Gender as risk factor for autoimmune diseases

Most autoimmune diseases occur significantly more frequently in women than men. This female preponderance for abnormal autoimmune function has largely gone unexplained. Many investigations have concentrated on the effects of female and male sex hormones on immune function, by suggesting that estrogens favor the antibody production-enhancing Th2 response and, by doing so, possibly, increase the risk towards abnormal autoimmune function. Others have suggested that women are genetically predisposed towards abnormal autoimmune function, possibly because the X chromosome may confer susceptibility towards tolerance breakdown. Recent developments have, however, opened new research avenues. The possible association between persistent fetal-maternal microchimerism and the development of autoimmune diseases has attracted special interest. Since, in analogy to allogeneic organ transplantation, fetal-maternal (and maternal-fetal) microchimerism may play an important role in the immunologic tolerance of the fetal semi-allograft, female preponderance for autoimmune diseases may be understood as a consequence of increased allogeneic cell traffic in females (in comparison to males), increased risk for long-term microchimerism and, therefore, as a consequence of the former two, the development of abnormal autoimmunity. Under an evolutionary view point the occurrence of autoimmune diseases, in general, can be seen as the price to be paid for successful reproduction. In view of increased exposure to cell traffic, women, of course, would be expected to pay a higher price, reflected in more autoimmunity.