter; Schwenk, Jochen M.
  Methods in Molecular Biology (New York, NY, United States) (2013), 1023 (Low Molecular Weight Proteome), 137-145CODEN: MMBIED; ISSN:1064-3745. (Springer)
  Alongside the increasing availability of affinity reagents, antibody microarrays have become a powerful tool to screen for target proteins in complex samples. Applying directly labeled samples onto arrays instead of using sandwich assays offers an approach to facilitate a systematic, high-throughput, and flexible exploration of protein profiles in body fluids such as serum or plasma. As an alternative to planar arrays, a system based on color-coded beads for the creation of antibody arrays in suspension has become available to offer a microtiter plate-based option for screening larger no. of samples with variable sets of capture reagents. A procedure was established for analyzing biotinylated samples without the necessity to remove excess labeling substance. We have shown that this assay system allows detecting proteins down into lower pico-molar and higher pg/mL levels with dynamic ranges over three orders of magnitude. Presently, this workflow enables the profiling of 384 samples for up to 384 proteins per assay.
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23. 23
  Haggmark, A. Antibody-based profiling of cerebrospinal fluid within multiple sclerosis Proteomics 2013, 13 (15) 2256– 2267
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  Antibody-based profiling of cerebrospinal fluid within multiple sclerosis
  Haggmark Anna; Bystrom Sanna; Ayoglu Burcu; Qundos Ulrika; Uhlen Mathias; Khademi Mohsen; Olsson Tomas; Schwenk Jochen M; Nilsson Peter
  Proteomics (2013), 13 (15), 2256-67 ISSN:.
  Antibody suspension bead arrays have proven to enable multiplexed and high-throughput protein profiling in unfractionated plasma and serum samples through a direct labeling approach. We here describe the development and application of an assay for protein profiling of cerebrospinal fluid (CSF). While setting up the assay, systematic intensity differences between sample groups were observed that reflected inherent sample specific total protein amounts. Supplementing the labeling reaction with BSA and IgG diminished these differences without impairing the apparent sensitivity of the assay. We also assessed the effects of heat treatment on the analysis of CSF proteins and applied the assay to profile 43 selected proteins by 101 antibodies in 339 CSF samples from a multiple sclerosis (MS) cohort. Two proteins, GAP43 and SERPINA3 were found to have a discriminating potential with altered intensity levels between sample groups. GAP43 was detected at significantly lower levels in secondary progressive MS compared to early stages of MS and the control group of other neurological diseases. SERPINA3 instead was detected at higher levels in all MS patients compared to controls. The developed assay procedure now offers new possibilities for broad-scale protein profiling of CSF within neurological disorders.
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  Forsstrom, B. Proteome-wide epitope mapping of antibodies using ultra-dense peptide arrays Mol. Cell. Proteomics 2014, 13, 1585– 1597
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  Proteome-wide epitope mapping of antibodies using ultra-dense peptide arrays
  Forsstrom Bjorn; Nilsson Peter; Axnas Barbara Bislawska; Hu Francis Jingxin; Hudson Elton P; Rockberg Johan; Stengele Klaus-Peter; Buhler Jochen; Albert Thomas J; Richmond Todd A; Uhlen Mathias
  Molecular & cellular proteomics : MCP (2014), 13 (6), 1585-97 ISSN:.
  Antibodies are of importance for the field of proteomics, both as reagents for imaging cells, tissues, and organs and as capturing agents for affinity enrichment in mass-spectrometry-based techniques. It is important to gain basic insights regarding the binding sites (epitopes) of antibodies and potential cross-reactivity to nontarget proteins. Knowledge about an antibody's linear epitopes is also useful in, for instance, developing assays involving the capture of peptides obtained from trypsin cleavage of samples prior to mass spectrometry analysis. Here, we describe, for the first time, the design and use of peptide arrays covering all human proteins for the analysis of antibody specificity, based on parallel in situ photolithic synthesis of a total of 2.1 million overlapping peptides. This has allowed analysis of on- and off-target binding of both monoclonal and polyclonal antibodies, complemented with precise mapping of epitopes based on full amino acid substitution scans. The analysis suggests that linear epitopes are relatively short, confined to five to seven residues, resulting in apparent off-target binding to peptides corresponding to a large number of unrelated human proteins. However, subsequent analysis using recombinant proteins suggests that these linear epitopes have a strict conformational component, thus giving us new insights regarding how antibodies bind to their antigens.
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  Dieterle, F. Probabilistic quotient normalization as robust method to account for dilution of complex biological mixtures. Application in ¹H NMR metabonomics Anal. Chem. 2006, 78 (13) 4281– 4290
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  Probabilistic Quotient Normalization as Robust Method to Account for Dilution of Complex Biological Mixtures. Application in 1H NMR Metabonomics
  Dieterle, Frank; Ross, Alfred; Schlotterbeck, Goetz; Senn, Hans
  Analytical Chemistry (2006), 78 (13), 4281-4290CODEN: ANCHAM; ISSN:0003-2700. (American Chemical Society)
  For the anal. of the spectra of complex biofluids, preprocessing methods play a crucial role in rendering the subsequent data analyses more robust and accurate. Normalization is a preprocessing method, which accounts for different dilns. of samples by scaling the spectra to the same virtual overall concn. In the field of 1H NMR metabonomics integral normalization, which scales spectra to the same total integral, is the de facto std. In this work, it is shown that integral normalization is a suboptimal method for normalizing spectra from metabonomic studies. Esp. strong metabonomic changes, evident as massive amts. of single metabolites in samples, significantly hamper the integral normalization resulting in incorrectly scaled spectra. The probabilistic quotient normalization is introduced in this work. This method is based on the calcn. of a most probable diln. factor by looking at the distribution of the quotients of the amplitudes of a test spectrum by those of a ref. spectrum. Simulated spectra, spectra of urine samples from a metabonomic study with cyclosporin-A as the active compd., and spectra of more than 4000 samples of control animals demonstrate that the probabilistic quotient normalization is by far more robust and more accurate than the widespread integral normalization and vector length normalization.
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  Biometrical journal. Biometrische Zeitschrift (2010), 52 (1), 70-84 ISSN:.
  This article presents a novel algorithm that efficiently computes L(1) penalized (lasso) estimates of parameters in high-dimensional models. The lasso has the property that it simultaneously performs variable selection and shrinkage, which makes it very useful for finding interpretable prediction rules in high-dimensional data. The new algorithm is based on a combination of gradient ascent optimization with the Newton-Raphson algorithm. It is described for a general likelihood function and can be applied in generalized linear models and other models with an L(1) penalty. The algorithm is demonstrated in the Cox proportional hazards model, predicting survival of breast cancer patients using gene expression data, and its performance is compared with competing approaches. An R package, penalized, that implements the method, is available on CRAN.
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  Cytoscape 2.8: new features for data integration and network visualization
