Autoimmunity

In certain individuals, the immune system fails to recognize one's healthy tissue as self, and a humoral and/or cellular immune response develops, leading to the afflictions collectively known as autoimmune diseases. Historically, women have suffered from a greater (up to ninefold) prevalence of many autoimmune diseases. Such female-predominant diseases include systemic lupus erythematosus (SLE), rheuma toid arthritis, primary biliary cirrhosis and Graves' disease. This gender preference makes sex steroids an obvious starting point for investigations into the issue. Yet, despite clear-cut results in a number of laboratories, our knowledge of how sex steroids influence the development of autoimmune disease remains largely conjectural.

There are two well-studied, sexually dimorphic autoimmune diseases in laboratory mice modeling SLE and diabetes. In both, the manipulation of sex steroids profoundly influences the course of disease. The first example involves offspring (F1 hybrids) of NZB and NZW strain mice. Although almost all females from this NZB/NZW breeding die of a lupus-like disease within the first year of life, tenfold fewer males die of disease. However castration of NZB/NZW males causes them to suffer a similarly high death rate, and treatment with the male hormone androgen (testosterone or dihydrotestosterone) protects female mice from early fatality. In this experimental model of human lupus, the thymus is an important participant in androgen-induced protection. The second example is the NOD mouse strain, which suffers a high incidence of insulin-dependent diabetes mellitus. By 6 months of age, approximately 80% of NOD strain females are diabetic, whereas only 20% of the males have obvious disease. After castration, these male mice undergo a significant increase in the incidence of diabetes, an effect heightened by removal of the thymus. As in the NZB/NZW hybrid mice, NOD females given androgen do not get the disease. However, when the androgen-treated females are injected with spleen cells from diabetic animals, diabetes develops. Therefore, the hormone is likely acting on immune cells, not the pancreas - the organ attacked by this disease.

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