Schultz D R, Tozman E C
Department of Medicine, University of Miami School of Medicine, FL 33101, USA.
Semin Arthritis Rheum. 1995 Dec;25(3):143-59. doi: 10.1016/s0049-0172(95)80027-1.
Antineutrophil cytoplasmic antibodies (ANCA) are important serological markers for the primary systemic vasculitides, including microscopic polyarteritis and necrotizing crescentic glomerulonephritis. Numerous reports have established the clinical utility of ANCA titer in monitoring disease activity, relapses, and response to treatment. ANCA, detected by indirect immunofluorescence (IIF) assays using patient's serum and ethanol-fixed human neutrophils, produce two common fluorescent staining patterns: cytoplasmic (C-ANCA), involving a 29-kD neutral serine protease termed proteinase 3 (PR3), and perinuclear (P-ANCA), the result mainly of myeloperoxidase (MPO), but occasionally by other components of the azurophilic granules including lysozyme, elastase, cathepsins, and lactoferrin. Some sera contain granulocyte-specific antinuclear antibodies (GS-ANA), which require formaldehyde fixation of neutrophils to cross link cytoplasmic antigens for distinguishing between ANCA and the GS-ANA by IIF. Positive IIF is confirmed by Western blot analysis or specific enzyme-linked immunosorbent assay for PR3, MPO, and other neutrophil granule antigens. The C-ANCA pattern is highly specific for Wegener's granulomatosis, a disease characterized by granulomatous inflammation, necrotizing and crescentic glomerulonephritis, and vasculitis; P-ANCA is found in sera of individuals with vasculitis, glomerulonephritis, and several other diseases. ANCA are predominantly immunoglobulin (Ig)G isotype, but may be IgM and IgA. Various pathophysiologic mechanisms have been proposed involving ANCA-mediated neutrophil activation in a hypothetical model of vasculitic diseases: positive signals via the FcgammaRII (CD32) receptor after IgG-ANCA binding to membrane-associated PR3, relevant cytokines, production of adhesion molecules on both activated neutrophils and endothelial cells, and the release of neutrophil reactive oxygen species and degranulation causing endothelial cell damage. Interference of C-ANCA with PR3 proteolysis and PR3 inhibition physiologically by the alpha1-proteinase inhibitor may have a pathogenic role. No convincing data have been reported for the existence of autoreactive T lymphocytes reactive to any degree with the neutrophil azurophilic enzymes. Studies of various drug- and infectious agent-related diseases and ANCA may contribute to understanding the mechanism(s) involved in some vasculitides.
抗中性粒细胞胞浆抗体（ANCA）是原发性系统性血管炎的重要血清学标志物，包括显微镜下多血管炎和坏死性新月体性肾小球肾炎。大量报告证实了ANCA滴度在监测疾病活动、复发及治疗反应方面的临床应用价值。通过使用患者血清和乙醇固定的人中性粒细胞进行间接免疫荧光（IIF）检测来检测ANCA，可产生两种常见的荧光染色模式：胞浆型（C-ANCA），涉及一种名为蛋白酶3（PR3）的29-kD中性丝氨酸蛋白酶；核周型（P-ANCA），主要由髓过氧化物酶（MPO）产生，但偶尔也由嗜天青颗粒的其他成分产生，包括溶菌酶、弹性蛋白酶、组织蛋白酶和乳铁蛋白。一些血清含有粒细胞特异性抗核抗体（GS-ANA），需要用甲醛固定中性粒细胞以交联胞浆抗原，通过IIF来区分ANCA和GS-ANA。IIF阳性通过蛋白质印迹分析或针对PR3、MPO及其他中性粒细胞颗粒抗原的特异性酶联免疫吸附测定来确认。C-ANCA模式对韦格纳肉芽肿具有高度特异性，韦格纳肉芽肿是一种以肉芽肿性炎症、坏死性和新月体性肾小球肾炎以及血管炎为特征的疾病；P-ANCA见于血管炎、肾小球肾炎及其他几种疾病患者的血清中。ANCA主要为免疫球蛋白（Ig）G同种型，但也可能是IgM和IgA。在血管炎性疾病的假设模型中，已提出多种病理生理机制涉及ANCA介导的中性粒细胞活化：IgG-ANCA与膜相关PR3结合后通过FcγRII（CD32）受体产生阳性信号、相关细胞因子、活化的中性粒细胞和内皮细胞上粘附分子的产生，以及中性粒细胞活性氧的释放和脱颗粒导致内皮细胞损伤。C-ANCA对PR3蛋白水解的干扰以及α1-蛋白酶抑制剂对PR3的生理性抑制可能具有致病作用。尚未有令人信服的数据报道存在与中性粒细胞嗜天青酶有任何程度反应的自身反应性T淋巴细胞。对各种与药物和感染因子相关疾病及ANCA的研究可能有助于理解某些血管炎的发病机制。
