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

项目摘要 Sjögren综合征(SjS)的特征是唾液和泪水分泌受损，影响约100-300万人 在美国，人们可能会导致严重的并发症，如淋巴瘤。导致SjS的原因是 很复杂，也很难理解。SJS被认为是一种自身免疫性疾病，其中身体的免疫 系统对自身不利，导致腺体发炎和破坏。这一前提得到了 自身抗体的存在，免疫细胞对唾液腺的渗透，以及炎症水平的增加 大多数患者的中介物。然而，无论是免疫细胞渗透和自身抗体导致SjS，还是 腺体破坏和/或功能障碍的后果尚不清楚。我们的初步数据揭示了一个意想不到的 SjS与免疫系统细胞和唾液腺中的钙信号之间的联系。体内的钙离子 细胞控制免疫细胞和唾液腺细胞的功能。钙通过专门的渠道进入细胞 在细胞膜上形成毛孔。免疫细胞和唾液腺细胞中的重要钙通道 是调节钙内流的CRAC通道。我们发现编码CRAC的基因的缺失 T细胞中的通道，一种介导对感染的免疫的细胞类型，取消钙信号并导致SjS- 就像老鼠身上的疾病一样。当特定T细胞中的CRAC通道被删除时，这种表型甚至更强 亚群，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，这种疾病概括了人类SjS的许多特征。钙 信号也控制着许多分泌腺的功能。我们最近演示了CRAC渠道 通过控制氯离子通道的功能来调节汗液的产生，从而控制汗液中的水分分泌 腺体细胞。我们的数据进一步表明，唾液腺中缺乏CRAC通道的小鼠唾液受损 制作。这与Sjs有关，因为患者在腺体变成之前就会出现口干和眼睛干燥。 免疫细胞发炎和渗透，表明唾液腺功能改变先于免疫 激活。我们假设唾液腺细胞中的钙信号受损易使小鼠和人类 最终，患者会通过损害唾液和口腔天然免疫反应的产生而患上SjS 导致腺体发炎和免疫细胞渗入。这项提议的主要目标是 了解钙信号在SjS发生发展中的作用。(1)我们将描述如何 钙内流使Treg细胞发挥功能，预防SjS的发生。(2)我们将确定钙如何 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 将研究我们生成的SjS的两个小鼠模型。(3)我们将分析唾液腺和淋巴细胞 人干燥综合征患者钙内流及CRAC通道蛋白的表达。拟议的研究将 更好地了解SjS的病理和钙信号受损在SjS中的作用，这可能是 可作为SjS早期发现的一种新的诊断和预后指标。

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.