Primary Immune Deficiency Clinic

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

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 our main areas of focus: 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 were found to have an aberrant response to atherosclerosis with adventitial thinning and aneurysmal widening. Dr. Manfred Boehms lab in NHLBI 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, which was published this past year. Ongoing studies are focused on analyzing our vascular imaging over the last 15 years for incidence, change, and risk factors, as well as 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 prior bench-to-bedside award, and now hopefully with a U01 grant 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 recently systemically reviewed the autoimmune manifestations with DN STAT3, identifying several with lupus or lupus-like disease and autoimmune cytopenias. With our NIAMS collaborators we found increased interferon signature and neutrophil NET formation. This studies has been published. Through collaborators in Spain, in vitro studies with jak inhibition showing normalization of some of the abnormalities. We are currently preparing a clinical protocol to evaluate the use of Jak inhibition for those with autoimmunity and DN STAT3 mutations. 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, which was recently published. 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. We are preparing manuscripts covering the clinical and laboratory data for all the patients with DOCK8 deficiency seen at NIH as well as the bone marrow transplant data for those who have undergone transplant. With the COVID-19 pandemic, we have been interested in not only how our primary immune deficiency patients have responded to COVID illness, but also to the safety and efficacy of the COVID19 vaccine in this population. We have published an initial paper examining the vaccine response in our cohort and ongoing studies are underway.