  Smoot, Michael E.; Ono, Keiichiro; Ruscheinski, Johannes; Wang, Peng-Liang; Ideker, Trey
  Bioinformatics (2011), 27 (3), 431-432CODEN: BOINFP; ISSN:1367-4803. (Oxford University Press)
  Summary: Cytoscape is a popular bioinformatics package for biol. network visualization and data integration. Version 2.8 introduces two powerful new features-Custom Node Graphics and Attribute Equations-which can be used jointly to greatly enhance Cytoscape's data integration and visualization capabilities. Custom Node Graphics allow an image to be projected onto a node, including images generated dynamically or at remote locations. Attribute Equations provide Cytoscape with spreadsheet-like functionality in which the value of an attribute is computed dynamically as a function of other attributes and network properties. Availability and implementation: Cytoscape is a desktop Java application released under the Library Gnu Public License (LGPL). Binary install bundles and source code for Cytoscape 2.8 are available for download from http://cytoscape.org. Contact: [email protected]
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  Waterhouse, A. M. Jalview Version 2--a multiple sequence alignment editor and analysis workbench Bioinformatics 2009, 25 (9) 1189– 1191
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  Waterhouse, Andrew M.; Procter, James B.; Martin, David M. A.; Clamp, Michele; Barton, Geoffrey J.
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  Summary: Jalview Version 2 is a system for interactive WYSIWYG editing, anal. and annotation of multiple sequence alignments. Core features include keyboard and mouse-based editing, multiple views and alignment overviews, and linked structure display with Jmol. Jalview 2 is available in two forms: a lightwt. Java applet for use in web applications, and a powerful desktop application that employs web services for sequence alignment, secondary structure prediction and the retrieval of alignments, sequences, annotation and structures from public databases and any DAS 1.53 compliant sequence or annotation server. Availability: The Jalview 2 Desktop application and JalviewLite applet are made freely available under the GPL, and can be downloaded from www.jalview.org.
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  Crooks, G. E. WebLogo: a sequence logo generator Genome Res. 2004, 14 (6) 1188– 90
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  Genome Research (2004), 14 (6), 1188-1190CODEN: GEREFS; ISSN:1088-9051. (Cold Spring Harbor Laboratory Press)
  WebLogo generates sequence logos, graphical representations of the patterns within a multiple sequence alignment. Sequence logos provide a richer and more precise description of sequence similarity than consensus sequences and can rapidly reveal significant features of the alignment otherwise difficult to perceive. Each logo consists of stacks of letters, one stack for each position in the sequence. The overall height of each stack indicates the sequence conservation at that position (measured in bits), whereas the height of symbols within the stack reflects the relative frequency of the corresponding amino or nucleic acid at that position. WebLogo has been enhanced recently with addnl. features and options, to provide a convenient and highly configurable sequence logo generator. A command line interface and the complete, open WebLogo source code are available for local installation and customization.
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  Suk, K. Combined analysis of the glia secretome and the CSF proteome: neuroinflammation and novel biomarkers Expert Rev. Proteomics 2010, 7 (2) 263– 274
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  Suk, Kyoungho
  Expert Review of Proteomics (2010), 7 (2), 263-274CODEN: ERPXA3; ISSN:1478-9450. (Expert Reviews Ltd.)
  A review. Glial cells in the CNS are likely to communicate with other glial cells and neurons through secreted proteins. Glia-derived proteins also participate in neuroinflammation, which is a major component of neurodegenerative disease. Cerebrospinal fluid (CSF) is the biol. fluid that best reflects the physiol. or pathol. conditions of the CNS. Proteins secreted from glial cells are often detected in the CSF. One of the major cellular sources of the highly abundant CSF proteins is glia. Combined anal. of secreted proteins of glial cells and CSF proteins of patients with inflammatory CNS disorders can provide new knowledge to the field of glia biol. and neuron-glia interaction. The comparative anal. of the glia secretome and the CSF proteome would also facilitate the targeted proteomics-based discovery of new biomarkers for brain disease. Omics and systems biol. approaches to glia and neuroinflammation will be a focus of future investigation and will enable an integrative understanding of inflammatory CNS disorders, such as neurodegenerative disease.
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  Stoop, M. P. Proteomics comparison of cerebrospinal fluid of relapsing remitting and primary progressive multiple sclerosis PLoS One 2010, 5 (8) e12442
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  Sakurai, T. Identification of antibodies as biological markers in serum from multiple sclerosis patients by immunoproteomic approach J. Neuroimmunol. 2011, 233 (1–2) 175– 180
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  Identification of antibodies as biological markers in serum from multiple sclerosis patients by immunoproteomic approach
  Sakurai, Takeo; Kimura, Akio; Yamada, Megumi; Koumura, Akihiro; Hayashi, Yu-Ichi; Tanaka, Yuji; Hozumi, Isao; Inuzuka, Takashi
  Journal of Neuroimmunology (2011), 233 (1-2), 175-180CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)
  The authors identified the antibody against mitochondrial heat shock protein 70 (mtHSP70) in serum from multiple sclerosis (MS) patients by proteomics-based anal. The prevalence of the anti-mtHSP70 antibody is significantly higher in serum from MS patients than in serum from Parkinson disease patients, multiple cerebral infarction patients, infectious meningoencephalitis patients, and healthy controls (HCs) (68% sensitivity; 74% specificity). The authors studied the clin. features and magnetic resonance imaging findings of MS patients with the anti-mtHSP70 antibody. As a result, there were no significant differences between the anti-mtHSP70-antibody-pos. and -neg. MS patients. Addnl., in the authors' comprehensive anal. of the prevalence of both the anti-mtHSP70 antibody and the anti-phosphoglycerate mutase 1 (PGAM1) antibody, which was previously reported by the authors to also show a higher prevalence in serum from MS patients, the positivity rates of both these antibodies were significantly higher in serum from MS patients than in serum from patients with other neurol. diseases and from HCs; moreover, the specificity of this combination assay was higher than that of the assay of only one antibody (57% sensitivity; 93% specificity). Results of the authors' study suggest that not only the anti-PGAM1 antibody but also the anti-mtHSP70 antibody is good diagnostic markers of MS and the combination of both these antibodies is useful for a more specific diagnosis of MS.
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  Ottervald, J. Multiple sclerosis: Identification and clinical evaluation of novel CSF biomarkers J. Proteomics 2010, 73 (6) 1117– 1132
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  Multiple sclerosis: Identification and clinical evaluation of novel CSF biomarkers
  Ottervald, Jan; Franzen, Bo; Nilsson, Kerstin; Andersson, Lars I.; Khademi, Mohsen; Eriksson, Bodil; Kjellstroem, Sven; Marko-Varga, Gyoergy; Vegvari, Akos; Harris, Robert A.; Laurell, Thomas; Miliotis, Tasso; Matusevicius, Darius; Salter, Hugh; Ferm, Mats; Olsson, Tomas
  Journal of Proteomics (2010), 73 (6), 1117-1132CODEN: JPORFQ; ISSN:1874-3919. (Elsevier B.V.)
