Complement in ANCA-Associated Vasculitis
Section snippets
Pathologic Features of ANCA-ASSOCIATED VASCULITIS
Any proposed pathogenic mechanism for ANCA disease must be in accord with the pathologic features of the observed acute vascular inflammation. Based on observations in animal models of ANCA disease as well as examination of biopsy specimens from patients, the initial inflammatory and necrotizing injury in ANCA vasculitis is characterized histologically by segmental lytic necrosis with admixed and adjacent neutrophils that are undergoing karyorrhexis (leukocytoclasia) (Fig. 1A).2, 4, 5 Monocyte
Experimental Evidence for Pathogenic Complement Activation in ANCA Disease
Numerous in vitro studies and multiple animal models substantiate a pathogenic role for ANCA.2 The evidence shows that cytokine-primed neutrophils display ANCA antigens (MPO and proteinase 3 [PR3]) at the cell surface where interaction with ANCA causes neutrophil activation by both Fc receptor engagement and by F(ab’)2 binding to antigen on the neutrophil surface. ANCA-activated neutrophils adhere to and penetrate vessel walls, and release destructive enzymes and oxygen radicals that cause
Evidence for Pathogenic Complement Activation in ANCA Disease Patients
A role for complement activation in the pathogenesis of ANCA disease is supported by the experimental evidence from in vitro studies showing that patient MPO-ANCA and PR3-ANCA IgG can activate neutrophils to release factors that in turn activate complement, and by experimental animal studies that clearly show an important role for alternative complement pathway activation in models of MPO-ANCA disease. The absence of overt depression of serum C3 and C4 in ANCA disease patients, along with the
Summary
Thus, multiple lines of experimental data in animal models, in vitro experiments using human neutrophils and patient ANCA, and observations in patients with ANCA disease all support the hypothesis that an important event in ANCA-mediated glomerulonephritis and vasculitis is alternative complement pathway activation by ANCA-activated neutrophils, which generates C5a, which engages C5a receptors on neutrophils, which in turn primes the neutrophils for activation by ANCA (Fig. 2). In addition, C5a
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