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Review
. 2012 Aug;45(5):364-76.
doi: 10.3109/08916934.2012.665528.

B cells as effectors and regulators of sex-biased arthritis

David Luckey  1 , Kay Medina, Veena Taneja
Affiliations
Review

B cells as effectors and regulators of sex-biased arthritis

David Luckey et al. Autoimmunity. 2012 Aug.

Abstract

B cells have been implicated both with pathogenic as well as protective capabilities in induction and regulation of autoimmune diseases. Rheumatoid arthritis (RA) is an autoimmune disease that occurs more often in women than men. A significant role of B cells as antibody producing and antigen-presenting cells has been demonstrated in RA. Predisposition to RA is associated with the presence of certain HLA class II alleles that share sequences with DRB1*0401. To determine the role of HLA genes and B cells in vivo, we have generated transgenic mice carrying HLA genes, DRB1*0401 and DQ8, known to be associated with susceptibility to RA. Humanized mice can be induced to develop arthritis that mimics human disease in clinical, histopathological and sex bias. Effect of hormones on immune cells and their function has been described in humans and mice and has been suggested to be the major reason for female bias of autoimmune diseases. An immune response to an antigen requires presentation by HLA molecules thus suggesting a critical role of MHC in combination with sex hormones in susceptibility to develop rheumatoid arthritis. Based on our observations, we hypothesize that modulation of B cells by estrogen, presentation of modified antigens by DR4 and production of antigen-specific B cell modulating cytokines leads to autoreactivity in females. These data suggest that considering patient's sex may be crucial in selecting the optimal treatment strategy. Humanized mice expressing RA susceptible and resistant haplotype provide a means to investigate mechanism sex-bias of arthritis and future strategies for therapy.

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Figures

Figure 1
Figure 1
Checkpoints for B cell tolerance during maturation.
Figure 2
Figure 2
Genetic (HLA) and environmental (Cigarette smoke, infections) factors predispose an individual to develop autoimmunity. The onset of clinical symptoms of autoimmune disease are preceded by several years of activation of T and B cells leading to production of autoantibodies and ultimate a break in tolerance, tissue damage and epitope spreading of the organ-specific autoantigen.
Figure 3
Figure 3
HLA-DQ8 mice are susceptible to collagen-induced arthritis and HLA-DQ6 mice are resistant. DQ8 mice produce higher amounts of anti-type II collagen antibodies against chick type II collagen (CII) and mouse CII (MCII) compared to DQ6 mice upon immunization with CII. Naïve DQ8 and DQ6 mice do not differ in absolute numbers of splenic antigen presenting cells, CD11c and B cells.
Figure 4
Figure 4
DRB1*0401-restricted antigen presentation by B cells regulates sex bias of arthritis. Estrogen modulates B cell functions; increasing their survival, antigen presentation and autoantibody production. Males have higher numbers of B regulatory cells that may expand during immune response and produce IL-10 thus inhibiting T cell proliferation and limiting autoreactivity and autoantibody production. Antigen presentation via B cells in females leads to production of B cell modulating cytokines that increase their survival and proliferation thus enhancing autoreactive immune response. This suggests that males need to have a higher genetic load to develop autoimmunity.
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