CRAC Channel Deficiency in Immunity to Infection

CRAC 通道缺乏感染免疫力

基本信息

批准号：
10395936
负责人：
STEFAN FESKE
金额：
$ 54.13万
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 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10395936
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 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 pathogenic bacteria pathogenic fungus pathogenic virus 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内流缺陷如何导致调节钙内流基因遗传突变的患者的免疫缺陷。既然同患者还患有由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的目的是了解钙流入如何维持免疫自我耐受并预防自身免疫。我们的中心假设是 CRAC 通道，它介导钙离子流入细胞膜，是免疫系统先天性和适应性臂中不同细胞功能所必需的提供对感染的免疫力并预防自身免疫的系统。 CRAC渠道是主要来源大多数免疫细胞中的钙流入。它们由通道蛋白 ORAI1 形成，并由 STIM1 和 STIM2。我们已经确定了第一批患有 ORAI1 和 STIM1 基因突变的患者来自一种我们称为 CRAC 通道病的疾病，其特征是免疫缺陷、自身免疫和一些非免疫缺陷。因为 CRAC 通道病是一种罕见疾病，并且患者样本是有限，我们培育了 T 细胞中缺乏 CRAC 通道的小鼠。通过研究这些中的免疫反应小鼠并通过验证 CRAC 通道病患者样本的关键结果，我们已经能够定义了 CRAC 通道在 T 细胞介导的免疫反应中的关键作用，特别是对于细胞和抗体介导的感染免疫力以及限制慢性感染期间的免疫反应否则会引起有害的炎症。然而，我们还远未全面了解 CRAC 是如何运作的通道调节对感染的免疫力。除了 T 细胞之外，CRAC 通道也可能调节先天免疫由树突状细胞和中性粒细胞介导的反应。迄今为止的研究得出了相互矛盾的数据： CRAC 通道是先天免疫细胞功能所必需的，它们在抵抗感染的先天免疫中的作用已被证实。没有被研究过。除了对感染的免疫力外，CRAC 通道对于免疫自我耐受也至关重要通过控制调节性 T 细胞的发育，抑制其他免疫细胞的功能，从而预防自身免疫。 CRAC 通道缺陷患者的 Treg 细胞较少，这可能解释他们的自身免疫。 CRAC通道如何控制Treg细胞的功能并预防自身免疫尚不清楚明白了。针对这些问题，我们提出以下三个具体目标：（1）我们将分析患者ORAI1和STIM1基因遗传缺陷，了解CRAC通道对免疫的作用 CRAC 通道的功能和分子调控。 (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，以对抗细菌和真菌感染。 (3) 我们将决定 CRAC 通道如何控制调节性 T 细胞功能并预防自身免疫，特别是通过研究 CRAC 通道缺陷小鼠和患者来治疗自身免疫性溶血性贫血。我们的研究将提供 CRAC 通道如何调节感染免疫力和预防自身免疫的基本见解。

项目成果

期刊论文数量（25）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Diseases caused by mutations in ORAI1 and STIM1.

ORAI1 和 STIM1 突变引起的疾病。

DOI：
发表时间：
2015-11
期刊：
影响因子：
5.2
作者：
Lacruz, Rodrigo S;Feske, Stefan
通讯作者：
Feske, Stefan

STIM1 and STIM2-mediated Ca(2+) influx regulates antitumour immunity by CD8(+) T cells.

STIM1 和 STIM2 介导的 Ca(2) 流入通过 CD8() T 细胞调节抗肿瘤免疫。

DOI：
发表时间：
2013-09
期刊：
影响因子：
11.1
作者：
Weidinger, Carl;Shaw, Patrick J;Feske, Stefan
通讯作者：
Feske, Stefan

STIM2 enhances receptor-stimulated Ca²⁺ signaling by promoting recruitment of STIM1 to the endoplasmic reticulum-plasma membrane junctions.

STIM2 通过促进 STIM1 募集到内质网-质膜连接处来增强受体刺激的 Ca2+ 信号传导。

DOI：
发表时间：
2015-01-13
期刊：
影响因子：
7.3
作者：
Ong, Hwei Ling;de Souza, Lorena Brito;Zheng, Changyu;Cheng, Kwong Tai;Liu, Xibao;Goldsmith, Corinne M;Feske, Stefan;Ambudkar, Indu S
通讯作者：
Ambudkar, Indu S

Store-operated Ca2+ entry (SOCE) regulates melanoma proliferation and cell migration.

钙库操纵的 Ca2 进入 (SOCE) 调节黑色素瘤增殖和细胞迁移。

DOI：
发表时间：
2014
期刊：
影响因子：
3.7
作者：
Umemura, Masanari;Baljinnyam, Erdene;Feske, Stefan;De Lorenzo, Mariana S;Xie, Lai;Feng, Xianfeng;Oda, Kayoko;Makino, Ayako;Fujita, Takayuki;Yokoyama, Utako;Iwatsubo, Mizuka;Chen, Suzie;Goydos, James S;Ishikawa, Yoshihiro;Iwatsubo, Kousak
通讯作者：
Iwatsubo, Kousak

Preserved effector functions of human ORAI1- and STIM1-deficient neutrophils.

人类 ORAI1 和 STIM1 缺陷的中性粒细胞保留了效应功能。

DOI：
10.1016/j.jaci.2015.09.047
发表时间：
2016-05
期刊：
The Journal of allergy and clinical immunology
影响因子：
0
作者：
Elling R;Keller B;Weidinger C;Häffner M;Deshmukh SD;Zee I;Speckmann C;Ehl S;Schwarz K;Feske S;Henneke P
通讯作者：
Henneke P