Principal Project: B cell response underlying Celiac disease antibody and autoantibody responses

主要项目：乳糜泻抗体和自身抗体反应的 B 细胞反应

• 批准号: 10413990
• 负责人: Patrick Christopher Wilson
• 金额: $ 24.3万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-10 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10413990
• 关键词: 16S ribosomal RNA sequencing; Active Sites; Affinity; Anatomy; Anti-Inflammatory Agents; Antibodies; Antigens; Autoantibodies; Autoantigens; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Barley; Binding; Biopsy; Blood; Celiac Disease; Cell physiology; Cell surface; Cells; Cellular Indexing of Transcriptomes and Epitopes by Sequencing; Chicago; Complement; Complex; Cytokine Receptors; Data; Deposition; Disease; Disease Marker; Duodenum; Enzymes; Etiology; Exhibits; Flow Cytometry; Genes; Gluten; HLA-DQ2; HLA-DQ8 antigen; High-Throughput Nucleotide Sequencing; Immune; Immune Tolerance; Immune response; Immunoglobulin A; Immunoglobulin Genes; Immunoglobulin-Secreting Cells; Immunoglobulins; Individual; Inflammation; Light; Link; Location; Lymphoid Follicle; Mediating; Metabolism; Microbe; Modeling; Monoclonal Antibodies; Mucous Membrane; Pathology; Patients; Peptides; Peyer' s Patches; Phenotype; Plasma; Plasma Cells; Population; Process; Production; Reaction; Recombinants; Rye cereal; Specificity; T-Lymphocyte; Technology; Testing; Therapeutic Intervention; Time; Tissues; Universities; Wheat; Withdrawal; autoreactive B cell; disorder control; experience; insight; microbiota; novel; oral tolerance; peripheral blood; response; single-cell RNA sequencing; tool; transcriptome; transglutaminase 2

PROJECT SUMMARY Celiac disease (CD) is an immune mediated disorder in which there is an immune response to the exogenous antigen gluten (from wheat, rye, and barley) in individuals who are HLA restricted. The disease causes duodenal inflammation but can be reversed by withdrawal from gluten. Patients experience loss of oral tolerance (LOT) to gluten, with T cells and B cells reactive. Patients also produce mucosal autoantibodies to the enzyme transglutaminase 2 (TG2) which is involved in gluten metabolism. We previously found that TG2- specific plasma represent 10% of antibody-secreting cells (ASCs) within the duodenal mucosa of patients with active CD. These anti-TG2 B cells and antibodies are believed to enhance or perpetuate disease either directly through antibody-mediated effector mechanisms, such as compliment deposition, or by presentation of gluten peptides, perpetuating the LOT by T cells. It is therefore important to understand the origin of anti-TG2 autoantibody responses. We also previously found that anti-TG2 antibodies were encoded by a highly restricted repertoire of Ig genes, consisting predominantly of VH5-51 and two other VH genes. Repertoire restrictions such as this are often reminiscent of a distinct subset of B cells, predominantly expressing Ig encoded by VH5-51. We now have preliminary data identifying a recirculating subset of IgA+ B cells that exhibit the same repertoire restrictions as the anti-TG2 antibodies but found in the blood of all healthy subjects. Notably, the recirculating population of IgA+ B cells and antibody-secreting cells (ASCs) in particular, has been associated with microbiota interactions. We hypothesize that these cells represent a distinct functional subset of the IgA peripheral blood repertoire that normally provides mucosal protection, but that can be induced to secrete anti-TG2 autoantibodies in susceptible individuals upon gluten exposure. In aim 1 we will characterize the functional phenotype and transcriptome of this subset and we will determine if the subset is clonally linked to anti-TG2 mucosal ASCs in patients. In aim 2 we will characterize the microbiota specificity of these blood- borne IgA ASCs from the blood and biopsied mucosal ASCs from patients with active disease and from control subjects at the monoclonal level. Finally, in aim 3 we will explore the origin of the TG2 autoantibody response in mucosal tissues. Particular cellular functions or distinct targeting of particular microbes, plus differences from control subject cells could provide important insight into the etiology of celiac disease. A novel cell-surface phenotype, such as expression of a particular CD marker, for example, or a particular cytokine receptor, could provide distinct targets useful for therapeutic intervention into disease.

项目摘要 乳糜泻（CD）是一种免疫介导的疾病，其中对外源有免疫反应 HLA受到限制的人的抗原面筋（来自小麦，黑麦和大麦）。疾病引起的 十二指肠炎症，但可以通过从面筋退出而逆转。患者遭受口服损失 对面筋的耐受性（批次），T细胞和B细胞反应性。患者还会产生粘膜自身抗体 与麸质代谢有关的酶转谷氨酰胺酶2（TG2）。我们以前发现TG2- 特定的血浆代表十二指肠粘膜中10％的分泌细胞（ASC）的患者 活性CD。这些抗TG2 B细胞和抗体被认为可以直接增强或永久性疾病 通过抗体介导的效应器机制（例如称赞沉积）或通过麸质表示 肽，使T细胞延伸。因此，重要的是要了解抗TG2的起源 自身抗体反应。我们以前还发现，抗TG2抗体是由高度编码的 Ig基因的受限曲目，主要由VH5-51和其他两个VH基因组成。曲目 诸如此类的限制通常让人联想到B细胞的独特子集，主要表达Ig 由VH5-51编码。现在，我们有初步数据识别IgA+ B细胞的循环子集 表现出与抗TG2抗体相同的曲目限制，但在所有健康受试者的血液中发现。 值得注意的是，尤其是IgA+ B细胞和分泌抗体细胞（ASC）的循环种群一直是 与微生物群相互作用有关。我们假设这些细胞代表了独特的功能子集 通常提供粘膜保护的IgA外周血库，但可以引起 在面筋暴露后，分泌抗TG2自身抗体。在AIM 1中，我们将描述 该子集的功能表型和转录组，我们将确定子集是否是克隆链接的 到患者的抗TG2粘膜ASC。在AIM 2中，我们将表征这些血液的微生物群特异性 来自活性疾病患者的血液和活检粘膜ASC的传播IgA ASC以及对照 单克隆水平的受试者。最后，在AIM 3中，我们将探索TG2自动抗体响应的起源 在粘膜组织中。特定的细胞功能或特定微生物的独特靶向，以及与 对照受试者可以为乳糜泻的病因提供重要的见解。一个新颖的细胞表面 表型，例如特定CD标记的表达，例如，特定的细胞因子受体可以 提供不同的靶标，可用于治疗干预疾病。