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: 10432111
• 负责人: Umesh S Deshmukh
• 金额: $ 21.85万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10432111
• 关键词: 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 virus; Epithelial Cells; Etiology; Exocrine Glands; Fluids and Secretions; Genes; Genetic; Genetic Predisposition to Disease; Genetic Research; Genetic Variation; Histocompatibility Antigens Class II; Human; Human Genetics; Immune; Immune response; Individual; Infiltration; Inflammatory; Innate Immune Response; Interferon Type I; Interferons; L1 Elements; Laboratory mice; Lacrimal gland structure; Literature; Lymphocyte; Lymphocytic Infiltrate; Lymphocytic choriomeningitis virus; Mouse Strains; Mus; Natural Immunity; Nucleic Acids; Participant; Pathogenesis; Pathway interactions; Patients; Play; Poly I-C; Population; Predisposition; Process; 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 Diseases; West Nile virus; Xerostomia; body system; chemokine; cytokine; cytokine release syndrome; eye dryness; gene environment interaction; genetic makeup; genetic signature; genetic variant; genome wide association study; high reward; high risk; immune activation; influenzavirus; 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 干燥综合征是一种累及多个器官的全身性自身免疫性疾病 系统。以外分泌腺和泪腺为靶点的失调免疫反应 减少液体分泌，表现为SS的口干和眼干症状。近期 文献中的证据表明，先天性免疫激活是一个显著的病因因素。 然而，系统性或局部性的先天性免疫反应是如何转变为适应性的 自身免疫反应和外分泌腺的靶点仍不清楚。这个问题也是高度关注的 在当前新冠肺炎大流行的背景下具有相关性。在遗传上易受影响 个人、SARS-CoV-2感染和唾液引发的系统性细胞因子风暴 这种病毒的腺体嗜性可能会增加发生SS或加重其严重性的风险。 外分泌腺中淋巴细胞的存在是SS的一个重要特征。 这些浸润物主要发生在导管周围，提示导管细胞参与了 引发炎症细胞渗入唾液腺。通过使用创新的 协作交叉小鼠和聚(I：C)作为病毒感染的替代品，这项提议将 研究唾液腺上皮细胞天然免疫的遗传调控 (SGEC)影响SS的发育。我们将测试总体假设，即在基因上 易感个体，SGEC对先天免疫刺激的反应决定淋巴细胞 唾液腺的浸润与SS的发育。为了验证这一假设，在目标1中，我们 将研究协作性杂交小鼠的系统性干扰素反应的层级 影响唾液腺内的淋巴细胞渗透。在目标2中，我们将调查 SGEC的基因构成是否决定了它们对先天反应的大小 免疫调节剂。 这项提案的成功完成将有助于破译 SS发病机制中先天免疫应答的不同梯度。此外，党卫军 在本提案中使用的任何协作杂交小鼠中的开发将提供SS 研究社区一个更适合患者的模型系统来研究基因环境 互动(S)在疾病中的作用。