title: Delineating the role of the HLA-DR4 "shared epitope" in susceptibility versus resistance to develop arthritis.
abstract: In humans, HLA-DR alleles sharing amino acids at the third hypervariable region with DRB1*0401(shared epitope) are associated with a predisposition to rheumatoid arthritis, whereas DRB1*0402 is not associated with such a predisposition. Both DRB1*0402 and DRB1*0401 occur in linkage with DQ8 (DQB1*0302). We have previously shown that transgenic (Tg) mice expressing HLA-DRB1*0401 develop collagen-induced arthritis. To delineate the role of "shared epitope" and gene complementation between DR and DQ in arthritis, we generated DRB1*0402, DRB1*0401.DQ8, and DRB1*0402.DQ8 Tg mice lacking endogenous class II molecules, AE(o). DRB1*0402 mice are resistant to develop arthritis. In double-Tg mice, the DRB1*0401 gene contributes to the development of collagen-induced arthritis, whereas DRB1*0402 prevents the disease. Humoral response to type II collagen is not defective in resistant mice, although cellular response to type II collagen is lower in *0402 mice compared with *0401 mice. *0402 mice have lower numbers of T cells in thymus compared with *0401 mice, suggesting that the protective effect could be due to deletion of autoreactive T cells. Additionally, DRB1*0402 mice have a higher number of regulatory T cells and show increased activation-induced cell death, which might contribute toward protection. In DRB1*0401.DQ8 mice, activated CD4(+) T cells express class II genes and can present DR4- and DQ8-restricted peptides in vitro, suggesting a role of class II(+) CD4 T cells locally in the joints. The data suggest that polymorphism in DRB1 genes determines predisposition to develop arthritis by shaping the T cell repertoire in thymus and activating autoreactive or regulatory T cells.
authors.affiliation: Department of Immunology, Mayo Clinic, Rochester, MN 55905, USA. taneja.veena@mayo.edu
authors.forename: Veena
authors.initials: V
authors.lastname: Taneja
authors.forename: Marshall
authors.initials: M
authors.lastname: Behrens
authors.forename: Eati
authors.initials: E
authors.lastname: Basal
authors.forename: Josh
authors.initials: J
authors.lastname: Sparks
authors.forename: Marie M
authors.initials: MM
authors.lastname: Griffiths
authors.forename: Harvinder
authors.initials: H
authors.lastname: Luthra
authors.forename: Chella S
authors.initials: CS
authors.lastname: David
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology* / Q000517:prevention & control; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000517:prevention & control; D017637:Clonal Deletion / Q000235:genetics; D018984:Epitopes, T-Lymphocyte / Q000235:genetics* / Q000502:physiology; D005260:Female; D020022:Genetic Predisposition to Disease; D006683:HLA-DQ Antigens / Q000235:genetics; D006684:HLA-DR Antigens / Q000235:genetics* / Q000502:physiology; D059811:HLA-DRB1 Chains; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D018984:Epitopes, T-Lymphocyte; D006683:HLA-DQ Antigens; C109756:HLA-DQ8 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; C553506:HLA-DRB1*04:02 antigen