ASSOCIATION BETWEEN HLA CLASS II GENES AND AUTOANTIBODIES TO CYCLIC CITRULLINATED PEPTIDES (CCP) AFFECTS SEVERITY OF RHEUMATOID ARTHRITIS

Background: The 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.Objectives: The relationship between HLA class II gene polymorphisms and RA specific IgG anti-cyclic citrullinated peptides (CCP) antibodies was investigated.Methods: High resolution HLA-DR and DQ typing and anti-CCP2 antibody testing was performed in 279 RA patients from the Leiden Early Arthritis cohort. 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 four years by scoring radiographs of hands and feet using the Sharp/Van der Heijde method.Results: 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 (OR 2.9; 95% CI 1.6 – 5.2 and OR 10.2; 95% CI 3.8 – 28.5, respectively).In SE carrying, anti-CCP antibody positive patients an increased rate of joint destruction was observed (mean Sharp-score 7.6 points/year) compared to non-SE carrying, anti-CCP positive (2.4 points, p=0.03), SE carrying, anti-CCP-negative patients (1.6 points, p<0.001) and non-SE carrying, anti-CCP negative patients (1.6 points, p<0.001).Conclusion: HLA class II RA susceptibility alleles are associated with production of anti-CCP antibodies. In addition, a more severe disease progression is found in RA patients with both anti-CCP antibodies and SE alleles even compared to patients with either anti-CCP antibodies or SE alleles alone.As the principal role of HLA class II molecules is antigen presentation to T-cells, these data point towards a pivotal role of citrulline-directed T cells in the production of anti-CCP antibodies.Citation: , volume , supplement , year 2004, page Session: Advances in genetics – A molecular basis of inflammatory diseases