de Menthon Mathilde, Lambert Marion, Guiard Elsa, Tognarelli Sara, Bienvenu Boris, Karras Alexandre, Guillevin Loïc, Caillat-Zucman Sophie
INSERM, U986, Hôpital Saint-Vincent de Paul, Hôpital Cochin, Assistance Publique Hôpitaux de Paris, Paris, France.
Arthritis Rheum. 2011 Jul;63(7):2116-26. doi: 10.1002/art.30355.
Granulomatosis with polyangiitis (Wegener's) (GPA) is a rare systemic vasculitis of unknown etiology. Contribution of T cell-mediated immunity is suggested by the presence of granulomatous inflammation and T cell infiltrates in different tissues. We undertook this study to determine whether CD4+ T cells aberrantly expressing the NKG2D activating receptor might participate in the pathophysiology of the disease.
We performed a detailed phenotype and functional analysis of CD4+ T cells in a cohort of 90 GPA patients (37 with localized GPA and 53 with generalized GPA) in comparison with 39 age-matched controls.
We observed circulating innate-like CD4+ T cells expressing an assortment of activating natural killer (NK) cell receptors (NKG2D, 2B4, DNAX-associated molecule 1, and some killer cell Ig-like receptors) and their signaling partners. Expansions of NKG2D+CD4+ T cells greater than a critical threshold of 3% yielded 100% specificity for generalized vasculitis versus localized granulomatosis, suggesting their participation in endothelium damage. Excessive interleukin-15 (IL-15) transpresentation through increased expression of IL-15 receptor α (IL-15Rα), together with abnormal expression of major histocompatibility complex (MHC) class I chain-related A protein on monocyte/macrophages, induced abnormal expansion of NKG2D+CD4+ T cells. These cells were primed in vivo to exert direct, MHC-independent cytotoxicity toward microvascular endothelial cells expressing the cognate ligands of NK cell receptors.
Our results suggest that NK cell-like CD4+ T cells might be the driving force of the vasculitis in GPA, and point to IL-15 as an important mediator in the progression of GPA toward generalized vasculitis. IL-15/IL-15Rα antagonists may thus become novel therapeutic tools to decrease the pool of NK cell receptor-positive CD4+ T cells in selected GPA patients.
肉芽肿性多血管炎（韦格纳氏）（GPA）是一种病因不明的罕见系统性血管炎。肉芽肿性炎症以及不同组织中的T细胞浸润提示了T细胞介导的免疫作用。我们开展本研究以确定异常表达NKG2D激活受体的CD4⁺ T细胞是否参与该疾病的病理生理过程。
我们对90例GPA患者（37例局限性GPA和53例全身性GPA）队列中的CD4⁺ T细胞进行了详细的表型和功能分析，并与39例年龄匹配的对照进行比较。
我们观察到循环中的固有样CD4⁺ T细胞表达多种激活自然杀伤（NK）细胞受体（NKG2D、2B4、DNAX相关分子1以及一些杀伤细胞免疫球蛋白样受体）及其信号伴侣。NKG2D⁺CD4⁺ T细胞的扩增超过3%的临界阈值时，对全身性血管炎与局限性肉芽肿的诊断特异性为100%，表明它们参与了内皮损伤。通过增加白细胞介素-15受体α（IL-15Rα）的表达导致的白细胞介素-15（IL-15）过度反式呈递，以及单核细胞/巨噬细胞上主要组织相容性复合体（MHC）I类链相关A蛋白的异常表达，诱导了NKG2D⁺CD4⁺ T细胞的异常扩增。这些细胞在体内被激活，对表达NK细胞受体同源配体的微血管内皮细胞发挥直接的、不依赖MHC的细胞毒性作用。
我们的结果表明，NK细胞样CD4⁺ T细胞可能是GPA血管炎的驱动因素，并指出IL-15是GPA向全身性血管炎进展的重要介质。因此，IL-15/IL-15Rα拮抗剂可能成为减少特定GPA患者中NK细胞受体阳性CD4⁺ T细胞数量的新型治疗工具。
