Gender and risk of autoimmune diseases: Possible role of estrogenic compounds

A striking common feature of many autoimmune diseases in humans and experim ental animals, despite differences in pathology, is that females are highly susceptible to autoimmune conditions compared to males. In several animal models, estrogens promote, whereas androgens abrogate, B-cell-mediated auto immune diseases. To understand mechanisms by which estrogens regulate autoi mmunity, it is first necessary to decipher estrogen effects on the normal i mmune system. Estrogen treatment of nonautoimmune mice diminished lymphocyt e numbers in both developmental and mature lymphoid organs. Estrogen dysreg ulated T- and B-cell balance by inducing selective T-cell hypoactivity and B-cell hyperactivity. Even though estrogen did not alter the relative perce ntages of splenic T-cell subsets, splenic lymphocytes had a reduced prolife rative response to T-cell stimulants and were refractory to rescue from act ivation-induced apoptosis compared to cells from placebo-treated mice. In c ontrast, estrogen induced B-cell hyperactivity (promoted autoantibodies to double-stranded DNA and phospholipids, increased numbers of plasma cells, a nd increased autoantibody yield per B cell). Note that treatment of normal mice with estrogen can alter T- and B-cell regulation and overcome B-cell t olerance to result in autoimmunity in normal individuals. Could environment al estrogens promote some human autoimmune disorders? Is there a link betwe en environmental estrogens and autoimmune disorders, especially since these disorders are reported possibly more frequently? These provocative questio ns warrant investigation. Our findings on immunomodulatory effects may serv e as a benchmark to examine whether endocrine-disrupting chemicals will hav e similar immunologic effects.