Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, University of Groningen, The Netherlands.
Clin Exp Rheumatol. 2009 Jan-Feb;27(1 Suppl 52):S108-14.
Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are a group of autoimmune disorders including Wegener's granulomatosis (WG), microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and renal-limited vasculitis (RLV). This paper reviews updated information on the pathogenesis of AAV. Additional clinical evidence for a pathogenic role of ANCA comes from the observation that patients with severe acute renal failure treated with plasma exchange had a lower risk for progression to end-stage renal disease than patients who received intravenous methylprednisolone therapy, both in addition to standard treatment. Recent data also suggest that antibodies to complementary proteinase-3 (cPR3), probably cross-reacting with plasminogen, may induce PR3-ANCA. Furthermore, a new ANCA, directed against human lysosome membrane protein-2 (LAMP-2), concurrent with PR3-ANCA or MPO-ANCA, was described as a sensitive and specific marker for renal AAV. In vitro, ANCA can further activate primed neutrophils to release reactive oxygen species and lytic enzymes, and, in conjunction with neutrophils, damage and lyse endothelial cells. In vivo, transfer of splenocytes from myeloperoxidase-deficient mice immunized with mouse myeloperoxidase into wild-type mice resulted in pauci-immune systemic vasculitis. A similar experiment in PR3-deficient mice did not cause significant vasculitic lesions. In the anti-MPO induced vasculitis mouse model, a critical role of complement activation was suggested. The anti- LAMP-2 antibody can also induce pauci-immune necrotizing crescentic glomerulonephritis in rats. Rats developed both cross-reactive antibodies to LAMP-2 and crescentic glomerulonephritis when immunized with FimH, an adhesin from Gram-negative bacteria which has strong homology with human LAMP-2. Together, clinical, in vitro and in vivo data support a pathogenic role for ANCA in AAV, although this role is more evident for myeloperoxidase-ANCA than for PR3-ANCA. The role of anti- LAMP-2 requires further studies.
抗中性粒细胞胞质抗体（ANCA）相关性血管炎（AAV）是一组自身免疫性疾病，包括韦格纳肉芽肿（WG）、显微镜下多血管炎（MPA）、Churg-Strauss 综合征（CSS）和肾局限性血管炎（RLV）。本文综述了 AAV 发病机制的最新信息。ANCA 在发病机制中的作用的更多临床证据来自于这样的观察结果，即接受血浆置换治疗的严重急性肾衰竭患者比接受静脉注射甲基强的松龙治疗的患者进展为终末期肾病的风险更低，两者均在标准治疗之外。最近的数据还表明，针对补体蛋白酶-3（cPR3）的抗体，可能与纤溶酶原交叉反应，可能诱导 PR3-ANCA。此外，一种新的针对人溶酶体膜蛋白-2（LAMP-2）的 ANCA，与 PR3-ANCA 或 MPO-ANCA 同时存在，被描述为肾 AAV 的敏感和特异性标志物。在体外，ANCA 可以进一步激活致敏的中性粒细胞释放活性氧和溶酶，与中性粒细胞一起损伤和溶解内皮细胞。在体内，将缺乏髓过氧化物酶的小鼠的脾细胞从用鼠髓过氧化物酶免疫的小鼠转移到野生型小鼠中，导致少免疫性系统性血管炎。在缺乏 PR3 的小鼠中进行的类似实验并没有导致明显的血管炎病变。在抗 MPO 诱导的血管炎小鼠模型中，补体激活起关键作用。抗 LAMP-2 抗体也可以在大鼠中诱导少免疫性坏死性新月体肾小球肾炎。当用革兰氏阴性菌的粘附素 FimH 免疫大鼠时，大鼠既产生了针对 LAMP-2 的交叉反应性抗体，也产生了新月体肾小球肾炎，FimH 与人类 LAMP-2 具有很强的同源性。总之，临床、体外和体内数据支持 ANCA 在 AAV 中的致病作用，尽管在髓过氧化物酶-ANCA 中比在 PR3-ANCA 中更为明显。抗 LAMP-2 的作用需要进一步研究。
