Membrane-bound proteinase 3 and its receptors: Relevance for the pathogenesis of Wegenerʹs Granulomatosis

Wegenerʹs 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.