Introduction
Granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) belong to a group of systemic vasculitides characterized by necrotizing inflammation of small to medium-sized blood vessels. Anti-neutrophil cytoplasmic antibody (ANCA) in the circulation are present in a majority of patients with generalized disease. ANCA target neutrophil cytoplasmic constituents, in particular proteinase 3 (PR3) and myeloperoxidase (MPO), cause activation of neutrophils that release inflammatory cytokines, reactive oxygen species and lytic enzymes and induce excessive formation of neutrophil extracellular traps (NETs) [1]. These mechanisms underline, at least in part, the pathogenicity of ANCA and their involvement in the development of inflammation and injury of endothelial vascular cells. Disease manifestations are usually characterized by a pauci-immune phenomenon as biopsy finding with little, if any, immunoglobulin and complement deposition in the vessel walls. Complement C3 and C4 levels measured in the blood are in general normal.
However, recent experimental and clinical evidence suggests that activation of the alternative complement pathway is crucial in the pathogenesis of AAV [2, 3]. In 2007, Xiao et al. published the first study that highlighted a role of the complement system in the development of AAV [4]. In an animal model of pauci-immune crescentic glomerulonephritis induced by a single injection of anti-MPO IgG, the complement activation pathways were studied using mice with knockout of the common pathway component C5, classic and lectin binding pathway component C4, and alternative pathway component factor B. C5 and factor B deficient mice were found to be resistant to the development of crescentic glomerulonephritis, whereas deficiency of C4 that is required for activation of C3 convertase and C5 convertase via both classic and lectin pathways did not prevent the disease. On the contrary, Hilhorst et al. found C4d in the majority of renal biopsies, suggesting classical pathway activation as well [5]. Incubation of MPO-ANCA or PR3-ANCA, unlike IgG from healthy controls, with human neutrophils was associated with release of factors that activated complement. These findings suggested that ANCA can cause an amplification loop between neutrophils and complement, that is, ANCA-induced activation of neutrophils leading to the generation of C5a, which in turn enhances neutrophil recruitment and priming and amplifies the inflammatory response [2, 6].
The role of the complement system in the development of AAV was further substantiated by clinical studies that analyzed various complement components in patients during different states of disease activity and healthy controls [7-10]. However, these studies were performed with a relatively small number of patients. Therefore, we aimed to compare the common pathway components C3a, C5a and membrane attack complex (MAC), also known as C5b-9, and the alternate pathway components factor B and properdin in patients with AAV and healthy controls, and to conduct a meta-analysis of the available clinical evidence for the role of complement activation in the pathogenesis of AAV.