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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

基本信息

批准号：
10631980
负责人：
Patrick Christopher Wilson
金额：
$ 23.62万
依托单位：
UNIVERSITY OF CHICAGO
依托单位国家：
美国
项目类别：
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/10631980
关键词：
16S ribosomal RNA sequencing Active Sites Affinity Anatomy 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 Deamination Deposition Disease Disease Marker Duodenum Enzymes Etiology Exhibits Flow Cytometry Genes Genetic Complementation Test 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 Inflammatory Light Link Location Lymphoid Follicle Mediating Metabolism Microbe Modeling Monoclonal Antibodies Mucous Membrane Pathology Patients Peptides Peyer&apos s Patches Phenotype Plasma Plasma Cells Population Predisposition Process Production Reaction Recombinants Rye cereal Specificity T-Lymphocyte Technology Therapeutic Intervention Time Tissues Universities Wheat Withdrawal autoreactive B cell experience insight microbiota novel oral tolerance peripheral blood response single-cell RNA sequencing tool transcriptome transglutaminase 2

项目摘要

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.

项目总结