Allergic diseases have long been considered multifactorial disorders arising from the complex interplay of multiple genetic susceptibilities and environmental factors. However, accumulating evidence has shown that, in a subset of patients with severe or treatment-refractory disease, single-gene mutations may underlie the pathogenesis. In 2022, we identified gain-of-function (GoF) mutations in STAT6 as the cause of a patient who exhibited severe atopic dermatitis, eosinophilic gastrointestinal disease characterized by lymphoid follicular hyperplasia in the stomach and duodenum, elevated serum IgE levels, and eosinophilia. Within just a few years, more cases of severe allergic disease caused by STAT6-GoF have been reported worldwide, revealing a broad and heterogeneous clinical spectrum, with marked interindividual differences in disease severity and organ involvement. STAT6-GoF is now becoming established as a distinct form of IEI predominantly characterized by allergic phenotypes. In addition, patients with GoF mutations in JAK1 have also been identified. These patients likewise show diverse clinical manifestations, including refractory atopic dermatitis accompanied by autoimmune disorders. At the same time, both the shared and distinct features among cases, as well as phenotypic differences related to the location of each mutation and the degree of pathway activation, are gradually becoming clearer. In this lecture, I will provide an overview of the clinical characteristics, immunological background, and pathogenic mechanisms of refractory allergic diseases caused by monogenic variants, with a particular focus on STAT6-GoF and JAK1-GoF.
