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: 10392382
• 负责人: STEFAN FESKE
• 金额: $ 52.71万
• 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/10392382
• 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; Disease; Epithelial Cells; Estrogen Receptors; Etiology; Female; Fluids and Secretions; Functional disorder; Gene Deletion; Gene Expression; Genes; Genetic; Gland; Goals; Human; Immune; Immune mediated destruction; 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; Persons; Phenotype; Play; Population; Production; Prognostic Marker; Property; Proteins; Receptor Signaling; Regulatory T-Lymphocyte; Rheumatism; 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; diagnostic criteria; 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.

项目摘要 Sjögren's综合征（SJS）的特征是产生唾液和泪水影响约1-300万 美国的人们可能导致严重的并发症，例如淋巴瘤。 SJ的原因是 复杂且理解不足。 SJS被认为是一种自身免疫性疾病 系统反对自身，并导致腺体注射和破坏。这个前提得到了 自身抗体的存在，免疫细胞浸润唾液腺和炎症水平增加 大多数患者的介体。但是，免疫细胞浸润和自身抗体是否引起SJ或 腺体破坏和/或功能障碍的结果尚不清楚。我们的初步数据显示出意外 SJS和钙系统细胞中的钙信号之间的联系。钙离子内部 细胞控制免疫和唾液腺细胞的功能。钙通过专业通道进入细胞 该形成细胞膜中的毛孔。免疫和唾液腺细胞中的重要钙通道 是介导钙影响的CRAC通道。我们发现编码CRAC的基因缺失 T细胞中的通道，一种介导免疫学感染的细胞类型，废除钙信号并导致SJS- 喜欢小鼠疾病。当在特定的T细胞中删除CRAC通道时，该表型甚至更强 子集，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。这些小鼠发展出一种概括人类SJ的许多特征的疾病。钙 信号还控制许多秘密网格的功能。我们最近证明了CRAC频道 通过控制氯化物通道的功能，从而调节汗水的产生 腺细胞。我们的数据进一步表明，缺乏唾液腺中缺乏CRAC通道的小鼠唾液受损 生产。这与SJ相关，因为患者可以在腺体变成腺体之前发育干嘴和眼睛 免疫细胞发炎和浸润，表明唾液腺功能改变之前是免疫 激活。我们假设唾液腺细胞中的钙信号受损会使小鼠和人类容易 患者通过损害唾液和口服先天免疫调查的患者而发展SJ，最终 导致腺体炎症和免疫细胞浸润。该提议的主要目标是 了解钙信号在SJS的发展和发展中的作用。 （1）我们将表征如何 钙影响使Treg细胞功能并防止SJ的发作。 （2）我们将确定钙如何 涌入调节唾液腺功能和口服免疫反应，从而防止SJ。为此，我们 将研究我们生成的两个SJ的小鼠模型。 （3）我们将分析唾液腺和淋巴细胞 人类SJS患者的钙影响和CRAC通道蛋白的表达。拟议的研究将 对SJS病理学和SJ中钙信号受损的作用提供更好的了解，这可能是 可作为SJS早期检测的新诊断和预后标记。