Scleroderma

Disease Background

Scleroderma is a chronic autoimmune disease. Its hallmark feature is fibrosis, which means hardening of the skin (derived from "sklero" or hard and "derma" referring to skin). In autoimmune diseases, a person's immune system attacks the body, resulting in inflammation of various organs or tissues. The components of the immune system responsible for this effect are antibodies and cells. Antibodies are proteins produced by white blood cells typically made in response to infection caused by pathogens like bacteria and viruses. In autoimmune diseases like scleroderma, normal molecules of the body are mistakenly recognized by immune-system cells and antibodies, and are targeted for destruction.

Scleroderma can range from a localized disease that primarily affects the skin to a more serious illness known as systemic sclerosis, causing damage to multiple parts of the body. Tissues that can be affected include the skin, joints, digestive tract, lung and kidney.

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About 100,000 Americans have scleroderma. Like many other autoimmune diseases, scleroderma occurs much more frequently in women than men, with about four times as many women developing the disease compared to men.

Although the cause of scleroderma is unknown, research conducted at the Hutchinson Center suggests that fetal cells that persist in the mother after childbirth may somehow contribute to the disease.

Genetic and environmental factors also are likely to play a role in the disease. Although scleroderma does not often run in families, there may be certain gene variants that increase likelihood of the disease. In addition, as is the case with other autoimmune diseases, scleroderma might be triggered by viral infections in individuals who are predisposed to develop the disease.

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Our Research

Overview of Hutchinson Center Research

Hutchinson Center research is directed toward understanding what causes systemic sclerosis and developing improved therapies for people with severe forms of the disease.

Researchers have found that fetal cells persisting in a mother's bloodstream years after pregnancy — a condition called microchimerism — are associated with scleroderma. Persistence of fetal cells in a mother's peripheral blood may help explain why women are more susceptible to the disease. Recent studies have shown that not only do fetal cells pass from fetus to mother, but cells also can pass from mother to fetus, meaning that men — who harbor trace cells from their mother — can exhibit microchimerism as well. Researchers now hope to isolate the fetal and maternal cells and to analyze their role in the disease process.

Other studies are aimed at developing treatments for patients with autoimmune disease. Center researchers are leading clinical trials that use stem-cell transplantation for treating severe forms of scleroderma. Prior to the procedure, a patient's stem cells are collected, and cells that react against the patient's own tissue are removed. Next, patients are treated with high-dose chemotherapy and drugs to suppress their immune system. Patients then receive an infusion of the stem cells that were collected before treatment. These cells will rebuild a new, healthier immune system free of the self-reactive cells responsible for the autoimmune disease. Preliminary results from such studies have been promising.

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Innovative new treatments for autoimmune diseases

A Hutchinson Center team led by Dr. Richard Nash is examining the feasibility of using stem-cell transplantation as a treatment for autoimmune diseases. These diseases are a group of about 50 ailments whose symptoms range from mild rashes to life-threatening conditions that attack major organ systems. Though each disease is different, all begin with an immune-system malfunction: destruction of the body's own normal tissue by cells that typically fight infections caused by bacteria, viruses and other micro-organisms.

The rationale for the approach is that the high-dose radiation and chemotherapy used to wipe out cancers of blood and bone marrow may be used to suppress the immune system. This high-dose therapy eliminates not only the immune system's ability to fight infection, but also its ability to attack the patient's tissues. The new immune system that regrows from selected stem cells taken from the patient's own blood will be composed of immature cells that will not include the reactive cells that trigger the immune system to attack the body. Because many autoimmune diseases begin during middle age, it is thought this stem-cell transplantation will "turn back the clock" on immune system development in these patients.

The early phase studies showed that transplantation provides promising improvement in patients' conditions, and that larger randomized comparison studies are needed to determine the long-term benefit to patients.

Nash's team is leading a multicenter trial using autologous stem-cell transplantation for scleroderma, lupus, multiple sclerosis and juvenile rheumatoid arthritis. For more information, Search Clinical Trials.

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Uncovering the genetic secrets of autoimmune disease

The causes of autoimmune diseases, in which the immune system begins attacking the body's own tissues, are unknown. What triggers these diseases? How do they progress? Why do they strike women much more often than men? These form the core research questions of scientists in Dr. J. Lee Nelson's laboratory. Answering them requires a variety of approaches involving collaborations with laboratory, population and clinical scientists.

Nelson's laboratory studies focus on understanding the genetics that underlies the complex system by which the immune system distinguishes between the body's own cells and foreign invaders. Women with rheumatoid arthritis often experience a remission of symptoms during pregnancy, suggesting that incompatibility between the immune systems of mother and fetus may play a role in these diseases.

In collaboration with clinical researchers, Nelson's team is investigating the similarities of scleroderma and chronic graft-vs.-host disease. Graft-vs.-host disease results from an incompatibility of the donor's immune cells and the patient's tissues. Nelson's team has shown that persistent fetal immune system cells in the mother's blood is quantitatively greater in women with scleroderma compared to healthy women. More recently, they showed that among the cell-surface proteins that form the identification system of the immune system, those produced with certain characteristics called human leukocyte antigen (HLA-DRB1) were associated with increased risk of subsequent scleroderma in mothers studied.

To determine the role of genetic predisposition and environmental factors involves collaborating with population scientists in the Hutchinson Center. Nelson's studies have shown that immune cell incompatibility can apply to men and women who have not been pregnant because incompatible cells can engraft from a twin or from a blood transfusion. More recently her team found that cells from a mother can persist in her children into adult life.

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Relevant Articles

• "There is such a big difference in my life now" — Patients with autoimmune diseases are finding success with treatments originally developed to fight cancer
  
  
• The scleroderma dilemma: Loyal defender turns traitor — Genetics play role in persistence of fetal cells, say studies by Nelson, Lambert

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