Hu Nan, Westra Johanna, Kallenberg Cees G M
Department of Rheumatology and Clinical Immunology, University Medical Center Groningen, Groningen, The Netherlands.
Autoimmun Rev. 2009 May;8(6):510-4. doi: 10.1016/j.autrev.2008.01.003. Epub 2009 Feb 4.
Wegener's Granulomatosis (WG) is a life-threatening autoimmune disease. A pathogenic role for anti-neutrophil cytoplasmic autoantibodies (ANCAs) by inducing necrotizing damage to the vessel wall has been strongly suggested by in vitro and in vivo experimental data. Proteinase 3 (PR3), a serine protease mainly stored in the azurophilic granules of neutrophils, has been identified as a major ANCA-antigen in WG. Elevated expression levels of membrane-bound PR3 (mPR3) has been observed in WG and some other chronic inflammatory diseases, suggesting a pathogenic role of mPR3 by allowing interaction with PR3-ANCA. Recent studies revealed CD177 as a receptor for mPR3 on the neutrophil membrane. However, we recently showed that CD177 negative neutrophils also express mPR3 and are susceptible to PR3-ANCA induced neutrophil activation. Therefore, it is of interest to further investigate the functional consequences of binding of mPR3 to CD177, to explore other binding partners for mPR3 on the neutrophil membrane, and to study the relevance of colocalization of these molecules for disease pathogenesis. This review gives updated information on the mechanism of mPR3 expression and the relevance of colocalization of mPR3 with other molecules on the neutrophil membrane for the pathophysiological events occurring in WG.
韦格纳肉芽肿（WG）是一种危及生命的自身免疫性疾病。体外和体内实验数据强烈提示抗中性粒细胞胞浆自身抗体（ANCA）通过诱导血管壁坏死性损伤发挥致病作用。蛋白酶3（PR3）是一种主要储存在中性粒细胞嗜天青颗粒中的丝氨酸蛋白酶，已被确定为WG中的主要ANCA抗原。在WG和其他一些慢性炎症性疾病中观察到膜结合PR3（mPR3）表达水平升高，提示mPR3通过与PR3-ANCA相互作用发挥致病作用。最近的研究揭示CD177是中性粒细胞膜上mPR3的受体。然而，我们最近发现CD177阴性的中性粒细胞也表达mPR3，并且易受PR3-ANCA诱导的中性粒细胞活化影响。因此，进一步研究mPR3与CD177结合的功能后果、探索中性粒细胞膜上mPR3的其他结合伙伴以及研究这些分子共定位与疾病发病机制的相关性具有重要意义。本综述提供了关于mPR3表达机制以及mPR3与中性粒细胞膜上其他分子共定位与WG中发生的病理生理事件相关性的最新信息。
