Citrulline-specific Th1 cells are increased in rheumatoid arthritis and their frequency is influenced by disease duration and therapy

Arthritis Rheumatol. 2014 Jul;66(7):1712-22. doi: 10.1002/art.38637.


Objective: Rheumatoid arthritis (RA) is thought to be a T cell-mediated disease, based on its strong association with HLA class II alleles, clinical responsiveness to T cell-directed therapies, and the presence of CD4+ T cells in rheumatoid joints. The presence of anti-citrullinated protein antibodies (ACPAs) in RA serum and the association of these antibodies with HLA-DR4 alleles implicate citrulline-specific autoreactive T cells in the development and progression of RA. The goal of this study was to determine the characteristics and specificity of autoreactive T cell responses in RA.

Methods: We developed a panel of HLA-DRB1*04:01 tetramers, selecting citrullinated peptides from synovial antigens and verifying their immunogenicity in DRB1*04:01-transgenic mice. Seven tetramers were used to examine the ex vivo frequency and surface phenotype of citrulline-specific (Cit-specific) T cells in patients with RA and healthy subjects with DRB1*04:01 haplotypes, using a magnetic enrichment procedure.

Results: Cit-specific T cells were detectable in peripheral blood samples from both healthy subjects and RA patients. In comparison to healthy subjects, RA patients had significantly higher frequencies of Cit-specific T cells, and a greater proportion of these cells displayed a Th1 memory phenotype. Among RA patients, the frequency of Cit-specific T cells was highest within the first 5 years after diagnosis of RA and was decreased in patients taking biologic agents, irrespective of disease duration.

Conclusion: These findings link the presence of ACPAs in RA with Th1 cells specific for citrullinated epitopes and provide tools for disease-specific immunomonitoring of autoreactive T cells.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Animals
  • Arthritis, Rheumatoid / drug therapy*
  • Arthritis, Rheumatoid / immunology*
  • Arthritis, Rheumatoid / pathology
  • Biological Factors / therapeutic use
  • Citrulline / immunology*
  • Citrulline / metabolism
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism
  • HLA-DRB1 Chains / genetics
  • HLA-DRB1 Chains / immunology
  • HLA-DRB1 Chains / metabolism
  • Haplotypes
  • Humans
  • Immunologic Memory / immunology*
  • Immunophenotyping
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Middle Aged
  • Synovial Membrane / immunology
  • Synovial Membrane / metabolism
  • Th1 Cells / cytology
  • Th1 Cells / immunology*
  • Th1 Cells / metabolism
  • Vimentin / immunology
  • Vimentin / metabolism


  • Biological Factors
  • Epitopes, T-Lymphocyte
  • HLA-DRB1 Chains
  • HLA-DRB1*04:01 antigen
  • Vimentin
  • Citrulline