B cells as effectors and regulators of sex-biased arthritis

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.

Keywords::

• B regulatory cells
• antigen presentation
• MHC polymorphism
• HLA transgenic mice
• Rheumatoid arthritis

Acknowledgements

We thank Marshall Behrens and Michele Smart for their help with the arthritis model in transgenic mice. Studies are supported by NIH grants AI 75262, AR60077 and AR30752.

Declaration of Interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.