title: Class II major histocompatibility complex-associated response to type XI collagen regulates the development of chronic arthritis in rats.
abstract: OBJECTIVE
  Chronic inflammation of the peripheral joints is a hallmark of rheumatoid arthritis (RA). The autoantibody response in RA has been shown to be directed mainly to ubiquitous antigens, whereas the response to cartilage proteins has been less extensively investigated. This study was undertaken to characterize the immune response in pristane-induced arthritis (PIA) in the rat to the cartilage-specific proteins type II collagen (CII) and type XI collagen (CXI) and to genetically fine-map their underlying major histocompatibility complex (MHC) associations.
  
  
  METHODS
  The genetic control of CII and CXI immunity was mapped using intra-MHC-recombinant inbred strains immunized with the respective collagens. Reactivity with CII and CXI was tested in acute and chronic PIA and in 356 HLA-typed patients with recently diagnosed RA.
  
  
  RESULTS
  Mapping of arthritis susceptibility within the MHC region revealed a 144-223-kb locus containing <12 genes, including paralogs for HLA-DQ and HLA-DR. Susceptibility to CII and CXI was linked to haplotypes RT1(av1)  (DA) and RT1(f)  (DA.1F), respectively. After injection of pristane, rats of both strains developed weak T cell and IgG responses to CII, but not to CXI. In chronic arthritis, however, collagen reactivity was stronger, specific for CXI, and restricted to rats with RT1(f)  MHC. Among RA patients, 12% exhibited a specific IgG response to CXI, 6% to CII, and 6% to both collagens.
  
  
  CONCLUSIONS
  These findings demonstrate a shift in cartilage recognition in early and chronic arthritis in the rat, suggesting that CXI autoreactivity contributes to the perpetuation of chronic disease. The results provide evidence of the importance of joint antigens in arthritis development.
authors.affiliation: Karolinska Institute, Stockholm, Sweden.
authors.forename: Jonatan
authors.initials: J
authors.lastname: Tuncel
authors.forename: Sabrina
authors.initials: S
authors.lastname: Haag
authors.forename: Stefan
authors.initials: S
authors.lastname: Carlsén
authors.forename: Anthony C Y
authors.initials: AC
authors.lastname: Yau
authors.forename: Shemin
authors.initials: S
authors.lastname: Lu
authors.forename: Harald
authors.initials: H
authors.lastname: Burkhardt
authors.forename: Rikard
authors.initials: R
authors.lastname: Holmdahl
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D000818:Animals; D001168:Arthritis / Q000097:blood / Q000209:etiology* / Q000276:immunology*; D015415:Biomarkers / Q000097:blood; D016022:Case-Control Studies; D002908:Chronic Disease; D024161:Collagen Type XI / Q000276:immunology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D005260:Female; D000949:Histocompatibility Antigens Class II / Q000032:analysis / Q000097:blood*; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D008285:Major Histocompatibility Complex / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D051381:Rats; D011919:Rats, Inbred Strains
chemical_list: D015415:Biomarkers; D024161:Collagen Type XI; D000949:Histocompatibility Antigens Class II; D007074:Immunoglobulin G