DescriptionAn in-depth report on the causes, diagnosis, treatment, and prevention of scleroderma.
Alternative NamesSystemic Sclerosis
The disease process leading to scleroderma appears to occur as an autoimmune response, in which a defective immune system attacks or sets conditions that damage the body itself. In scleroderma, this response produces inflammation and an overproduction of collagen, the tough fibrous protein that helps construct connective tissues, such as tendons, bones, and ligaments as well as scar tissue. Most likely this disease process is regulated by a number of genetic defects with environmental factors playing the role of trigger.
Inflammatory Response and Autoimmunity
The Normal Immune System Response. The inflammatory process is a byproduct of the body's immune system, which fights infection and heals wounds and injuries:
The Infection Fighters. The primary infection-fighting units are two types of white blood cells: lymphocytes and leukocytes.
Lymphocytes include two subtypes known as T-cells and B-cells. Both types of cells are designed to recognize foreign invaders (antigens) and to launch an offensive or defensive action against them:
T-cells are further categorized as killer T-cells or helper T-cells (TH cells).
Helper T-Cells and Autoantibodies. The actions of the helper T-cells are of special interest in scleroderma. For some unknown reason, the T-cells become overactive in scleroderma and mistake the body's own collagen as an antigen and trigger a series of immune responses to destroy the false enemy:
Cytokines and the Inflammatory Response. TH-cells also secrete or stimulate the production of powerful immune factors called cytokines. In small amounts, cytokines are indispensable for healing. If overproduced, however, they can cause serious damage, including inflammation and injury during the scleroderma process.
A cytokine known as connective transforming growth factor (CTGF) appears to be particularly important. It acts in concert with another compound called TGF-beta to stimulate the growth of fibroblasts. Fibroblasts are immature cells that regulate production of collagen. Collagen is the tough protein used to build the fibrous structures that form bones, ligaments, and skin. It is also the basic building block in scar tissue, a major component in scleroderma.
Other cytokines that may have major roles in scleroderma include tumor necrosis factor and interleukins.
Neutrophils. Cytokines attract to the scene large numbers of other white blood cells known as neutrophils. Neutrophils stimulate the production of arachidonic acid, which triggers about 30 different chemicals, including leukotrienes. Specific leukotrienes called LTB(4) and LTE(4) are elevated in scleroderma patients and may contribute specifically to lung disease.
Fetal Cell Theory and Microchimerism
Increasing evidence supports a cause of scleroderma called microchimerism. It arose from the observation that scleroderma occurs in mostly women and that its symptoms resembled those of graft-versus-host disease (GVHD). GVHD occurs in bone transplant patients when the transplanted donor cells launch an attack against the host-patient's cells.
To understand the process, it is useful to define chimerism, which occurs when cells from two different individuals exist in the same body. When there is a low number of cells of one body in another, the condition is referred to as microchimerism.
The theory that links microchimerism to scleroderma is roughly as follows:
On-going research is detecting a greater prevalence of fetal cells in women with scleroderma than in the general population. In 2002, for example, researchers detected microchimerism in the saliva gland cells of 45% of women with systemic sclerosis who had a history of pregnancy with male babies.
The following has been suggested to explain how microchimerism may trigger scleroderma in men or in women who had never been pregnant:
In any case, however, if microchimerism plays a role, it most likely does so only in a subset of patients.
Triggering the Immune Response
It is still not clear why the immune system responds abnormally. Some experts believe that environmental factors, such as a virus or chemical, may trigger the response in individuals with genetically abnormal immune systems.
Oxygen-Free Radicals and Abnormal Metal Accumulation. Another focus for researchers involves an observation that in scleroderma, as blood vessels narrow and become inflamed, destructive particles known as oxygen-free radicals are produced. Oxygen free radicals are unstable molecules produced by the natural chemical processes in the body. They cause harm in the following way:
Researchers have detected abnormal molecules in these damaged cells that appear to occur only with abnormally high levels of certain metals, particularly zinc, iron, and copper. Researchers postulate that these defective molecules may be the antigens targeted by some of the autoantibodies that trigger the development of scleroderma.
Chemicals. Occupational exposure to certain chemicals can cause blood vessel constriction and Raynaud's phenomena. Although some cases of actual scleroderma are believed to be occupationally induced, no specific factors have been proven to cause the disorder itself. Industrial and pharmaceutical chemicals being investigated include the following:
Unfortunately it is nearly impossible to determine if specific chemicals may actually cause systemic scleroderma. The reasons for this include the following:
Repetitive Stress Injuries. Raynaud's phenomena and symptoms of scleroderma have been associated with jobs that require intense repetitive hand and arm movements, such as working jackhammers or other vibrating tools. As with chemical industries, many workers are involved in such occupations but scleroderma is very rare, even in this group. If there is a link, the disease would most likely develop in individuals with genetic factors that make them susceptible to disease in the first place.
Radiation. Radiation therapy has been reported to induce morphea (local scleroderma patches) or exacerbate preexisting scleroderma in a few patients. In some cases, it may occur years after treatments.
Researchers theorize that infections may play a role in triggering the process leading to some cases of scleroderma. There is no significant evidence of any single organism that might be responsible, although some are of particular interest.
Lyme Disease. Some studies reported an association between Borrelia burgdorferi, the infectious agent in Lyme Disease, and some cases of morphea (localized scleroderma patches). However, the evidence is weak and if it exists is possibly limited to a specific variant in Europe and Asia. There is no association with systemic scleroderma and Lyme disease.
Parvovirus. In one study there was a higher prevalence of antibodies to a virus called parvovirus 19 in patients with systemic sclerosis than in patients without the disorder. The association probably warrants more research.
Hepatitis C. Scleroderma has been reported in some patients with hepatitis C, although a causal relationship is unclear.
Genetic factors appear to play a role in triggering the disease, but most cases are unlikely to be inherited. There are some exceptions. Scientists in 1999 discovered a probable link between the gene for the protein fibrillin-1 and the development of scleroderma in certain populations. The gene was detected in Choctaw Native Americans, who have a higher risk for scleroderma than other groups. Elevated levels of autoantibodies to this protein have also been detected in other ethnic groups, including African American and Japanese patients, but not in Caucasians.