OK COBRE: NEUTROPHIL PROTEINASE-3 AUTOANTIGEN EXPRESSION AND REGULATION

该子项目是利用NIH/NCRR资助的中心赠款提供的资源的许多研究子项目之一。子项目和研究者（PI）可能从另一个NIH来源获得主要资金，因此可以在其他CRISP条目中表示。所列机构为中心，不一定是研究者所在机构。中性粒细胞蛋白酶-3是一种丝氨酸蛋白酶，与韦格纳肉芽肿病和相关的自身免疫性血管炎的病理生理密切相关。这些患者产生抗PR 3抗体（ANCA），并具有高水平的循环肿瘤坏死因子（TNF）。PR 3切割膜结合的TNF前体以释放促炎细胞因子。早期，我们发现可溶性内皮蛋白C受体（sEPCR），蛋白C抗凝和抗炎途径的成员，通过受体复合物结合活化的中性粒细胞，该受体复合物包括蛋白酶3（PR 3）和CD 11b/CD 18（a？2整联蛋白）。sEPCR结合被来自一些但不是全部韦格纳病患者的ANCA抑制，表明sEPCR的调节作用。 我们目前的数据证实TNF是PR 3的底物，并提出了新的观察结果，即PR 3对TNF的活性被sEPCR下调。由于sEPCR与中性粒细胞PR 3结合，并且大多数PR 3在活化后仍与中性粒细胞膜结合，因此这些观察结果导致我们的假设，即膜结合的PR 3的表达提供了对攻击的立即宿主应答，以及sEPCR结合和随后的炎症下调的模板。由ANCA识别的共同或独特的PR 3表位可能会改变这种反应途径，并导致韦格纳病患者的血管损伤。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Neutrophil proteinase-3 is a serine proteinase intimately involved in the pathophysiology of Wegener's granulomatosis and related autoimmune vasculitides. These patients develop anti-PR3 antibodies (ANCA) and have high levels of circulating tumor necrosis factor (TNF). PR3 cleaves the membrane-bound TNF precursor to release the pro-inflammatory cytokine. Earlier, we showed that the soluble endothelial protein C receptor (sEPCR), a member of the protein C anticoagulant & anti-inflammatory pathway, binds to activated neutrophils via a receptor complex that includes proteinase-3 (PR3) and CD11b/CD18 (a ?2 integrin). sEPCR binding was inhibited by ANCA from some, but not all, Wegener's patients, suggesting an modulatory role for sEPCR. Our current data confirm that TNF is a substrate for PR3 and present the novel observations that PR3 activity toward TNF is down-modulated by sEPCR. Since sEPCR binds to neutrophil PR3, and most of the PR3 remains associated with the neutrophil membrane after activation, these observations lead to our hypothesis that expression of membrane-bound PR3 provides for both an immediate host response to challenge, as well as a template for sEPCR binding and subsequent down-modulation of inflammation. Common or unique PR3 epitopes recognized by ANCA may alter this response pathway and contribute to vascular damage in Wegener's patients.