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.