Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCP) affects severity of rheumatoid arthritis

Objective

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. The relationship between HLA class II polymorphisms and RA-specific IgG anti-cyclic citrullinated peptide (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 4 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 frequently 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 with 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).

Conclusions

Anti-CCP antibodies are associated with HLA class II RA susceptibility alleles and presence of both factors is indicative of a severe disease course. As the principal role of HLA class II molecules is antigen presentation to T cells, these data point toward a pivotal role of citrulline-directed T cells in the production of anti-CCP antibodies.