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 about 200 affected individuals seen. Identification of dominant negative 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 (Collaborators: Manfred Boehm, NHLBI, Ahmed Gharib, NIDDK, Chris Nagao, NIAMS, Heidi Kong, NIAMS, Ian Myles, NIAID). 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 has been published. Ongoing studies are focused on analyzing our vascular imaging over the last 15 years for incidence, change, and risk factors, primarily with Dr. Ahmed Gharib. In addition, we are performing repeated skin biopsies to further delineate wound healing, including before and after hematopoietic stem cell transplantation, in collaboration with Drs. Kong, Nagao and Myles. Pulmonary Clearance, Infection Susceptibility (Collaborators: Kenneth Olivier, UNC, Richard Boucher, UNC). Over the years through managing the STAT3 DN 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 a more recent U01 grant with Dr. Ken Olivier and Dr. Richard Boucher, we have been 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 with a recently published manuscript describing abnormalities in bronchial epithelium. Studies are ongoing looking at modulation of factors such as CFTR and the impact on mucociliary clearance. Autoimmune/Arthritis Phenotyping (Collaborator: Sarthak Gupta, NIAMS) We have published that a subset of the STAT3 DN HIES patients have autoimmune manifestations, identifying several with lupus or lupus-like disease and autoimmune cytopenias. With our NIAMS collaborators we found increased interferon signature and neutrophil NET formation. In collaboration with 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/or atopic dermatitis and STAT3 DN mutations. DOCK8 Deficiency (Collaborators: Helen Su, NIAID; Heidi Kong, NIAMS, Corina Gonzalez, NCI). DOCK8 deficiency was described at NIAID, and we remain a major referral center for these patients, having evaluated over 50 patients, and performed hematopoietic cell transplant on about 40 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. 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. We are currently publishing the reversion to normal in the skin microbiome after transplant. We are preparing manuscripts covering the clinical and laboratory data for all the patients with DOCK8 deficiency seen at NIH, including the clinical impact of reversion mutations on the clinical course, which remains a controversial clinical question. Inborn Errors of Immunity (IEI) beyond STAT3 DN and DOCK8 deficiency: Primarily through the PID clinic, we see patients with varying IEI, and dependent on the disease and its manifestations, we have set up collaborations. Through Dr. Notarangelo and Dr. Delmonte's laboratories we are studying the immune defects of STAT1 GOF as well as other combined immune deficiencies. We collaborate with the NCI group studying Kaposi sarcoma to identify underlying IEI in patients with HIV negative Kaposi sarcoma. We collaborate with the NCI IEI transplant group to consider hematopoietic stem cell transplant, including for patients with IL-12R/IFNg defects STAT3 DN, DOCK8 deficiency RAG deficiency, and leaky IL2RG. We collaborate with the NIAMS dermatology microbiome team to better understand pathogen susceptibility including in patients with IEI and Merkel cell cancers as well as Rubella associated granulomas.