NIAID and NIH has been a leader in the clinical and laboratory research in STAT3 deficient Hyper IgE (Jobs) syndrome for decades. In 2005, I became the primary clinician and clinical research for our cohort of patients, which has risen to over 130 individuals. Identification of loss of function STAT3 mutations as the genetic etiology in 2007 led to intensification of the research studies. Our goal through intensely studying this patient population and their multi-system clinical phenotype is to understand how STAT3 controls is involved in such diffuse pathways as Candida and Staphylococcal control, allergy, atherosclerosis, osteoporosis and scoliosis, and dental abnormalities. The following are some of the key advances in the last year. Vascular abnormalities and Abnormal Tissue Remodeling (Collaborator: Manfred Boehm, NHLBI, Ahmed Gharib, NIDDK). Over the last decade we have recognized that tissue remodeling is aberrant in those with dominant negative STAT3 mutations. This is evident in the lung through the persistent pneumatoceles forming after infection, and prolonged air leaks after lung surgery. In the vasculature, middle sized artery aneurysm and tortuosity are common and lead to morbidity and mortality with myocardial infarction, subarachnoid hemorrhage, lung hemorrhage and gastro-intestinal hemorrhage. Since 2006, we have been systematically imaging the coronary arteries and more recently the cerebral arteries to allow for early detection of abnormalities. Through imaging and pathological studies, the vessels are not to have an aberrant response to atherosclerosis with adventitial thinning and aneurysmal widening. Dr. Manfred Boehms lab has been leading the bench research focused on abnormal wound healing with disordered matrix metalloproteinase responses, as well as aberrant angiogenesis related to deficient HIF-1alpha signaling. Ongoing studies are focused on repeated skin biopsies to further delineate wound healing, and pharmacologic in vitro studies to stabilize HIF1alpha to improve angiogenesis and tissue remodeling. Pulmonary Clearance, Infection Susceptibility (Collaborators: Kenneth Olivier, NHLBI, Richard Boucher, UNC). Over the years through managing the DN STAT3 patients through pulmonary infections and exacerbations of bronchiectasis, we have noted that the sputum is frequently very tenacious. Through our bench-to-bedside award with Dr. Ken Olivier and Dr. Richard Boucher, we are investigating the mucin composition, airway epithelial cell as well as airway immunologic host defenses (such as antimicrobial peptides) through collection of sputum and research bronchoscopies. Autoimmune/Arthritis Phenotyping (Collaborator: Sarthak Gupta, NIAMS) We are currently systemically reviewing the autoimmune manifestations with DN STAT3. We now have several with lupus or lupus-like disease and autoimmune cytopenias. We are doing both neutrophil studies and examining interferon signatures for those with and without autiommmunity and closely evaluating the kidney disease with our nephrology collaborators. DOCK8 Deficiency (Collaborators: Helen Su, NIAID; Heidi Kong, NIAMS, Nirali Shah and Dennis Hickstein, NCI). DOCK8 deficiency was described at NIAID, and we remain a major referral center for these patients, having evaluated over 50 patients. We have a unique ability, therefore, to further define the clinical phenotype, understand the pathogenesis, and improve therapy. Increasingly we are recognizing the vascular abnormalities, with cerebral artery stenosis, and aortic dilation and calcification. Although infections explain some vasculitis, others remain without a microbial diagnosis and treatment and long-term follow-up after hematopoietic stem cell transplant (HSCT) are ongoing projects. In addition, improved molecular diagnostics for cryptosporidium have led to identification of higher numbers affected in the GI tract leading to biliary and liver complications. Our relatively large cohort has allowed collaborator Dr. Heidi Kong, dermatology branch NIAMS, to define the skin microbiome in this population, identifying high DNA viral burden even in areas without obvious cutaneous disease, including novel HPV viruses. Ongoing prospective studies are continuing following HSCT. In recent years, there have been other monogenic diseases described in our cohort of patients referred for Hyper IgE syndrome (Main Collaborator Josh MIlner, LAD, NIAID). In the last two years, our cohort has been integral in defining both loss of function heterozygous CARD11 mutations leading to atopy and immune defcieincy, as well as loss of function heterozgyous CARD14 mutations leading to atopy CARD11 and CARD14 are involved in NFKB stimulation, with CARD11 being expressed primarily in immune cells and CARD14 being expressed primarily in keratinocytes.

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