Role of gut protists in celiac disease

项目摘要 乳糜泻（CeD）是由对小麦、大麦、 和黑麦，估计在美国普通人群中的患病率为1%。通常，致耐受性树突状细胞 树突状细胞（DC）从肠腔中采集食物抗原，在建立和维持口腔免疫中起着核心作用。 宽容在患有CeD的人中，谷蛋白特异性免疫应答的抑制受损（口服免疫应答丧失）。 公差（LOT））。LOT的特征在于抑制的调节性T细胞（Treg）应答，导致 在遗传易感个体中，炎症性T辅助细胞1（Th 1）对麸质的免疫应答， 人类白细胞抗原（HLA）DQ 2或DQ 8等位基因。Th 1对麸质的反应是CeD的核心 发病机制和之前的绒毛萎缩的发展，病理学标志的CeD。HLA DQ 2或 DQ 8增加了CeD的风险，并且是CeD发展所必需的，但两者都是不够的。流行病学 免疫学观察结果支持其他遗传和环境因素在CeD中的作用 发病机制根据这一假设，我们和其他人已经发现，白细胞介素-15（IL-15） 在肠道和肠道病毒感染中的过度表达通过诱导促炎性因子而促进LOT转化为麸质。 在其他致耐受性DC中的程序，这反过来又触发了对麸质的不良炎症Th 1应答， CeD相关小鼠模型。一个有希望的策略，以促进口服耐受性，并防止或逆转LOT在 CeD是利用肠道微生物的免疫调节潜力。计划中的研究是基于 我们刚刚从宿主-原生生物相互作用中了解到的一种新现象： 为了促进对饮食抗原的致耐受性粘膜免疫应答， 预防病毒诱导的LOT。我们假设肠道Parabasalia促进对膳食麸质的口服耐受， 通过直接调节饮食抗原呈递，在CeD小鼠模型中预防LOT并将LOT恢复为谷蛋白 CD103+ DC。我们进一步证实，患有Parabasalia的人患上糖尿病的风险降低。 CED.这些都是CeD领域的原创概念。本提案的技术创新源于： 定义明确且高度相关的人源化CeD小鼠模型，研究人类肠道定殖的新方法 口腔耐受性的Parabasalia，以及确定Parabasalia的尖端下一代测序工具- 诱导CD 103 + DC的功能变化，以阐明Parabasalia如何促进口腔粘膜上皮细胞的功能， 对麸质的耐受性和保护作用。总之，我们将在概念上和技术上使用 创新的研究，以获得新的见解如何肠道Parabasalia促进口服耐受性和预防/逆转LOT 在CED中添加谷蛋白。此外，这项研究将激励设计新的基于Parabasalia的治疗方法，以预防 LOT对处于发展CeD风险中的个体的谷蛋白，并重建对谷蛋白的口服耐受性， 最终有可能从根本上影响免疫学和细胞生物学领域。

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.