Role of gut protists in celiac disease

肠道原生生物在乳糜泻中的作用

• 批准号: 10656821
• 负责人: Reinhard Hinterleitner
• 金额: $ 43.18万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-08 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10656821
• 关键词: Affect; Alleles; Antigen Presentation; Antigens; Aryl Hydrocarbon Receptor; Autoimmune Diseases; Barley; Biomedical Research; Celiac Disease; Cell Culture Techniques; Cells; Cellular biology; Data; Dendritic Cells; Development; Diet; Disease; Disease model; Effector Cell; Environmental Risk Factor; Epidemiology; Food; Food Hypersensitivity; General Population; Genetic; Genetic Transcription; Gluten; Gluten-free diet; Gnotobiotic; Goals; HLA Antigens; Health; Health Care Costs; High Prevalence; Homeostasis; Human; Immune; Immune response; Immunity; Immunologics; Immunology; Impairment; In Vitro; Individual; Indoles; Inflammatory; Inflammatory Response; Ingestion; Interleukin-15; Intestines; Knowledge; Lead; Learning; Malignant Neoplasms; Mediating; Metabolism; Microbe; Mucosal Immune Responses; Mucosal Immunity; Mus; Norovirus; Pathogenesis; Pathologic; Patients; Persons; Play; Population; Predisposition; Prevalence; Prevention; Probability; Receptor Signaling; Regulatory T-Lymphocyte; Reovirus; Research; Risk; Role; Rye cereal; Sampling; T-Lymphocyte; Testing; Therapeutic Intervention; Time; Tritrichomonas; Tryptophan; Villous Atrophy; Virus; Wheat; aryl hydrocarbon receptor ligand; cohort; design; dietary; disability; effective therapy; enteric virus infection; gut health; gut microbes; gut microbiota; immunoregulation; innovation; insight; microbiota; mouse model; next generation sequencing; novel; novel strategies; novel therapeutic intervention; novel therapeutics; oral tolerance; overexpression; pre-clinical; prevent; programs; protective effect; response; standard of care; stem; stool sample; tool

Project Summary Celiac disease (CeD) is mediated by abnormal immune responses to gluten antigens found in wheat, barley, and rye and has an estimated prevalence of 1% in the general US population. Normally, tolerogenic dendritic cells (DCs) sample dietary antigens from the intestinal lumen and are central in establishing and maintaining oral tolerance. In persons with CeD the suppression of gluten-specific immune responses is impaired (loss of oral tolerance (LOT)). LOT is characterized by dampened regulatory T cell (Treg) responses, resulting in inflammatory T helper 1 (Th1) immune responses against gluten in genetically susceptible individuals expressing the human leukocyte antigen (HLA) DQ2 or DQ8 alleles. The Th1 response against gluten is central to CeD pathogenesis and precedes the development of villous atrophy, the pathological hallmark of CeD. HLA DQ2 or DQ8 increases the risk of CeD and is required for CeD development, but neither is sufficient. Epidemiological and immunological observations support a role for additional genetic and environmental factors in CeD pathogenesis. In line with this hypothesis, we and others have discovered that both, interleukin-15 (IL-15) overexpression in the intestine and enteric virus infections promote LOT to gluten by inducing a proinflammatory program in otherwise tolerogenic DCs, which in turn triggers adverse inflammatory Th1 responses to gluten in CeD-relevant mouse models. One promising strategy to promote oral tolerance and to prevent or revert LOT in CeD is to use the immunoregulatory potential of commensal gut microbes. The planned research is based on a novel phenomenon that we just learned from host-protist interactions: commensal gut colonizing protists of the order Parabasalia promote tolerogenic mucosal immune responses to dietary antigens, resulting in the prevention of virus-induced LOT. We hypothesize that gut Parabasalia promote oral tolerance to dietary gluten, prevent LOT and revert LOT to gluten in CeD mouse models by directly modulating dietary-antigen presenting CD103+ DCs. We further posit that individuals colonized with Parabasalia have decreased risk of developing CeD. These are all original concepts in the field of CeD. The technical innovation in this proposal stems from: well-defined and highly relevant humanized CeD mouse models, new approaches to study human gut colonizing Parabasalia in oral tolerance, and cutting-edge next-generation sequencing tools to determine Parabasalia- induced functional changes in CD103+ DCs to delineate the mechanism of how Parabasalia promote oral tolerance and protect from LOT to gluten in CeD. Taken together, we will use conceptually and technically innovative studies to gain novel insights into how gut Parabasalia promote oral tolerance and prevent/revert LOT to gluten in CeD. Furthermore, this study will motivate the design of novel Parabasalia-based therapies to prevent LOT to gluten in individuals at-risk for developing CeD and to re-establish oral tolerance to gluten and thus ultimately has the potential to impact fields of immunology and cell biology fundamentally.

项目摘要 乳糜泻(CED)是由对小麦、大麦和小麦中发现的面筋抗原的异常免疫反应引起的。 和黑麦，估计在美国总人口中的流行率为1%。正常情况下，致耐受树突状细胞 细胞(DC)从肠腔采集食物抗原，并在建立和维持口腔中起中心作用 宽容。在CED患者中，面筋特异性免疫反应的抑制受到损害(失去口服 公差(LOT))。LOT的特征是调节性T细胞(Treg)反应受抑，导致 表达谷蛋白的遗传易感个体的炎性T辅助细胞1(Th1)免疫反应 人类白细胞抗原(HLA)DQ2或DQ8等位基因。针对面筋蛋白的Th1反应是CED的核心 CED的病理标志是绒毛萎缩，其发病机制先于绒毛萎缩。人类白细胞抗原DQ2或 DQ8增加了CED的风险，是CED发展所必需的，但这两者都是不够的。流行病学 免疫学观察支持额外的遗传和环境因素在CED中的作用 发病机制。根据这一假设，我们和其他人发现，白介素15(IL-15) 肠道中的过度表达和肠道病毒感染通过诱导促炎作用促进大量面筋形成 程序，这反过来又触发对面筋蛋白不利的炎症性Th1反应 与CED相关的小鼠模型。一个很有希望的策略是促进口服耐受性，预防或恢复Lot CED是利用共生肠道微生物的免疫调节潜力。计划中的研究是基于一项 我们刚刚从宿主-原生生物相互作用中了解到的新现象：共生肠道定植原生生物 Parabasalia目促进对饮食抗原的耐受性粘膜免疫反应，导致 预防病毒诱导的批次。我们假设肠道副胃促进了对膳食面筋的口服耐受性， 通过直接调节膳食抗原递呈来预防和恢复CED小鼠模型的Lot和Rot到面筋 CD103+DC。我们进一步假设，患有副寄生虫的人患癌症的风险较低。 CED。这些都是CED领域的原创概念。这项建议的技术创新源于： 定义明确且高度相关的人源化CED小鼠模型，研究人类肠道定植的新方法 口腔耐受性的Parabasalia，以及用于确定Parabasalia的尖端下一代测序工具- 诱导CD103+树突状细胞功能改变探讨副肺吸虫促进口腔功能的机制 在CED中从批量到面筋的耐受和保护。综上所述，我们将在概念和技术上使用 创新研究，以获得关于肠道副胃如何促进口腔耐受和预防/恢复Lot的新见解 在CED中添加面筋。此外，这项研究将推动基于副体位的新疗法的设计，以防止 大量的面筋蛋白用于CED的高危人群，并重新建立对面筋的口服耐受性，从而 最终有可能从根本上影响免疫学和细胞生物学领域。