The influence of HLA-DR4 (0401) on the immune response to type II collagen and the development of collagen induced arthritis in mice.
Rheumatoid arthritis (RA) is an autoimmune disease that is genetically associated with the MHC class II molecule HLA-DRbeta1*0401 (DR4). In order to determine if this MHC can influence the immune response to the candidate autoantigen type II collagen (CII), we have studied collagen induced arthritis (CIA) resistant C57BL/6 mice, made transgenic (Tg) for human DR4. These DR4 Tg mice exhibited a strong T cell proliferative response to CII and its DR4 restricted peptide p261-273 after immunization with these antigens that was not seen in the C57BL/6 wild type mice. DR4 Tg mice also exhibited an increase in IFN-gamma production in response to CII, indicating the activation of Th1 cells. While these Tg mice produced IgM anti-CII antibodies, they failed to produce a detectable level of IgG2a (Th1 type) anti-bCII antibody and did not develop CIA. This study shows that a Th1 type T cell response to CII can be established in CIA non-susceptible mice by introducing the human transgene, DR4. This T cell response, however, is not sufficient to induce an antibody isotype switch to IgG2a, nor is it sufficient for the induction of CIA. These results may help to explain why many individuals expressing HLA-DRbeta1*0401 do not develop RA.
Wang
Dequn
D
Department of Medicine, Division of Rheumatology, The University of Western Ontario, London, Ontario, N6A 5A5, Canada.
Hill
Jonathan A
JA
Cairns
Ewa
E
Bell
David A
DA
D000595:Amino Acid Sequence; D000818:Animals; D001169:Arthritis, Experimental / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D001323:Autoantibodies / Q000096:biosynthesis; D001324:Autoantigens / Q000235:genetics; D024043:Collagen Type II / Q000235:genetics / Q000276:immunology*; D015804:HLA-DR4 Antigen / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007114:Immunization; D007074:Immunoglobulin G / Q000096:biosynthesis; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D024043:Collagen Type II; D015804:HLA-DR4 Antigen; D007074:Immunoglobulin G; D015847:Interleukin-4; D007371:Interferon-gamma