Fine specificity of the anti–citrullinated protein antibody response is influenced by the shared epitope alleles

Objective In classic studies on the genetic background of antibody production, the major histocompatibility complex (MHC) has been shown to act as the most prominent immune response gene that controls the magnitude and the specificity of antibody production. The strongest genetic risk factor for rheumatoid arthritis (RA), the human MHC HLA–DRB1 shared epitope (SE) alleles, predisposes for antibodies against citrullinated proteins (ACPAs). ACPA levels are higher in SE‐positive patients with RA than in SE‐negative patients with RA. The aim of the present study was to determine whether SE influences not only the magnitude but also the specificity of the ACPA response. Methods In 2 cohorts of anti–citrullinated peptide 2–positive patients with RA, one from a study of recent‐onset arthritis (n = 206) and the other from a treatment strategy study (n = 141), serum antibodies against a citrullinated peptide derived from vimentin (cVim) and antibodies against a citrullinated fibrinogen peptide (cFibr) were determined by enzyme‐linked immunosorbent assay. HLA–DRB1 genotyping was performed. Results In the first cohort, SE alleles were significantly associated with the presence of antibodies against cVim (odds ratio [OR] 4.95, 95% confidence interval [95% CI] 1.87–15.3) and were not significantly associated with the presence of antibodies against cFibr (OR 1.71, 95% CI 0.70–4.14). These results were replicated in the second cohort (OR 5.05, 95% CI 1.92–13.6 and OR 1.19, 95% CI 0.30–3.97, respectively). Conclusion In 2 cohorts of ACPA‐positive patients with RA, SE alleles predisposed for the development of antibodies against cVim but not for the development of antibodies against cFibr. These data indicate that SE alleles act as “classic” immune response genes in the ACPA response, because they influence both the magnitude and the specificity of this RA‐specific antibody response.