Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice

Marshall Behrens, Theodore Trejo, Harvinder Luthra, Marie Griffiths, Chella S. David, Veena Taneja

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

HLA class II allele DRB1*0401 is associated with predisposition to Rheumatoid Arthritis in humans as well as collagen-induced arthritis in mice. Predominantly females develop arthritis in humans and DR4 transgenic mice; however the mechanism of sex-bias is still unknown. We have investigated the molecular basis by which DR4 is associated with sex-bias of arthritis. Here we show that differential antigen-specific immune mechanisms in DR4 male and female mice lead to increased susceptibility in female mice. B cells are hyperactive and present DR-restricted peptides robustly in females compared to males. Antigen-specific response showed that females produced B cell modulating cytokines like IL-13 while males produced IFNγ. Male transgenic mice have higher number of T and B regulatory cells. An exogenous supply of 17β estradiol in male mice led to enhanced expression of DR4 and antigen-specific response to DR4-restricted peptides. On the other hand, castration increased the incidence of arthritis. We propose that sex-bias in arthritis involves B cells and presentation of antigen by HLA-DR4 leading to activation of autoreactive cells and autoantibodies production in females, while regulatory B cells in males protect them from pathogenesis. The transgenic mice expressing RA susceptible haplotype simulate human RA and may be valuable to study gender differences observed in patients.

Original languageEnglish (US)
Pages (from-to)1-9
Number of pages9
JournalJournal of Autoimmunity
Volume35
Issue number1
DOIs
StatePublished - Aug 1 2010

Keywords

  • Antigen presentation
  • HLA-DR4
  • Rheumatoid arthritis
  • Sex-bias
  • Transgenic mice

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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