BACKGROUND: The Th17 subset has been implicated in the pathogenesis of a number of autoimmune diseases. However, little is known about its role in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). We measured serum levels of IL-17A and associated upstream cytokines and the frequency of IL-17-producing autoantigen-specific T cells in patients with AAV. METHODS: ELISA on sera from acute (n = 28) and convalescent (n = 65) patients with AAV from Hammersmith Hospital was performed for IL-17A and the associated upstream cytokines IL-23, IL-6 and IL-1beta, as well as the Th1 cytokine IFN-gamma. ELISPOT was performed to measure autoantigen-specific recall T cell responses in convalescent patients and the frequency of IL-17- and IFN-gamma-producing cells. RESULTS: Serum IL-17A and IL-23 levels were significantly elevated in acute AAV patients compared to healthy controls (P < 0.01 and P < 0.001, respectively), but importantly, remained elevated in a proportion of convalescent patients. By contrast, no significant differences in IFN-gamma levels were detected between patient groups and controls. Patients with elevated levels of IL-23 compared to those with low IL-23 had more active disease as measured by Birmingham Vasculitis Activity Score (P < 0.05) and had higher ANCA titres (P < 0.05). Critically, immunosuppressive therapy did not always effectively suppress IL-23 or IL-17 production. Additionally, autoantigen-specific IL-17-producing, but not IFN-gamma-producing, cells were significantly elevated in patients during disease convalescence compared to healthy controls. CONCLUSIONS: These data implicate the Th17 axis and specifically IL-23 as mediators of more severe disease in AAV. Their persistence despite conventional treatment may contribute to high relapse rates.
BACKGROUND: The Th17 subset has been implicated in the pathogenesis of a number of autoimmune diseases. However, little is known about its role in anti-neutrophil cytoplasm antibody (ANCA)-associated vasculitis (AAV). We measured serum levels of IL-17A and associated upstream cytokines and the frequency of IL-17-producing autoantigen-specific T cells in patients with AAV. METHODS: ELISA on sera from acute (n = 28) and convalescent (n = 65) patients with AAV from Hammersmith Hospital was performed for IL-17A and the associated upstream cytokines IL-23, IL-6 and IL-1beta, as well as the Th1 cytokine IFN-gamma. ELISPOT was performed to measure autoantigen-specific recall T cell responses in convalescent patients and the frequency of IL-17- and IFN-gamma-producing cells. RESULTS: Serum IL-17A and IL-23 levels were significantly elevated in acute AAV patients compared to healthy controls (P < 0.01 and P < 0.001, respectively), but importantly, remained elevated in a proportion of convalescent patients. By contrast, no significant differences in IFN-gamma levels were detected between patient groups and controls. Patients with elevated levels of IL-23 compared to those with low IL-23 had more active disease as measured by Birmingham Vasculitis Activity Score (P < 0.05) and had higher ANCA titres (P < 0.05). Critically, immunosuppressive therapy did not always effectively suppress IL-23 or IL-17 production. Additionally, autoantigen-specific IL-17-producing, but not IFN-gamma-producing, cells were significantly elevated in patients during disease convalescence compared to healthy controls. CONCLUSIONS: These data implicate the Th17 axis and specifically IL-23 as mediators of more severe disease in AAV. Their persistence despite conventional treatment may contribute to high relapse rates.
Authors: Kim M O'Sullivan; Camden Y Lo; Shaun A Summers; Kirstin D Elgass; Paul J McMillan; Anthony Longano; Sharon L Ford; Poh-Yi Gan; Peter G Kerr; A Richard Kitching; Stephen R Holdsworth Journal: Kidney Int Date: 2015-07-15 Impact factor: 10.612