Primary Immune Deficiency Clinic

原发性免疫缺陷诊所

• 批准号: 10927915
• 负责人: Alexandra Freeman
• 金额: $ 112.93万
• 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/10927915
• 关键词: Air; Aneurysm; Aorta; Area; Arteries; Arthritis; Atherosclerosis; Autoimmune; Autoimmunity; Award; Biopsy; Blood Vessels; Bone Marrow Transplantation; Bronchiectasis; Bronchoscopy; COVID-19 pandemic; COVID-19 vaccine; Candida; Clinic; Clinical; Clinical Protocols; Clinical Research; Collaborations; Collection; Complex; Connective Tissue; Coronary artery; Data; Defect; Dental; Dermatology; Diagnosis; Diffuse; Disease; Dominant-Negative Mutation; Early Diagnosis; Eczema; Education; Epithelial Cells; Etiology; Gastrointestinal Hemorrhage; Genetic Predisposition to Disease; Genus staphylococcus; Goals; Grant; HIF1A gene; HIV Seronegativity; Hematopoietic Stem Cell Transplantation; Hemorrhage; Hereditary Disease; Host Defense; Human Papillomavirus; Hypersensitivity; IL2RG gene; IgE; Image; Immune; Immune response; Immunity; Immunologics; In Vitro; Incidence; Individual; Infection; Interferons; Job' s Syndrome; Kaposi Sarcoma; Laboratories; Laboratory Research; Laboratory Study; Liver diseases; Longterm Follow-up; Lung; Lung diseases; Lung infections; Lupus; Malignant Neoplasms; Manuscripts; 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; Occupations; Operative Surgical Procedures; Osteoporosis; Paper; Pathogenesis; Pathologic; Pathway interactions; Patient Selection; Patients; Phenotype; Population; Predisposition; Prospective Studies; Protocols documentation; Publishing; Research; Risk Factors; STAT1 gene; STAT3 gene; Safety; Signal Transduction; Site; Skin; Spain; Sputum; Subarachnoid Hemorrhage; Syndrome; System; Thinness; Tissues; Training; Transplantation; United States National Institutes of Health; Vascular Diseases; Vasculitis; Viral Load result; Virus; airway epithelium; angiogenesis; antimicrobial peptide; artery stenosis; bench to bedside; biomedical referral center; calcification; cerebral artery; clinical care; clinical phenotype; cohort; congenital immunodeficiency; coronavirus disease; cytopenia; improved; insight; interest; interleukin-12 receptor; loss of function; lupus-like; microbial; microbiome; mortality; neutrophil; novel; pathogen; patient oriented; patient population; research study; response; scoliosis; skeletal abnormality; skin disorder; skin microbiome; transplant centers; vaccine response; 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 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 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 a more recent 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 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 DN STAT3 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. 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. Ongoing prospective studies are examining the microbiome post 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 as we are the largest single site center for transplant in DOCK8 deficiency. 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's laboratory 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. 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 previously published an initial paper examining the vaccine response in our cohort and ongoing studies are underway.

