B cell-T cell crosstalk in celiac disease

项目总结/摘要 乳糜泻（CeD）是一种复杂的肠道炎症性疾病，由饮食麸质引发， 在表达HLA-DQ 2或HLA-DQ 8分子的遗传易感个体中发展。1%的 全世界的人口都受到这种疾病的影响，唯一有效的治疗方法是终身治疗， 限制性无麸质饮食（GFD）。然而，持续的症状和肠病仍然很常见， 在坚持GFD的CeD患者中。这就强调了发展非饮食干预措施的必要性， CED.然而，由于我们的不完整性，新疗法的开发已被证明具有挑战性。 了解CeD发病机制的免疫机制和缺乏合适的小鼠 模型CeD的特征在于对谷蛋白的口服耐受性的丧失，其表现为HLA-DQ 2或HLA-DQ 8。 限制性抗谷蛋白炎性CD 4 T细胞在小肠粘膜和大规模扩张， 细胞毒性上皮内CD 8+淋巴细胞（IE-CTL）参与杀死肠上皮细胞。 这些观察结果导致了CeD主要是T细胞介导的免疫疾病的一般想法。我们 然而，假设B细胞也起关键作用。这一假设源于几个观察结果。 首先，CeD的特征在于CeD患者的粘膜中浆细胞的相当大的扩增 随着抗脱酰胺谷蛋白肽（DGP）抗体和抗脱酰胺谷蛋白肽的自身抗体的发展， 组织转氨酶2（TG 2）。第二，主要模型来解释抗DGP的产生和 抗TG 2抗体是麸质特异性CD 4 + T细胞为B细胞提供帮助，表明B细胞可以发挥作用 作为T细胞的抗原呈递细胞，并促进抗谷蛋白CD 4 T细胞应答的扩增。 最后，几个与其他自身免疫性疾病相关的CeD患者的病例报告表明， B细胞去除疗法可以在CeD中提供临床益处，并且我们已经证明B细胞 消耗显著降低了我们的CeD小鼠模型中的肠组织损伤。的目的 本申请的目的是在体内表征B细胞在放大抗谷蛋白T细胞应答中的作用，并使其 以达到足以促进组织破坏的强度。这个项目是创新的，因为它采用了独特的 CeD小鼠模型允许操纵B淋巴细胞、谷蛋白特异性T细胞、谷蛋白抗原， CeD易感HLA分子，以1）评估B细胞作为抗原呈递细胞的贡献， 抗谷蛋白CD 4 + T细胞应答的活化和扩增，以及2）评估B细胞的作用， 抗体激活IE-CTL和组织破坏。从这项研究中获得的知识将 为B细胞介导的免疫促进免疫系统的机制提供了前所未有的见解。 CeD的发病机制，并将首次评估B细胞耗竭疗法在一个 CeD的实验小鼠模型。

PROJECT SUMMARY/ABSTRACT Celiac disease (CeD) is a complex intestinal inflammatory disorder that is triggered by dietary gluten and develops in genetically susceptible individuals expressing HLA-DQ2 or HLA-DQ8 molecules. 1% of the worldwide population is affected by this disease for which the only effective treatment is a lifelong and restrictive gluten-free diet (GFD). Yet, persistent symptoms and enteropathy remain commonplace even among CeD patients that adhere to a GFD. This stresses the need to develop non-dietary interventions for CeD. The development of new therapies has however proven challenging because of our incomplete understanding of the immune mechanisms underlying CeD pathogenesis and the lack of a suitable mouse model. CeD is characterized by the loss of oral tolerance to gluten manifested by HLA-DQ2 or HLA-DQ8- restricted anti-gluten inflammatory CD4 T cells in the small intestinal mucosa and by a massive expansion of cytotoxic intraepithelial CD8+ lymphocytes (IE-CTLs) that are involved in the killing of intestinal epithelial cells. These observations have led to the general idea that CeD is primarily a T cell-mediated immune disorder. We hypothesize, however, that B cells also play a critical role. This hypothesis stems from several observations. First, CeD is characterized by a considerable expansion of plasma cells in the mucosa of CeD patients as well as the development of anti-deamidated gluten peptides (DGP) antibodies and autoantibodies against the enzyme tissue transglutaminase 2 (TG2). Second, the main model to explain the production of anti-DGP and anti-TG2 antibodies is that gluten-specific CD4+ T cells provide help to B cells suggesting that B cells could act as antigen-presenting cells for T cells and promote the amplification of the anti-gluten CD4 T cell response. Finally, several case reports on patients having CeD associated with another autoimmune disease suggest that B cell depletion therapy can provide clinical benefit in CeD, and we have demonstrated that B cell depletion significantly reduces intestinal tissue damage in our mouse model of CeD. The objective of this application is to characterize in vivo the role of B cells in amplifying the anti-gluten T cell response and allow it to reach a sufficient magnitude to promote tissue destruction. This project is innovative as it employs unique mouse models of CeD allowing to manipulate B lymphocytes, gluten-specific T cells, the gluten antigen, and the CeD predisposing HLA molecule to 1) assess the contribution of B cells as antigen-presenting to the activation and amplification of the anti-gluten CD4+ T cell response, and 2) assess the role of B cells and antibodies in the activation of IE-CTLs and tissue destruction. The knowledge gained from this study will provide unprecedented insights into the mechanisms by which B cell-mediated immunity contribute to the pathogenesis of CeD and will assess for the first time the therapeutic potential of B cell depletion therapy in an experimental mouse model of CeD.