title: Antibodies to type II collagen and HLA disease susceptibility markers in rheumatoid arthritis.
abstract: OBJECTIVE
  To seek associations between antibodies to native and denatured type II collagen (NCII and DCII) and HLA in rheumatoid arthritis (RA).
  
  
  METHODS
  One hundred fourteen patients with clinically well-defined RA were HLA-DR and DQ typed. Those who were DR4 positive were subtyped for DRB1*0401-*0408 alleles by polymerase chain reaction using allele-specific oligonucleotide probes. Antibodies to human NCII and DCII (heat-denatured) were measured by enzyme-linked immunosorbent assay. The frequency of HLA alleles was compared in patients grouped according to the presence and absence of antibodies to NCII and DCII.
  
  
  RESULTS
  Twenty-seven patients (24%) were positive for antibodies to NCII. There was a significant increase in the frequency of HLA-DR7 in anti-NCII-positive patients compared with anti-NCII-negative patients (30% versus 9%; P = 0.019) and a significant decrease in HLA-DR3 (7% versus 28%; P = 0.044). Repeating the analyses after excluding the 16 patients who were DR7 positive revealed a significant increase in the frequency of HLA-DR1 in anti-NCII-positive patients compared with anti-NCII-negative patients (63% versus 27%; P = 0.045). Moreover, antibodies to NCII were associated with the third hypervariability region susceptibility sequence QRRAA that is present in DRB1*0101, *0404, *0405, and *0408 (84% versus 47%; P = 0.0085); 24 of 27 anti-NCII-positive patients were positive for either DR7, DR1, or DRB1*0404 or *0408. Thirty patients (26%) were positive for antibodies to DCII. There was a significant increase in the frequency of HLA-DR3 in anti-DCII-positive patients compared with anti-DCII-negative patients (40% versus 18%; P = 0.028).
  
  
  CONCLUSIONS
  The genetic associations between HLA-DR alleles and antibodies to CII in RA patients is in keeping with the collagen-induced arthritis model and implicates autoimmunity to CII as a major component in the multifactorial pathogenesis of RA.
authors.affiliation: Monash University, Clayton, Victoria, Australia.
authors.forename: A D
authors.initials: AD
authors.lastname: Cook
authors.forename: A
authors.initials: A
authors.lastname: Stockman
authors.forename: C A
authors.initials: CA
authors.lastname: Brand
authors.forename: B D
authors.initials: BD
authors.lastname: Tait
authors.forename: I R
authors.initials: IR
authors.lastname: Mackay
authors.forename: K D
authors.initials: KD
authors.lastname: Muirden
authors.forename: C C
authors.initials: CC
authors.lastname: Bernard
authors.forename: M J
authors.initials: MJ
authors.lastname: Rowley
mesh_terms: D000483:Alleles; D000906:Antibodies; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D003094:Collagen / Q000276:immunology*; D004198:Disease Susceptibility / Q000276:immunology*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005838:Genotype; D006680:HLA Antigens / Q000276:immunology*; D006684:HLA-DR Antigens / Q000235:genetics; D006801:Humans; D011110:Polymorphism, Genetic
chemical_list: D000906:Antibodies; D006680:HLA Antigens; D006684:HLA-DR Antigens; D003094:Collagen