Estrogen alters thresholds for B cell apoptosis and activation

Abstract

Estrogen is thought to contribute to the increased frequency of autoimmune disorders occurring in females, but a molecular basis for its effects on autoimmunity remains to be elucidated. We have shown previously that estrogen leads to the survival and activation of autoreactive cells in the naive repertoire. To identify the molecular pathways involved in B cell tolerance, we sought to identify genes that are differentially regulated by estrogen in mouse B cells. Several genes involved in B cell activation and survival, including cd22, shp-1, bcl-2, and vcam-1, were upregulated by estrogen in B cells. We found that overexpression of CD22 and SHP-1 in B cells decreased B cell receptor signaling. Estrogen receptors α and β are expressed on B cells and are functional, since they can directly upregulate expression of CD22, SHP-1, and Bcl-2. Estrogen treatment protected isolated primary B cells from B cell receptor-mediated apoptosis. These results suggest that estrogen induces a genetic program that alters survival and activation of B cells in a B cell-autonomous fashion and thus skews the naive immune system toward autoreactivity.

Sex differences in Tfh cell help to B cells contribute to sexual dimorphism in severity of rat collagen-induced arthritis

“…In a model of RA induced by transfer of hematopoietic stem cells from RA patients into immunodeficient mice, more B cells were retrieved from peripheral blood of female recipients compared with male recipients, indicating that sex-specific extrinsic microenvironmental factors rather than B-cell intrinsic factors contributed to the sex differences in the B-cell number 56 . Additionally, it was shown that estrogen increases the number of autoreactive B cells in the naive repertoire by protecting/increasing the survival of the immature B cells that would normally be deleted 57 . The greater proliferation of B cells in CII-stimulated dLN cell cultures from female compared with male rats is fully consistent with this finding.…”

“…The greater proliferation of B cells in CII-stimulated dLN cell cultures from female compared with male rats is fully consistent with this finding. Furthermore, it was found that estrogen acting directly on B cells upregulates not only genes involved in B-cell survival but also in their activation 57 . These findings have been associated with an increased propensity towards the development of autoimmune diseases in female compared with male rats 57 .…”

“…Furthermore, it was found that estrogen acting directly on B cells upregulates not only genes involved in B-cell survival but also in their activation 57 . These findings have been associated with an increased propensity towards the development of autoimmune diseases in female compared with male rats 57 . In the same vein, androgens were shown to have the opposite effect on B-cell survival providing an additional explanation for sex differences in susceptibility to antibody-mediated autoimmune diseases 58 .…”

Immune Tumor Microenvironment in Breast Cancer and the Participation of Estrogen and Its Receptors in Cancer Physiopathology

“…These effects were observed in splenic B cells derived from ovariectomized mice (or not) administered with it. Interestingly, these results were reverted in mice treated with ICI 182,780 (128). Regarding the effects of GPR30 on B lymphocytes, some reports have mentioned that different chemokines can activate it, triggering different roles of B subsets such as migration, chemotaxis, proliferation, and apoptosis, among others.…”

“…B lymphocytes are part of the adaptive immune system that is specialized in antibody production, which is part of humoral immunity (127). It has been described that B lymphocytes have the expression of both nuclear ERs in all B cell subsets (39, 128). In this sense, E2 has stimulatory effects on B-differentiated lymphocytes derived from human PBMCs.…”