CRAC Channel Deficiency in Immunity to Infection

总结 我们研究的目的是了解免疫系统细胞中钙离子内流的缺陷是如何导致 遗传性钙内流基因突变的免疫缺陷患者。因为相同的 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内流如何维持免疫自身耐受， 自身免疫我们的中心假设是，CRAC通道，介导钙离子流入细胞 免疫系统的先天和适应性臂中的不同细胞的功能都需要膜 提供对感染免疫和防止自身免疫系统。CRAC通道是 大多数免疫细胞中的钙内流。它们由通道蛋白ORAI1形成，并被激活， STIM1和STIM2。我们已经确定了第一个患有ORAI1和STIM1基因突变的患者， 我们称之为CRAC通道病，其特征是免疫缺陷，自身免疫， 一些非免疫缺陷。由于CRAC通道病是一种罕见疾病， 有限，我们产生了在T细胞中缺乏CRAC通道的小鼠。通过研究这些动物的免疫反应， 通过验证CRAC通道病患者样本中的关键结果，我们已经能够 定义了CRAC通道在T细胞介导的免疫应答中的关键作用，特别是对于细胞和 抗体介导的对感染的免疫以及在慢性感染期间限制免疫应答， 否则会引起有害的炎症。然而，我们仍然远远没有一个完整的图片如何CRAC 经络调节对感染的免疫力。除了T细胞，CRAC通道还可以调节先天免疫 由树突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，并且它们在先天免疫中对感染的作用已经被证实。 没有被研究过。除了对感染的免疫外，CRAC通道对于免疫自身耐受是必不可少的 通过控制调节性T细胞的发育，抑制其他免疫细胞的功能， 从而防止自身免疫。CRAC通道缺陷患者的Treg细胞较少，这可能解释了 自身免疫CRAC通道如何控制Treg细胞的功能并防止自身免疫， 明白为了解决这些问题，我们提出了以下三个具体目标：（1）我们将分析 患者的ORAI1和STIM1基因的遗传缺陷，以了解CRAC通道在免疫中的作用。 功能和CRAC通道的分子调节。(2)我们将确定是否需要CRAC通道 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 将确定CRAC通道如何控制调节性T细胞功能并防止自身免疫，特别是 自身免疫性溶血性贫血，通过研究CRAC通道缺陷小鼠和患者。我们的研究将 提供CRAC通道如何调节对感染的免疫力并预防自身免疫的基本见解。

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.