Susceptibility to autoimmunity and B cell resistance to apoptosis in mice lacking androgen receptor in B cells

Saleh Altuwaijri, Kuang Hsiang Chuang, Kuo Pao Lai, Jiann Jyh Lai, Hung Yun Lin, Faith M. Young, Andrea Bottaro, Meng Yin Tsai, Wei Ping Zeng, Hong Chiang Chang, Shuyuan Yeh, Chawnshang Chang

Research output: Contribution to journalArticlepeer-review

56 Scopus citations

Abstract

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 thetargeted mice, together with bone marrowtransplantation 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. (Molecular Endocrinology 23: 444-453, 2009)

Original languageEnglish (US)
Pages (from-to)444-453
Number of pages10
JournalMolecular Endocrinology
Volume23
Issue number4
DOIs
StatePublished - Apr 2009
Externally publishedYes

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Endocrinology

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