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Perturbation of B cell anergy in T1D

T1D 中 B 细胞无反应性的扰动

基本信息

批准号：
9121223
负责人：
John C Cambier
金额：
$ 23.33万
依托单位：
UNIVERSITY OF COLORADO DENVER
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-02-16 至 2018-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9121223
关键词：
Address Affect Affinity Alleles American Antigen Presentation Antigen Receptors Antigens Autoantibodies Autoimmune Diseases Autoimmunity B-Lymphocytes Beta Cell Binding Biological Assay Blood Blood Cells Blood typing procedure Cell physiology Cells Characteristics Chromatin Development Disease Environmental Exposure Etiology Event Family member First Degree Relative Frequencies Functional disorder Genes Genetic Genotype Goals Human Immune system Inbred NOD Mice Individual Insulin Insulin-Dependent Diabetes Mellitus Islets of Langerhans Left Ligands Lipopolysaccharides Lupus Measures MicroRNAs Nature Onset of illness Organ Donor Pancreas Patients Production Publications Publishing Receptor Signaling Regulation Research Risk Role Signal Transduction Systemic Lupus Erythematosus T-Lymphocyte Technology Thyroglobulin antibody Thyrotropin Receptor Tissues Treatment Efficacy Work World Health anergy autoimmune thyroid disease autoreactive B cell diabetic diabetic patient diabetogenic human disease insulin dependent diabetes mellitus onset islet mouse model peripheral blood public health relevance research study risk variant rituximab single cell analysis success type I diabetic

项目摘要

DESCRIPTION (provided by applicant): Type 1 Diabetes (T1D) is an autoimmune disease characterized by immune system attack and destruction of insulin-producing islet beta cells in the pancreas. The disease affects an estimated three million Americans and 30 million people worldwide, and continues to increase in frequency. Given the impact of this disease on world health and the absence of a cure, there is critical need for studies directed at understanding its etiology and pathophysiology. Although it is well accepted that T cells function as the beta cell executioners, it is unclear what events precede and precipitate their activity in disease. The studies proposed here will extend our recently published findings suggesting a role for insulin-reactive B cells in T1D development. Studies in the Non-Obese Diabetic (NOD) mouse model demonstrate that islet antigen-reactive B cells are required for development of T1D, and further indicate that these B cells are necessary for activation and proliferation of diabetogenic T cells in the pancreas. The function of B cells in human disease is less well understood. However, a role for these cells is supported by the success of B cell depleting therapy (Rituximab) in T1D. We have recently shown that in healthy subjects B cells bearing high affinity insulin-binding antigen receptors reside in the anergic, so-called BND, compartment, but leave this compartment in all new onset diabetic and prediabetic patients, and, perhaps most importantly, in a proportion of their healthy but "at risk" first degree relatives (FDRs). These findings suggest that B cell anergy can be lost in healthy individuals with similar environmental exposure and genotype as type 1 diabetics, and thus may be a predisposing or initiating event in T1D driven by these factors. We have further shown that insulin-reactive antigen receptors expressed by BND B cells are crossreactive with chromatin and lipopolysaccharide. Thus, in the context of disease development, BNDs may be activated by chromatin aggregates carrying co-stimulatory TLR ligands, rather than insulin. In this R21 application we propose to extend these findings in three aims. In Aim 1 we will determine whether escape of BNDs occurs only in FDRs carrying particular genetic alleles that confer risk of autoimmunity. Might certain risk alleles compromise B cell anergy? In Aim 2 we will analyze B cells derived from pancreatic islets of new-onset diabetic patients, determining whether they are activated and express high insulin affinity, polyreactive antigen receptors, consistent with BND origin. Could these cells be activated BNDs that have lodged in islets? In Aim 3 we will assess whether early escape of BND cells is peculiar to T1D, or also occurs in other autoimmune diseases, i.e. lupus or autoimmune thyroid disease. Is this a generalized event in autoimmunity?