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

J Autoimmun. 2010 Aug;35(1):1-9. doi: 10.1016/j.jaut.2009.12.007. Epub 2010 Jan 12.


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 IFNgamma. Male transgenic mice have higher number of T and B regulatory cells. An exogenous supply of 17beta 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.

Publication types

  • Comparative Study
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigen Presentation / drug effects
  • Arthritis, Rheumatoid / epidemiology
  • Arthritis, Rheumatoid / genetics
  • Arthritis, Rheumatoid / immunology*
  • Autoantigens / immunology
  • B-Lymphocytes / drug effects
  • B-Lymphocytes / immunology
  • B-Lymphocytes / metabolism*
  • B-Lymphocytes / pathology
  • Castration
  • Cells, Cultured
  • Estradiol / administration & dosage
  • Female
  • Genetic Predisposition to Disease
  • HLA-DR Antigens / genetics
  • HLA-DR Antigens / immunology
  • HLA-DR Antigens / metabolism*
  • HLA-DRB1 Chains
  • Humans
  • Immune Tolerance
  • Incidence
  • Interferon-gamma / metabolism
  • Interleukin-13 / metabolism
  • Lymphocyte Activation / drug effects
  • Male
  • Mice
  • Mice, SCID
  • Mice, Transgenic
  • Peptide Fragments / immunology
  • Sex Factors*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / metabolism*
  • T-Lymphocytes / pathology


  • Autoantigens
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen
  • Interleukin-13
  • Peptide Fragments
  • Estradiol
  • Interferon-gamma