B cell-T cell crosstalk in celiac disease

项目摘要/摘要 乳糜泻(CED)是一种复杂的肠道炎症性疾病，由饮食中的面筋和 在表达人类白细胞抗原-DQ2或人类白细胞抗原-DQ8分子的遗传易感个体中发生。1%的 全世界的人都受到这种疾病的影响，唯一有效的治疗方法是终身和 限制性无面筋饮食(GFD)。然而，持续的症状和肠病仍然很常见 在坚持使用GFD的CED患者中。这强调了开发非饮食干预措施的必要性 CED。然而，新疗法的开发被证明是具有挑战性的，因为我们的 了解CED发病的免疫机制和缺乏合适的小鼠 模特。CED的特征是丧失对面筋的口服耐受性，表现为HLA-DQ2或HLA-DQ8- 限制了小肠粘膜中抗面筋蛋白炎症的CD4T细胞，并通过大量扩增 细胞毒性上皮内CD8+淋巴细胞(IE-CTL)，参与杀死肠道上皮细胞。 这些观察结果导致了这样的普遍观点，即CED主要是一种T细胞介导的免疫疾病。我们 然而，假设B细胞也扮演着关键角色。这一假设源于几个观察结果。 首先，CED的特征是CED患者粘膜中浆细胞的大量扩张。 随着抗脱胺谷蛋白多肽(DGP)抗体和自身抗体的发展 酶组织转谷氨酰胺酶2(TG2)。第二，主要用模型来解释抗DGP的产生和 抗TG2抗体是面筋特异性的CD4+T细胞为B细胞提供帮助，表明B细胞可以 作为抗原提呈细胞为T细胞，并促进扩增抗面筋的CD4T细胞反应。 最后，几个CED患者与另一种自身免疫性疾病相关的病例报告表明 B细胞去除疗法可以在CED中提供临床益处，我们已经证明B细胞 在我们的CED小鼠模型中，耗竭显著减少了肠道组织的损伤。这样做的目的是 应用是在体内表征B细胞在放大抗面筋T细胞反应中的作用并允许它 以达到足以促进组织破坏的程度。该项目具有创新性，因为它采用了独特的 CED小鼠模型允许操纵B淋巴细胞、面筋特异性T细胞、面筋抗原和 CED使人类白细胞抗原分子1)评估作为抗原提呈的B细胞对人类免疫缺陷的贡献 激活和放大抗面筋的CD4+T细胞反应，以及2)评估B细胞和 抗体在激活IE-CTL和破坏组织中的作用。从这项研究中获得的知识将 提供了对B细胞介导的免疫促进 CED的发病机制，并将首次评估B细胞耗竭疗法在急性胰腺炎中的治疗潜力。 实验性CED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.