Primary Immune Deficiency Clinic

原发性免疫缺陷诊所

• 批准号: 10272244
• 负责人: Alexandra Freeman
• 金额: $ 113.11万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10272244
• 关键词: Affect; Air; Aneurysm; Area; Arteries; Atherosclerosis; Autoimmune Process; Autoimmunity; Award; Benefits and Risks; Biliary; Biopsy; Blood Vessels; Bronchiectasis; Bronchoscopy; Candida; Clinic; Clinical; Clinical Research; Clinical Trials; Collaborations; Collection; Complex; Connective Tissue; Coronary artery; Cryptosporidium; Defect; Dental; Dermatology; Diagnosis; Diffuse; Disease; Dominant-Negative Mutation; Early Diagnosis; Eczema; Education; Epithelial Cells; Etiology; Gastrointestinal Hemorrhage; Gastrointestinal tract structure; Genetic Predisposition to Disease; Genus staphylococcus; Goals; HIF1A gene; Hematopoietic Stem Cell Transplantation; Hemorrhage; Host Defense; Human Papillomavirus; Hypersensitivity; IL6ST gene; IgE; Image; Immune; Immune response; Immunologics; In Vitro; Incidence; Individual; Infection; Interferons; Job' s Syndrome; Laboratories; Laboratory Research; Lead; Liver; Liver diseases; Longterm Follow-up; Lung; Lung diseases; Lung infections; Malignant Neoplasms; Matrix Metalloproteinases; Mendelian disorder; Morbidity - disease rate; Mucins; Mutation; Myocardial Infarction; National Heart, Lung, and Blood Institute; National Institute of Allergy and Infectious Disease; National Institute of Arthritis and Musculoskeletal and Skin Diseases; National Institute of Diabetes and Digestive and Kidney Diseases; Natural History; Operative Surgical Procedures; Osteoporosis; Pathogenesis; Pathologic; Pathway interactions; Patient Selection; Patients; Pharmacology; Phenotype; Population; Predisposition; Prospective Studies; Protocols documentation; Publishing; Research; Risk Factors; STAT3 gene; Signal Transduction; Skin; Spain; Sputum; Subarachnoid Hemorrhage; Syndrome; Thinness; Tissues; Training; United States National Institutes of Health; Universities; Vascular Diseases; Vasculitis; Viral Load result; Virus; airway epithelium; angiogenesis; antimicrobial peptide; artery stenosis; atopy; autoimmune arthritis; bench to bedside; biomedical referral center; calcification; cerebral artery; clinical care; clinical phenotype; cohort; cytopenia; improved; insight; loss of function; lupus-like; microbial; molecular diagnostics; mortality; neutrophil; novel; patient oriented; patient population; research study; response; scoliosis; skeletal abnormality; skin disorder; skin microbiome; vascular abnormality; viral DNA; wound healing

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 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 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 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. Through collaborators in Spain, in vitro studies with jak inhibition showing normalization of some of the abnormalities. Further studies are ongoing to determine the risks and benefits for a clinical trial of jak inhibition. 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. In recent years, there have been other monogenic diseases described in our cohort of patients referred for Hyper IgE syndrome (Main Collaborator Josh Milner, previously LAD, NIAID, current Columbia University). In the last few years, our cohort has been integral in defining both loss of function heterozygous CARD11 mutations leading to atopy and immune deficiency, as well as loss of function heterozygous CARD14 mutations leading to atopy. With outside collaboration, we identified dominant negative mutations in IL6ST causing a syndrome with clinical overlap to DN STAT3 with destructive lung disease and connective tissue manifestations.