  Multiple sclerosis (MS) is a neuro-inflammatory and neurodegenerative disease that results in damage to myelin sheaths and axons in the central nervous system and which preferentially affects young adults. We performed a proteomics-based biomarker discovery study in which cerebrospinal fluid (CSF) from MS and control individuals was analyzed (n = 112). Ten candidate biomarkers were selected for evaluation by quant. immunoassay using an independent cohort of MS and control subjects (n = 209). In relapsing-remitting MS (RRMS) patients there were significant increases in the CSF levels of alpha-1 antichymotrypsin (A1AC), alpha-1 macroglobulin (A2MG) and fibulin 1 as compared to control subjects. In secondary progressive MS (SPMS) four addnl. proteins (contactin 1, fetuin A, vitamin D binding protein and angiotensinogen (ANGT)) were increased as compared to control subjects. In particular, ANGT was increased 3-fold in SPMS, indicating a potential as biomarker of disease progression in MS. In PPMS, A1AC and A2MG exhibit significantly higher CSF levels than controls, with a trend of increase for ANGT. Classification models based on the biomarker panel could identify 70% of the RRMS and 80% of the SPMS patients correctly. Further evaluation was conducted in a pilot study of CSF from RRMS patients (n = 36), before and after treatment with natalizumab.
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39. 39
  Noben, J. P. Lumbar cerebrospinal fluid proteome in multiple sclerosis: characterization by ultrafiltration, liquid chromatography, and mass spectrometry J. Proteome Res. 2006, 5 (7) 1647– 1657
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  Lumbar Cerebrospinal Fluid Proteome in Multiple Sclerosis: Characterization by Ultrafiltration, Liquid Chromatography, and Mass Spectrometry
  Noben, Jean-Paul; Dumont, Debora; Kwasnikowska, Natalia; Verhaert, Peter; Somers, Veerle; Hupperts, Raymond; Stinissen, Piet; Robben, Johan
  Journal of Proteome Research (2006), 5 (7), 1647-1657CODEN: JPROBS; ISSN:1535-3893. (American Chemical Society)
  Neurol. diseases, including multiple sclerosis (M.S.), often provoke changes in the functioning of the endothelial and epithelial brain barriers and give rise to disease-assocd. alterations of the cerebrospinal fluid (CSF) proteome. In the present study, pooled and ultrafiltered CSF of M.S. and non-M.S. patients was digested with trypsin and analyzed by off-line strong cation-exchange chromatog. (SCX) coupled to online reversed-phase LC-ESI-MS/MS. In an alternative approach, the trypsin-treated subproteomes were analyzed directly by LC-ESI-MS/MS and gas-phase fractionation in the mass spectrometer. Taken together, both proteomic approaches in combination with a three-step evaluation process including the search engines Sequest and Mascot, and the validation software Scaffold, resulted in the identification of 148 proteins. Sixty proteins were identified in CSF for the first time by mass spectrometry. For validation purposes, the concn. of cystatin A was detd. in individual CSF and serum samples of M.S. and non-M.S. patients using ELISA.
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40. 40
  Hammack, B. N. Proteomic analysis of multiple sclerosis cerebrospinal fluid Mult. Scler. 2004, 10 (3) 245– 260
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  Proteomic analysis of multiple sclerosis cerebrospinal fluid
  Hammack, B. N.; Fung, K. Y. C.; Hunsucker, S. W.; Duncan, M. W.; Burgoon, M. P.; Owens, G. P.; Gilden, D. H.
  Multiple Sclerosis (2004), 10 (3), 245-260CODEN: MUSCFZ; ISSN:1352-4585. (Arnold, Hodder Headline)
  Two-dimensional gel electrophoresis and peptide mass fingerprinting were used to identify proteins in cerebrospinal fluid (CSF) pooled from three patients with multiple sclerosis (MS) and in CSF pooled from three patients with non-MS inflammatory central nervous system (CNS) disorders. Resoln. of CSF proteins on three pH gradients (3-10, 4-7 and 6-11) enabled identification of a total of 430 spots in the MS CSF proteome that represented 61 distinct proteins. The gels contg. MS CSF revealed 103 protein spots that were not seen on control gels. All but four of these 103 spots were proteins known to be present in normal human CSF. The four exceptions were: CRTAC-IB (cartilage acidic protein), tetranectin (a plasminogen-binding protein), SPARC-like protein (a calcium binding cell signaling glycoprotein), and autotaxin t (a phosphodiesterase). It remains unknown whether these four proteins are related to the cause and pathogenesis of MS.
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41. 41
  Alexander, J. S. Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-beta1b Mult. Scler. 2010, 16 (7) 801– 809
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  Alterations in serum MMP-8, MMP-9, IL-12p40 and IL-23 in multiple sclerosis patients treated with interferon-β1b
  Alexander, J. S.; Harris, M. K.; Wells, S. R.; Mills, G.; Chalamidas, K.; Ganta, V. C.; McGee, J.; Jennings, M. H.; Gonzalez-Toledo, E.; Minagar, A.
  Multiple Sclerosis (2010), 16 (7), 801-809CODEN: MUSCFZ; ISSN:1352-4585. (Sage Publications Ltd.)
  Background: Interferon-β1b (IFN-β1b), an effective treatment for multiple sclerosis (MS), lessens disease severity in MS patients. However, the mechanisms of its immunoregulatory and anti-inflammatory effects in MS remain only partially understood. Matrix metalloproteinases (MMP) and tissue inhibitor of matrix metalloproteinase-1 (TIMP-1) are involved in blood brain barrier disruption and formation of MS lesions. Th1/Th17 cytokines e.g. interleukins IL-12p40, IL-17, and IL-23, are assocd. with MS disease activity and are significant players in pathogenesis of MS. Objective: During a 1-yr prospective study, we serially measured serum MMP-8, MMP-9, TIMP-1, IL-12p40, IL-17, and IL-23 in 24 patients with relapsing-remitting MS. We compared the results to clin. course and to brain magnetic resonance imaging. IFN-β1b decreased serum MMP-8 and MMP-9 (not TIMP-1). Results: The sustained treatment with IFN-β1b attenuated the pro-inflammatory environment by significantly reducing the serum IL-12p40, IL-23, and showed a trend for decreasing IL-17. Decreased serum MMP-8, MMP-9, IL-12 and IL-23 levels were correlated with a decrease in the no. of contrast-enhanced T2-weighted lesions. Conclusion: Early treatment of MS with IFN-β1b may stabilize clin. disease by attenuating levels of inflammatory cytokines and MMPs. Serial measurement of inflammatory mediators may serve as sensitive markers to gauge therapeutic responses to IFN-β1b during the first year of treatment.
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  Sawcer, S. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis Nature 2011, 476 (7359) 214– 219
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  Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis
