Impaired angiogenesis and extracellular matrix metabolism in Autosomal-Dominant Hyper-IgE Syndrome.

: There are more than 7000 described rare diseases, most lacking specific treatment. Autosomal-dominant hyper-IgE syndrome (AD-HIES, Job's syndrome) is caused by mutations in signal transducer and activator of transcription 3 (STAT3). These patients present with immunodeficiency accompanied by severe non-immunological features including skeletal, connective tissue and vascular abnormalities, poor post-infection lung healing, and subsequent pulmonary failure. No specific therapies are available for these abnormalities. Here we investigated underlying mechanisms in order to identify therapeutic targets. Histological analysis of skin wounds demonstrated delayed granulation tissue formation and vascularization during skin wound healing in AD-HIES patients. Global gene expression analysis in AD-HIES patient skin fibroblasts identified deficiencies in a STAT3 controlled transcriptional network regulating extracellular matrix (ECM) remodeling and angiogenesis, with hypoxia inducible factor 1α (HIF1α) being a major contributor. Consistent with this, histological analysis of skin wounds and coronary arteries from AD-HIES patients showed decreased HIF1α expression, and revealed abnormal organization of the ECM and altered formation of the coronary vasa vasorum. Disease modeling utilizing cell culture and mouse models of angiogenesis and wound healing confirmed these predicted deficiencies and demonstrated therapeutic benefit of HIF1α stabilizing drugs. The study provides mechanistic insights into AD-HIES pathophysiology and finds new treatment option for this rare disease.