Innate and adaptive immunity in celiac disease

项目总结 乳糜泻(CED)是一种由饮食面筋引起的复杂的T细胞介导的肠病，表现为HLADQ2或HLADQ2。 DQ8人，目前影响全球1%的人口。虽然CD4T细胞是人类免疫所必需的 绒毛萎缩(VA)是介导肠上皮细胞破坏(IEC)的效应细胞 上皮内细胞毒性淋巴细胞(IE-CTLS)。目前，唯一有效的CED治疗方法是终身面筋- 免费饮食(GFD)。然而，30%-40%的成年CED患者未能恢复完全正常的肠道 GFD上的形态，以及完全避免面筋可能是具有挑战性的。在上一个资助期内， 我们建立了第一个依赖于人类白细胞抗原和面筋的CED小鼠模型(CED-TG)，该模型概括了 CED发病机制的错综复杂。我们将利用CED-TG小鼠模型和我们在 人类免疫学，以(I)进一步剖析组织破坏的机制，以及(Ii)描述 利用高维单细胞技术鉴定新的CED临床谱系 预测组织破坏的治疗途径和生物标记物。我们的核心假设来自于 研究表明，IE-CTL整合来自CD4T细胞和IEC的信号，成为特许杀伤细胞并介导 组织破坏。此外，虽然IEC在IE-CTL激活中发挥了作用，但它们在 CED的发病机制及其对IE-CTL激活的影响尚未被研究。建议的具体内容 目的是：1)利用CED TG建立上皮细胞在T细胞介导的CED免疫病理中的作用 2)建立γδ、CD4T细胞、干扰素γ、IL-15对CED-TG小鼠IE-CTL活性的影响； (3)描述潜在和主动CED的非均质性。目标是提供一个知识库，它将 帮助确定针对个别患者的适当治疗策略，并帮助预测哪些潜在的CED 患者(有炎症性抗面筋免疫但保留正常肠道的患者 架构)发展为退伍军人病症的风险很高。建议的研究将对以下方面产生重大的积极影响 人类健康，因为它们将有助于确定治疗和预防战略，有可能 防止乳糜泻时的组织破坏。

PROJECT SUMMARY Celiac disease (CeD), a complex T cell-mediated enteropathy induced by dietary gluten in HLA-DQ2 or HLA- DQ8 individuals, currently affects 1% of the global population. While CD4 T cells are required for the development of villus atrophy (VA), the effector cells mediating intestinal epithelial cell destruction (IEC) are intraepithelial cytotoxic lymphocytes (IE-CTLS). Currently, the only effective CeD treatment is a lifelong gluten- free diet (GFD). However, 30-40% of adult CeD patients fail to restore a completely normal intestinal morphology on a GFD, and complete avoidance of gluten can be challenging. During the last funding period, we generated the first HLA and gluten-dependent mouse model of CeD (CeD-tg) that recapitulates the intricacies of CeD pathogenesis. We will take advantage of the CeD-tg mouse model and our expertise in human immunology, to (i) further dissect the mechanisms underlying tissue destruction, and (ii) profile the clinical spectrum of CeD using high dimensional single cell technologies with the goal of identifying new therapeutic avenues and biomarkers predicting tissue destruction. The central hypothesis emerging from our studies is that IE-CTL integrate signals from CD4 T cells and IEC to become licensed killer cells and mediate tissue destruction. Furthermore, while it is acknowledged that IEC play a role in IE-CTL activation, their role in CeD pathogenesis and how they impact on IE-CTL activation has not been investigated. The proposed specific aims are:1) Establish the role of epithelial cells in T cell-mediated CeD immunopathology using the CeD Tg mouse model; 2) Establish the Impact of γδ and CD4 T cells, IFNγ, IL-15 on IE-CTL activation in CeD-tg mice; and 3) Profile the heterogeneity of potential and active CeD. The goal is to provide a knowledge base that will help identify appropriate treatment strategies to individual patients, and help predict which potential CeD patients (patients who have develop inflammatory anti-gluten immunity but conserve a normal intestinal architecture) are at high risk of developing VA. The studies proposed will have a significant positive impact on human health because they will help define curative and preventive strategies that have the potential to prevent tissue destruction in celiac disease.