IL-5/IL-5Rα blockade provides clinically validated benefit in EGPA but requires phenotype-specific evidence for other conditionsTargeting Eosinophils Shows Promise for Specific Autoimmune Conditions

Eosinophils are best known for their host defence against helminths and for their effector role in type 2 inflammation, but an expanding evidence base indicates that their functions extend to immune regulation, tissue repair, fibrosis, and selected autoimmune phenotypes. This narrative review critically evaluates eosinophil biology across inflammatory arthritis, systemic lupus erythematosus (SLE), antineutrophil cytoplasmic antibody-associated vasculitis (AAV), autoimmune neurological and endocrine disorders, autoimmune dermatoses, inflammatory bowel disease (IBD), and fibrosing connective-tissue disorders. We organize the evidence around four recurring processes: tissue recruitment and niche imprinting, degranulation and eosinophil extracellular trap formation, cross talk with innate and adaptive immune cells, and context-dependent repair or fibrotic remodelling. The strength of evidence is highly disease dependent. Human mechanistic and interventional data are strongest in eosinophilic granulomatosis with polyangiitis (EGPA) and selected eosinophil-rich dermatoses, whereas many proposed roles in RA, SLE, central nervous system autoimmunity, endocrinopathies, and IBD remain observational or preclinical. Proposed resident/regulatory and inflammatory eosinophil states support functional plasticity, but several frequently used marker schemes derive predominantly from mouse studies and do not yet constitute a standardized human taxonomy. Therapeutically, IL-5/IL-5Rα blockade provides clinically validated benefit in EGPA, but efficacy should not be extrapolated across autoimmune diseases without phenotype-specific evidence. Transient blood eosinophilia and rare eosinophilic complications during IL-4Rα blockade are clinically recognized; however, compensatory IL-5 signaling, altered trafficking, and unmasking of pre-existing eosinophilic disease remain competing, incompletely resolved explanations. Across the field, causal inference is constrained by species differences, limited access to representative human tissue, heterogeneous biomarker definitions, and a scarcity of controlled trials. Eosinophils should therefore be viewed not as universal drivers of autoimmunity but as context-dependent immune modulators whose pathogenic or protective contribution varies by tissue, disease stage, and cellular state. Human tissue–resolved studies and phenotype-guided trials will be essential for translating this heterogeneity into precision therapy.