First described in the 18th century, scleroderma literally means “hard skin” and is characterized by thickened, stonelike skin that may become hyperpigmented. However, the real damage is being done under the surface of the skin. The immune system damages the small blood vessels and any area where collagen-producing cells are located. Initially, the excess collagen causes thick, tight skin, that burns and is very painful. More seriously, the lungs, heart, gastrointestinal tract, kidneys, muscles, and joints may be targets of excessive buildup of fibrous connective tissue that is primarily composed of collagen.

About 100,000 people in the United States have scleroderma, and 80% are women between the ages of 30 and 60. The condition affects each individual differently: It is mild in some cases and life-threatening in others. There is no known cure, although drugs may alleviate symptoms.

Nicholas Flavahan and researchers at Ohio State University have demonstrated that the autoimmune response originally may be set off by ischemia associated with Raynaud’s phenomenon, a condition in which the extremities react to cold by becoming white, then red and blue. The cold-induced vasospasm is caused by an increase in the activity of a protein called -2C-adrenoceptors. This protein is present in the vascular smooth muscles that constrict arteries and arterioles and therefore regulate blood flow to organs.

In Raynaud’s phenomenon, -2C-adrenoceptors may become 300 times more active than normal, causing blood vessels to close. The associated injury stops the blood flow to the limbs and return of the blood flow, called retrofusion, generates reactive oxidants that may contribute to the microvascular lesions and the generation of auto-antibodies. The two kinds of antibodies involved in scleroderma are anticentromere and anti-topoisomerase-1.

DNA topoisomerase-1. PROTEIN DATA BANK

A team from Johns Hopkins University led by Anthony Rosen found that the immune response in scleroderma is highly disease-specific and targets a unique group of self-molecules. The novel cell death pathway changes the structure of these self-molecules, so the immune system treats them as foreign invaders. The reversible ischemia and hyperfusion as described by Flavahan in Raynaud’s phenomenon produce toxic oxygen that causes certain tissue molecules to break apart only in the presence of iron, copper, zinc, and other metals. Fragmentation of these molecules makes compounds that the body treats as foreign invaders. Abnormal metal concentrations in the body are a possible principle of scleroderma.

When these events result in a positive feedback, they give rise to a vicious cycle of oxygen free radicals (OFRs) leading to endothelial damage and fibrosis. Ischemia and reperfusion induce oxidative stress and inactivation of antioxidant enzymes. The OFRs mediate more injury.

Another Ohio State University team, led by Pascal Goldschmidt, is investigating transforming growth-factor (TGF-) for clues relating to scleroderma. TGF- regulates the production of proteins, like collagen. In studying the TGF- pathway, the team found a group of proteins called Smads, which carry messages in the TGF- pathway. Most Smads are positive, but in scleroderma skin, Smad7 is lost, resulting in unchecked activity in the TGF- pathway. Comparing fibroplasts from patients and controls, researchers demonstrated that with the loss of Smad 7, gene expression response is amplified. Gene therapy by adding an extrinsic Smad 7 to restore the normal response to TGF- could open avenues for intervention.

The prevalent feeling has always been that scleroderma is environmental, but a recent study has found a possible gene site. Using genetic markers and old Choctaw tribal records going back to the 18th century, University of Utah researchers have implicated the protein fibrillin-1 gene on chromosome 15q. This may influence the search for therapeutics.

Sources: Scleroderma Foundation, www.scleroderma.org; Scleroderma Research Foundation, www.srfcure.org; American Autoimmune Related Diseases Association, Research Report, www.aarda.org/research16.html; Rosen, L. J. Exper. Med. 1997, 185, 71–80.