Tissue destruction and healing in Celiac Disease

项目总结 乳糜泻(CED)是一种复杂的T细胞介导的肠道疾病，由饮食中的面筋蛋白引起的HLADQ2+和/或 人类白细胞抗原-DQ8+个体，目前影响全球1%的人口。无麸质饮食(GFD)就是这样 日期，CED的首选治疗方法。然而，50%的CED患者无法有效地坚持饮食 这可持续地排除面筋，许多患者无意中接触了面筋。而且，结束了 30%的CED患者有持续的高症状负担，这是由于持续的粘膜损害，尽管 坚持使用GFD。GFD上的持续性粘膜损伤与几个严重的并发症有关， 包括恶性肿瘤，特别是淋巴瘤和骨病。此外，患有活动期CED的患者显示 广泛的临床表现，包括代谢缺陷(维生素、铁和胆固醇) 与组织损伤的程度有关。虽然对CED的理解已经取得了很大的进展， 仍然存在重大差距，特别是在不同临床表现所涉及的生物学机制和 不一致的愈合过程。例如，人们很难理解为什么，独立于 绒毛萎缩，某些患者表现出营养和血脂缺乏，而另一些患者则表现为正常水平 维生素、胆固醇和铁。此外，虽然有证据表明微生物组在CED中发挥了作用，但我们缺乏 关于人类CED(更有可能对代谢产生影响)的小肠粘膜微生物区系的信息 并直接与免疫系统相互作用)。最后，我们对面筋和面筋之间的相互作用知之甚少。 肠上皮细胞(IECS)、免疫细胞和微生物区系，以及它们如何与不同的CED相关联 临床表型。我们的RC2提案将测试CED是一种异质性疾病的假设，而 试图定义IECS、微生物区系、免疫系统和遗传学之间的相互作用 在临床表现、组织破坏的严重程度和愈合能力方面的差异。它还将 解决我们对CED发病机制和临床表现的理解中的关键差距，并开发 用于CED患者非侵入性监测的工具。我们已经组建了一支国际知名的团队 CED、上皮细胞生物学、粘膜免疫学、微生物群和化学领域的专家。RC2 建议的基础是在横断面和干预性背景下进行的多组学研究 对445名特征良好的成人和儿童患者进行的面筋挑战和去挑战研究。建议数 具体目标是：1)在CED中开发一种精确医学的方法；2)破译机制 与CED的组织破坏和愈合有关，3)开发非侵入性监测CED的工具 患者，以及4)为科学和医学界开发研究资源，以促进患者护理 以及基于发现和假设生成的科学。此应用程序旨在生成更多- 需要知识库和资源来加深我们对CED发病机制及其异质性的理解， 改善个性化患者护理和随访，开发新的治疗和预防目标。

PROJECT SUMMARY Celiac disease (CeD) is a complex T cell-mediated enteropathy induced by dietary gluten in HLA-DQ2+ and/or HLA-DQ8+ individuals, which currently affects 1% of the global population. A gluten-free diet (GFD) is, to this date, the treatment of choice for CeD. However, 50% of CeD patients are unable to effectively adhere to a diet that sustainably excludes gluten, with many patients suffering from inadvertent gluten exposure. Moreover, over 30% of CeD patients have persistent high symptom burdens, resulting from continued mucosal damage, despite adhering to a GFD. Persistent mucosal damage on a GFD is associated with several severe complications, including malignancies, especially lymphomas and bone diseases. In addition, patients with active CeD display a wide range of clinical presentations, including metabolic defects (vitamins, iron, and cholesterol) that are not correlated to the degree of tissue damage. Although much progress has been made in understanding CeD, major gaps remain, notably regarding the biological mechanisms involved in different clinical presentations and the inconsistent healing process. For instance, it is poorly understood why, independently from the degree of villous atrophy, certain patients display nutrient and lipid deficiencies, whereas others have normal levels of vitamins, cholesterol, and iron. Furthermore, while there is evidence for a role of the microbiome in CeD, we lack information on small-intestinal mucosal microbiota in human CeD (which is more likely to have metabolic effects and directly interact with the immune system). Finally, we have little knowledge about interactions between gluten, intestinal epithelial cells (IECs), immune cells, and the microbiota, and how they are linked to the different CeD clinical phenotypes. Our RC2 proposal will test the hypothesis that CeD is a heterogeneous disorder, while attempting to define interactions between IECs, microbiota, immune system, and genetics that underlie differences in clinical presentation, severity of tissue destruction, and the ability to heal. It will also address critical gaps in our understanding of CeD pathogenesis and clinical presentations, and develop tools for non-invasive monitoring of CeD patients. We have assembled a team of internationally recognized experts in the field of CeD, epithelial cell biology, mucosal immunology, microbiome, and chemistry. The RC2 proposal is anchored around multi-omics studies performed in the context of cross-sectional and interventional gluten challenge and de-challenge studies, on 445 well-characterized adult and pediatric patients. The proposed specific aims are: 1) Developing an approach to precision medicine in CeD; 2) Deciphering the mechanisms associated with tissue destruction and healing in CeD, 3) Developing non-invasive tools for monitoring CeD patients, and 4) Developing research resources for the scientific and medical community to advance patient care as well as discovery-based and hypothesis-generating science. This application aims to generate the much- needed knowledge base and resources to further our understanding of CeD pathogenesis and its heterogeneity, improve individualized patient care and follow-up, and develop new therapeutic and preventive targets.