Translating basic science into patient therapy for ANCA-associated small vessel vasculitis

Abstract

ANCA (anti-neutrophil cytoplasm antibody)-associated small vessel vasculitis is an inflammatory condition associated with the production of autoantibodies to neutrophil cytoplasmic components. The disorder results in destruction of the microvasculature, infiltration of neutrophils into tissues, which is followed later by mononuclear cells, leading to injury and the formation of granulomatous lesions. Initiators for the disease are undetermined but a pro-inflammatory environment is required. Other influencing factors may include environmental triggers, genetic propensity or infectious agents. The primary cellular event in the condition involves the neutrophils, which are likely to be responsible for the majority of tissue injury. Binding of the autoantibody to neutrophils initiates cell activation via a complex intracellular signalling cascade, culminating in the release of pro-inflammatory mediators, proteolytic enzymes and reactive oxygen species. Adhesion of neutrophils to endothelial cells is observed in vitro and more investigations in this area may explain the focussing of the disease to certain vessels/tissues. Current treatment regimens have substantial toxicity. Although newer developments are an improvement there is still a pressing need for more targeted therapies, which could be provided by extrapolating information emerging from basic scientific research.

Pathogenesis of Vascular Inflammation by Anti-Neutrophil Cytoplasmic Antibodies

“…Experimental studies from many laboratories have shown that both PR3-ANCA and MPO-ANCA IgG activate neutrophils in vitro to release mediators of acute inflammation (18,19). Figure 1 illustrates a hypothetical sequence of pathogenic events that could result in ANCA-mediated vascular inflammation (20).…”

Anti-Neutrophil Cytoplasmic Antibody Pathogenesis in Small-Vessel Vasculitis

“…ANCA-induced intracellular signal transduction pathways differ according to whether the signal is initiated by the F(abЈ)2 or Fc portion of the autoantibody. 39 The ANCA IgG F(abЈ)2 fragment can activate inhibitory G proteins and RAS p21 protein activator but not tyrosine kinases (sarcoma virus kinases, Syk, phosphatidylinositol-3 kinase, protein kinase B, and protein kinase C), whose activation probably relies on Fc-␥ receptor binding. 39,40 Tyrosine kinase pathways are thought to induce respiratory burst through activation of NADH oxidase.…”

“…39 The ANCA IgG F(abЈ)2 fragment can activate inhibitory G proteins and RAS p21 protein activator but not tyrosine kinases (sarcoma virus kinases, Syk, phosphatidylinositol-3 kinase, protein kinase B, and protein kinase C), whose activation probably relies on Fc-␥ receptor binding. 39,40 Tyrosine kinase pathways are thought to induce respiratory burst through activation of NADH oxidase. Inhibitory G protein and tyrosine kinase pathways may cooperate in oxidative burst generation because they converge on the GTPase RAS p21 protein activator.…”

A Long-term Follow-up of Serum Myeloperoxidase Antineutrophil Cytoplasmic Antibodies (MPO-ANCA) in Patients with Graves Disease Treated with Propylthiouracil

“…although the precise mechanism(s) how MPo-anca develops remain unclear, PTU has been shown to accumulate in the neutrophils [16] and to bind the MPo antigen with altering its structure [17]. it has been, therefore, suggested that the structural change of MPo antigen induced might promote development of anca in susceptible individuals [18]. our study showed that higher serum levels of MPoanca remained positive for more than 5 years after PTU withdrawal.…”