ANCA-associated vasculitis and immunity

This presentation was given by Ming-hui Zhao from the Renal Division of Peking University First Hospital and Peking-Tsinghua Center for Life Sciences (CLS). It was presented at the ISN’s Forefronts Symposium 2015 taking place in Shenzhen, China, on October 22-25, 2015 for which the theme was ‘Immunomodulation of Cardio-Renal Function’ during Session 5: Immunogenetics, Autoimmunity and Inflammasome.


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Presentation Abstract: 

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a systemic autoimmune disease. Majority of the Chinese patients with AAV is myeloperoxidase (MPO)-ANCA positive microscopic polyangiitis (MPA), which is predominant in elderly and more frequently affects kidney. The histopathological hallmark of patients with AAV is “pauci-immune” necrotizing crescentic glomerulonephritis (NCGN). 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, involved in the development of AAV. 

Recent studies indicated that the interaction between C5a and C5a receptors (C5aR, CD88) on neutrophils composes an amplification loop and thus, play a central role in the pathogenesis of AAV. In human studies, circulating levels of C5a in active AAV were significantly higher than that of remission. 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. 

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. Sphingosine-1-phosphate (S1P) is an important second messenger in the process of C5a activating neutrophils.  

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 on neutrophils play a central role. The clinical trials of CCX168, a small molecule antagonist of human C5aR, in human is underway.  

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Last modified on Monday, 30 November 2015 09:45

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