Pathophysiology of ANCA vasculitis

Abstract

ANCA vasculitides (AAV) are autoimmune diseases responsible for damage to small-size vessels. Three entities are distinguished from clinical, histological and biological criteria: micropolyangiitis (MPA), granulomatosis with polyangiitis (GPA) and eosinophilic granulomatosis with polyangiitis (EGPA). The neutrophil-ANCA couple is central to the pathophysiology of AAV. The mechanisms that lead to the breakdown of tolerance to myeloperoxidase or proteinase-3 remain hypothetical, however, probably multifactorial, occurring on a predisposing genetic background. The understanding of the injury mechanisms involved in AAV has made great progress thanks to the study of a murine model of immunization against myeloperoxidase. This work has made it possible to show the central role of the PNN in vivo, which are activated under sterile conditions, under the effect of the ANCAs which recognize the self-antigen expressed on their surface. Understanding the role of the alternative complement pathway and in particular that of C5a, a powerful anaphylatoxin, was a major advance. C5a acts as an amplifying factor for PNN activation and blocking its receptor (C5aR) prevents the occurrence of vasculitis lesions in the mouse model. These discoveries led to therapeutic trials in humans highlighting the interest of blocking C5aR and validating this therapeutic strategy. It should be emphasized that the AAV study model is, above all, an anti-MPO model and that the mechanisms involved in anti-PR3 ANCA or ANCA negative vasculitis remain very hypothetical. Finally, the mechanisms that account for the heterogeneity relating to the presentation or severity of AAV remain poorly understood.