Eosinophils in vasculitis: characteristics and roles in pathogenesis

Abstract

Eosinophils are multifunctional granular leukocytes that are implicated in the pathogenesis of a wide variety of disorders, including asthma, helminth infection, and rare hypereosinophilic syndromes. Although peripheral and tissue eosinophilia can be a feature of many types of small-vessel and medium-vessel vasculitis, the role of eosinophils has been best studied in eosinophilic granulomatosis with polyangiitis (EGPA), where eosinophils are a characteristic finding in all three clinical stages of the disorder. Whereas numerous studies have demonstrated an association between the presence of eosinophils and markers of eosinophil activation in the blood and tissues of patients with EGPA, the precise role of eosinophils in disease pathogenesis has been difficult to ascertain owing to the complexity of the disease process. In this regard, results of clinical trials using novel agents that specifically target eosinophils are providing the first direct evidence of a central role of eosinophils in EGPA. This Review focuses on the aspects of eosinophil biology most relevant to the pathogenesis of vasculitis and provides an update of current knowledge regarding the role of eosinophils in EGPA and other vasculitides.

Figure 1

Characteristics of eosinophils. Eosinophils are multifunctional, bi-lobed granulocytes that contain granular proteins including MBP, ECP, EPO and EDN. Eosinophils can degranulate by exocytosis or by piecemeal degranulation whereby individual granule contents are differentially secreted by activated eosinophils without disruption of the cell membrane. Sombrero vesicles are morphologically distinct vesicles that carry granules to the plasma membrane. Lipid bodies are structurally distinct sites within eosinophils that are responsible for synthesis of paracrine eicosanoid mediators of inflammation. Functions of eosinophils include the production of numerous chemokines, cytokines, and growth factors that mediate allergic inflammation, thrombosis, and fibrosis. A nonexhaustive list of these products are shown in boxes. Abbreviations: 15-HETE, 15-hydroxyeicosatetraenoic acid; APRIL, a proliferation-inducing ligand; CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CXCL, CXC-chemokine ligand; CXCR, CXC-chemokine receptor; ECP, eosinophil cationic protein; EDN, eosinophil-derived neurotoxin; EPO, eosinophil peroxidase; GM-CSF, granulocyte-macrophage colony-stimulating factor; GRO-α, growth regulated-α protein; LIF, leukaemia inhibitory factor; LT, leukotriene; MBP, major basic protein; NGF, nerve growth factor; PAF, platelet activating factor; PDGF, platelet-derived growth factor; SCF, stem cell factor; TF, tissue factor; TGF, transforming growth factor; VEGF, vascular endothelial growth factor.

Figure 2

Schematic representation of eosinophil trafficking. In the bone marrow, eosinophils differentiate from haematopoietic progenitor cells into mature eosinophils under the influence of transcription factors (GATA-1, PU.1, c/EBP) and their subsequent expansion is regulated by eosinophilopoietins (IL-3, IL-5, GM-CSF). Eosinophil migration into circulation is regulated primarily by IL-5. Circulating eosinophils interact with endothelial cells, migrate through the vessel wall, and infiltrate a target organ by a regulated process involving the interaction between adhesion molecules, chemokine receptors on eosinophils (CCR3) via their respective chemokine gradients (eotaxins), and cytokines (in particular products of T_H2 and ILC2 cells, such as IL-4, IL-5, IL-13). The characteristic pathologic findings of eosinophil involvement in vasculitis include eosinophilic infiltration in tissue, and intravascular and extravascular granuloma formation with a zone of centralized eosinophilic necrosis and surrounding epithelioid cells, histiocytes, multinucleated giant cells, and neutrophils. Eosinophilic vasculitis of the small arteries and veins can be present, depending on the stage of disease. Abbreviations: CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; c/EBP, CCAAT/enhancer-binding protein; GATA-1, GATA-binding factor 1 (also known as erythroid transcription factor); GM-CSF, granulocyte-macrophage colony-stimulating factor; ILC2, type 2 innate lymphoid cell; T_H2, type 2 T helper cell.

Figure 3

Histopathology of EGPA. Biopsy-obtained transbronchial lung tissue from a patient with EGPA showing an affected blood vessel with a dense inflammatory infiltrate, composed of plasma cells (arrows) and eosinophils (arrowheads) (magnification ×40). Abbreviation: EGPA, eosinophilic granulomatosis with polyangiitis.