Skewed distribution of Th17 lymphocytes in patients with Wegener's granulomatosis in remission

Abstract

Objective: The recently characterized interleukin-17 (IL-17)-producing T helper cell lineage (Th17), rather than the Th1 lineage, is involved in several autoimmune diseases. The possible role of Th17 cells in Wegener's granulomatosis (WG) has not yet been elucidated. We undertook this study to assess the distribution of Th1/Th2/Th17 cells and to investigate the presence of Th17 cells specific for the WG autoantigen proteinase 3 (PR3) in WG.

Methods: Peripheral blood from patients with WG in remission (n = 26) and healthy controls (n = 10) was stimulated in vitro with PR3 or with the control stimuli staphylococcal enterotoxin B (SEB), tetanus toxoid (TT), or phorbol myristate acetate/calcium ionophore, together with anti-CD28 and anti-CD49d. The frequencies of the various CD4+ T cell phenotypes responsive to stimuli were determined by 7-color flow cytometric detection of CD3, CD8, an early activation marker (CD69), and intracellular cytokines (IL-2, interferon-gamma [IFNgamma], IL-17, and IL-4).

Results: The percentage of CD69+,CD4+ T cells in patients with WG in remission was significantly decreased in response to PR3 and tended to be lower in response to other stimuli compared with the percentage in healthy controls. The percentages of Th17 cells (IL-4-,IL-17+,IFNgamma-) and Th2 cells (IL-4+,IL-17-,IFNgamma-) within the activated CD69+,CD4+ T cell population were significantly increased in patients with WG in remission, while no difference was found in Th1 cells (IL-4-,IL-17-,IFNgamma+) compared with the percentage in healthy controls. Increased percentages of Th17 cells in response to TT and SEB were found both in antineutrophil cytoplasmic antibody (ANCA)-positive and in ANCA-negative patients, while an increased frequency of PR3-specific Th17 cells was restricted to ANCA-positive patients.

Conclusion: A skewed Th17 response found in ANCA-positive WG patients following stimulation with the autoantigen PR3 suggests that IL-17 is involved in disease pathogenesis and could constitute a new therapeutic target.