Elsevier

Seminars in Nephrology

Volume 33, Issue 6, November 2013, Pages 557-564
Seminars in Nephrology

Complement in ANCA-Associated Vasculitis

https://doi.org/10.1016/j.semnephrol.2013.08.006Get rights and content

Summary

Antineutrophil cytoplasmic autoantibodies (ANCA) are the likely cause for necrotizing small-vessel vasculitis and crescentic glomerulonephritis. Unlike other forms of crescentic glomerulonephritis induced by immune complexes or anti–glomerular basement membrane antibodies that have conspicuous vessel wall immunoglobulin and complement, there is a paucity, although usually not an absence, of vessel wall immunoglobulin and complement in ANCA-associated glomerulonephritis. Despite this comparatively lower level and more localized distribution of vessel wall complement, experimental and clinical observations strongly incriminate alternative complement pathway activation as critically important in the pathogenesis of ANCA disease. Experimental data in animal models and in vitro experiments has shown that primed neutrophils are activated by ANCA, which generates C5a, which engages C5a receptors on neutrophils. This attracts and in turn primes more neutrophils for activation by ANCA. In patients with ANCA disease, plasma levels of C3a, C5a, soluble C5b-9, and Bb have been reported to be higher in active disease than in remission, whereas no difference was reported in plasma C4d in active versus ANCA disease remission. Thus, experimental and clinical data support the hypothesis that ANCA-induced neutrophil activation activates the alternative complement pathway and generates C5a. C5a not only recruits additional neutrophils through chemotaxis but also primes neutrophils for activation by ANCA. This creates a self-fueling inflammatory amplification loop that results in the extremely destructive necrotizing vascular injury.

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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