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 干燥综合征（SS）是一种累及多个器官的全身性自身免疫性疾病， 系统.一种针对外分泌唾液腺和泪腺的免疫反应失调 减少液体分泌，这表现为干燥综合征的口干和干眼症。最近 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，系统性或局部先天性免疫反应如何转变为适应性免疫反应， 自身免疫反应和目标外分泌腺仍不清楚。这个问题也是高度 在2019冠状病毒病疫情持续的背景下相关。在遗传易感的 个体，由SARS-CoV-2感染引起的全身性细胞因子风暴和唾液分泌 这种病毒的嗜腺性可能会增加发展SS或恶化其严重程度的风险。 外分泌腺淋巴细胞浸润是SS的一个重要特征。 这些浸润主要位于导管周围，表明导管细胞参与了 引发炎性细胞浸润到唾液腺中。通过使用创新的 协作杂交小鼠和poly（I：C）作为病毒感染的替代物，该提议将 研究唾液腺上皮细胞先天免疫的遗传调控 （SGEC）影响SS的发展。我们将测试总体假设，在遗传学上， 在易感个体中，SGEC对先天免疫刺激的反应决定了淋巴细胞 浸润到唾液腺和SS的发展。为了验证这一假设，在目标1中，我们 将研究协作杂交小鼠中系统性IFN应答的层次是否 影响唾液腺内的淋巴细胞浸润。在目标2中，我们将研究 SGEC的遗传组成是否决定了它们对先天性免疫缺陷的反应程度， 免疫介质 这项建议的成功完成将有助于破译一个 先天性免疫反应性在SS发病机制中的差异梯度。此外，SS 在本提案中使用的任何协作交叉小鼠的开发将提供SS 研究社区一个更与患者相关的模型系统来研究基因-环境 疾病中的相互作用。