Eosinophilic Granulomatosis With Polyangiitis: Dissecting the Pathophysiology

Abstract

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is a rare multisystemic disease classified both amongst hypereosinophilic disorders and ANCA-associated vasculitis. Vessel inflammation and eosinophilic proliferation are the hallmarks of the disease and main effectors of organ damage. Two distinct disease phenotypes have classically been described according to ANCA-status: the ANCA-negative subset with eosinophil-driven manifestation and the ANCA-positive one with vasculitic manifestations. An analogous dichotomization has also been backed by histological findings and a distinct genetic background. EGPA is typically consider a Th2-mediated disease and blood and tissue eosinophilia represent the cornerstone of diagnosis. Besides, ANCA are known for inducing endothelial injury and vascular inflammation by activating the circulating neutrophils. Thus, the pathogenesis of EGPA seems to be mediated by two coexisting mechanisms. However, the verbatim application of this strict dualism cannot always be translated into routine clinical practice. In the present review we describe the current knowledge on the eosinophilic and ANCA-mediated aspects of EGPA pathogenesis. Finally, we review the rationale of the currently proposed EGPA dichotomy and future research perspectives.

Keywords: ANCA-associated vasculitis; Churg-Strauss syndrome; EGPA classification; Eosinophilic Granulomatosis with Polyangiitis; eosinophils; hypereosinophilic syndromes; myeloperoxidase; neutrophils.

Figure 1

Overview of eosinophil-mediated and ANCA-mediated mechanisms of EGPA immunopathogenesis. On top, a schematic representation of the spectral distribution of clinical features in MPO-ANCA-negative (red triangle) and MPO-ANCA-positive EGPA (green triangle). At the extreme ends of the spectrum, lung involvement and rapidly progressive pauci-immune glomerulonephritis come as the result of predominantly eosinophilic and vasculitic mechanisms of organ damage, respectively. In contrast, the other clinical manifestations of EGPA result from the combination of the two processes. (A) Eosinophil-mediated pathogenesis of EGPA. Eosinophil granule proteins are highly cationic compounds that act synergically to mediate the cell's cytotoxicity. Mayor Basic Protein (MBP) is associated with airway remodeling and asthma, fibrogenesis, and procoagulant activity. NADPH-oxidase (NADPH) and Eosinophil Peroxidase (EPO) generate high quantities of reactive oxygen species that contribute to endothelial dysfunction and thrombosis. Eosinophil Cationic Proteins (ECP) is implied in cardiac toxicity, procoagulant activity, and nerve fibers degeneration. Eosinophil Neurotoxin (ENT) has marked neurotoxic potential in vivo. (B) Putative sequence of neutrophil-mediated endothelial injury. Circulating neutrophils get primed for ANCA activation by inflammatory cytokines and C5a complement factor. Priming induces the exposition on neutrophils cell-surface of ANCA antigens. Circulating ANCA bind to ANCA-antigens through F(ab)2 fragment and activate neutrophils by interaction with Fc receptor. Activated neutrophils release cytotoxic enzymes and factors that activate the alternative complement pathway, producing C5a that further enhances neutrophils priming. ANCA-activated neutrophils marginate and penetrate the vessel wall, where they undergo respiratory burst, degranulation, NETosis, and necrosis causing endothelial damage.