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. (
1
) 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 (
2
) and Sette's data on 200 peptides from vimentin and collagen (3
) 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 (4
).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.
References
- The interplay between citrullination and HLA-DRB1 polymorphism in shaping binding hierarchies in rheumatoid arthritis.J. Biol. Chem. 2018; 293 (29317506): 3236-3251
- Influence of HLA-DR genes on the production of rheumatoid arthritis-specific autoantibodies to citrullinated fibrinogen.Arthritis Rheum. 2005; 52 (16255019): 3424-3432
- Citrullination only infrequently impacts peptide binding to HLA class II MHC.PLoS One. 2017; 12 (28481943)e0177140
- 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-E10177
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Published online: May 04, 2018
Edited by Peter CresswellFootnotes
The authors declare that they have no conflicts of interest with the contents of this article.
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