Clinical Studies Of Abnormal Host Defense

宿主防御异常的临床研究

基本信息

批准号：
8555734
负责人：
JOHN I GALLIN
金额：
$ 15.09万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
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/8555734
关键词：
Abnormal Neutrophil Antigens Arterial Fatty Streak Atherosclerosis Autoimmune Diseases Autoimmune Process B-Lymphocytes Base Sequence Biochemical Blood Vessels Calcium Cardiac Cell physiology Cells Chemotaxis Chronic Clinical Clinical Data Clinical Research Collaborations Communicable Diseases Data Defect Deposition Development Diagnosis Disease Enzyme-Linked Immunosorbent Assay Enzymes Exposure to Family Frequencies General Population Genetic Heart Diseases Host Defense Host Defense Mechanism Human Hypergammaglobulinemia Image Immune System Diseases Immunoblotting Immunoglobulin G Immunoglobulins Immunologic Deficiency Syndromes In Vitro Incidence Infection Infectious Agent Inflammation Inflammatory Inflammatory Bowel Diseases Informatics Investigation Journals Laboratories Laboratory Study Link Magnetic Resonance Imaging Measures Methanol Methodology Molecular Molecular Target Monitor Morphology Neutropenia Nuclear Nucleic acid sequencing Oxidoreductase Pathogenesis Patients Phagocytes Phenotype Play Prevalence Production Protocols documentation Publications Publishing Reactive Oxygen Species Reporting Role Screening procedure Serological Serum Structure Therapeutic Intervention Time United States National Institutes of Health Western Blotting Work base cohort congenital immunodeficiency data mining epidemiologic data human subject immune function neutrophil novel pathogen patient population tool

项目摘要

1) The Neutrophil Monitoring Laboratory (NML), our clinical laboratory collaboration managed by Douglas Kuhns, has characterized the molecular defects by western blotting of 38 subjects and identified 29 new CGD patients. Diagnosis was confirmed by nucleic acid sequencing of a total of 55 CGD patients or carriers. 2) Our group has been involved in the clinical and laboratory studies of the novel Gram-negative CGD pathogen, Granulibacter bethesdensis. During FY12, we have purified the dominant antigen recognized by patient sera, methanol dehydrogenase (MDH), and have begun the biochemical characterization of this enzyme. In collaboration with the LCID, we have participated in serologic studies of the CGD cohort using both immunoblotting and an ELISA based on MDH. These studies have identified several additional CGD patients with evidence of likely prior infections with Granulibacter and provide tools for larger-scale screening of other patient population in which this infection may be suspected. This project has been published in the Journal of Infectious Diseases. 3) During FY2012, we have studied 24 more patients on NIH Protocol #10-I-0029 Non-invasive Assessment of Atherosclerosis in Patients with CGD and other Disorders of the Immune System (current total = 73 subjects). Atherosclerosis, the major cause of heart disease, is thought to relate to dysregulated inflammation in the cardiac blood vessels and over production of reactive oxygen species (ROS) has been implicated. We hypothesize that CGD patients, who have deficient production of reactive oxygen species by their phagocytes and other cells, may be protected from developing atherosclerosis. The primary endpoint of this study is the assessment of atherosclerotic plaque formation/calcium deposition by CT, MRI and other imaging methodologies, in these and other patients with in-born disorders of immune function. Inflammatory bowel disease provides a group of patients with similar chronic inflammation but with intact ROS production for comparison. Importantly, this study may determine for the first time in humans, whether ROS indeed play a role in the pathogenesis of atherosclerosis, a finding that could have broad importance for the general population as it would provide a validated molecular target for therapeutic intervention. 4) This year we initiated a study of immunoglobulin production in CGD. One of the earliest reported phenotypes of CGD patients was the observation of abnormally high amounts of IgG and dysregulation of IgG production has been linked hypothetically to the increased frequency of autoimmune disorders in these subjects. We undertook, in collaboration with James Cimino (NIH Laboratory for Informatics Development), an extensive clinical data-mining study to characterize both total and autoimmune immunoglobulin levels and incidence in the NIH Clinical Center CGD cohort as well as correlate these parameters with other genotypic and phenotypic data. In vitro laboratory studies measuring B-cell function and immunoglobulin secretion have revealed potentially important differences between normal and CGD B-cells. This work has been submitted for publication. 5) Several years ago, two patients with an undiagnosed disease characterized by increased infections and neutropenia were seen at the NIH. These subjects bore similarities to 2 other families of patients seen over a time frame of 30 years by the LHD. Cellular studies indicated an abnormal neutrophil morphology with frequent nuclear herniations, subnormal chemotaxis, and aberrant cytoskeletal structure. We have identified by biochemical and molecular approaches the molecular defect in this disease and are currently preparing this publication for submission.

1）我们由道格拉斯·库恩斯（Douglas Kuhns）管理的中性粒细胞监测实验室（NML）是通过蛋白质印迹38名受试者的分子缺陷来表征的，并确定了29名新的CGD患者。通过总共55名CGD患者或载体的核酸测序确认诊断。 2）我们的小组参与了新型革兰氏阴性CGD病原体，肉芽肿杆菌贝塞斯氏菌的临床和实验室研究。在2012财年期间，我们纯化了由患者血清，甲醇脱氢酶（MDH）识别的主要抗原，并开始了该酶的生化表征。与LCID合作，我们使用免疫印迹和基于MDH的ELISA参加了CGD队列的血清学研究。这些研究已经确定了几名可能先前感染粒细胞感染的CGD患者，并提供了对可能怀疑这种感染的其他患者群体进行大规模筛查的工具。该项目已发表在《传染病杂志》上。 3）在2012财年期间，我们在NIH方案＃10-I-0029中又研究了24名患者，对CGD患者和免疫系统的其他疾病的动脉粥样硬化评估（当前总数= 73名受试者）。动脉粥样硬化是心脏病的主要原因，被认为与心脏血管中的炎症失调有关，并且已经涉及反应性氧（ROS）的过度产生。我们假设通过吞噬细胞和其他细胞生产不足的活性氧的CGD患者可能会受到保护，免受动脉粥样硬化的影响。这项研究的主要终点是在这些和其他患有免疫功能疾病的患者中评估CT，MRI和其他成像方法对动脉粥样硬化斑块形成/钙的沉积。炎症性肠病为一组具有相似慢性炎症但完整的ROS产生的患者提供了比较。重要的是，这项研究可以在人类中首次确定，ROS是否确实在动脉粥样硬化的发病机理中起作用，这一发现对普通人群可能具有广泛的重视，因为它将为治疗干预提供验证的分子靶标。 4）今年我们开始了CGD中免疫球蛋白产生的研究。最早报道的CGD患者表型之一是观察到异常高的IgG和IgG产生的失调与这些受试者中自身免疫性疾病的频率增加有关。我们在与James Cimino（NIH信息学开发实验室）合作进行了一项广泛的临床数据挖掘研究，以表征NIH临床中心CGD群体中的总和自身免疫性免疫球蛋白水平以及发病率，并将这些参数与其他基因型和现象型数据相关联。测量B细胞功能和免疫球蛋白分泌的体外实验室研究表明，正常和CGD B细胞之间存在潜在的重要差异。这项工作已提交出版。 5）几年前，在NIH时出现了两名未诊断疾病的患者，其特征是感染和中性粒细胞减少症。这些受试者与LHD 30年以来30年的其他2例患者家属具有相似之处。细胞研究表明中性粒细胞形态异常，频繁核疝，亚正常趋化性和异常的细胞骨架结构。我们已经通过生化和分子方法确定了该疾病中的分子缺陷，目前正在准备该出版物进行提交。