Estrogen alters thresholds for B cell apoptosis and activation
Christine M. Grimaldi, … , Dariush Moussai, Betty Diamond
Christine M. Grimaldi, … , Dariush Moussai, Betty Diamond
Published June 15, 2002
Citation Information: J Clin Invest. 2002;109(12):1625-1633. https://doi.org/10.1172/JCI14873.
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Article Immunology

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.

Authors

Christine M. Grimaldi, James Cleary, A. Selma Dagtas, Dariush Moussai, Betty Diamond

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IgM-mediated apoptosis in E2-treated splenic B cells. Levels of activate...
IgM-mediated apoptosis in E2-treated splenic B cells. Levels of activated caspase 3 were measured by flow cytometry to identify (a) B220+/CD24hi (transitional) and (b) B220+/CD24lo (mature) cells undergoing apoptosis. Representative histograms of splenocytes from P- and E2-treated mice incubated with anti-IgM (solid line) or without anti-IgM (dashed line) are shown. For anti-IgM–treated splenocytes, 26,661 (P) and 12,075 (E2) transitional B cell–gated events and 139,416 (P) and 127,235 (E2) mature B cell–gated events were examined, respectively. For untreated splenocytes, 20,912 (P) and 10,437 (E2) transitional B cell–gated events and 57,600 (P) and 64,489 (E2) mature B cell–gated events were examined, respectively. The experiment was performed on B cells from five mice in each treatment group, and similar results were observed for all mice within a group. The percentage of transitional B cells from E2-treated mice undergoing apoptosis was significantly reduced (P < 0.02) compared with P-treated mice. There was no significant reduction in the percentage of mature B cells undergoing apoptosis. (c) Splenic B cells isolated from ovariectomized mice BALB/c mice (n = 5) were incubated with E2 or the E2 antagonist ICI 182,780 5 hours before the addition of anti-IgM. Representative histograms from one of three experiments are shown. For B cells incubated with anti-IgM plus ICI 182,780, 2,382 lymphocyte-gated events were examined; for B cells incubated with anti-IgM plus E2, 4,161 lymphocyte-gated events were examined; for B cells incubated with ICI 182,780 alone, 6,426 lymphocyte-gated events were examined; and for B cells incubated with E2 alone, 7109 lymphocyte-gated events were examined. Anti–IgM-induced apoptosis was reduced in cells pretreated with E2 (P < 0.05).