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Arthritis Res Ther. 2016 Nov 3;18(1):254.

The increased ability to present citrullinated peptides is not unique to HLA-SE molecules: arginine-to-citrulline conversion also enhances peptide affinity for HLA-DQ molecules.

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Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, Leiden, 2300, RC, The Netherlands.
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Department of Organic Farming and Food Technology, Technological Educational Institute of Ionian Islands, Argostoli, Greece.
Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece.



Presentation of citrullinated neo-epitopes by HLA-DRB1 molecules that carry the shared epitope (SE) sequence was proposed to explain the association between HLA and seropositive RA. Although it is shown that several HLA-DRB1-SE molecules display enhanced binding affinities for citrullinated ligands, the ability of other HLA molecules to present citrullinated epitopes has not been investigated in a systematic manner. To better understand the HLA-RA connection, we aimed to investigate if the enhanced capacity to present arginine-to-citrulline-converted peptides is unique for HLA-SE alleles.


We selected four HLA molecules (one HLA-DR and three HLA-DQ molecules) that could potentially prefer citrulline over arginine residues in specific pockets and in addition two HLA-SE alleles as a method validation control. The affinity of peptides containing arginine/citrulline residues at positions interacting with the various peptide-binding pockets was compared by HLA class II peptide affinity assays.


Pocket 4 of HLA-DRB1*04:04 and -DRB1*04:05 displayed a preference for citrulline over arginine, a property found in other pockets as well. HLA-DRB1*03:01 did not display an enhanced affinity for peptides containing a citrulline. In contrast, several peptide-binding pockets of the analyzed HLA-DQ molecules showed enhanced affinities for citrulline compared to arginine residues: i.e., pockets 4, 6, 7, and 9 of HLA-DQ2 and pockets 1, 6, and 9 of HLA-DQ7 and HLA-DQ8.


Arginine-to-citrulline conversion of peptides can also enhance the binding affinity for non-HLA-SE molecules. Hence the capacity to present citrullinated neo-epitopes is not confined to HLA-SE molecules, opening the possibility that also other HLA molecules could potentiate a possible breach of T cell tolerance toward citrullinated antigens.


ACPA; Citrulline; Rheumatoid arthritis; Shared epitope; Smoking

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