Reduced expression of the regulatory CD4+ T cell subset is related to Th1/Th2 balance and disease severity in rheumatoid arthritis

Arthritis Rheum. 2000 Mar;43(3):617-27. doi: 10.1002/1529-0131(200003)43:3<617::AID-ANR19>3.0.CO;2-B.


Objective: To elucidate the involvement of the regulatory CD4+ T cells that produce high levels of interleukin-10 (IL-10) and low levels of IL-4 and IL-2 in the pathogenesis of rheumatoid arthritis (RA), we investigated whether the frequency of this type of CD4+ T cell subset in peripheral blood lymphocytes (PBL) or synovial lymphocyte infiltrates of patients with RA correlated with disease severity and histologic features in rheumatoid synovium.

Methods: PBL and synovial lymphocyte infiltrates were isolated from peripheral blood samples and synovial tissues obtained from 25 patients with RA. Control specimens were obtained from 18 patients with osteoarthritis (OA) and 10 patients with traumatic injuries of the knee joint. CD4+ T cell subsets were categorized as Th1 (production of interferon-gamma [IFNgamma], but not IL-4), Th2 (production of IL-4, but not IFNgamma), or CD4+ T cell subsets producing IL-10, IL-2, or IL-4. The percentages of these T helper subsets among PBL and among synovial infiltrating lymphocytes were determined by an intracellular staining assay with flow cytometric analysis.

Results: The level of expression of CD4+ T cells producing IL-10 but not IL-2 and IL-4 in the peripheral blood and synovial tissue was significantly lower in RA patients than in OA patients and trauma patients. In RA patients, the frequency of this type of CD4+ T cell subset among synovial infiltrating CD4+ T cells was inversely correlated with the frequency of Th1 cells and the Th1/Th2 balance in synovial lymphocytes, serum C-reactive protein value, disease activity score, and the degree of synovial lining hyperplasia and lymphocyte infiltration in rheumatoid synovium. There was a reciprocal relationship between the frequency of Thl cells and CD4+ T cells producing IL-10 but not IL-2 and IL-4 in the peripheral blood of RA patients.

Conclusion: In RA, reduced expression of the CD4+ T cell subset producing IL-10 but not IL-2 and IL-4 may be responsible for the dominance of Th1 over Th2 cells at sites of inflamed synovium and in the peripheral blood. Decreases in this type of CD4+ T cell subset may induce the down-regulation of T cell tolerance and exacerbate the inflammatory process in RA.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Arthritis, Rheumatoid / immunology
  • Arthritis, Rheumatoid / pathology*
  • Arthritis, Rheumatoid / physiopathology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD4-Positive T-Lymphocytes / pathology*
  • Female
  • Flow Cytometry
  • Humans
  • Interleukin-10 / blood
  • Interleukin-10 / metabolism
  • Lymphocytes / cytology
  • Male
  • Middle Aged
  • Severity of Illness Index
  • Synovial Membrane / chemistry
  • Synovial Membrane / cytology
  • Synovial Membrane / pathology
  • Th1 Cells / pathology*
  • Th2 Cells / pathology*


  • Interleukin-10