  Sawcer, Stephen; Hellenthal, Garrett; Pirinen, Matti; Spencer, Chris C. A.; Patsopoulos, Nikolaos A.; Moutsianas, Loukas; Dilthey, Alexander; Su, Zhan; Freeman, Colin; Hunt, Sarah E.; Edkins, Sarah; Gray, Emma; Booth, David R.; Potter, Simon C.; Goris, An; Band, Gavin; Bang Oturai, Annette; Strange, Amy; Saarela, Janna; Bellenguez, Celine; Fontaine, Bertrand; Gillman, Matthew; Hemmer, Bernhard; Gwilliam, Rhian; Zipp, Frauke; Jayakumar, Alagurevathi; Martin, Roland; Leslie, Stephen; Hawkins, Stanley; Giannoulatou, Eleni; D'Afonso, Sandra; Blackburn, Hannah; Boneschi, Filippo Martinelli; Liddle, Jennifer; Harbo, Hanne F.; Perez, Marc L.; Spurkland, Anne; Waller, Matthew J.; Mycko, Marcin P.; Ricketts, Michelle; Comabella, Manuel; Hammond, Naomi; Kockum, Ingrid; McCann, Owen T.; Ban, Maria; Whittaker, Pamela; Kemppinen, Anu; Weston, Paul; Hawkins, Clive; Widaa, Sara; Zajicek, John; Dronov, Serge; Robertson, Neil; Bumpstead, Suzannah J.; Barcellos, Lisa F.; Ravindrarajah, Rathi; Abraham, Roby; Alfredsson, Lars; Ardlie, Kristin; Aubin, Cristin; Baker, Amie; Baker, Katharine; Baranzini, Sergio E.; Bergamaschi, Laura; Bergamaschi, Roberto; Bernstein, Allan; Berthele, Achim; Boggild, Mike; Bradfield, Jonathan P.; Brassat, David; Broadley, Simon A.; Buck, Dorothea; Butzkueven, Helmut; Capra, Ruggero; Carroll, William M.; Cavalla, Paola; Celius, Elisabeth G.; Cepok, Sabine; Chiavacci, Rosetta; Clerget-Darpoux, Francoise; Clysters, Katleen; Comi, Giancarlo; Cossburn, Mark; Cournu-Rebeix, Isabelle; Cox, Mathew B.; Cozen, Wendy; Cree, Bruce A. C.; Cross, Anne H.; Cusi, Daniele; Daly, Mark J.; Davis, Emma; de Bakker, Paul I. W.; Debouverie, Marc; D'Hoghe, Marie Beatrice; Dixon, Katherine; Dobosi, Rita; Dubois, Benedicte; Ellinghaus, David; Elovaara, Irina; Esposito, Federica; Fontenille, Claire; Foote, Simon; Franke, Andre; Galimberti, Daniela; Ghezzi, Angelo; Glessner, Joseph; Gomez, Refujia; Gout, Olivier; Graham, Colin; Grant, Struan F. A.; Guerini, Franca Rosa; Hakonarson, Hakon; Hall, Per; Hamsten, Anders; Hartung, Hans-Peter; Heard, Rob N.; Heath, Simon; Hobart, Jeremy; Hoshi, Muna; Infante-Duarte, Carmen; Ingram, Gillian; Ingram, Wendy; Islam, Talat; Jagodic, Maja; Kabesch, Michael; Kermode, Allan G.; Kilpatrick, Trevor J.; Kim, Cecilia; Klopp, Norman; Koivisto, Keijo; Larsson, Malin; Lathrop, Mark; Lechner-Scott, Jeannette S.; Leone, Maurizio A.; Leppae, Virpi; Liljedahl, Ulrika; Lima Bomfim, Izaura; Lincoln, Robin R.; Link, Jenny; Liu, Jianjun; Lorentzen, Aslaug R.; Lupoli, Sara; Macciardi, Fabio; Mack, Thomas; Marriott, Mark; Martinelli, Vittorio; Mason, Deborah; McCauley, Jacob L.; Mentch, Frank; Mero, Inger-Lise; Mihalova, Tania; Montalban, Xavier; Mottershead, John; Myhr, Kjell-Morten; Naldi, Paola; Ollier, William; Page, Alison; Palotie, Aarno; Pelletier, Jean; Piccio, Laura; Pickersgill, Trevor; Piehl, Fredrik; Pobywajlo, Susan; Quach, Hong L.; Ramsay, Patricia P.; Reunanen, Mauri; Reynolds, Richard; Rioux, John D.; Rodegher, Mariaemma; Roesner, Sabine; Rubio, Justin P.; Rueckert, Ina-Maria; Salvetti, Marco; Salvi, Erika; Santaniello, Adam; Schaefer, Catherine A.; Schreiber, Stefan; Schulze, Christian; Scott, Rodney J.; Sellebjerg, Finn; Selmaj, Krzysztof W.; Sexton, David; Shen, Ling; Simms-Acuna, Brigid; Skidmore, Sheila; Sleiman, Patrick M. A.; Smestad, Cathrine; Sorensen, Per Soelberg; Sondergaard, Helle Bach; Stankovich, Jim; Strange, Richard C.; Sulonen, Anna-Maija; Sundqvist, Emilie; Syvaenen, Ann-Christine; Taddeo, Francesca; Taylor, Bruce; Blackwell, Jenefer M.; Tienari, Pentti; Bramon, Elvira; Tourbah, Ayman; Brown, Matthew A.; Tronczynska, Ewa; Casas, Juan P.; Tubridy, Niall; Corvin, Aiden; Vickery, Jane; Jankowski, Janusz; Villoslada, Pablo; Markus, Hugh S.; Wang, Kai; Mathew, Christopher G.; Wason, James; Palmer, Colin N. A.; Wichmann, H.-Erich; Plomin, Robert; Willoughby, Ernest; Rautanen, Anna; Winkelmann, Juliane; Wittig, Michael; Trembath, Richard C.; Yaouanq, Jacqueline; Viswanathan, Ananth C.; Zhang, Haitao; Wood, Nicholas W.; Zuvich, Rebecca; Deloukas, Panos; Langford, Cordelia; Duncanson, Audrey; Oksenberg, Jorge R.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Olsson, Tomas; Hillert, Jan; Ivinson, Adrian J.; De Jager, Philip L.; Peltonen, Leena; Stewart, Graeme J.; Hafler, David A.; Hauser, Stephen L.; McVean, Gil; Donnelly, Peter; Compston, Alastair
  Nature (London, United Kingdom) (2011), 476 (7359), 214-219CODEN: NATUAS; ISSN:0028-0836. (Nature Publishing Group)
  Multiple sclerosis is a common disease of the central nervous system in which the interplay between inflammatory and neurodegenerative processes typically results in intermittent neurol. disturbance followed by progressive accumulation of disability. Epidemiol. studies have shown that genetic factors are primarily responsible for the substantially increased frequency of the disease seen in the relatives of affected individuals, and systematic attempts to identify linkage in multiplex families have confirmed that variation within the major histocompatibility complex (MHC) exerts the greatest individual effect on risk. Modestly powered genome-wide assocn. studies (GWAS) have enabled more than 20 addnl. risk loci to be identified and have shown that multiple variants exerting modest individual effects have a key role in disease susceptibility. Most of the genetic architecture underlying susceptibility to the disease remains to be defined and is anticipated to require the anal. of sample sizes that are beyond the nos. currently available to individual research groups. In a collaborative GWAS involving 9,772 cases of European descent collected by 23 research groups working in 15 different countries, we have replicated almost all of the previously suggested assocns. and identified at least a further 29 novel susceptibility loci. Within the MHC we have refined the identity of the HLA-DRB1 risk alleles and confirmed that variation in the HLA-A gene underlies the independent protective effect attributable to the class I region. Immunol. relevant genes are significantly overrepresented among those mapping close to the identified loci and particularly implicate T-helper-cell differentiation in the pathogenesis of multiple sclerosis.
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  Gandhi, K. S. The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis Hum. Mol. Genet. 2010, 19 (11) 2134– 2143
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  The multiple sclerosis whole blood mRNA transcriptome and genetic associations indicate dysregulation of specific T cell pathways in pathogenesis
  Gandhi, Kaushal S.; McKay, Fiona C.; Cox, Mathew; Riveros, Carlos; Armstrong, Nicola; Heard, Robert N.; Vucic, Steve; Williams, David W.; Stankovich, Jim; Brown, Matthew; Danoy, Patrick; Stewart, Graeme J.; Broadley, Simon; Moscato, Pablo; Lechner-Scott, Jeannette; Scott, Rodney J.; Booth, David R.; Griffiths, Lyn; Slee, Mark; Browning, Sharon; Browning, Brian L.; Kilpatrick, Trevor; Rubio, Justin; Perreau, Victoria; Butzkeuven, Helmut; Tanner, Mary; Wiley, Jim; Foote, Simon; Stankovich, Jim; Taylor, Bruce; Kermode, Allan; Carroll, Bill; Bahlo, Melanie
  Human Molecular Genetics (2010), 19 (11), 2134-2143CODEN: HMGEE5; ISSN:0964-6906. (Oxford University Press)
  Multiple sclerosis (MS) is an autoimmune disease with a genetic component, caused at least in part by aberrant lymphocyte activity. The whole blood mRNA transcriptome was measured for 99 untreated MS patients: 43 primary progressive MS, 20 secondary progressive MS, 36 relapsing remitting MS and 45 age-matched healthy controls. The ANZgene Multiple Sclerosis Genetics Consortium genotyped more than 300,000 SNPs for 115 of these samples. Transcription from genes on translational regulation, oxidative phosphorylation, immune synapse and antigen presentation pathways was markedly increased in all forms of MS. Expression of genes tagging T cells was also upregulated (P < 10-12) in MS. A T cell gene signature predicts disease state with a concordance index of 0.79 with age and gender as co-variables, but the signature is not assocd. with clin. course or disability. The ANZgene genome wide assocn. screen identified two novel regions with genome wide significance: one encoding the T cell co-stimulatory mol., CD40; the other a region on chromosome 12q13-14. The CD40 haplotype assocd. with increased MS susceptibility has decreased gene expression in MS (P < 0.0007). The second MS susceptibility region includes 17 genes on 12q13-14 in tight linkage disequil. Of these, only 13 are expressed in leukocytes, and of these the expression of one, FAM119B, is much lower in the susceptibility haplotype (P < 10-14). Overall, these data indicate dysregulation of T cells can be detected in the whole blood of untreated MS patients, and supports targeting of activated T cells in therapy for all forms of MS.
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  Zeis, T. Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection Brain 2008, 131 (Pt 1) 288– 303
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  Normal-appearing white matter in multiple sclerosis is in a subtle balance between inflammation and neuroprotection
