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: 10626980
• 负责人: STEFAN FESKE
• 金额: $ 52.67万
• 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 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10626980
• 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; Lymphocytic Infiltrate; Lymphoma; Malignant Lymph Node Neoplasm; Mediating; Mus; Mutation; Natural Immunity; Oral; Pathogenesis; Pathology; Pathway interactions; Patients; Persons; Phenotype; Play; Population; Predisposition; 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; Virus Diseases; Water; Woman; Xerostomia; cell type; cytokine; diagnostic biomarker; diagnostic criteria; early detection biomarkers; eye dryness; human disease; immune activation; immune cell infiltrate; immune function; immunogenic; mouse model; new therapeutic target; novel; novel diagnostics; prevent; response; restraint; 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.

项目总结