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HLA-DRB1 polymorphism, anti-citrullinated protein antibodies, and rheumatoid arthritis

  • Jean Roudier
    Correspondence
    To whom correspondence should be addressed
    Affiliations
    INSERM UMRs1097, Marseille-Luminy 13009, France

    Aix Marseille Université, Marseille 13007, France

    Department of Rheumatology, Institut du Mouvement et de l’appareil Locomoteur, Assistance Publique Hôpitaux de Marseille, Marseille 13005, France
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  • Nathalie Balandraud
    Affiliations
    INSERM UMRs1097, Marseille-Luminy 13009, France

    Aix Marseille Université, Marseille 13007, France

    Department of Rheumatology, Institut du Mouvement et de l’appareil Locomoteur, Assistance Publique Hôpitaux de Marseille, Marseille 13005, France
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  • Isabelle Auger
    Affiliations
    INSERM UMRs1097, Marseille-Luminy 13009, France

    Aix Marseille Université, Marseille 13007, France
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Open AccessPublished:May 04, 2018DOI:https://doi.org/10.1074/jbc.L118.002761
      IgG autoantibodies to citrullinated proteins (ACPA) precede the development of rheumatoid arthritis (RA). HLA-DR alleles with a 5-amino acid stretch called “shared epitope (SE)” in their P4 pocket are associated with ACPA and RA. The recent article by Ting et al. (
      • Ting Y.T.
      • Petersen J.
      • Ramarathinam S.H.
      • Scally S.W.
      • Loh K.L.
      • Thomas R.
      • Suri A.
      • Baker D.G.
      • Purcell A.W.
      • Reid H.H.
      • Rossjohn J.
      The interplay between citrullination and HLA-DRB1 polymorphism in shaping binding hierarchies in rheumatoid arthritis.
      ) suggests that the basis for this association is preferential binding of citrullinated peptides by SE-positive HLA-DR molecules. It shows binding of 13 selected peptides (3 from vimentin and 2 from fibrinogen) and their 18 citrullinated variants to 3 SE-positive alleles and presents 8 crystal structures of 3 SE-positive HLA-DR alleles complexed with a citrullinated peptide.
      Our binding data on 96 overlapping peptides from fibrinogen and their 71 citrullinated variants (
      • Auger I.
      • Sebbag M.
      • Vincent C.
      • Balandraud N.
      • Guis S.
      • Nogueira L.
      • Svensson B.
      • Cantagrel A.
      • Serre G.
      • Roudier J.
      Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen.
      ) and Sette's data on 200 peptides from vimentin and collagen (
      • Sidney J.
      • Becart S.
      • Zhou M.
      • Duffy K.
      • Lindvall M.
      • Moore E.C.
      • Moore E.L.
      • Rao T.
      • Rao N.
      • Nielsen M.
      • Peters B.
      • Sette A.
      Citrullination only infrequently impacts peptide binding to HLA class II MHC.
      ) do not show preferential binding of citrullinated peptides to SE-positive HLA-DR alleles. Solving the RA/ACPA/HLA-DR association will require the identification of T cells that help the production of ACPA. In normal mice, PAD (peptidyl arginyl deiminase, the citrullinating enzyme) immunization triggers anti-citrullinated fibrinogen antibodies by a hapten carrier mechanism (
      • Arnoux F.
      • Mariot C.
      • Peen E.
      • Lambert N.C.
      • Balandraud N.
      • Roudier J.
      • Auger I.
      Peptidyl arginyl deiminase immunization induces anti-citrullinated protein antibodies in mice with particular MHC types.
      ).
      The “shared epitope binds citrullinated peptide” hypothesis requires many T helper cells specific for many citrullinated peptides. We suggest the “shared epitope binds PAD peptides” alternative, which may open the field of PAD vaccination to prevent RA.

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        Citrullination only infrequently impacts peptide binding to HLA class II MHC.
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