Imperial College Kidney and Transplant Institute, Division of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
Nephrol Dial Transplant. 2010 Jul;25(7):2209-17. doi: 10.1093/ndt/gfp783. Epub 2010 Jan 25.
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.
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.
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.
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.
Th17 亚群已被牵涉到多种自身免疫性疾病的发病机制中。然而，人们对其在抗中性粒细胞胞浆抗体（ANCA）相关性血管炎（AAV）中的作用知之甚少。我们测量了 AAV 患者血清中白介素-17A（IL-17A）及其相关上游细胞因子的水平，以及产生白介素-17A 的自身抗原特异性 T 细胞的频率。
对来自 Hammersmith 医院的急性（n=28）和恢复期（n=65）AAV 患者的血清进行 ELISA 检测，以检测 IL-17A 及其相关上游细胞因子白细胞介素-23（IL-23）、白细胞介素-6（IL-6）和白细胞介素-1β（IL-1β），以及 Th1 细胞因子干扰素-γ（IFN-γ）。ELISPOT 用于测量恢复期患者的自身抗原特异性回忆 T 细胞反应以及产生白介素-17A 和 IFN-γ的细胞的频率。
与健康对照组相比，急性 AAV 患者的血清 IL-17A 和 IL-23 水平显著升高（P<0.01 和 P<0.001），但重要的是，在一部分恢复期患者中仍升高。相比之下，患者组与对照组之间 IFN-γ水平没有显著差异。与低 IL-23 患者相比，IL-23 水平升高的患者，如伯明翰血管炎活动评分（Birmingham Vasculitis Activity Score）所示，疾病更为活跃（P<0.05），且抗中性粒细胞胞浆抗体（ANCA）滴度更高（P<0.05）。关键的是，免疫抑制治疗并不总是能有效抑制 IL-23 或 IL-17 的产生。此外，与健康对照组相比，在疾病恢复期，患者的自身抗原特异性产生白介素-17A 的细胞，但不是产生 IFN-γ 的细胞，显著升高。
这些数据表明 Th17 轴，特别是白细胞介素-23，是 AAV 更严重疾病的介质。尽管采用了常规治疗，但它们的持续存在可能导致高复发率。
