Ca2+ signaling via SOCE in the pathogenesis of Sjögren’s syndrome

项目摘要 干燥综合征（SjS）的特征是唾液和眼泪的产生受损，影响约1 - 3百万人 在美国的人可能导致严重的并发症，如淋巴瘤。SjS的原因是 复杂且不为人知。SjS被认为是一种自身免疫性疾病， 系统会对自身产生反作用，导致腺体炎症和破坏。这一前提得到了 自身抗体的存在，免疫细胞浸润唾液腺和炎症水平增加 在大多数患者中，然而，无论是免疫细胞浸润和自身抗体引起的SjS， 腺体破坏和/或功能障碍的后果尚不清楚。我们的初步数据显示 SjS与免疫系统和唾液腺细胞中的钙信号之间的联系。内钙离子 细胞控制免疫和唾液腺细胞的功能。钙通过特殊的通道进入细胞 在细胞膜上形成小孔。免疫和唾液腺细胞中的一种重要钙通道 是CRAC通道，其介导钙内流。我们发现编码CRAC的基因的缺失 T细胞是一种介导对感染的免疫力的细胞类型，它可以消除钙信号并引起SjS- 就像老鼠的疾病一样。当CRAC通道在特定T细胞中缺失时，这种表型甚至更强 T细胞亚群，即所谓的T调节（Treg）细胞，抑制其他免疫细胞，从而防止 自身免疫性疾病这些小鼠发展出一种疾病，重现了人类SjS的许多特征。钙 信号还控制许多分泌腺的功能。我们最近证明了CRAC通道 通过控制氯离子通道的功能来调节汗液的产生，从而调节汗液中的水分分泌 腺细胞我们的数据进一步表明，小鼠唾液腺中缺乏CRAC通道， 生产这与SjS有关，因为患者在腺体变小之前可能会出现口干和眼睛干燥。 炎症和免疫细胞浸润，表明唾液腺功能的改变先于免疫 activation.我们假设唾液腺细胞中受损的钙信号使小鼠和人类 患者通过损害唾液和口腔先天免疫反应的产生而发展SjS， 导致腺体炎症和免疫细胞浸润。本提案的主要目标是 了解钙信号在SjS的发展和进展中的作用。(1)我们将描述 钙内流使Treg细胞发挥功能并防止SjS的发作。(2)我们将确定钙 内流调节唾液腺功能和口腔免疫反应，从而预防SjS。为此我们 将研究我们制造的两种SjS小鼠模型。(3)我们将分析唾液腺和淋巴细胞， 人SjS患者的钙内流和CRAC通道蛋白的表达。拟议的研究将 提供了更好的理解SjS病理和受损的钙信号在SjS中的作用，这可能是 作为一种新的诊断和预后标志物，用于早期检测SjS。

Project Summary Sjögren’s syndrome (SjS) is characterized by impaired production of saliva and tears affecting ~1-3 million people in the US potentially leading to severe complications such as lymphoma. The causes of SjS are complex and poorly understood. SjS is considered an autoimmune disease in which the body's immune system turns against itself and causes gland inflammation and destruction. This premise is supported by the presence of autoantibodies, infiltration of salivary glands by immune cells and increased levels of inflammatory mediators in most patients. However, whether immune cell infiltration and autoantibodies cause SjS or are the consequence of gland destruction and/or dysfunction is unknown. Our preliminary data reveal an unexpected link between SjS and calcium signals in cells of the immune system and salivary glands. Calcium ions within cells control the function of immune and salivary gland cells. Calcium enters cells through specialized channels that form pores in the cell's membrane. An important calcium channel in both immune and salivary gland cells is the CRAC channel, which mediates calcium influx. We found that deletion of genes encoding the CRAC channel in T cells, a cell type that mediates immunity to infection, abolishes calcium signals and causes SjS- like disease in mice. This phenotype is even stronger when CRAC channels are deleted in a specific T cell subset, so-called T regulatory (Treg) cells, that suppresses other immune cells and thereby prevents autoimmune diseases. These mice develop a disease that recapitulates many features of human SjS. Calcium signals also control the function of many secretory glands. We recently demonstrated that CRAC channels regulate sweat production by controlling the function of chloride channels and thus water secretion in sweat glands cells. Our data further show that mice lacking CRAC channels in salivary glands have impaired saliva production. This is relevant to SjS as patients can develop dry mouth and eyes before their glands become inflamed and infiltrated by immune cells, suggesting that altered salivary gland function precedes immune activation. We hypothesize that impaired calcium signals in salivary gland cells predisposes mice and human patients to develop SjS by impairing the production of saliva and oral innate immune responses, ultimately resulting in gland inflammation and immune cell infiltration. The MAIN GOALS of this proposal are to understand the role of calcium signals in the development and progression of SjS. (1) We will characterize how calcium influx enables Treg cells to function and prevent the onset of SjS. (2) We will determine how calcium influx regulates salivary gland function and oral immune responses, thereby preventing SjS. To this end, we will study two mouse models of SjS that we generated. (3) We will analyze salivary glands and lymphocytes of human SjS patients for calcium influx and the expression of CRAC channel proteins. The proposed studies will provide a better understanding of SjS pathology and the role of impaired calcium signals in SjS, which may be useful as a new diagnostic and prognostic marker for the early detection of SjS.