B cell-T cell crosstalk in celiac disease

乳糜泻中的 B 细胞-T 细胞串扰

• 批准号: 10491265
• 负责人: Valerie Abadie
• 金额: $ 42.75万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491265
• 关键词: Address; Adherence; Affect; Antibodies; Antibody Formation; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoimmune Diseases; Automobile Driving; B cell therapy; B-Cell Activation; B-Lymphocytes; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; Case Study; Celiac Disease; Cells; Cellular Immunity; Chronic; Clinical; Complex; Data; Development; Disease; Enzymes; Epithelial Cells; Exposure to; Functional disorder; Gene Expression Profile; Genetic Transcription; Gluten; Gluten-free diet; HLA-DQ2; HLA-DQ8 antigen; Immune; Immune System Diseases; Immunoglobulin-Secreting Cells; Immunology; Impairment; Individual; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Intestinal Mucosa; Intestines; Knowledge; Laboratories; Lamina Propria; Light; Mediating; Modeling; Monitor; Mucous Membrane; Mus; Pathogenesis; Pathway interactions; Patients; Peptide antibodies; Peptides; Peyer' s Patches; Phenotype; Plasma Cells; Play; Population; Production; Property; Research Proposals; Role; Severity of illness; Small Intestines; Small intestine mucous membrane; Stress; T cell response; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Therapeutic; Time; Tissues; Transgenic Mice; Villous Atrophy; cell mediated immune response; cytokine; cytotoxic; dietary; effective therapy; effector T cell; immunopathology; in vivo; innovation; insight; intestinal epithelium; intraepithelial; mesenteric lymph node; mouse model; novel therapeutics; oral tolerance; persistent symptom; prevent; programs; response; stem; therapeutic target; therapeutically effective; tositumomab; transcriptome sequencing; transglutaminase 2; uptake

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.

项目摘要/摘要 乳糜泻（CED）是一种复杂的肠道炎症性疾病，由饮食面筋和 在表达HLA-DQ2或HLA-DQ8分子的遗传易感个体中发展。 1％ 全球人口受这种疾病的影响，唯一有效的治疗方法是终身 限制性无麸质饮食（GFD）。然而，持续的症状和肠病仍然很普遍 在遵守GFD的CED患者中。这强调了为开发非白野干预措施的必要性 CED。然而，由于我们的不完整，新疗法的发展已被证明具有挑战性 了解CED发病机理的背后的免疫机制和缺乏合适的小鼠 模型。 CED的特征是因HLA-DQ2或HLA-DQ8-表现出对麸质的口服耐受性丧失。 小肠粘膜中受限的抗谷子炎性CD4 T细胞，并通过大量扩张 杀死肠上皮细胞的细胞毒性上皮内CD8+淋巴细胞（IE-CTL）。 这些观察结果导致了CED的一般观念，主要是T细胞介导的免疫疾病。我们 但是，假设B细胞也起着关键作用。该假设源于几个观察。 首先，CED的特征是CED患者粘膜中血浆细胞的大量扩张 随着抗打扰麸质肽（DGP）抗体和自身抗体的发展 酶组织转谷氨酰胺酶2（TG2）。其次，解释抗DGP的产生的主要模型和 抗TG2抗体是，麸质特异性CD4+ T细胞为B细胞提供帮助，表明B细胞可以作用 作为T细胞的抗原呈递细胞，并促进抗渗透CD4 T细胞反应的扩增。 最后，关于与另一种自身免疫性疾病相关的患者的一些病例报告表明 B细胞耗竭疗法可以在CED中提供临床益处，我们证明了B细胞 耗竭可显着减少我们CED小鼠模型中的肠道组织损伤。这个目的 应用是在体内表征B细胞在扩增抗粉刺T细胞反应中的作用，并允许它 达到足够的大小以促进组织破坏。该项目具有创新性，因为它采用了独特 CED的小鼠模型允许操纵B淋巴细胞，面筋特异性T细胞，面筋抗原和 CED倾向于HLA分子1）评估B细胞的贡献是抗原对抗原的贡献 激活和扩增抗谷物CD4+ T细胞反应，2）评估B细胞和 IE-CTL和组织破坏激活中的抗体。从这项研究中获得的知识将 对B细胞介导的免疫力有助于该机制提供前所未有的见解 CED的发病机理，并将首次评估B细胞耗竭治疗在A中的治疗潜力 CED的实验小鼠模型。