Response of Th17 cells to a citrullinated arthritogenic aggrecan peptide in patients with rheumatoid arthritis

Arthritis Rheum. 2010 Jan;62(1):143-9. doi: 10.1002/art.25064.

Abstract

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.

Conclusion: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aggrecans / metabolism
  • Aggrecans / pharmacology*
  • Arthritis, Rheumatoid / blood
  • Arthritis, Rheumatoid / immunology*
  • Autoantibodies
  • Autoantigens
  • Biomarkers / blood
  • CD4-Positive T-Lymphocytes / drug effects*
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / metabolism
  • Cells, Cultured
  • Citrulline / metabolism
  • Culture Media, Conditioned / chemistry
  • Cytokines / metabolism
  • Enzyme-Linked Immunosorbent Assay
  • Epitopes, T-Lymphocyte / immunology
  • Humans
  • Leukocytes, Mononuclear / drug effects*
  • Leukocytes, Mononuclear / immunology
  • Leukocytes, Mononuclear / metabolism
  • Lymphocyte Activation / drug effects*
  • Lymphocyte Activation / immunology
  • Peptide Fragments / metabolism
  • Peptide Fragments / pharmacology*

Substances

  • Aggrecans
  • Autoantibodies
  • Autoantigens
  • Biomarkers
  • Culture Media, Conditioned
  • Cytokines
  • Epitopes, T-Lymphocyte
  • Peptide Fragments
  • Citrulline