Rheumatoid arthritis (RA) is associated with HLA-DRB1 alleles expressing the "shared epitope". RA is usually preceded by the emergence of anti-citrullinated protein autoantibodies (ACPAs). ACPAs recognize citrulline residues on numerous proteins. Conversion of arginine into citrulline is performed by enzymes called peptidyl arginine deiminases (PADs). We have previously demonstrated that C3H mice immunized with PADs can produce ACPAs by a hapten-carrier mechanism. Here, we address the influence of HLA-DR alleles in this model in mice expressing RA-associated HLA-DRB1*04:01 (KO/KI*04:01) or HLA-DRB1*04:04 (KO/KI*04:04) or non RA-associated HLA-DRB1*04:02 (KO/KI*04:02) after murine PAD2 (mPAD2) immunization. Immunization with mPAD2 triggers production of ACPAs in wild type (WT) and HLA-DR4 C57BL/6 mice. Both I-Ab and HLA-DR are involved in the activation of mPAD2 specific T lymphocytes. Among HLA-DR4 mice, mice expressing RA-associated HLA-DRB1*04:01 are the best responders to mPAD2 and the best anti-citrullinated peptide antibody producers. This article is protected by copyright. All rights reserved.