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Multiple antibody reactivities to citrullinated antigens in sera from rheumatoid arthritis patients – association with HLA-DRB1 alleles
  1. Omri Snir
  1. Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Sweden
    1. Mona Widhe
    1. Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Sweden
      1. Caroline von Spee
      1. Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Sweden
        1. Johan Lindberg
        1. Department of Gene Technology, AlbaNova University Center, Royal Institute of Technology, Sweden
          1. Leonid Padyukov
          1. Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Sweden
            1. Karin Lundberg
            1. Kennedy Institute of Rheumatology, Imperial College, United Kingdom
              1. Åke Engström
              1. Uppsala Bimediacal Center, IMBIM, Sweden
                1. Patrick J Venables
                1. Kennedy Institute of Rheumatology, Imperial College, United Kingdom
                  1. Joakim Lundeberg
                  1. Department of Gene Technology, AlbaNova University Center, Royal Institute of Technology, Sweden
                    1. Rikard Holmdahl
                    1. Medical Inflammation Research, Lund University, Sweden
                      1. Lars Klareskog
                      1. Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Sweden
                        1. Vivianne Malmström (vivianne.malmstrom{at}ki.se)
                        1. Rheumatology Unit, Department of Medicine at Karolinska University Hospital, Karolinska Institute, Sweden

                          Abstract

                          Objective: Autoantibodies to cyclic citrullinated peptides (CCP) are present in the majority of rheumatoid arthritis (RA) patients, and associate with HLA-DRB1 shared epitope (SE) alleles. Here we investigated reactivities to various citrullinated proteins/peptides, which represent potential autoantigens in RA. We studied the relationship between such antibodies as well as their association with genetic variants within HLA-DRB1 SE alleles.

                          Methods: Sera from 291 patients with established RA and 100 sex and age matched healthy subjects were included in this study. Sera were first analyzed for presence of anti-CCP antibodies and further for IgG and IgA antibodies toward candidate autoantigens in both their native and citrullinated form including: fibrinogen, alpha-enolase peptide-1 and the C1-epitope of type-II collagen (C1III). Antibody specificity was confirmed by cross reactivity tests. HLA-DR genotyping was performed.

                          Results: 72% of the RA patients were anti-CCP positive. Amongst the candidate autoantigens examined, IgG antibodies to citrullinated-fibrinogen were found in 66% of patients’ sera and in 41% for both citrullinated alpha-enolase peptide-1 and citrullinated C1III. These antibodies were mainly seen in the anti-CCP-positive patient group, they were specific for their respective antigen and displayed limited cross-reactivity. IgA responses were also detected, but less frequent than IgG. Anti-CCP as well as anti citrullinated protein antibodies were associated with the HLA-DRB1*04 rather than with HLA-DRB1*01.

                          Conclusions: Antibodies directed against several citrullinated antigens are present in CCP-positive RA, with many patients displaying multi-reactivity. All specific reactivities were primarily associated with the HLA-DRB1*04 alleles, suggesting common pathways of anti-citrulline immunity.

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