  Zeis Thomas; Graumann Ursula; Reynolds Richard; Schaeren-Wiemers Nicole
  Brain : a journal of neurology (2008), 131 (Pt 1), 288-303 ISSN:.
  Multiple sclerosis is a chronic inflammatory disease of the CNS. Although progressive axonal injury and diffuse inflammatory damage has been shown in the chronic phase of the disease, little is known about the molecular mechanisms underlying these pathological processes. In order to identify these mechanisms, we have studied the gene expression profile in non-lesion containing tissue, the so-called normal-appearing white matter (NAWM). We performed differential gene expression analysis and quantitative RT-PCR on subcortical white matter from 11 multiple sclerosis and 8 control cases. Differentially expressed genes were further analysed in detail by in situ hybridization and immunofluorescence studies. We show that genes known to be involved in anti-inflammatory and protective mechanisms such as STAT6, JAK1, IL-4R, IL-10, Chromogranin C and Hif-1alpha are consistently upregulated in the multiple sclerosis NAWM. On the other hand, genes involved in pro-inflammatory mechanisms, such as STAT4, IL-1beta and MCSF, were also upregulated but less regularly. Immunofluorescence colocalization analysis revealed expression of STAT6, JAK1, IL-4R and IL-13R mainly in oligodendrocytes, whereas STAT4 expression was detected predominantly in microglia. In line with these data, in situ hybridization analysis showed an increased expression in multiple sclerosis NAWM of HIF-1alpha in oligodendrocytes and HLA-DRalpha in microglia cells. The consistency of the expression levels of STAT6, JAK1, JAK3 and IL-4R between the multiple sclerosis cases suggests an overall activation of the STAT6-signalling pathway in oligodendrocytes, whereas the expression of STAT4 and HLA-DRalpha indicates the activation of pro-inflammatory pathways in microglia. The upregulation of genes involved in anti-inflammatory mechanisms driven by oligodendrocytes may protect the CNS environment and thus limit lesion formation, whereas the activation of pro-inflammatory mechanisms in microglia may favour disease progression. Altogether, our data suggests an endogenous inflammatory reaction throughout the whole white matter of multiple sclerosis brain, in which oligodendrocytes actively participate. This reaction might further influence and to some extent facilitate lesion formation.
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  Valdo, P. Enhanced expression of NGF receptors in multiple sclerosis lesions J. Neurol., Neurosurg. Psychiatry 2002, 61 (1) 91– 98
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  Thangarajh, M. Increased levels of APRIL (a proliferation-inducing ligand) mRNA in multiple sclerosis J. Neuroimmunol. 2005, 167 (1–2) 210– 214
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  Increased levels of APRIL (A Proliferation-Inducing Ligand) mRNA in multiple sclerosis
  Thangarajh, Mathula; Masterman, Thomas; Rot, Uros; Duvefelt, Kristina; Brynedal, Boel; Karrenbauer, Virginija Danylaite; Hillert, Jan
  Journal of Neuroimmunology (2005), 167 (1-2), 210-214CODEN: JNRIDW; ISSN:0165-5728. (Elsevier B.V.)
  B cells play an indispensable, yet indeterminate, role in the pathogenesis of multiple sclerosis (MS). We measured mRNA of APRIL-a promotor of B-cell survival-in peripheral blood and quantified protein levels in plasma and cerebrospinal fluid in MS patients and controls. APRIL mRNA levels in monocytes and T cells were significantly higher in MS patients than in controls. Levels of sol. APRIL in plasma were higher in patients with chronic progressive MS than in patients with relapsing-remitting MS, albeit not significantly. MS may thus be assocd. with increased transcription in peripheral blood of factors promoting B-cell survival, including APRIL.
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47. 47
  Tanaka, M. Anti-aquaporin 4 antibody in Japanese multiple sclerosis: the presence of optic spinal multiple sclerosis without long spinal cord lesions and anti-aquaporin 4 antibody J. Neurol., Neurosurg. Psychiatry 2007, 78 (9) 990– 992
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  Anti-aquaporin 4 antibody in Japanese multiple sclerosis: the presence of optic spinal multiple sclerosis without long spinal cord lesions and anti-aquaporin 4 antibody
  Tanaka Masami; Tanaka Keiko; Komori Mika; Saida Takahiko
  Journal of neurology, neurosurgery, and psychiatry (2007), 78 (9), 990-2 ISSN:.
  BACKGROUND: Anti-aquaporin 4 (AQP4) antibodies were found in patients with neuromyelitis optica (NMO) and Japanese optic-spinal multiple sclerosis (OSMS). OBJECTIVE: To review the clinical features and investigate anti-AQP4 antibodies of Japanese patients with multiple sclerosis (MS), with or without long spinal cord lesions (LCL). METHODS: Anti-AQP4 antibodies were examined in the sera of 128 consecutive Japanese patients by the immunofluorescence method using AQP4 transfected cells. RESULTS: The 45 LCL-MS patients included 28 with a long spinal cord lesion extending contiguously over three vertebral segments on sagittal T2 weighted images (long T2 lesion) and 17 with segmental cord atrophy extending more than three vertebral segments. We identified 25 patients with anti-AQP4 antibody with LCL and anti-AQP4 antibody. Anti-AQP4 antibody was found in 12/17 (70.6%) LCL-MS patients with segmental cord atrophy, and in 13/28 (46.4%) LCL-MS patients without segmental long cord atrophy (p = 0.135, Fisher's exact test). Seropositive MS patients with LCL had more relapses than seronegative patients (p = 0.0004, Mann-Whitney U test). 9 patients with OSMS were negative for anti-AQP4 antibody who did not show LCL. CONCLUSION: These results suggest that an anti-AQP4 antibody is found not only in MS patients with long T2 lesions but also in patients with segmental cord atrophy extending more than three vertebral segments. It is a marker of LCL-MS showing frequent exacerbations. Japanese OSMS cases comprised those that were identical to NMO cases and those that were more closely related to classic MS.
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  Solomon, B. D. Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis Proc. Natl. Acad. Sci. U. S. A. 2011, 108 (5) 2040– 2045
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  Neuropilin-1 attenuates autoreactivity in experimental autoimmune encephalomyelitis
  Solomon, Benjamin D.; Mueller, Cynthia; Chae, Wook-Jin; Alabanza, Leah M.; Bynoe, Margaret S.
  Proceedings of the National Academy of Sciences of the United States of America (2011), 108 (5), 2040-2045, S2040/1-S2040/5CODEN: PNASA6; ISSN:0027-8424. (National Academy of Sciences)
  Neuropilin-1 (Nrp1) is a cell surface mol. originally identified for its role in neuronal development. Recently, Nrp1 has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T (Treg) cells. In this study, we provide evidence for a central role of Nrp1 in the regulation of CD4 T-cell immune responses in exptl. autoimmune encephalitis (EAE). EAE serves as an animal model for the central nervous system (CNS) inflammatory disorder multiple sclerosis (MS). EAE is mediated primarily by CD4+ T cells that migrate to the CNS and mount an inflammatory attack against myelin components, resulting in CNS pathol. Using a tissue-specific deletion system, we obsd. that the lack of Nrp1 on CD4+ T cells results in increased EAE severity. These conditional knockout mice exhibit preferential TH-17 lineage commitment and decreased Treg-cell functionality. Conversely, CD4+ T cells expressing Nrp1 suppress effector T-cell proliferation and cytokine prodn. both in vivo and in vitro independent of Treg cells. Nrp1-mediated suppression can be inhibited by TGF-β blockade but not by IL-10 blockade. These results suggest that Nrp1 is essential for proper maintenance of peripheral tolerance and its absence can result in unchecked autoreactive responses, leading to diseases like EAE and potentially MS.
