CRAC Channel Deficiency in Immunity to Infection

CRAC 通道缺乏感染免疫力

基本信息

批准号：
9602202
负责人：
STEFAN FESKE
金额：
$ 53.62万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-06-01 至 2023-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9602202
关键词：
Acute Address Anemia Antibody-mediated protection Autoantibodies Autoimmune hemolytic anemia Autoimmunity B-Lymphocytes Bacteria Bacterial Infections Benefits and Risks Book Chapters CD8-Positive T-Lymphocytes Calcium Calcium Channel Candida albicans Cell Differentiation process Cell membrane Cell physiology Cells Cellular Immunity Chronic Conflict (Psychology)Data Defect Dendritic Cells Development Disease Ectodermal Dysplasia Erythrocytes Functional disorder Genes Genus Mycobacterium Goals Helper-Inducer T-Lymphocyte Homologous Gene Human Humoral Immunities Immune Immune response Immune system Immunity Immunologic Deficiency Syndromes Impairment In Vitro Infection Inflammation Inherited Innate Immune Response Link Lymphoid Mediating Memory Metabolic Metabolism Molecular Mus Muscle hypotonia Mutation Mycoses Myelogenous Names Natural Immunity Paper Patients Pharmaceutical Preparations Physiological Predisposition Production Proteins Publishing Rare Diseases Regulation Regulatory T-Lymphocyte Research Risk Role STIM1 gene Sampling Source Staphylococcus aureus Streptococcus pneumoniae Sweat Glands Symptoms Syndrome T-Lymphocyte Therapeutic Thymus Gland Tooth structure Viral Virus Virus Diseases adaptive immunity arm cell mediated immune response chronic infection congenital immunodeficiency fighting fungus genetic analysis immune function immune self tolerance in vivo insight macrophage neutrophil novel therapeutics pathogen prevent

项目摘要

Summary The goal of our research is to understand how defects in calcium influx in cells of the immune system cause immunodeficiency in patients with inherited mutations in genes regulating calcium influx. Since the same patients also suffer from anemia caused by autoantibodies against red blood cells, a second goal of our research is to understand how calcium influx maintains immunological self-tolerance and prevents autoimmunity. Our central hypothesis is that CRAC channels, which mediate calcium influx across the cell membrane, are required for the function of different cells in the innate and adaptive arms of the immune system that provide immunity to infection and prevent autoimmunity. CRAC channels are the main source of calcium influx in most immune cells. They are formed by the channel protein ORAI1 and are activated by STIM1 and STIM2. We have identified the first patients with mutations in ORAI1 and STIM1 genes who suffer from a disease we called CRAC channelopathy that is characterized by immunodeficiency, autoimmunity, and several non-immunological defects. Because CRAC channelopathy is a rare disease and patient samples are limited, we generated mice that lack CRAC channels in T cells. By investigating immune responses in these mice and by validating key results in samples of patients with CRAC channelopathy, we have been able to define a critical role of CRAC channels in T cell-mediated immune responses, in particular for cellular and antibody-mediated immunity to infection and for limiting immune responses during chronic infection that would otherwise cause harmful inflammation. However, we are still far from having a complete picture of how CRAC channels regulate immunity to infection. Beyond T cells, CRAC channels may also regulate innate immune responses mediated by dendritic cells and neutrophils. Studies so far have yielded conflicting data whether CRAC channels are required for innate immune cell function, and their role for innate immunity to infection has not been studied. Besides immunity to infection, CRAC channels are essential for immunological self-tolerance by controlling the development of regulatory T cells, which suppress the function of other immune cells and thereby prevent autoimmunity. CRAC channel-deficient patients have fewer Treg cells, potentially explaining their autoimmunity. How CRAC channels control the function of Treg cells and prevent autoimmunity is not understood. To address these questions, we propose the following three specific aims: (1) We will analyze inherited defects in ORAI1 and STIM1 genes of patients to understand the role of CRAC channels for immune function and the molecular regulation of CRAC channels. (2) We will determine if CRAC channels are required for innate immune responses by dendritic cells and neutrophils to fight bacterial and fungal infections. (3) We will determine how CRAC channels control regulatory T cell function and prevent autoimmunity, in particular autoimmune hemolytic anemia, by studying CRAC channel-deficient mice and patients. Our studies will provide fundamental insights how CRAC channels regulate immunity to infection and prevent autoimmunity.

概括我们研究的目的是了解免疫系统细胞钙涌入的缺陷如何导致调节钙涌入的基因遗传突变患者的免疫缺陷。自从一样患者还患有针对红细胞的自身抗体引起的贫血，这是我们的第二个目标研究是了解钙涌入如何保持免疫学自我耐受性并防止自身免疫性。我们的中心假设是CRAC通道介导了整个细胞的钙涌入膜是在免疫的先天和适应性臂中不同细胞的功能所必需的为感染和防止自身免疫提供免疫力的系统。 CRAC通道是主要来源大多数免疫细胞的钙流入。它们由通道蛋白ORAI1形成，并被激活 stim1和stim2。我们已经确定了遭受ORAI1和Stim1基因突变的第一批患者从一种疾病中，我们称为CRAC通道病，其特征是免疫缺陷，自身免疫性和几种非免疫学缺陷。因为CRAC通道病是一种罕见的疾病，患者样本是有限，我们产生了缺乏T细胞中CRAC通道的小鼠。通过研究这些免疫反应通过验证CRAC通道病患者样本的关键结果，我们已经能够定义CRAC通道在T细胞介导的免疫反应中的关键作用，特别是细胞和抗体介导的对感染的免疫力和在慢性感染期间限制免疫反应的免疫力否则会引起有害的炎症。但是，我们还远没有完整地了解如何克拉克通道调节感染的免疫力。除T细胞外，CRAC通道还可能调节先天免疫树突状细胞和中性粒细胞介导的反应。到目前为止的研究产生了相互矛盾的数据 CRAC通道是先天免疫细胞功能所必需的，并且它们对感染的先天免疫的作用没有被研究。除了免疫感染外，CRAC通道对于免疫自我耐受至关重要通过控制调节性T细胞的发展，从而抑制其他免疫细胞的功能和从而防止自身免疫性。 CRAC通道缺陷患者的Treg细胞较少，有可能解释他们的自身免疫性。 CRAC通道如何控制Treg细胞的功能并预防自身免疫性不是理解。为了解决这些问题，我们提出以下三个具体目标：（1）我们将分析 ORAI1和Stim1基因的遗传缺陷了解CRAC通道免疫的作用 CRAC通道的功能和分子调节。（2）我们将确定是否需要CRAC通道用于树突状细胞和中性粒细胞的先天免疫反应，以抵抗细菌和真菌感染。（3）我们将确定CRAC通道如何控制调节性T细胞功能并预防自身免疫性，特别是通过研究CRAC通道缺陷型小鼠和患者，自身免疫性溶血性贫血。我们的研究将提供基本的见解，即CRAC通道如何调节感染的免疫力并防止自身免疫性。