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.
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.
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands. a.s.b.kampstra@lumc.nl.|Department of Rheumatology C1-R, Leiden University Medical Center, Albinusdreef 2, PO Box 9600, Leiden, 2300, RC, The Netherlands. a.s.b.kampstra@lumc.nl.
Arieke S B
AS
Kampstra
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Jurgen
J
van Heemst
Department of Organic Farming and Food Technology, Technological Educational Institute of Ionian Islands, Argostoli, Greece.
Antonis K
AK
Moustakas
Laboratory of Biochemistry and Biophysics, Faculty of Agricultural Technology, Epirus Institute of Technology, Arta, Greece.
George K
GK
Papadopoulos
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
Tom W J
TW
Huizinga
Department of Rheumatology, Leiden University Medical Center, Leiden, The Netherlands.
René E M
RE
Toes
D017951:Antigen Presentation / Q000276:immunology*; D001120:Arginine / Q000276:immunology; D001172:Arthritis, Rheumatoid / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D002460:Cell Line; D002956:Citrulline / Q000276:immunology; D006683:HLA-DQ Antigens / Q000276:immunology*; D006801:Humans; D008958:Models, Molecular; D010456:Peptides, Cyclic / Q000276:immunology
D001324:Autoantigens; D006683:HLA-DQ Antigens; D010456:Peptides, Cyclic; D002956:Citrulline; D001120:Arginine
ACPA; Citrulline; Rheumatoid arthritis; Shared epitope; Smoking