Type 2 inflammation through the lens of inborn errors of immunity

Type 2 inflammation contributes to host defense and tissue repair but, when dysregulated, can cause a broad spectrum of allergic diseases. Although atopy has traditionally been considered the result of interactions between environmental factors and polygenic susceptibility, the identification of primary atopic disorders (PADs) has revealed that single-gene defects can drive severe allergic phenotypes. In this review, we discuss selected paradigmatic disorders to illustrate how distinct molecular defects can converge on type 2 inflammation and a shared atopic phenotype, including impaired antigen-receptor signaling in CARD11-associated atopy, enhanced cytokine signaling in STAT6 gain-of-function disease, loss of immune tolerance in FOXP3 deficiency, cytoskeletal and immune-synapse dysfunction in DOCK8 deficiency, and epithelial barrier and signaling abnormalities in Netherton syndrome. We also highlight the clinical features that should raise suspicion of an underlying monogenic disorder in patients with severe atopy and discuss how molecular diagnosis may inform targeted therapeutic strategies. Collectively, insights from rare PADs provide a framework for understanding the molecular heterogeneity of type 2 inflammation and may reveal mechanisms and therapeutic targets relevant to more common allergic diseases.