Systemic lupus erythematosus (SLE) is an autoimmune disease mediated by the production of pathogenic? autoantibodies. As with many autoimmune disorders, the factors that contribute to SLE are complex, but it is? clear that genetics, environment and gender contribute to disease susceptibility and pathogenesis. For decades? it has been speculated that the sex hormone estrogen contributes to the increased occurrence of SLE in? females. A recently completed clinical study demonstrated that SLE patients receiving hormone replacement? therapy experienced significantly more flares than patients receiving placebo, thus, providing clear evidence? that estrogen can exacerbate disease in some patients. Since little is known about the immunomodulatory? effects of estrogen, we have been studying the effects of estrogen administration on B cell tolerance. Our? laboratory have shown that administration of 17 beta-estradiol into nonautoimmune BALB/c mice that harbor? the R4A transgene for the heavy chain of a pathogenic anti-DNA antibody results in the loss of B cell? tolerance and induces a lupus phenotype in these mice.? To further understand how estrogen alters B cell tolerance, we have obtained mice with targeted deletions in? the estrogen receptor genes. To date, two estrogen receptors (ER), ERalpha and ERbeta, have been identified.? When bound by estrogen, these receptors act as transcription factors to induce the expression of numerous? gene products. The functional distinctions between ERalpha and ERbeta remain to be elucidated, but there is? evidence that they may differ in gene activation. Since B cells express both ERalpha and ERbeta, we hypothesize? that B cells are directly estrogen responsive and the that activation of these receptors by estrogen induces a? genetic program that alters B cell tolerance. From these studies we will determine if one or both estrogen? receptors affects the selection, survival and activation of autoreactive B cells and whether these receptors act? in a synergistic or antagonistic manner. Results from these studies have important clinical implications since? selective estrogen receptor modulators can potentially be developed that act as clinically focused therapeutic? agents in lupus patients with an estrogen exacerbated disease.
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