PMID- 24190431
OWN - NLM
STAT- MEDLINE
DCOM- 20140121
LR  - 20240109
IS  - 1540-9538 (Electronic)
IS  - 0022-1007 (Print)
IS  - 0022-1007 (Linking)
VI  - 210
IP  - 12
DP  - 2013 Nov 18
TI  - A molecular basis for the association of the HLA-DRB1 locus, citrullination, and 
      rheumatoid arthritis.
PG  - 2569-82
LID - 10.1084/jem.20131241 [doi]
AB  - 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.
FAU - Scally, Stephen W
AU  - Scally SW
AD  - Department of Biochemistry and Molecular Biology, School of Biomedical Sciences, 
      Monash University, Clayton, Victoria 3800, Australia.
FAU - Petersen, Jan
AU  - Petersen J
FAU - Law, Soi Cheng
AU  - Law SC
FAU - Dudek, Nadine L
AU  - Dudek NL
FAU - Nel, Hendrik J
AU  - Nel HJ
FAU - Loh, Khai Lee
AU  - Loh KL
FAU - Wijeyewickrema, Lakshmi C
AU  - Wijeyewickrema LC
FAU - Eckle, Sidonia B G
AU  - Eckle SB
FAU - van Heemst, Jurgen
AU  - van Heemst J
FAU - Pike, Robert N
AU  - Pike RN
FAU - McCluskey, James
AU  - McCluskey J
FAU - Toes, Rene E
AU  - Toes RE
FAU - La Gruta, Nicole L
AU  - La Gruta NL
FAU - Purcell, Anthony W
AU  - Purcell AW
FAU - Reid, Hugh H
AU  - Reid HH
FAU - Thomas, Ranjeny
AU  - Thomas R
FAU - Rossjohn, Jamie
AU  - Rossjohn J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20131104
PL  - United States
TA  - J Exp Med
JT  - The Journal of experimental medicine
JID - 2985109R
RN  - 0 (ACAN protein, human)
RN  - 0 (Aggrecans)
RN  - 0 (Autoantigens)
RN  - 0 (Epitopes)
RN  - 0 (HLA-DR beta-Chains)
RN  - 0 (HLA-DR4 Antigen)
RN  - 0 (HLA-DRB1 Chains)
RN  - 0 (Vimentin)
RN  - 29VT07BGDA (Citrulline)
SB  - IM
MH  - Aggrecans/genetics/immunology/metabolism
MH  - Amino Acid Sequence
MH  - Animals
MH  - Antigen Presentation
MH  - Arthritis, Rheumatoid/*genetics/*immunology/metabolism
MH  - Autoantigens/chemistry/genetics/metabolism
MH  - CD4-Positive T-Lymphocytes/immunology/metabolism
MH  - Citrulline/metabolism
MH  - Epitopes/chemistry/genetics/metabolism
MH  - Genetic Association Studies
MH  - HLA-DR beta-Chains/chemistry/genetics/metabolism
MH  - HLA-DR4 Antigen/chemistry/genetics/metabolism
MH  - HLA-DRB1 Chains/chemistry/*genetics/*metabolism
MH  - Humans
MH  - Mice
MH  - Mice, Transgenic
MH  - Models, Molecular
MH  - Molecular Sequence Data
MH  - Polymorphism, Genetic
MH  - Vimentin/genetics/immunology/metabolism
PMC - PMC3832918
EDAT- 2013/11/06 06:00
MHDA- 2014/01/22 06:00
PMCR- 2014/05/18
CRDT- 2013/11/06 06:00
PHST- 2013/11/06 06:00 [entrez]
PHST- 2013/11/06 06:00 [pubmed]
PHST- 2014/01/22 06:00 [medline]
PHST- 2014/05/18 00:00 [pmc-release]
AID - jem.20131241 [pii]
AID - 20131241 [pii]
AID - 10.1084/jem.20131241 [doi]
PST - ppublish
SO  - J Exp Med. 2013 Nov 18;210(12):2569-82. doi: 10.1084/jem.20131241. Epub 2013 Nov 
      4.