Abstract Autosomal dominant hyper-IgE syndrome (AD-HIES), or Job’s syndrome, is a rare primary immunodeficiency caused by dominant-negative mutations in STAT3. Patients experience recurrent pulmonary infections and chronic inflammation, leading to severe complications and heightened mortality risk. To investigate whether neutrophil-intrinsic dysfunction contributes to lung pathology in AD-HIES, we used a murine model expressing the STAT3V463Δ mutation, a common disease-associated variant. Following intratracheal infection with Pseudomonas aeruginosa, STAT3V463Δ mice exhibited pronounced alveolar damage, increased vascular congestion, and extensive leukocyte infiltration compared to wild-type (WT) controls. These changes were accompanied by elevated bacterial burden and significantly increased levels of pro-inflammatory cytokines and chemokines in the lung. Neutrophil recruitment to the lungs was markedly elevated, and surface expression of degranulation markers was enhanced in STAT3V463Δ neutrophils in vivo. To determine whether neutrophil hyperactivation was driven by intrinsic defects independent of microbial load, mice were challenged intratracheally with purified lipopolysaccharide (LPS), revealing similarly enhanced neutrophil degranulation and NETosis in STAT3V463Δ mice despite controlled PAMP exposure. Mechanistically, bone marrow–derived neutrophils (BMDNs) from STAT3V463Δ mice displayed heightened degranulation and NETosis in response to PMA or f-MLF stimulation. Together, these findings demonstrate that STAT3V463Δ drives neutrophil hyperresponsiveness, contributing to dysregulated inflammation and pulmonary tissue damage in AD-HIES.
Brewer et al. (Sun,) studied this question.