Understanding the Type 2 Immunity: An Evolving View Beyond Allergic Diseases

Type 2 (T2) immunity is classically associated with defense against helminths and environmental threats, from a physiological perspective, and with allergies and eosinophilic inflammatory diseases, in a pathological sense. However, growing evidence reveals that T2 pathways also support other essential homeostatic functions, including tissue protection and repair. There are major clues from the early evolution of T2 responses for protection against massive tissue damage and positive selection for survival against parasites starting over 500 million years ago. These responses likely co-evolved stepwise with immune-regulatory circuits, culminating in the emergence of the fully functional human-type IgG4 in the great apes (Hominidae) within the last ~10 million years. The involvement of body barriers along with the strong influence of local epithelial cells and their interaction with the microbiome and the immune system is a common characteristic of T2 inflammation. An expanding list of new T2 diseases is being reported, characterized by epithelial cell and immune system activation, epithelial barrier damage, and microbial dysbiosis, including opportunistic pathogen colonization and loss of commensals. This evolving understanding coincides with the clinical success of biologics targeting key T2 mediators such as IL-4, IL-5, IL-13, IL-31, TSLP, and IgE, which have transformed the management of severe allergic diseases and other T2-driven pathologies. However, the contribution of T2 immunity to homeostatic programs raises questions about the long-term consequences of sustained T2 suppression. In this review, we examine the dual role of T2 immunity in health and disease, revisit its evolutionary origins, highlight its protective functions beyond allergy, and discuss the potential implications of prolonged T2 pathway blockade.

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Publication Details

Journal
Allergy
Published
2026-09-09
DOI
https://doi.org/10.1111/all.70512
Primary Topic
Dermatology and Skin Diseases
Type
article
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article

Understanding the Type 2 Immunity: An Evolving View Beyond Allergic Diseases

D.А. Kudlаy, Huseyn Babayev, Rodrigo Jiménez‐Saiz, Mustafa Sevım et al.
Allergy
Dermatology and Skin Diseases
article

Understanding the Type 2 Immunity: An Evolving View Beyond Allergic Diseases

D.А. Kudlаy, Huseyn Babayev, Rodrigo Jiménez‐Saiz, Mustafa Sevım, Oral Alpan, Mübeccel Akdiş, Luo Zhang, Kari C. Nadeau, Ruperto González‐Pérez, Yadong Gao, Carlos Blanco, Cezmi A. Akdiş, Emilio Nuñez‐Borque, Musa Khaitov, Mohamed H. Shamji, Tuncay Göksel, İsmail Öğülür, Salvador Iborra, Özlem Göksel, Marie‐Charlotte Brüggen, Can Zeyneloglu, Ming Wang, Marı́a José Torres
article en

Abstract

Type 2 (T2) immunity is classically associated with defense against helminths and environmental threats, from a physiological perspective, and with allergies and eosinophilic inflammatory diseases, in a pathological sense. However, growing evidence reveals that T2 pathways also support other essential homeostatic functions, including tissue protection and repair. There are major clues from the early evolution of T2 responses for protection against massive tissue damage and positive selection for survival against parasites starting over 500 million years ago. These responses likely co-evolved stepwise with immune-regulatory circuits, culminating in the emergence of the fully functional human-type IgG4 in the great apes (Hominidae) within the last ~10 million years. The involvement of body barriers along with the strong influence of local epithelial cells and their interaction with the microbiome and the immune system is a common characteristic of T2 inflammation. An expanding list of new T2 diseases is being reported, characterized by epithelial cell and immune system activation, epithelial barrier damage, and microbial dysbiosis, including opportunistic pathogen colonization and loss of commensals. This evolving understanding coincides with the clinical success of biologics targeting key T2 mediators such as IL-4, IL-5, IL-13, IL-31, TSLP, and IgE, which have transformed the management of severe allergic diseases and other T2-driven pathologies. However, the contribution of T2 immunity to homeostatic programs raises questions about the long-term consequences of sustained T2 suppression. In this review, we examine the dual role of T2 immunity in health and disease, revisit its evolutionary origins, highlight its protective functions beyond allergy, and discuss the potential implications of prolonged T2 pathway blockade.

Allergy
Beijing Tongren Hospital (CN), Harvard University (US), Sechenov University (RU), Universidad de Alcalá (ES), University of Zurich (CH), Universidad Francisco de Vitoria (ES), UCLA Health (US), American Society for Clinical Laboratory Science (US), Hospital Universitario de Canarias (ES), McMaster University Medical Centre (CA), Pirogov Russian National Research Medical University (RU), Ege University (TR), University Hospital of Zurich (CH), Institute of Immunology and Physiology (RU), Inmunotek (Spain) (ES), Hospital Regional Universitario de Málaga (ES), CK-CARE (CH), Istinye University (TR), Hospital Universitario de La Princesa (ES), Beijing Municipal Education Commission (CN), Universidad Alfonso X el Sabio (ES), Andalusian Centre for Nanomedicine and Biotechnology (ES), First Affiliated Hospital Zhejiang University (CN), Imperial College London (GB), Universidad de Málaga (ES)
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Dermatology and Skin Diseases
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