Response of Th17 cells to a citrullinated arthritogenic aggrecan peptide in patients with rheumatoid arthritis.
OBJECTIVE
Rheumatoid arthritis (RA) is considered to be a prototypical autoimmune disease. However, the autoantigens that play an important role in the development of RA remain unclear. The aim of this study was to investigate whether T cells specific for citrullinated epitopes from self proteins are present in patients with RA.


METHODS
Peripheral blood mononuclear cells (PBMCs) from 28 RA patients and 18 healthy controls were stimulated with citrullinated or noncitrullinated aggrecan peptide Agg(84-103), and proliferative and cytokine responses were assessed using (3)H-thymidine incorporation assay, enzyme-linked immunosorbent assay, and intracellular cytokine analysis.


RESULTS
A proliferative response to the citrullinated aggrecan peptide was detected in >60% of RA patients but not in healthy controls. Furthermore, citrullinated aggrecan peptide-stimulated PBMCs from RA patients produced high levels of the proinflammatory cytokine interleukin-17 (IL-17), accompanied by an induction of IL-17+CD4+ T cells. In contrast, PBMCs from RA patients and healthy controls exhibited no response to stimulation with the noncitrullinated aggrecan peptide.


CONCLUSIONS
Proinflammatory T cell responses to stimulation with a citrullinated arthritogenic aggrecan peptide were detected in RA patients but not in healthy individuals, suggesting a role for these autoantigen-specific T cells in the pathogenesis of RA. Our results suggest that the lack of response to the noncitrullinated analog peptide not only implicates the citrulline residue in T cell recognition but also highlights the potential value of citrullinated aggrecan peptide-specific responses as biomarkers of RA. To our knowledge, this is the first study to demonstrate the presence of citrullinated antigen-specific T cells in human RA.
von Delwig
Alexei
A
Newcastle University, Newcastle upon Tyne, UK.
Locke
James
J
Robinson
John H
JH
Ng
Wan-Fai
WF
D053674:Aggrecans / Q000378:metabolism / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000097:blood / Q000276:immunology*; D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers / Q000097:blood; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D002956:Citrulline / Q000378:metabolism; D017077:Culture Media, Conditioned / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects* / Q000276:immunology; D010446:Peptide Fragments / Q000378:metabolism / Q000494:pharmacology*
D053674:Aggrecans; D001323:Autoantibodies; D001324:Autoantigens; D015415:Biomarkers; D017077:Culture Media, Conditioned; D016207:Cytokines; D018984:Epitopes, T-Lymphocyte; D010446:Peptide Fragments; D002956:Citrulline