title: Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis.
abstract: OBJECTIVE
  The functional role of HLA class II molecules in the pathogenesis of rheumatoid arthritis (RA) is unclear. HLA class II molecules are involved in the interaction between T and B lymphocytes required for long-lived B cell responses and generation of high-affinity IgG antibodies. We undertook this study to investigate the relationship between HLA class II gene polymorphisms and RA-specific IgG antibodies against cyclic citrullinated peptides (anti-CCP antibodies).
  
  
  METHODS
  High-resolution HLA-DR and DQ typing and anti-CCP-2 antibody testing were performed on 268 RA patients from the Early Arthritis Clinic cohort at the Department of Rheumatology of the Leiden University Medical Center. The presence of anti-CCP antibodies was analyzed in carriers of the different DR and DQ alleles. Disease progression was measured over a period of 4 years by scoring radiographs of the hands and feet using the Sharp/van der Heijde method.
  
  
  RESULTS
  Carriership of the individual alleles HLA-DRB1*0401, DRB1*1001, DQB1*0302, and DQB1*0501 was associated with the presence of anti-CCP antibodies. Carriers of DQ-DR genotypes containing proposed RA susceptibility alleles were significantly more often anti-CCP antibody positive. Carriership of one or two HLA-DRB1 shared epitope (SE) alleles was significantly associated with production of anti-CCP antibodies (odds ratio [OR] 3.3, 95% confidence interval [95% CI] 1.8-6.0 and OR 13.3, 95% CI 4.6-40.4, respectively). An increased rate of joint destruction was observed in SE+, anti-CCP+ patients (mean Sharp score 7.6 points per year) compared with that in SE-, anti-CCP+ patients (2.4 points per year) (P = 0.04), SE+, anti-CCP- patients (1.6 points per year) (P < 0.001), and SE-, anti-CCP- patients (1.6 points per year) (P < 0.001).
  
  
  CONCLUSIONS
  HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. Moreover, more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles.
authors.affiliation: Leiden University Medical Center, Leiden, The Netherlands. f.a.van_gaalen@lumc.nl
authors.forename: Floris A
authors.initials: FA
authors.lastname: van Gaalen
authors.forename: Jill
authors.initials: J
authors.lastname: van Aken
authors.forename: Tom W J
authors.initials: TW
authors.lastname: Huizinga
authors.forename: Geziena M Th
authors.initials: GM
authors.lastname: Schreuder
authors.forename: Ferdinand C
authors.initials: FC
authors.lastname: Breedveld
authors.forename: Eric
authors.initials: E
authors.lastname: Zanelli
authors.forename: Walther J
authors.initials: WJ
authors.lastname: van Venrooij
authors.forename: Cornelis L
authors.initials: CL
authors.lastname: Verweij
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.forename: René R P
authors.initials: RR
authors.lastname: de Vries
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D000917:Antibody Formation; D001172:Arthritis, Rheumatoid / Q000000981:diagnostic imaging / Q000235:genetics* / Q000276:immunology*; D001323:Autoantibodies / Q000032:analysis*; D015415:Biomarkers; D015331:Cohort Studies; D018450:Disease Progression; D000939:Epitopes / Q000235:genetics; D005260:Female; D005802:Genes, MHC Class II / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006683:HLA-DQ Antigens / Q000235:genetics; D059866:HLA-DQ beta-Chains; D006684:HLA-DR Antigens / Q000235:genetics; D059811:HLA-DRB1 Chains; D006579:Heterozygote; D006801:Humans; D007074:Immunoglobulin G / Q000032:analysis; D008297:Male; D008875:Middle Aged; D010456:Peptides, Cyclic / Q000276:immunology*; D011110:Polymorphism, Genetic; D011859:Radiography; D012720:Severity of Illness Index; D016037:Single-Blind Method
chemical_list: D001323:Autoantibodies; D015415:Biomarkers; D000939:Epitopes; D006683:HLA-DQ Antigens; D059866:HLA-DQ beta-Chains; C069051:HLA-DQB1 antigen; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C553505:HLA-DRB1*04:01 antigen; D007074:Immunoglobulin G; D010456:Peptides, Cyclic; C487763:cyclic citrullinated peptide