JAK3 is primarily expressed in hematopoietic cells and mediates cytokine signaling via the common γ chain. Classically, autosomal recessive loss-of-function (LOF) JAK3 variants cause severe combined immunodeficiency (SCID). In contrast, somatic gain-of-function (GOF) variants in JAK3 have been described across T and B cell malignancies, acute megakaryoblastic leukemia, and solid tumors, and a germline GOF variant (c.1520A>C, p.Q507P) has been reported in a family with chronic natural killer (NK) cell lymphoproliferative disease, autoimmunity, and hypogammaglobulinemia, notably without allergic disease.
We report five unrelated pediatric patients (3 females and 2 males) identified through a genomic study of atopic disease. The median age at evaluation was 11 years (range: 3–15) (supplementary table). All patients exhibited severe atopic dermatitis (AD), including one complicated by molluscum contagiosum and Methicillin-resistant Staphylococcus aureus (MRSA) infections. Only one patient had an IgE-mediated food allergy. None had asthma, allergic rhinitis, eosinophilic gastrointestinal disease, short stature, or lymphoproliferative disease. Exome sequencing revealed two previously identified heterozygous JAK3 variants (c.394 C>A, p.P132T, MAF: 0.0046 and c.2164 G>A, p.V722I, minor allele frequency [MAF]: 0.0098). All patients had eosinophilia (median: 1,360 cells/μL, range: 490–1,610), with normal hemoglobin, platelet, neutrophil, and lymphocyte counts. In one patient, elevated NK (1,062 cells/μL) and NKT (1,071 cells/μL) cells were observed on immunophenotyping; no additional abnormalities were detected in the remaining patients. All patients had elevated IgE (median: 7,540 UI/mL, range: 139–17,472); other immunoglobulins and vaccine titers were within normal limits.
While pathogenicity annotations for these variants are inconsistent, ex vivo studies from lymphoproliferative disease samples harboring p.P132T (FERM domain) and p.V722I (JH2 domain) variants demonstrated constitutive JAK3 with enhanced STAT5 phosphorylation, supporting a GOF mechanism. Compared with strongly activating JAK3 variants linked to lymphoproliferation, these germline variants may confer a subtler activating signal, preferentially amplifying STAT5 signaling. Notably, somatic STAT5B GOF causes a syndrome featuring nonclonal eosinophilia and severe AD, although with additional features absent in our cohort. Finally, JAK3 overexpression has been observed in human AD skin cells, and JAK3 inhibition reduces inflammatory responses in both in vivo and in vitro. Collectively, these data suggest that germline JAK3 GOF variants may contribute to atopic diatheses, potentially expanding the phenotype of JAK3-associated disease.
