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

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.