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STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder., (© 2023 Sharma et al.)

Kawasaki syndrome (KS) has been reported to be associated with selective expansion of Vbeta2+ T cells and either staphylococcal toxic shock syndrome toxin-1 or streptococcal pyrogenic exotoxin C in uncomplicated cases. However, there have been no previous studies on the role of superantigens in KS associated with coronary artery disease, the major complication of this illness. The present study characterized bacteria isolated from three acute KS patients who developed coronary artery disease. Staphylococcus aureus secreting either TSST-1 (n = 3) or exfoliative toxin A (n = 1), both known to stimulate expansion of Vbeta2+ T cells, were isolated from all three patients. The percent Vbeta2+ T cells was determined in three patients with coronary artery disease. On presentation, one patient demonstrated reduction, whereas the other two showed expansion, of Vbeta2+ T cells. Repeat analyses of the latter two children showed their percent Vbeta2+ T cells to decrease toward normal. These observations suggest that coronary artery disease in KS may result from superantigenic stimulation of Vbeta2+ T cells. This is also the first demonstration of an association of staphylococcal exfoliative toxin with acute KS. The observation that three different bacterial toxins associated with KS are potent activators of Vbeta2+ T cells suggests an important role for this T cell subset in the pathogenesis of this autoimmune disease.