A DOUBLE-EDGED SWORD: EOSINOPHILS AND THE PATHOGENESIS OF ALLERGIC AND AUTOIMMUNE DISEASES

Abstract

Traditionally, eosinophils are regarded as terminally differentiated cells that play an essential role in host defense against helminths. However, the role of eosinophils has been redefined based on recent advances in transcriptomics and single-cell RNA sequencing (scRNA-seq) between 2015 and 2026. Eosinophils are regarded as pleiotropic immunomodulatory architects that play an essential role in both homeostatic regulation and tissue destruction in disease. The discovery of eosinophils, comprising resident homeostatic (iEos) and inflammatory (rEos) cells, has resolved the long-standing paradox of their functional heterogeneity. The essential regulators of eosinophils include the transcription factor GATA-1, which is involved in eosinophil lineage commitment, and the IL-5/JAK1/STAT5 axis, which is involved in terminal differentiation and survival. Eosinophils play an essential role in the pathogenesis of diseases through their effector functions, which include the release of four main cationic proteins, MBP-1, ECP, EPO, and EDN, and eosinophil extracellular traps (EETs). Severe Eosinophilic Asthma affects about half of patients with severe asthma, and Eosinophilic Esophagitis (EOE) is an emerging condition that has increased many fold in incidence since the mid-2000s, leading to dysphagia and fibrosis in the esophagus. Autoimmune Disorders, like Eosinophilic Granulomatosis with Polyangiitis (EGPA) and Bullous Pemphigoid (BP), are characterized by eosinophils, leading to organ-specific destructive pathology and vasculitis. The biotherapeutic revolution in the management of eosinophilic disorders, targeting IL-5 (mepolizumab, reslizumab), IL-5Rα (benralizumab), and IL-4Rα (dupilumab), has been significant. Precision medicine, based on combined biomarkers like ECP, EDN, and their ratios like rEos/iEos, is being developed to tackle the about one third non-responder rates seen with current therapies. Eosinophil biology represents a complex interplay between helpful immune regulation and unhelpful tissue damage. Future therapeutic success will be based on precision medicine approaches to tailor therapy to particular disease endotypes and the particular molecular signature of particular subpopulations of eosinophils.