Estrogen alters thresholds for B cell apoptosis and activation.
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 alpha and beta 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.
Grimaldi
Christine M
CM
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York 10461, USA.
Cleary
James
J
Dagtas
A Selma
AS
Moussai
Dariush
D
Diamond
Betty
B
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D000944:Antigens, Differentiation, B-Lymphocyte / Q000235:genetics*; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology / Q000378:metabolism*; D015815:Cell Adhesion Molecules; D002478:Cells, Cultured; D004958:Estradiol / Q000008:administration & dosage / Q000494:pharmacology*; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D015870:Gene Expression; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D011960:Receptors, Estrogen / Q000235:genetics; D051918:Sialic Acid Binding Ig-like Lectin 2; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics*
D015703:Antigens, CD; D000944:Antigens, Differentiation, B-Lymphocyte; C497867:CD22 protein, human; C497868:Cd22 protein, mouse; D015815:Cell Adhesion Molecules; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D047908:Intracellular Signaling Peptides and Proteins; D037102:Lectins; D019253:Proto-Oncogene Proteins c-bcl-2; D011960:Receptors, Estrogen; D051918:Sialic Acid Binding Ig-like Lectin 2; D019010:Vascular Cell Adhesion Molecule-1; D004958:Estradiol; C509249:PTPN6 protein, human; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C509248:Ptpn6 protein, mouse