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49. 49
  Reder, A. T. MxA: a biomarker for predicting multiple sclerosis disease activity Neurology 2010, 75 (14) 1222– 1223
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  MxA: a biomarker for predicting multiple sclerosis disease activity
  Reder Anthony T
  Neurology (2010), 75 (14), 1222-3 ISSN:.
  There is no expanded citation for this reference.
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50. 50
  Ramanathan, M. In vivo gene expression revealed by cDNA arrays: the pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects J. Neuroimmunol. 2001, 116 (2) 213– 219
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  In vivo gene expression revealed by cDNA arrays: the pattern in relapsing-remitting multiple sclerosis patients compared with normal subjects
  Ramanathan, M.; Weinstock-Guttman, B.; Nguyen, L. T.; Badgett, D.; Miller, C.; Patrick, K.; Brownscheidle, C.; Jacobs, L.
  Journal of Neuroimmunology (2001), 116 (2), 213-219CODEN: JNRIDW; ISSN:0165-5728. (Elsevier Science B.V.)
  Objectives: To use DNA arrays to identify differences in gene expression assocd. with relapsing-remitting (RR) MS. Methods: Total RNA was isolated from monocyte depleted peripheral blood mononuclear cells of 15 RR MS patients and 15 age- and sex-matched controls. The RNA was reverse transcribed to radiolabeled cDNA and the resultant cDNA was used to probe a DNA array contg. over 4000 named human genes. The binding of radiolabeled cDNA to the probes on the array was measured by phosphorimager. Results: Of >4000 genes tested, only 34 were significantly different in RR-MS patients from controls. Of these, 25 were significantly increased and 9 significantly decreased in the RR MS patients. Twelve of these genes have inflammatory and/or immunol. functions that could be relevant to the MS disease process. The potentially relevant genes that were elevated (15% to 28%) were P protein, LCK, cAMP responsive element modulator, IL-7 receptor, matrix metalloproteinase-19, M130 antigen, and peptidyl-prolyl isomerase. Those that were significantly decreased (15% to 35%) were SAS transmembrane 4 superfamily protein, STRL22 (C-C chemokine receptor 6), AFX protein, DNA fragmentation factor-45 and Ig gamma 3 (Gm marker). Conclusions: The RR-MS disease effect was relatively restricted and most of the mRNAs tested were not different from the normal controls. However, there were significant differences identified in the expression of a subset of mRNAs, including 13 with inflammatory/immune functions that could be relevant to MS. The systematic use of DNA arrays can provide insight into the dynamic cellular pathways involved in MS pathogenesis and its phenotypic heterogeneity.
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  Mc Guire, C. Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination J. Immunol. 2010, 185 (12) 7646– 7653
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  Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination
  Mc Guire Conor; Volckaert Thomas; Wolke Uta; Sze Mozes; de Rycke Riet; Waisman Ari; Prinz Marco; Beyaert Rudi; Pasparakis Manolis; van Loo Geert
  Journal of immunology (Baltimore, Md. : 1950) (2010), 185 (12), 7646-53 ISSN:.
  Apoptosis of oligodendrocytes (ODCs), the myelin-producing glial cells in the CNS, plays a central role in demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To investigate the mechanism behind ODC apoptosis in EAE, we made use of conditional knockout mice lacking the adaptor protein FADD specifically in ODCs (FADD(ODC-KO)). FADD mediates apoptosis by coupling death receptors with downstream caspase activation. In line with this, ODCs from FADD(ODC-KO) mice were completely resistant to death receptor-induced apoptosis in vitro. In the EAE model, FADD(ODC-KO) mice followed an ameliorated clinical disease course in comparison with control littermates. Lymphocyte and macrophage infiltration into the spinal cord parenchyma was significantly reduced, as was the extent of demyelination and proinflammatory gene expression. Collectively, our data show that FADD is critical for ODC apoptosis and the development of autoimmune demyelinating disease.
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  Lindsey, J. W.; Agarwal, S. K.; Tan, F. K. Gene expression changes in multiple sclerosis relapse suggest activation of T and non-T cells Mol. Med. 2011, 17 (1–2) 95– 102
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  Gene expression changes in multiple sclerosis relapse suggest activation of T and non-T cells
  Lindsey, J. William; Agarwal, Sandeep K.; Tan, Filemon K.
  Molecular Medicine (Manhasset, NY, United States) (2011), 17 (1-2), 95-102CODEN: MOMEF3; ISSN:1076-1551. (Feinstein Institute for Medical Research)
  A defining feature of multiple sclerosis (MS) is the occurrence of clin. relapses sepd. by periods of clin. stability. Better understanding of the events underlying clin. relapse might suggest new approaches to treatment. The objective of this study was to measure changes in the expression of RNA in the blood during relapse. We used microarrays to measure mRNA expression in paired samples from 14 MS patients during clin. relapse and while stable. Seventy-one transcripts changed expression at the P < 0.001 significance level. The most notable finding was decreased expression of transcripts with regulatory function, expressed primarily in non-T cells. These decreased transcripts included the interleukin-1 receptor antagonist, which had a corresponding decrease in the protein concn. in serum. Transcripts with increased expression were expressed primarily in T cells. Pathways anal. suggested involvement of the cytokine network, coagulation and complement cascades, IL-10 signaling and NF-κB signaling. We conclude that there are alterations of mRNA expression in both T cells and non-T cells during MS relapse.
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53. 53
  Harris, V. K. Bri2–23 is a potential cerebrospinal fluid biomarker in multiple sclerosis Neurobiol. Dis. 2010, 40 (1) 331– 339
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  Bri2-23 is a potential cerebrospinal fluid biomarker in multiple sclerosis
  Harris, Violaine K.; Diamanduros, Andrew; Good, Pamela; Zakin, Elina; Chalivendra, Varun; Sadiq, Saud A.
  Neurobiology of Disease (2010), 40 (1), 331-339CODEN: NUDIEM; ISSN:0969-9961. (Elsevier B.V.)
  To identify potential multiple sclerosis (MS)-specific biomarkers, we used a proteomic approach to screen cerebrospinal fluid (CSF) from 40 MS patients and 13 controls. We identified seven proteins (Beta-2-microglobulin, Bri2-23, Fetuin-A, Kallikrein-6, Plasminogen, RNase-1, and Transferrin) that had significantly altered levels in MS compared to controls. Clin. subgroup anal. revealed that decreased CSF levels of Bri2-23, a peptide cleaved from Bri2, were significantly assocd. with patients having cerebellar dysfunction and cognition impairment. Furthermore, expression levels of Bri2 were specifically decreased in the cerebellum compared to other areas of same brain in MS but not in controls, suggesting that decreased cerebellar Bri2 expression may play a role in cerebellar dysfunction. The assocn. with cognition impairment is also of interest because Bri2 is linked to the amyloid processing pathway in the brain. CSF levels of Bri2-23 may serve as a biomarker of these functions in MS and merits further investigation.
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54. 54
  Alcina, A. The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis Genes Immun. 2010, 11 (5) 439– 445
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  The autoimmune disease-associated KIF5A, CD226 and SH2B3 gene variants confer susceptibility for multiple sclerosis
  Alcina, A.; Vandenbroeck, K.; Otaegui, D.; Saiz, A.; Gonzalez, J. R.; Fernandez, O.; Cavanillas, M. L.; Cenit, M. C.; Arroyo, R.; Alloza, I.; Garcia-Barcina, M.; Antigueedad, A.; Leyva, L.; Izquierdo, G.; Lucas, M.; Fedetz, M.; Pinto-Medel, M. J.; Olascoaga, J.; Blanco, Y.; Comabella, M.; Montalban, X.; Urcelay, E.; Matesanz, F.