几十年来，NIAID 和 NIH 一直是 STAT3 缺陷性高 IgE（乔布斯）综合征临床和实验室研究的领导者。 2005 年，我成为主要临床医生并为我们的患者群体进行临床研究，该患者群体已增加到 130 多人。 2007 年，STAT3 功能丧失突变被确定为遗传病因，这导致了研究的深入。通过深入研究该患者群体及其多系统临床表型，我们的目标是了解 STAT3 控制如何参与念珠菌和葡萄球菌控制、过敏、动脉粥样硬化、骨质疏松和脊柱侧弯以及牙齿异常等扩散途径。以下是我们的一些主要关注领域： 血管异常和异常组织重塑（合作者：Manfred Boehm、NHLBI、Ahmed Gharib、NIDDK、Chris Nagao、NIAMS、Heidi Kong、NIAMS、Ian Myles、NIAID）。在过去的十年中，我们已经认识到，在 STAT3 显性失活突变的患者中，组织重塑是异常的。这在肺部表现得很明显，感染后形成持续性气肿，以及肺部手术后长时间漏气。在脉管系统中，中型动脉瘤和迂曲很常见，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和死亡。自 2006 年以来，我们一直在系统地对冠状动脉进行成像，最近又对脑动脉进行了系统成像，以便及早发现异常情况。通过影像学和病理学研究，发现血管对动脉粥样硬化有异常反应，表现为外膜变薄和动脉瘤扩大。 NHLBI 的 Manfred Boehms 博士实验室一直在领导一项实验室研究，重点关注基质金属蛋白酶反应紊乱导致的异常伤口愈合，以及与 HIF-1alpha 信号传导缺陷相关的异常血管生成，该研究已发表。正在进行的研究主要集中于艾哈迈德·加里布 (Ahmed Gharib) 博士的研究，重点分析过去 15 年的血管成像的发病率、变化和危险因素。 此外，我们正在与 Drs. 合作进行重复的皮肤活检，以进一步描绘伤口愈合情况，包括造血干细胞移植前后的情况。孔、长尾和迈尔斯。 肺部清除率、感染易感性（合作者：Kenneth Olivier，北卡罗来纳大学、理查德·鲍彻，北卡罗来纳大学）。多年来，通过对肺部感染和支气管扩张加重的 DN STAT3 患者进行治疗，我们注意到痰液常常非常顽固。通过我们之前的从实验室到临床的奖项，以及最近与 Ken Olivier 博士和 Richard Boucher 博士一起获得的 U01 资助，我们正在研究粘蛋白成分、气道上皮细胞以及气道免疫宿主防御（例如抗菌肽）通过收集痰液和研究支气管镜检查。 自身免疫/关节炎表型（合作者：Sarthak Gupta，NIAMS）我们已经发表了 STAT3 DN HIES 患者的一个子集具有自身免疫表现，确定了一些患有狼疮或狼疮样疾病和自身免疫性血细胞减少症的患者。通过我们的 NIAMS 合作者，我们发现干扰素信号和中性粒细胞 NET 的形成有所增加。 与西班牙的合作者合作，抑制 jak 的体外研究显示一些异常现象已正常化。 我们目前正在准备一项临床方案，以评估 Jak 抑制对具有自身免疫性和 DN STAT3 突变的患者的使用。 DOCK8 缺陷（合作者：Helen Su，NIAID；Heidi Kong，NIAMS；Corina Gonzalez，NCI）。 NIAID 描述了 DOCK8 缺陷，我们仍然是这些患者的主要转诊中心，已经评估了 50 多名患者。因此，我们拥有独特的能力来进一步定义临床表型、了解发病机制并改进治疗。我们越来越认识到血管异常，包括脑动脉狭窄、主动脉扩张和钙化。尽管感染可以解释一些血管炎，但其他血管炎仍然没有微生物诊断和治疗，造血干细胞移植（HSCT）后的长期随访也是正在进行的项目。 我们相对较大的队列使得合作者、NIAMS 皮肤科 Heidi Kong 博士能够定义该人群的皮肤微生物组，即使在没有明显皮肤疾病（包括新型 HPV 病毒）的区域也能识别出高 DNA 病毒负荷。正在进行的前瞻性研究正在检查 HSCT 后的微生物组。 我们正在准备手稿，涵盖 NIH 发现的所有 DOCK8 缺陷患者的临床和实验室数据以及骨髓移植数据，因为我们是最大的 DOCK8 缺陷移植单中心中心。 STAT3 DN 和 DOCK8 缺陷以外的先天性免疫缺陷 (IEI)：主要通过 PID 诊所，我们看到患有不同 IEI 的患者，并根据疾病及其表现，我们建立了合作。 通过 Notarangelo 博士的实验室，我们正在研究 STAT1 GOF 的免疫缺陷以及其他联合免疫缺陷。 我们与研究卡波西肉瘤的 NCI 小组合作，以确定 HIV 阴性卡波西肉瘤患者的潜在 IEI。 我们与 NCI IEI 移植小组合作考虑造血干细胞移植，包括针对具有 IL-12R/IFNg 缺陷 STAT3 DN、DOCK8 缺陷 RAG 缺陷和渗漏性 IL2RG 的患者。 我们与 NIAMS 皮肤科微生物组团队合作，更好地了解病原体的敏感性。 随着 COVID-19 大流行，我们不仅对原发性免疫缺陷患者对 COVID 疾病的反应如何，而且对 COVID19 疫苗在该人群中的安全性和有效性感兴趣。 我们之前发表了一篇初步论文，研究了我们队列中的疫苗反应，并且正在进行的研究正在进行中。

项目成果

STAT3 modulates reprogramming efficiency of human somatic cells; insights from autosomal dominant Hyper IgE syndrome caused by STAT3 mutations.

• DOI: 10.1242/bio.052662
• 发表时间: 2020-09-10
• 期刊: Biology open
• 影响因子: 2.4
• 作者: Yu Z;Dmitrieva NI;Walts AD;Jin H;Liu Y;Ping X;Ferrante EA;Qiu L;Holland SM;Freeman AF;Chen G;Boehm M
• 通讯作者: Boehm M

Lupus-like autoimmunity and increased interferon response in patients with STAT3-deficient hyper-IgE syndrome.

• DOI: 10.1016/j.jaci.2020.07.024
• 发表时间: 2021-03
• 期刊: The Journal of allergy and clinical immunology
• 作者: Goel RR;Nakabo S;Dizon BLP;Urban A;Waldman M;Howard L;Darnell D;Buhaya M;Carmona-Rivera C;Hasni S;Kaplan MJ;Freeman AF;Gupta S
• 通讯作者: Gupta S

Warts and DADA2: a Mere Coincidence?

• DOI: 10.1007/s10875-018-0565-0
• 发表时间: 2018-11-01
• 期刊: JOURNAL OF CLINICAL IMMUNOLOGY
• 影响因子: 9.1
• 作者: Arts, Katrijn;Bergerson, Jenna R. E.;Meyts, Isabelle
• 通讯作者: Meyts, Isabelle

STAT3 Hyper-IgE Syndrome-an Update and Unanswered Questions.

• DOI: 10.1007/s10875-021-01051-1
• 发表时间: 2021-07
• 期刊: Journal of clinical immunology
• 影响因子: 9.1
• 作者: Tsilifis C;Freeman AF;Gennery AR
• 通讯作者: Gennery AR

Malignancy in STAT3 Deficient Hyper IgE Syndrome.

STAT3 缺陷型高 IgE 综合征中的恶性肿瘤。

• DOI: 10.1007/s10875-021-01197-y
• 发表时间: 2022
• 期刊: Journal of clinical immunology
• 影响因子: 9.1
• 作者: Urban,Amanda;NCILymphomaPhysiciansConsortium;Pittaluga,Stefania;CaseWesternPhysiciansConsortium;Freeman,AlexandraF
• 通讯作者: Freeman,AlexandraF