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PDBsum entry 4md4
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Immune system
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PDB id
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4md4
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Contents |
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182 a.a.
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189 a.a.
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13 a.a.
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References listed in PDB file
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Key reference
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Title
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A molecular basis for the association of the hla-Drb1 locus, Citrullination, And rheumatoid arthritis.
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Authors
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S.W.Scally,
J.Petersen,
S.C.Law,
N.L.Dudek,
H.J.Nel,
K.L.Loh,
L.C.Wijeyewickrema,
S.B.Eckle,
J.Van heemst,
R.N.Pike,
J.Mccluskey,
R.E.Toes,
N.L.La gruta,
A.W.Purcell,
H.H.Reid,
R.Thomas,
J.Rossjohn.
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Ref.
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J Exp Med, 2013,
210,
2569-2582.
[DOI no: ]
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PubMed id
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Abstract
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Rheumatoid arthritis (RA) is strongly associated with the human leukocyte
antigen (HLA)-DRB1 locus that possesses the shared susceptibility epitope (SE)
and the citrullination of self-antigens. We show how citrullinated aggrecan and
vimentin epitopes bind to HLA-DRB1*04:01/04. Citrulline was accommodated within
the electropositive P4 pocket of HLA-DRB1*04:01/04, whereas the electronegative
P4 pocket of the RA-resistant HLA-DRB1*04:02 allomorph interacted with arginine
or citrulline-containing epitopes. Peptide elution studies revealed P4
arginine-containing peptides from HLA-DRB1*04:02, but not from
HLA-DRB1*04:01/04. Citrullination altered protease susceptibility of vimentin,
thereby generating self-epitopes that are presented to T cells in
HLA-DRB1*04:01(+) individuals. Using HLA-II tetramers, we observed citrullinated
vimentin- and aggrecan-specific CD4(+) T cells in the peripheral blood of
HLA-DRB1*04:01(+) RA-affected and healthy individuals. In RA patients,
autoreactive T cell numbers correlated with disease activity and were deficient
in regulatory T cells relative to healthy individuals. These findings reshape
our understanding of the association between citrullination, the HLA-DRB1 locus,
and T cell autoreactivity in RA.
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