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.

Polymorphisms in cytochrome P450 17A1 and risk of non‐Hodgkin lymphoma

“…The association of the CYP17A1 )34CC genotype and Hap3 haplotype with increased risk of DLBCL in both men and women suggests a role for oestrogen and possibly other cholesterol metabolites formed via CYP17A1 in the pathogenesis of DLBCL. Oestrogen exerts pleiotropic effects on lymphocyte activation, proliferation, cell cycle progression and apoptosis, factors that may influence lymphoma risk (Grimaldi et al, 2002). In B-cells, oestrogen mediates its anti-apoptotic effects through upregulation of BCL-2.…”

The influence of pregnancy on systemic immunity

“…Medina and Kincade have shown convincingly that estrogen reduces B-cell lymphopoiesis during pregnancy [41]. Grimaldi et al [42] have reported on the effects of estrogen on B-cell activity. We reported that this reduction is reflected by week 34 when peripheral CD19?…”

The X-files in immunity: sex-based differences predispose immune responses

“…oestrogens also affect B-cell development by decreasing negative selection of naive immature B cells, enhancing the survival of autoreactive B cells 31 and enhancing polyclonal activation of B cells, which leads to higher serum levels of IgG and Igm (mediated by CD95-CD95L interactions 32 ). These B-cell effects might contribute to the increased incidence of many autoimmune diseases in women.…”