  Genes and Immunity (2010), 11 (5), 439-445CODEN: GEIMA2; ISSN:1466-4879. (Nature Publishing Group)
  Genome-wide assocn. studies (GWAS) have revealed that different diseases share susceptibility variants. Twelve single-nucleotide polymorphisms (SNPs) previously assocd. with different immune-mediated diseases in GWAS were genotyped in a Caucasian Spanish population of 2864 multiple sclerosis (MS) patients and 2930 controls. Three SNPs were found to be assocd. with MS: rs1678542 in KIF5A (P=0.001, odds ratio (OR)=1.13, 95% confidence interval (CI)=1.05-1.23); rs3184504 in SH2B3 (P=0.00001, OR=1.19, 95% CI=1.10-1.27) and rs763361 in CD226 (P=0.00007, OR=1.16, 95%CI=1.08-1.25). These variants have previously been assocd. with rheumatoid arthritis and type 1 diabetes. The SH2B3 polymorphism has addnl. been assocd. with systemic lupus erythematosus. Our results, in addn. to validating some of these loci as risk factors for MS, are consistent with shared genetic mechanisms underlying different immune-mediated diseases. These data may help to shape the contribution of each pathway to different disorders.
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  Bachmann, J. Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria PLoS Pathog. 2014, 10 (4) e1004038
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  Affinity proteomics reveals elevated muscle proteins in plasma of children with cerebral malaria
  Bachmann, Julie; Burte, Florence; Pramana, Setia; Conte, Ianina; Brown, Biobele J.; Orimadegun, Adebola E.; Ajetunmobi, Wasiu A.; Afolabi, Nathaniel K.; Akinkunmi, Francis; Omokhodion, Samuel; Akinbami, Felix O.; Shokunbi, Wuraola A.; Kampf, Caroline; Pawitan, Yudi; Uhlen, Mathias; Sodeinde, Olugbemiro; Schwenk, Jochen M.; Wahlgren, Mats; Fernandez-Reyes, Delmiro; Nilsson, Peter
  PLoS Pathogens (2014), 10 (4), e1004038/1-e1004038/12, 12 pp.CODEN: PPLACN; ISSN:1553-7374. (Public Library of Science)
  Systemic inflammation and sequestration of parasitized erythrocytes are central processes in the pathophysiol. of severe Plasmodium falciparum childhood malaria. However, it is still not understood why some children are more at risks to develop malaria complications than others. To identify human proteins in plasma related to childhood malaria syndromes, multiplex antibody suspension bead arrays were employed. Out of the 1,015 proteins analyzed in plasma from more than 700 children, 41 differed between malaria infected children and community controls, whereas 13 discriminated uncomplicated malaria from severe malaria syndromes. Markers of oxidative stress were found related to severe malaria anemia while markers of endothelial activation, platelet adhesion and muscular damage were identified in relation to children with cerebral malaria. These findings suggest the presence of generalized vascular inflammation, vascular wall modulations, activation of endothelium and unbalanced glucose metab. in severe malaria. The increased levels of specific muscle proteins in plasma implicate potential muscle damage and microvasculature lesions during the course of cerebral malaria.
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  Autoantibody Profiling in Multiple Sclerosis Using Arrays of Human Protein Fragments
  Ayoglu, Burcu; Haeggmark, Anna; Khademi, Mohsen; Olsson, Tomas; Uhlen, Mathias; Schwenk, Jochen M.; Nilsson, Peter
  Molecular & Cellular Proteomics (2013), 12 (9), 2657-2672CODEN: MCPOBS; ISSN:1535-9484. (American Society for Biochemistry and Molecular Biology)
  Profiling the autoantibody repertoire with large antigen collections is emerging as a powerful tool for the identification of biomarkers for autoimmune diseases. Here, a systematic and undirected approach was taken to screen for profiles of IgG in human plasma from 90 individuals with multiple sclerosis related diagnoses. Reactivity pattern of 11,520 protein fragments (representing ∼38% of all human protein encoding genes) were generated on planar protein microarrays built within the Human Protein Atlas. For more than 2,000 antigens IgG reactivity was obsd., among which 64% were found only in single individuals. We used reactivity distributions among multiple sclerosis subgroups to select 384 antigens, which were then re-evaluated on planar microarrays, corroborated with suspension bead arrays in a larger cohort (n = 376) and confirmed for specificity in inhibition assays. Among the heterogeneous pattern within and across multiple sclerosis subtypes, differences in recognition frequencies were found for 51 antigens, which were enriched for proteins of transcriptional regulation. In conclusion, using protein fragments and complementary high-throughput protein array platforms facilitated an alternative route to discovery and verification of potentially disease-assocd. autoimmunity signatures, that are now proposed as addnl. antigens for large-scale validation studies across multiple sclerosis biobanks.
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  Global classification of the human proteins with regards to spatial expression patterns across organs and tissues is important for studies of human biol. and disease. Here, we used a quant. transcriptomics anal. (RNA-Seq) to classify the tissue-specific expression of genes across a representative set of all major human organs and tissues and combined this anal. with antibody-based profiling of the same tissues. To present the data, we launch a new version of the Human Protein Atlas that integrates RNA and protein expression data corresponding to ∼80% of the human protein-coding genes with access to the primary data for both the RNA and the protein anal. on an individual gene level. We present a classification of all human protein-coding genes with regards to tissue-specificity and spatial expression pattern. The integrative human expression map can be used as a starting point to explore the mol. constituents of the human body.
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  A review. The interferon regulatory factor (IRF) family, consisting of nine members in mammals, was identified in the late 1980s in the context of research into the type I interferon system. Subsequent studies over the past two decades have revealed the versatile and crit. functions performed by this transcription factor family. Indeed, many IRF members play central roles in the cellular differentiation of hematopoietic cells and in the regulation of gene expression in response to pathogen-derived danger signals. In particular, the advances made in understanding the immunobiol. of Toll-like and other pattern-recognition receptors have recently generated new momentum for the study of IRFs. Moreover, the role of several IRF family members in the regulation of the cell cycle and apoptosis has important implications for understanding susceptibility to and progression of several cancers.
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  A review. Interferon regulatory factor 8 (IRF8) is a member of the IRF family of transcription factors whose members play crit. roles in interferon (IFN) signaling pathways governing the establishment of innate immune responses by myeloid and dendritic cells. IRF8 is also expressed in lymphoid cells and recent studies have documented its involvement in B cell lineage specification, Ig light chain gene rearrangement, the distribution of mature B cells into the marginal zone and follicular B cell compartment, and the transcriptional regulation of crit. elements of the germinal center reaction. Here we review the contributions of IRF8 to B cell development from hematopoietic stem cells in the bone marrow and its place in the hierarchical regulatory network governing specification and commitment to the B cell fate.
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  Meta-analysis of genome scans and replication identify CD6, IRF8 and TNFRSF1A as new multiple sclerosis susceptibility loci