NIAID和NIH一直是STAT3缺乏性高IgE（Job）综合征的临床和实验室研究的领导者。 2005年，我成为了我们的一系列患者的主要临床医生和临床研究，该研究已增加到130多人。识别功能STAT3突变丧失为2007年的遗传病因，导致研究的加剧。通过深入研究该患者人群及其多系统临床表型，我们的目标是了解STAT3控制如何参与诸如念珠菌和葡萄球菌控制，过敏，动脉粥样硬化，骨质疏松症和脊柱侧弯以及牙齿异常等弥漫途径。以下是去年的一些主要进步。 血管异常和异常组织重塑（合作者：Manfred Boehm，NHLBI，Ahmed Gharib，Niddk）。在过去的十年中，我们认识到组织重塑在具有主要负STAT3突变的人中是异常的。在肺部通过感染后形成的持续性肺结核，在肺部手术后长时间泄漏，这是显而易见的。在脉管系统中，中大小的动脉瘤和曲折性很常见，并导致心肌梗塞，蛛网膜下腔出血，肺出血和胃肠道出血的发病率和死亡率。自2006年以来，我们一直在系统地对冠状动脉进行成像，最近的大脑动脉允许早期发现异常。通过成像和病理研究，发现血管对动脉粥样硬化有异常的反应，并且增强性动脉瘤。 NHLBI的Manfred Boehms Lab博士一直领导着板凳研究，该研究重点介绍了异常的伤口愈合，其基质金属蛋白酶反应以及与缺乏HIF-1Alpha信号相关的异常血管生成，该信号与HIF-1Alpha信号相关，该信号已于今年今年今年今年发表。正在进行的研究集中于分析过去15年来我们的血管成像，以了解发病率，变化和危险因素，以及重复的皮肤活检，以进一步描述伤口愈合，并在体外研究中稳定HIF1Alpha，以改善血管生成和组织重塑。 肺部清除，感染易感性（合作者：肯尼斯·奥利维尔（Kenneth Olivier），NHLBI，Richard Boucher，UNC）。多年来，通过通过肺部感染和支气管扩张病加重来管理DN STAT3患者，我们注意到痰液经常非常顽强。通过与Ken Olivier博士和Richard Boucher博士的基准奖，我们正在调查粘蛋白成分，气道上皮细胞以及气道免疫学宿主防御（例如抗菌肽），通过收集痰液和研究支气管检查。 自身免疫性/关节炎表型（合作者：Sarthak Gupta，Niams）最近系统地检查了使用DN Stat3的自身免疫性表现，鉴定了几种患有狼疮或狼疮样疾病和自身免疫性细胞质的疾病。在我们的NIAMS合作者中，我们发现干扰素签名和中性粒细胞网的形成增加。 通过西班牙的合作者，对JAK抑制作用的体外研究表明了某些异常的标准化。 正在进行进一步的研究，以确定JAK抑制临床试验的风险和益处。 Dock8缺乏症（合作者：Helen Su，Niaid； Heidi Kong，Niams，Nirali Shah和NCI Dennis Hickstein）。 NIAID描述了Dock8缺乏症，我们仍然是这些患者的主要转诊中心，对50多名患者进行了评估。因此，我们具有进一步定义临床表型，了解发病机理并改善治疗的独特能力。我们越来越多地认识到血管异常，脑动脉狭窄以及主动脉膨胀和钙化。尽管感染解释了一些血管炎，但其他人仍未进行微生物诊断和治疗，以及造血干细胞移植（HSCT）后的长期随访正在进行。此外，改进的隐孢子虫分子诊断已导致鉴定出在胃肠道中受影响的较高数量导致胆道和肝脏并发症，这是最近发表的。我们相对较大的队列允许合作者Heidi Kong博士Dermatology Branch Niams定义该人群中的皮肤微生物组，即使在没有明显的皮肤疾病（包括新型HPV病毒）的地区，也可以确定高DNA病毒负担。 HSCT之后，正在进行的前瞻性研究正在继续。 近年来，在我们的同类患者中描述了其他单身性疾病（主要合作者乔什·米尔纳（Josh Milner），以前是LAD，NIAID，现任哥伦比亚大学）。在过去的几年中，我们的队列在定义功能杂合CARD11突变的丧失方面一直是不可或缺的，导致特应性和免疫缺乏，以及功能杂合Card14突变的丧失导致了应变。 通过外部协作，我们确定了IL6ST中的显性负突变，导致综合征与DN STAT3临床重叠，并具有破坏性的肺部疾病和结缔组织表现。