Type 2–interferon imbalance in allergic barrier disease: An asthma-centered, cross-disease perspective

Shenghong Rao,¹ Shumei Li,² Haoyue Shen,¹ Tengchuan Jin³

Affiliations:
¹ Faculty of Modern Health Care, Anhui Sanlian University, Hefei, Anhui, China
² Department of Nursing, Clinical College of Anhui Medical University, Hefei, Anhui Province, China
³ Laboratory of Structural Immunology, the CAS Center for Excellence in Molecular Cell Science, the CAS Key Laboratory of Innate Immunity and Chronic Diseases, School of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230027, China; Institute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, Anhui, China

Abstract

Allergic diseases are typically regarded as type 2 inflammatory disorders driven by interleukin-4, interleukin-5, and interleukin-13, which mediate immunoglobulin E class switching, eosinophilic inflammation, mucus hypersecretion, pruritus, tissue remodeling, and epithelial barrier dysfunction. However, type 2 cytokine activity alone does not fully account for variations in exacerbation risk, susceptibility to infections, comorbidities, or responses to biologic therapy. This narrative review proposes an asthma-centered type 2–interferon imbalance framework and discusses its cautious, disease-specific extension to atopic dermatitis, chronic rhinosinusitis with nasal polyps, eosinophilic esophagitis, and food allergy. The model emphasizes that, particularly in asthma, allergic barrier inflammation arises and persists in injured tissues where excessive type 2 inflammation may coexist with impaired interferon-mediated host defense. Evidence is strongest in asthma, where deficiencies in type I and type III interferon responses are linked to rhinovirus susceptibility, delayed viral clearance, and recurrent exacerbations. In other allergic diseases, interferon dysfunction appears more variable, reflecting differences in tissue context, disease stage, and environmental exposure. In asthma, and potentially in selected allergic barrier diseases, persistent inflammation may result from a cycle of epithelial injury, alarmin release, cytokine amplification, impaired antiviral defense, ongoing exposure, and incomplete tissue repair. These mechanisms provide a rationale for tiered intervention, including blockade of upstream epithelial alarmins, inhibition of downstream type 2 effector pathways, and selected investigational approaches aimed at restoring mucosal host defense.