Web Bit 40-1: Autoimmunity: why does the immune system sometimes attack self?
By Allan Tobin and Jennie Dusheck
Although the immune system is largely successful in distinguishing self from nonself, about 5 percent of the population suffers from some autoimmune disease, in which the immune system attacks the body's own tissues, causing tissue damage or malfunction.
In the disease myasthenia gravis, for example, antibodies block the muscle cell receptors that normally respond to acetylcholine, the chemical signal that triggers muscle contraction. When autoantibody levels are high, the muscles cannot be activated, resulting in weakness or even paralysis. One treatment for myasthenia gravis is to remove the antibodies from the patient's blood, which involves removing the blood plasma and then cycling it back into the body.
In insulin-dependent diabetes mellitus (juvenile diabetes) which affects about 0.5 percent of the United States population, T cells attack and destroy the insulin-producing cells of the pancreas. Unable to make their own insulin, patients must inject themselves with insulin every day.
Until the early 1970s, biologists believed that such autoimmune diseases resulted from a failure of a mechanism that should have eliminated all self-reactive lymphocytes early in life. Researchers have discovered, however, that all healthy adults contain some self-reactive lymphocytes. In most people and for almost all antigens, such self-reactive lymphocytes are held in check. In patients with autoimmune disease, something goes wrong. What goes wrong is only partly understood.
Some of the circumstances that bring about the multiplication of self-reactive lymphocytes help explain how it can happen. For example, the streptococcal bacteria that cause strep throat have surface antigens that closely resemble antigens on the cells in heart muscle, a happenstance called molecular mimicry. The result is that antibodies and T lymphocytes recognize both antigens and attack and damage not only the strep bacteria but the heart muscle cells as well. Such an attack on the heart is called rheumatic fever, a serious and often fatal disease that was quite common in the days before antibiotics quickly cured strep throat infections.
In the case of insulin-dependent diabetes, T cells that recognize an antigen of a common virus (Coxsackievirus) also recognize a peptide segment of an enzyme called GAD (glutamic acid decarboxylase) found in the insulin-producing cells. Researchers hypothesize that T cells that have proliferated in response to the Coxsackievirus infection attack pancreatic cells and so cause diabetes.
Like other exogenous antigens, mimicking antigens are presented to the immune system with MHC molecules. It is not surprising, then, that individuals with different MHC alleles differ in their susceptibility to particular autoimmune diseases. For example, individuals who express one group of MHC Class II genes are 100 times more likely to develop insulin-dependent diabetes than the population as a whole.
If autoimmunity to a mimicking antigen is indeed responsible for insulin-dependent diabetes and other autoimmune diseases, then the disease might be prevented with the same kinds of immunosupressant drugs used to suppress the immune response when organs are transplanted.
Another possible approach would be to induce tolerance to the offending antigen - somehow reintroducing the antigen as self. This approach has worked for animal models of several autoimmune diseases, including insulin-dependent diabetes. A novel approach to inducing tolerance comes from the observation that most people are immunologically tolerant to the foods that they eat. By feeding the appropriate mimicking protein to people at risk for insulin-dependent diabetes and other autoimmune diseases, researchers hope to prevent a later autoimmune attack.