  De Jager, Philip L.; Jia, Xiaoming; Wang, Joanne; de Bakker, Paul I. W.; Ottoboni, Linda; Aggarwal, Neelum T.; Piccio, Laura; Raychaudhuri, Soumya; Tran, Dong; Aubin, Cristin; Briskin, Rebeccah; Romano, Susan; Baranzini, Sergio E.; McCauley, Jacob L.; Pericak-Vance, Margaret A.; Haines, Jonathan L.; Gibson, Rachel A.; Naeglin, Yvonne; Uitdehaag, Bernard; Matthews, Paul M.; Kappos, Ludwig; Polman, Chris; McArdle, Wendy L.; Strachan, David P.; Evans, Denis; Cross, Anne H.; Daly, Mark J.; Compston, Alastair; Sawcer, Stephen J.; Weiner, Howard L.; Hauser, Stephen L.; Hafler, David A.; Oksenberg, Jorge R.
  Nature Genetics (2009), 41 (7), 776-782CODEN: NGENEC; ISSN:1061-4036. (Nature Publishing Group)
  We report the results of a meta-anal. of genome-wide assocn. scans for multiple sclerosis (MS) susceptibility that includes 2624 subjects with MS and 7220 control subjects. Replication in an independent set of 2215 subjects with MS and 2116 control subjects validates new MS susceptibility loci at TNFRSF1A (combined P = 1.59 × 10-11), IRF8 (P = 3.73 × 10-9) and CD6 (P = 3.79 × 10-9). TNFRSF1A harbors two independent susceptibility alleles: rs1800693 is a common variant with modest effect (odds ratio = 1.2), whereas rs4149584 is a nonsynonymous coding polymorphism of low frequency but with stronger effect (allele frequency = 0.02; odds ratio = 1.6). We also report that the susceptibility allele near IRF8, which encodes a transcription factor known to function in type I interferon signaling, is assocd. with higher mRNA expression of interferon-response pathway genes in subjects with MS.
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  The Transcription Factor IRF8 Activates Integrin-Mediated TGF-β Signaling and Promotes Neuroinflammation
  Yoshida, Yuko; Yoshimi, Ryusuke; Yoshii, Hiroaki; Kim, Daniel; Dey, Anup; Xiong, Huabao; Munasinghe, Jeeva; Yazawa, Itaru; O'Donovan, Michael J.; Maximova, Olga A.; Sharma, Suveena; Zhu, Jinfang; Wang, Hongsheng; Morse, Herbert C.; Ozato, Keiko
  Immunity (2014), 40 (2), 187-198CODEN: IUNIEH; ISSN:1074-7613. (Elsevier Inc.)
  Recent epidemiol. studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in exptl. autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8-/- mice are resistant to EAE. Furthermore, expression of IRF8 in antigen-presenting cells (APCs, such as macrophages, dendritic cells, and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced αvβ8 integrin expression in APCs and activated TGF-β signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL-12) and IL-23 prodn., but inhibiting IL-27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS.
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  Cellular sources of dysregulated cytokines in relapsing-remitting multiple sclerosis
  Romme Christensen Jeppe; Bornsen Lars; Hesse Dan; Krakauer Martin; Sorensen Per Soelberg; Sondergaard Helle Bach; Sellebjerg Finn
  Journal of neuroinflammation (2012), 9 (), 215 ISSN:.
  BACKGROUND: Numerous cytokines are implicated in the immunopathogenesis of multiple sclerosis (MS), but studies are often limited to whole blood (WB) or peripheral blood mononuclear cells (PBMCs), thereby omitting important information about the cellular origin of the cytokines. Knowledge about the relation between blood and cerebrospinal fluid (CSF) cell expression of cytokines and the cellular source of CSF cytokines is even more scarce. METHODS: We studied gene expression of a broad panel of cytokines in WB from relapsing-remitting multiple sclerosis (RRMS) patients in remission and healthy controls (HCs). Subsequently we determined the gene expression of the dysregulated cytokines in isolated PBMC subsets (CD4+, CD8+T-cells, NK-cells, B-cells, monocytes and dendritic cells) from RRMS patients and HCs and in CSF-cells from RRMS patients in clinical relapse and non-inflammatory neurological controls (NIND). RESULTS: RRMS patients had increased expression of IFN-gamma (IFNG), interleukin (IL) 1-beta (IL1B), IL7, IL10, IL12A, IL15, IL23, IL27, lymphotoxin-alpha (LTA) and lymphotoxin-beta (LTB) in WB. In PBMC subsets the main sources of pro-inflammatory cytokines were T- and B-cells, whereas monocytes were the most prominent source of immunoregulatory cytokines. In CSF-cells, RRMS patients had increased expression of IFNG and CD19 and decreased expression of IL10 and CD14 compared to NINDs. CD19 expression correlated with expression of IFNG, IL7, IL12A, IL15 and LTA whereas CD14 expression correlated with IL10 expression. CONCLUSIONS: Using a systematic approach, we show that expression of pro-inflammatory cytokines in peripheral blood primarily originates from T- and B-cells, with an important exception of IFNG which is most strongly expressed by NK-cells. In CSF-cell studies, B-cells appear to be enriched in RRMS and associated with expression of pro-inflammatory cytokines; contrarily, monocytes are relatively scarce in CSF from RRMS patients and are associated with IL10 expression. Thus, our findings suggest a pathogenetic role of B-cells and an immunoregulatory role of monocytes in RRMS.
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  A METTL3-METTL14 complex mediates mammalian nuclear RNA N6-adenosine methylation
  Liu, Jianzhao; Yue, Yanan; Han, Dali; Wang, Xiao; Fu, Ye; Zhang, Liang; Jia, Guifang; Yu, Miao; Lu, Zhike; Deng, Xin; Dai, Qing; Chen, Weizhong; He, Chuan
  Nature Chemical Biology (2014), 10 (2), 93-95CODEN: NCBABT; ISSN:1552-4450. (Nature Publishing Group)
  N6-methyladenosine (m6A) is the most prevalent and reversible internal modification in mammalian messenger and noncoding RNAs. We report here that human methyltransferase-like 14 (METTL14) catalyzes m6A RNA methylation. Together with METTL3, the only previously known m6A methyltransferase, these two proteins form a stable heterodimer core complex of METTL3-METTL14 that functions in cellular m6A deposition on mammalian nuclear RNAs. WTAP, a mammalian splicing factor, can interact with this complex and affect this methylation.
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S-Table 1: Demographics of brain tissue samples. S-Table 2A: Antibodies suggested by discovery screening. S-Table 2B: Antibodies used for second, focused 101-plex bead array. S-Table 3: Antibody performance in plasma and CSF. S-Table 4: Antibodies used for analysis of brain tissue. S-Table 5: RNA expression levels (FPKM) related to candidate proteins. S-Figure 1: Protein profiles prior normalization. S-Figure 2: Experimental reproducibility of candidate profiles. S-Figure 3: ROC curves from multivariate analysis. S-Figure 4: Western blot and epitope mapping of IRF8. S-Figure 5: Candidate profiles in CSF. S-Figure 6: Hierarchical clustering of SPMS and CIS in CSF. This material is available free of charge via the Internet at http://pubs.acs.org.
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Affinity Proteomic Profiling of Plasma, Cerebrospinal Fluid, and Brain Tissue within Multiple Sclerosis

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Abstract

SPECIAL ISSUE

Introduction

Materials and Methods

Samples

Antibodies and Bead Array Generation

Plasma Profiling

CSF Profiling

Western Blot Analysis

Epitope Mapping

Data Analysis

Data Processing

Statistical Analysis

Tissue Analysis

Immunofluorescence

Slide Scanning Microscopy

Laser-Scanning Microscopy

Results

Figure 1

Initial Discovery Screening

First Targeted Discovery Across MS Subtypes

Second Targeted Analysis Across MS Subtypes

Figure 2

Verification Analysis for IRF8

Figure 3

Profiling of Paired CSF Samples

Correlation Networks Across MS Subtypes

Figure 4

Distribution of Identified Targets in the MS Brain

Figure 5

Discussion

Supporting Information

pdf

Terms & Conditions

Acknowledgment

Abbreviations

References

Cited By

Abstract

Figure 1

Figure 2

Figure 3

Figure 4

Figure 5

References

Supporting Information

Supporting Information

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STEP 2:

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