OK COBRE: NEUTROPHIL PROTEINASE-3 AUTOANTIGEN EXPRESSION AND REGULATION

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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.