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Susceptibility to Autoimmunity and B Cell Resistance to Apoptosis in Mice Lacking Androgen Receptor in B Cells

Departments of Pathology, Urology, Microbiology and Immunology, and the Cancer Center (S.A., K.-H.C., K.-P.L., J.-J.L., H.-Y.L., F.M.Y., A.B., M.-Y.T., W.-P.Z., H.-C.C., S.Y., C.C.), University of Rochester Medical Center, Rochester, New York 14642; Clinical Research Laboratory (S.A.), Saad Specialist Hospital, Al Khobar 31952, Saudi Arabia; Center for Menopause and Reproductive Medicine Research (M.-Y.T.)., Chang Gung University/Hospital, Kaohsiung 333, Taiwan; and Department of Urology (H.-C.C.), National Taiwan University/Hospital, Taipei 10603, Taiwan

Address all correspondence and requests for reprints to: Dr. Chawnshang Chang, Ph. D., University of Rochester Medical Center, 601 Elmwood Avenue, Box 626, Rochester, New York, 14642. E-mail: chang{at}URMC.rochester.edu.

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-B, 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.

NURSA Molecule Pages Link:

Nuclear Receptors:   AR

Ligands:   Dihydrotestosterone