Salivary gland response to innate immune mediators dictates Sjogren's syndrome development

唾液腺对先天免疫介质的反应决定了干燥综合征的发展

• 批准号: 10317601
• 负责人: Umesh S Deshmukh
• 金额: $ 26.22万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10317601
• 关键词: 2019-nCoV; Affect; Autoimmune Diseases; Autoimmune Responses; Autoimmunity; Biological Models; Biological Response Modifiers; COVID-19 pandemic; Cells; Chromosome Mapping; Chronic; Communities; Complex; Complex Genetic Trait; Development; Disease; Duct (organ) structure; Ductal Epithelial Cell; Ductal Epithelium; Ebola; Epithelial Cells; Etiology; Exocrine Glands; Fluids and Secretions; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Variation; Human; Human Genetics; Immune; Immune response; Individual; Infiltration; Inflammatory; Influenza; Innate Immune Response; Interferon Type I; Interferons; Laboratory mice; Lacrimal gland structure; Literature; Lymphocyte; Lymphocytic Choriomeningitis; Lymphocytic Infiltrate; MHC Class II Genes; Mouse Strains; Mus; Natural Immunity; Organ; Participant; Pathogenesis; Pathway interactions; Patients; Play; Poly I-C; Population; Predisposition; Regulation; Reporting; Research; Resistance; Resources; Risk; Role; SARS coronavirus; SARS-CoV-2 infection; Salivary Gland Diseases; Salivary Glands; Severities; Sjogren' s Syndrome; Stimulus; Symptoms; System; Testing; Time; Viral; Virus; Virus Diseases; West Nile virus; Xerostomia; body system; cytokine; cytokine release syndrome; eye dryness; gene environment interaction; genetic makeup; genetic variant; genome wide association study; high reward; high risk; immune activation; innovation; mouse model; novel; response; systemic autoimmune disease; tool; virus tropism

Project Summary Sjögren's syndrome (SS) is a systemic autoimmune disorder affecting multiple organ systems. A dysregulated immune response targeting the exocrine salivary and lacrimal glands reduces fluid secretion, which manifests into the dry mouth and dry eye symptoms of SS. Recent evidence in the literature suggests that innate immune activation is a prominent etiologic factor. Nevertheless, how a systemic or localized innate immune response transitions into an adaptive autoimmune response and targets the exocrine glands remains unclear. This issue is also highly relevant in the context of the ongoing COVID-19 pandemic. In genetically susceptible individuals, the systemic cytokine storm elicited by the SARS-CoV-2 infection and the salivary gland tropism of this virus may heighten the risk for developing SS or worsening its severity. The presence of lymphocytic infiltrates in exocrine glands is a significant feature of SS. These infiltrates are predominantly peri-ductal, suggesting that ductal cells are involved in initiating inflammatory cell infiltration into the salivary glands. By using the innovative collaborative cross mice and poly(I:C) as a surrogate for viral infection, this proposal will investigate how the genetic regulation of innate immunity in salivary gland epithelial cells (SGEC) influences SS development. We will test the overall hypothesis that in genetically susceptible individuals, the SGEC response to innate immune stimuli dictates lymphocytic infiltration into the salivary glands and SS development. To test this hypothesis, in Aim 1, we will investigate whether the hierarchy of systemic IFN responses in collaborative cross mice influences lymphocytic infiltration within the salivary glands. In Aim 2, we will investigate whether the genetic makeup of SGECs dictates the magnitude of their response to innate immune mediators. The successful completion of this proposal will help decipher the influence of a differential gradient of innate immune responsiveness in SS pathogenesis. Further, SS development in any of the collaborative cross mice used in this proposal will provide the SS research community a more patient-relevant model system to investigate gene-environment interaction(s) in the disease.

项目摘要 Sjögren综合征（SS）是一种系统性自身免疫性疾病，影响了多器官 系统。靶向外分泌唾液和泪珠的失调的免疫响应失调 减少了流体分泌，该分泌体现在干口和SS的干眼症状中。最近的 文献中的证据表明，先天免疫激活是一个突出的病因因素。 然而，系统或局部的先天免疫反应转变为适应性 自身免疫反应并靶向外分​​泌电网尚不清楚。这个问题也很高 与正在进行的Covid-19大流行有关的背景下相关。在普遍的易感性中 个体，SARS-COV-2感染引起的系统性细胞因子风暴和唾液 该病毒的腺体向西主义可能会增加患SS或担心其严重性的风险。 外分泌网格中淋巴细胞浸润的存在是SS的重要特征。 这些浸润物主要是导管的，表明导管细胞参与 引发炎症细胞浸润到唾液场。通过使用创新 协作杂交小鼠和poly（i：c）作为病毒感染的替代物，该建议将 研究如何在唾液腺上皮细胞中先天免疫的遗传调节 （SGEC）影响SS的发展。我们将测试总体假设 敏感的个体，SGEC对先天免疫刺激的反应决定了淋巴细胞 渗透到唾液网格和SS开发中。为了检验这一假设，在AIM 1中，我们 将研究合作杂交小鼠的全身IFN响应的层次结构 在AIM 2中，我们将调查 SGEC的遗传构成是否决定其对先天的反应的大小 免疫介质。 该提案的成功完成将有助于破译 SS发病机理中先天免疫响应的差异梯度。此外，SS 该提案中使用的任何协作杂交小鼠的开发都将为SS提供 研究社区与患者相关的模型系统，以调查基因环境 疾病中的相互作用。