Modulation of HLA-DQ-restricted collagen-induced arthritis by HLA-DRB1 polymorphism.
Mouse class II-deficient HLA-DQB1*0302, DQA1*0301 (DQ8) transgenic mice are susceptible to severe collagen-induced arthritis (CIA), an animal model for rheumatoid arthritis. To examine whether polymorphism at the DRB1 locus can modulate DQ-restricted arthritis, we generated double-transgenic (DR/DQ) mice. HLA-DRB1*1502 (DR2) and DRB1*0301 (DR3) were introduced separately into CIA susceptible DQ8.Abeta transgenic mice to generate DQ8/DR2.Abeta and DQ8/ DR3.AbetaO mice. The HLA-DR molecules in these mice were found to be functional on the basis of their positive/negative selection of the Vbeta T cell repertoire. Introduction of the DR2 gene led to a significant decrease in disease incidence in DQ8.Abeta mice, while the DR3 transgene had no effect. In vitro T cell proliferative responses against bovine Cll collagen in primed mice were higher in DQ8/DR3 mice compared with DQ8/DR2 mice. Cytokine analysis showed a Th2 profile in DQ8/DR2 mice, while DQ8/DR3 mice showed a Th1 profile. These results suggest that DRB1 polymorphism can modulate the disease.
Taneja
V
V
Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA.
Griffiths
M M
MM
Luthra
H
H
David
C S
CS
D000818:Animals; D001168:Arthritis / Q000139:chemically induced*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced; D003094:Collagen / Q000494:pharmacology; D004195:Disease Models, Animal; D006683:HLA-DQ Antigens / Q000096:biosynthesis / Q000276:immunology*; D006684:HLA-DR Antigens / Q000096:biosynthesis / Q000235:genetics*; D059811:HLA-DRB1 Chains; D007074:Immunoglobulin G / Q000097:blood; D015847:Interleukin-4 / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010455:Peptides / Q000494:pharmacology; D011110:Polymorphism, Genetic / Q000502:physiology; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology
D006683:HLA-DQ Antigens; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553502:HLA-DRB1*03:01 antigen; D007074:Immunoglobulin G; D010455:Peptides; D016693:Receptors, Antigen, T-Cell, alpha-beta; D015847:Interleukin-4; D003094:Collagen