The effects of estrogen and prolactin on the regulation and function of B cells
Cleary, James M.
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Sex hormones have been suggested to contribute to the female preponderance of autoimmunity. Supporting this hypothesis is the fact that estrogen treatment has been shown to exacerbate autoimmunity in mouse models of lupus. Our laboratory has previously shown that estrogen treatment breaks tolerance in a mouse transgenic for the heavy chain of the R4A anti-DNA antibody. However, the mechanism by which estrogen modulates autoimmunity in lupus has remained unclear.;We postulated that estrogen directly affects the regulation and function of B cells. Examination of primary B cells revealed developmentally regulated expression of both known estrogen receptors (alpha and beta). B cells in estrogen treated mice showed an upregulation of bc1--2, shp-1 and cd22. A constitutively active estrogen receptor directly upregulated these genes in B cell lines. Finally, estrogen treated primary B cells were less susceptible to anti-IgM mediated apoptosis, demonstrating functional consequences to the changes in gene expression. These data suggest that estrogen may directly induce resistance to apoptosis in B lymphocytes, leading to the persistence of autoreactive B cells.;While showing that estrogen can directly act upon B cells, we hypothesized that estrogen may also indirectly affect the regulation and function of B cells through its ability to increase prolactin secretion. Prolactin has been suggested to promote autoimmunity in studies performed in both humans and mice. We showed that prolactin treatment breaks B cell tolerance in the R4A transgenic mouse by increasing both the survival and activation of autoreactive B cells. Like estrogen treated R4A transgenic mice, prolactin treated R4A transgenic mice showed an increase in titer of anti-DNA antibodies, an expanded population of autoreactive B cells, a large number of B cells spontaneously secreting anti-DNA antibodies, and glomerular IgG deposition. However, unlike estrogen treated R4A transgenic mice, prolactin treated R4A transgenic mice did not show an expansion of autoreactive B cells in the absence of T cells. Estrogen and prolactin appear to utilize different pathways to increase the survival of autoreactive B cells.;To better understand the mechanisms by which estrogen breaks tolerance, we tested the ability of tamoxifen to inhibit estrogen effects on B cells. We found that tamoxifen was able to inhibit only a subset of the estrogen-mediated effects on B cells. Tamoxifen was able to block the activation of anti-DNA B cells as shown by the fact that mice treated with both estrogen and tamoxifen have low titers of anti-DNA antibodies and lack B cells spontaneously secreting anti-DNA antibodies. However, tamoxifen did not block the estrogen-mediated expansion of anti-DNA B cells. These data show that there are multiple estrogen dependent pathways that are involved in the estrogen-mediated breakdown of tolerance. Furthermore, it shows that the survival and activation of autoreactive B cells are regulated by different pathways.