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

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. (1Ting 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.J. Biol. Chem. 2018; 293 (29317506): 3236-325110.1074/jbc.RA117.001013Abstract Full Text Full Text PDF PubMed Scopus (53) Google Scholar) 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 (2Auger 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.Arthritis Rheum. 2005; 52 (16255019): 3424-343210.1002/art.21391Crossref PubMed Scopus (93) Google Scholar) and Sette's data on 200 peptides from vimentin and collagen (3Sidney 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.PLoS One. 2017; 12 (28481943)e0177140 10.1371/journal.pone.0177140Crossref PubMed Scopus (30) Google Scholar) 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 (4Arnoux 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.Proc. Natl. Acad. Sci. U.S.A. 2017; 114 (29109281): E10169-E1017710.1073/pnas.1713112114Crossref PubMed Scopus (32) Google Scholar). 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.