The histopathological hallmark in the kidney of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is “pauci-immune” necrotizing crescentic glomerulonephritis (NCGN), characterized by little or no glomerular staining for immunoglobulins and complements in renal histology by immunofluorescence microscopy examination. Therefore, it was previously assumed that the complement system is not involved in the pathogenesis of AAV. However, increasing studies suggest that activation of the complement system, via the alternative pathway, plays a crucial role in the development of AAV. In the mouse model of AAV, complement depletion, C5-/- or B-/- mice were completely protected from the disease. In human studies, the level of Bb, which is the unique factor in the alternative complement pathway, in circulation, urine and renal histology, were closed associated with the disease activity of AAV. These suggest that complement activation via the alternative pathway is critical in the pathogenesis of AAV.
Among a number of components in the complement system, the interaction between C5a and C5a receptors are the key factors. C5a receptors can be expressed in a number of cells, including neutrophils, lymphocytes, endothelial cells, and platelets. For AAV, the interaction between C5a and its receptor (C5aR, CD88) on neutrophils compose an amplification loop and thus, play a central role in the pathogenesis. In human studies, circulating levels of C5a in active AAV were significantly higher, compared with AAV in remission, and even active lupus nephritis. In the mouse model of AAV, C5aR-/- mice were protected from ANCA-induced NCGN, while C6-deficiency has no disease. In vitro study, C5a can dose-dependently prime neutrophils for ANCA-induced respiratory burst and degranulation. The activation of neutrophils by C5a and ANCA can release factors including reactive oxygen, MPO and proteases which are capable of stimulating complement amplification. Likewise, the generation of C5a could lead to infiltration and degranulation of more neutrophils at sites of complement activation which result in development of inflammation.
Regarding the cellular and molecular mechanism of C5a activating neutrophil, p38 mitogen-activated protein kinase (p38MAPK), extracellular signal-regulated kinase (ERK) and phosphoinositol 3-kinase (PI3K) are important steps in the translocation of ANCA antigens and C5a-induced activation of neutrophils by ANCA. C5a exerts its effects on neutrophils through two different receptors, i.e. CD88 and C5a receptor-like 2 (C5L2). Most of the functional effects of C5a occur through CD88, which contributes to the initiation of acute inflammatory responses, such as chemotaxis, enzyme release and the respiratory burst. Blockade of C5aR/CD88 might have therapeutic benefit in patients with ANCA-associated vasculitis and glomerulonephritis, while the role of C5L2 in the pathogenesis of AAV remains controversial. Sphingosine-1-phosphate (S1P) is an important second messenger in the process of C5a activating neutrophils. S1P triggered by C5a-primed neutrophils acted in an autocrine or paracrine manner, which can further activate neutrophils; the interaction between S1P and C5a might be involved in ANCA-mediated neutrophils respiratory burst and degranulation.
Collectively, activation of the complement system, via the alternative pathway, plays a crucial role in the development of AAV. The interaction between C5a and its receptor (C5aR, CD88) on neutrophils play a central role. The clinical trials of CCX168, a small molecule antagonist of human C5aR, in human is underway.
Disclosure of Interest None declared
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