Mechanism by which HLA-DR4 regulates sex-bias of arthritis in humanized mice.
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.
Behrens
Marshall
M
Department of Immunology, Mayo Clinic, 200 Ist St. S.W., Rochester, MN 55905, USA.
Trejo
Theodore
T
Luthra
Harvinder
H
Griffiths
Marie
M
David
Chella S
CS
Taneja
Veena
V
D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects; D001172:Arthritis, Rheumatoid / Q000453:epidemiology / Q000235:genetics / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002369:Castration; D002478:Cells, Cultured; D004958:Estradiol / Q000008:administration & dosage; D005260:Female; D020022:Genetic Predisposition to Disease; D006684:HLA-DR Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D059811:HLA-DRB1 Chains; D006801:Humans; D007108:Immune Tolerance; D015994:Incidence; D007371:Interferon-gamma / Q000378:metabolism; D018793:Interleukin-13 / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008822:Mice, Transgenic; D010446:Peptide Fragments / Q000276:immunology; D012737:Sex Factors; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology
D001324:Autoantigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D018793:Interleukin-13; D010446:Peptide Fragments; D004958:Estradiol; D007371:Interferon-gamma