Estrogens have been linked to a higher female incidence of autoimmune diseases. The role of androgen and the androgen receptor (AR) in autoimmune diseases, however, remains unclear. Here we report that the lack of AR in B cells in different strains of mice, namely general AR knockout, B cell-specific AR knockout, and naturally occurring testicular feminization mutation AR-mutant mice, as well as castrated wild-type mice, results in increased B cells in blood and bone marrow. Analysis of the targeted mice, together with bone marrow transplantation using Rag1−/− recipients, overexpression of retrovirally encoded AR-cDNA, and small interfering RNA-mediated AR mRNA knockdown approaches also show that the B cell expansion results from resistance to apoptosis and increased proliferation of bone marrow precursor B cells, accompanied by changes in several key modulators related to apoptosis, such as Fas/FasL signals, caspases-3/-8, nuclear factor-κB, and Bcl-2. We also show that the effects of AR loss are, in part, B cell intrinsic. Mice bearing AR-deficient B cells show increased levels of serum IgG2a and IgG3 as well as basal double-stranded DNA-IgG antibodies and are more vulnerable to development of collagen-induced arthritis. Together, these data indicate that androgen/AR play a crucial role in B cell homeostasis and tolerance. Therapies targeting AR might provide an alternative strategy with which to battle autoimmune diseases
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