Month: October 2023

2023 has been marked by the discovery of over 10 new inborn errors of immunity, as well as novel consequences of anticytokine antibodies and somatic disease-causing variants. Amongst these were three new diseases caused by mutations in the JAK-STAT pathway. Baris et al and Sharma et al independently described a novel atopic syndrome caused by heterozygous germline gain-of-function (GOF) mutations in STAT6 1,2. This included 11 separate families across multiple continents and included atopic dermatitis, peripheral hypereosinophilia, eosinophilic gastrointestinal disease, allergic asthma, elevated total serum IgE, food allergy, and anaphylaxis. Mutations were found in the DNA-binding, linker, and SH2 domains: functional evaluation revealed sustained STAT6 phosphorylation and enhanced Th2 differentiation. Three families with disabling pansclerotic morphea due to heterozygous STAT4 GOF were described by Bhagdassarian et al 3. All three activating mutations were in the SH2 domain of STAT4; the mutant protein exhibited enhanced basal (unstimulated) phosphorylation and delayed dephosphorylation kinetics in skin fibroblasts. Patient skin and serum was characterized by markedly increased expression of IL-6. Further supporting a primary role for JAK-STAT pathway activation, both STAT6 GOF and STAT4 GOF patients responded to treatment with systemic JAK inhibitions like ruxolitinib and baricitinib. [READ MORE]