Type 2 immunity and its role in allergic disorders

Abstract

The prevalence of allergic diseases, including allergic rhinitis, chronic rhinosinusitis, asthma, eosinophilic esophagitis, food and drug allergies, and atopic dermatitis, has been increasing globally over the past few decades. Allergic diseases are closely linked to type 2 immunity, which is characterized by the coordinated interplay between innate and adaptive immune responses. Significant advancements have been achieved in elucidating the cellular and molecular mechanisms that govern type 2 immunity, chiefly mediated by type 2 cytokines, including IL-4, IL-5, IL-9, and IL-13, which are primarily secreted by T helper 2 cells and group 2 innate lymphoid cells. In addition, a diverse array of effector cells, including mast cells, basophils, eosinophils, regulatory T cells, B lymphocytes, dendritic cells, and natural killer cells, are critically involved in orchestrating and modulating type 2 inflammatory responses. The activation of epithelial cells, secretion of alarmins and multiple chemokines, impairment of epithelial barrier integrity, and disruption of microbial dysbiosis serve as crucial mechanisms underlying not only the pathogenesis of allergic disorders but also the development of various systemic conditions. Biologic therapies targeting type 2 pathways-specifically effector functions of IL-4, IL-13, IL-5, thymic stromal lymphopoietin, and immunoglobulin E have-demonstrated promising efficacy. However, a subset of patients with severe allergic diseases remains unresponsive to these treatments, underscoring the need for deeper mechanistic insights and personalized therapeutic approaches. This review addresses the definition, evolution, cellular and molecular basis, and regulation of type 2 immunity. It then examines the common allergic diseases associated with type 2 responses and concludes by exploring the associations between inborn errors of immunity and type 2 responses.