In classic studies on the genetic background of antibody production, 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 (ACPA). ACPA levels are higher in SE-positive than in SE-negative RA patients. The present study determines whether SE not only influences the magnitude, but also the specificity of the ACPA response.

In two independent cohorts of anti-CCP2-positive RA patients (n = 206 and n = 214 patients, respectively), serum antibodies against a citrullinated peptide derived from vimentin (cVim) and antibodies against a citrullinated fibrinogen peptide (cFibr) were determined by ELISA. HLA-DRB1 genotyping was performed.

In the first cohort, SE alleles were significantly associated with the presence of antibodies against cVim (OR = 4.55, 95% CI = 1.78–12.9) and not significantly with the presence of antibodies against cFibr (OR = 1.81, 95% CI = 0.78–4.13). These results were replicated in the second cohort (OR = 4.13, 95% CI = 1.68–10.3 and OR = 1.08, 95% CI = 0.34–3.23, respectively).

In two cohorts of ACPA-positive RA patients, SE alleles predispose for the development of antibodies against cVim, and not for the development of antibodies against cFibr. These data indicate that SE alleles act as 'classic' immune-response genes in the ACPA response, as they influence both the magnitude and the specificity of this RA-specific antibody response.