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A molecular basis for the association of the HLA-DRB1 locus, citrullination, and rheumatoid arthritis
- Source :
- The Journal of Experimental Medicine, Journal of Experimental Medicine, 210(12), 2569-2582
- Publication Year :
- 2013
- Publisher :
- The Rockefeller University Press, 2013.
-
Abstract
- A comprehensive structural portrait of the association between citrullination, the HLA-DRB1 locus, and T cell autoreactivity in rheumatoid arthritis.<br />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.
- Subjects :
- musculoskeletal diseases
CD4-Positive T-Lymphocytes
Models, Molecular
T cell
Immunology
HLA-DR beta-Chains
Molecular Sequence Data
Vimentin
Mice, Transgenic
Human leukocyte antigen
Major histocompatibility complex
Autoantigens
Epitope
Article
Arthritis, Rheumatoid
chemistry.chemical_compound
Epitopes
Mice
immune system diseases
Citrulline
medicine
HLA-DR4 Antigen
Immunology and Allergy
Animals
Humans
Aggrecans
Amino Acid Sequence
skin and connective tissue diseases
HLA-DRB1
Genetic Association Studies
Antigen Presentation
Polymorphism, Genetic
biology
Citrullination
Molecular biology
medicine.anatomical_structure
chemistry
biology.protein
HLA-DRB1 Chains
Subjects
Details
- Language :
- English
- ISSN :
- 15409538 and 00221007
- Volume :
- 210
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- The Journal of Experimental Medicine
- Accession number :
- edsair.doi.dedup.....2e608f639763d94caa35ab8ee22afdc3