Susceptibility to autoimmunity and B cell resistance to apoptosis in mice lacking androgen receptor in B cells.
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-kappaB, 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.
Altuwaijri
Saleh
S
Department of Pathology, University of Rochester Medical Center, Rochester, New York 14642, USA.
Chuang
Kuang-Hsiang
KH
Lai
Kuo-Pao
KP
Lai
Jiann-Jyh
JJ
Lin
Hung-Yun
HY
Young
Faith M
FM
Bottaro
Andrea
A
Tsai
Meng-Yin
MY
Zeng
Wei-Ping
WP
Chang
Hong-Chiang
HC
Yeh
Shuyuan
S
Chang
Chawnshang
C
D019264:Adoptive Transfer; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001169:Arthritis, Experimental / Q000276:immunology; D015551:Autoimmunity / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000276:immunology / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology* / Q000502:physiology; D005260:Female; D006706:Homeostasis; D007136:Immunoglobulins / Q000097:blood; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism*
D007136:Immunoglobulins; D034741:RNA, Small Interfering; D011944:Receptors, Androgen