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.jpg): Failed to open stream: No such file or directory in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 117 Arthritis+Res+Ther
2016 ; 18
(1
): 254
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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
#MMPMID27809896
Kampstra AS
; van Heemst J
; Moustakas AK
; Papadopoulos GK
; Huizinga TW
; Toes RE
Arthritis Res Ther
2016[Nov]; 18
(1
): 254
PMID27809896
show ga
BACKGROUND: 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. METHODS:
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. RESULTS: 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. CONCLUSIONS: 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.