Abstract 703: Circulating Pr3-specific T-helper-17 Cells In Wegener's Granulomatosis
Phil Seo
Authors
Wayel H. Abdulahad, Coen A. Stegeman, Pieter C. Limburg, Cees G.M. Kallenberg.
University Medical Center, Groningen, The Netherlands
Background
The underlying cause of Wegener’s granulomatosis is unknown. The presence of granuloma implies that T-cells are important in the pathogenesis of this disease, and we have long assumed that Wegener’s granulomatosis is predominantly a TH1-mediated disease. Recently, TH17 cells (which produce IL-17) have been implicated in the pathogenesis of several autoimmune diseases. This study addressed whether this recently described cell type might also play an important role in the pathogenesis of Wegener’s granulomatosis, particularly among patients who are ANCA-positive.
Methods:
This study included T- cells from 26 patients with Wegener’s granulomatosis (in remission) and 10 healthy control patients. These cells were subjected to a variety of stimuli, including proteinase-3 and several non-specific antigens (including Staphylococcal enterotoxin B, tetaus toxoid, and phorbol-myristate-acetate/calcium ionophore). T-cell activation was detected using flow cytometry for CD69, a marker of early activation. TH1, TH2, and TH17 responses were detected by measuring levels of cytokines characteristic of these responses (i.e., interferon-gamma, IL-4, and IL-17, respectively).
Results:
T-cells from patients with Wegener’s granulomatosis demonstrated a diminished response to all stimuli when compared to cells from normal healthy controls. Both patients with Wegener’s and healthy control patients demonstrated a similar level of TH1 activation when exposed to non-specific stimuli; however, patients with Wegener’s demonstrated an enhanced TH2 and TH17 response when compared to the response seen in the control population. Finally, proteinase-3 (PR3) ANCA-positive patients demonstrated a specific TH17 response after exposure to PR3 that was not seen in ANCA-negative patients, implying that patients with PR3-ANCA positive Wegener’s granulomatosis are primed to react to this antigen.
Conclusion
Patients with Wegener’s granulomatosis, even during remission, demonstrate an atypical reaction to a variety of antigens, characterized by an enhanced TH2 and a TH17 response.
Editorial Comment
It is not surprising to learn that even during remission, patients with Wegener’s granulomatosis do not demonstrate a normal immune response; however, the results of this study, while intriguing, leave many questions unanswered. For example, the patients in this study received standard immunosuppressive therapy, and how chronic immunosuppression may have affected these results is not clear. Interestingly, not only did patients with Wegener’s granulomatosis demonstrate an enhanced TH17 response, this response was elicited by proteinase-3 in ANCA-positive (but not ANCA-negative) patients. These results imply that the pathogenesis of Wegener’s granulomatosis among ANCA-positive and ANCA-negative patients may be inherently different despite overlapping clinical phenotypes; this basic difference may account for the phenotypic differences observed between the ANCA-positive and ANCA-negative patients.
