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.

项目概要 乳糜泻 (CD) 是一种免疫介导的疾病，其中对外源性物质产生免疫反应 HLA 限制的个体中的抗原麸质（来自小麦、黑麦和大麦）。该病引起 十二指肠炎症，但可以通过戒断麸质来逆转。患者会出现口腔功能丧失的情况 对麸质的耐受性 (LOT)，T 细胞和 B 细胞有反应。患者还会产生粘膜自身抗体 转谷氨酰胺酶 2 (TG2) 参与麸质代谢。我们之前发现TG2- 特定血浆占十二指肠粘膜内抗体分泌细胞 (ASC) 的 10% 活动 CD。这些抗 TG2 B 细胞和抗体被认为可以直接增强或延续疾病 通过抗体介导的效应机制，例如补体沉积，或通过麸质的呈递 肽，通过 T 细胞使 LOT 永久化。因此，了解抗 TG2 的起源非常重要。 自身抗体反应。我们之前还发现抗 TG2 抗体是由高度编码的 Ig 基因的限制库，主要由 VH5-51 和其他两个 VH 基因组成。剧目 诸如此类的限制常常让人想起 B 细胞的一个独特子集，主要表达 Ig 由VH5-51编码。我们现在有了初步数据，确定了 IgA+ B 细胞的再循环子集， 表现出与抗 TG2 抗体相同的库限制，但在所有健康受试者的血液中都发现了这种抗体。 值得注意的是，特别是 IgA+ B 细胞和抗体分泌细胞 (ASC) 的再循环群体已被 与微生物群相互作用有关。我们假设这些细胞代表一个独特的功能子集 IgA 外周血库通常提供粘膜保护，但可以诱导 易感个体在接触麸质后会分泌抗 TG2 自身抗体。在目标 1 中，我们将描述 该子集的功能表型和转录组，我们将确定该子集是否是克隆连锁的 患者体内的抗 TG2 粘膜 ASC。在目标 2 中，我们将描述这些血液的微生物群特异性 从活动性疾病患者和对照的血液和活检粘膜 ASC 中携带 IgA ASC 单克隆水平的受试者。最后，在目标 3 中，我们将探索 TG2 自身抗体反应的起源 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 对照受试者细胞可以为乳糜泻的病因学提供重要的见解。一种新颖的细胞表面 表型，例如特定 CD 标记物或特定细胞因子受体的表达，可以 提供有助于疾病治疗干预的独特目标。