Endothelium-Neutrophil Interactions in ANCA-Associated Diseases

Abstract

The two salient features of ANCA-associated vasculitis (AAV) are the restricted microvessel localization and the mechanism of inflammatory damage, independent of vascular immune deposits. The microvessel localization of the disease is due to the ANCA antigen accessibility, which is restricted to the membrane of neutrophils engaged in b2-integrin-mediated adhesion, while these antigens are cytoplasmic and inaccessible in resting neutrophils. The inflammatory vascular damage is the consequence of maximal proinflammatory responses of neutrophils, which face cumulative stimulations by TNF-a, b2-integrin engagement, C5a, and ANCA by the FcgRII receptor. This results in the premature intravascular explosive release by adherent neutrophils of all of their available weapons, normally designed to kill IgG-opsonized bacteria after migration in infected tissues.

PF-1355, a Mechanism-Based Myeloperoxidase Inhibitor, Prevents Immune Complex Vasculitis and Anti–Glomerular Basement Membrane Glomerulonephritis

“…(Halbwachs and Lesavre, 2012;Gaffo, 2013). Small vessel vasculitis classification includes microscopic polyangiitis, eosinophilic granulomatosis with polyangiitis, and granulomatosis with polyangiitis.…”

The neutrophil serine protease PR3 induces shape change of platelets via the Rho/Rho kinase and Ca2+ signaling pathways

“…In severe sepsis, platelets are able to trigger the formation of neutrophil extracellular traps (NETs), which bind and clear pathogens [3]. ANCA-associated vasculitis (AAV) encompasses a variety of autoimmune diseases characterized by the presence of Anti-Neutrophil Cytoplasmic Antibodies (ANCA) associated with small vessel damage [4,5]. Platelets and leukocytes co-localize and interact at sites of vessel injury, haemorrhage, thrombosis and inflammation.…”

Myeloperoxidase Antineutrophil Cytoplasmic Antibody (MPO-ANCA) Associated Crescentic and Necrotizing Glomerulonephritis (GN) with Membranoproliferative GN Features

“…Zachem et al demonstrated, using a concanavalin A injection model (immune complex-induced GN model), that after the deposition of immune complexes, platelets adhere to glomerular endothelial cells and are activated to express P-selectin, mediating neutrophil accumulation and a subsequent inflammatory response (17). In the presence of ANCA, the inflammatory reaction triggered by activated neutrophils is intensified (18). Thus, persistent immune complex deposition could synergistically work with ANCA to aggravate intraglomerular inflammation, and this might explain the severity of proteinuria and renal dysfunction seen in ANCA-associated crescentic GN with immune deposits.…”