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

干燥综合征发病机制中通过 SOCE 的 Ca2 信号传导

• 批准号: 9980846
• 负责人: STEFAN FESKE
• 金额: $ 53.41万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9980846
• 关键词: Affect; Animal Model; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Biopsy; Calcium; Calcium Channel; Calcium Signaling; Calcium ion; Cell Count; Cell Death; Cell membrane; Cells; Chloride Channels; Chlorides; Complex; Data; Defect; Development; Diagnostic; Disease; Epithelial Cells; Estrogen Receptors; Estrogen receptor positive; Etiology; Female; Fluids and Secretions; Functional disorder; Gene Deletion; Gene Expression; Genes; Genetic; Gland; Goals; Human; Immune; Immune response; Immune system; Immunity; Impairment; Infection; Infiltration; Inflammation; Inflammation Mediators; Inflammatory; Innate Immune Response; Interferons; Lacrimal gland structure; Left; Link; Lymphocyte; Lymphoma; Malignant Lymph Node Neoplasm; Mediating; Mus; Mutation; Natural Immunity; Oral; Pathogenesis; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Production; Prognostic Marker; Property; Proteins; Receptor Signaling; Regulatory T-Lymphocyte; Role; STIM1 gene; Saliva; Salivary Glands; Serum; Sialadenitis; Signal Transduction; Sjogren' s Syndrome; Structure of germinal center of lymph node; Sweat Glands; Sweating; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Text; Tissues; Tumor-infiltrating immune cells; Virus Diseases; Water; Woman; Xerostomia; cell type; cytokine; diagnostic biomarker; early detection biomarkers; eye dryness; human disease; immune activation; immune function; immunogenic; mouse model; new therapeutic target; novel; novel diagnostics; prevent; response; targeted treatment; tool

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.

项目概要 干燥综合征 (SjS) 的特点是唾液和眼泪的产生受损，影响约 1-300 万人 美国人民可能会导致淋巴瘤等严重并发症。 SjS 的原因有 复杂且难以理解。 SjS 被认为是一种自身免疫性疾病，其中身体的免疫系统 系统与自身作对，导致腺体炎症和破坏。这个前提得到了支持 自身抗体的存在、免疫细胞对唾液腺的浸润以及炎症水平的增加 大多数患者中存在介质。然而，免疫细胞浸润和自身抗体是否会导致 SjS？ 腺体破坏和/或功能障碍的后果尚不清楚。我们的初步数据揭示了一个意想不到的结果 SjS 与免疫系统和唾液腺细胞中的钙信号之间的联系。内含钙离子 细胞控制免疫细胞和唾液腺细胞的功能。钙通过特殊通道进入细胞 在细胞膜上形成孔。免疫细胞和唾液腺细胞中重要的钙通道 是 CRAC 通道，介导钙内流。我们发现编码 CRAC 的基因缺失 T 细胞中的通道，T 细胞是一种介导感染免疫力的细胞类型，消除钙信号并导致 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 一个子集，即所谓的 T 调节 (Treg) 细胞，可抑制其他免疫细胞，从而防止 自身免疫性疾病。这些小鼠患上一种疾病，它概括了人类 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，唾液腺中缺乏 CRAC 通道的小鼠唾液功能受损 生产。这与 SjS 相关，因为患者在腺体变得干燥之前可能会出现口干和眼干。 发炎并被免疫细胞渗透，这表明唾液腺功能的改变先于免疫细胞的发生 激活。我们假设唾液腺细胞中的钙信号受损使小鼠和人类容易患病 患者通过损害唾液的产生和口腔先天免疫反应而发展成 SjS，最终 导致腺体炎症和免疫细胞浸润。该提案的主要目标是 了解钙信号在 SjS 发生和进展中的作用。 (1) 我们将描述如何 钙流入使 Treg 细胞发挥功能并预防 SjS 的发生。 (2)我们将确定钙的含量 流入调节唾液腺功能和口腔免疫反应，从而预防 SjS。为此，我们 将研究我们生成的两种 SjS 小鼠模型。 (3) 我们将分析唾液腺和淋巴细胞 人类 SjS 患者的钙流入和 CRAC 通道蛋白的表达。拟议的研究将 更好地了解 SjS 病理学以及钙信号受损在 SjS 中的作用，这可能是 作为 SjS 早期检测的新诊断和预后标志物。