Perturbation of B cell anergy in T1D

T1D 中 B 细胞无反应性的扰动

• 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
• 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

 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?

 描述（由申请人提供）：1 型糖尿病 (T1D) 是一种自身免疫性疾病，其特征是免疫系统攻击和胰腺中产生胰岛素的胰岛 β 细胞遭到破坏。据估计，这种疾病影响着 300 万美国人和全世界 3000 万人，而且发病率还在持续增加。鉴于这种疾病对世界健康的影响以及缺乏治愈方法，迫切需要开展旨在了解其病因学和病理生理学的研究。尽管人们普遍认为 T 细胞充当 β 细胞刽子手，但尚不清楚先发生什么事件并促成其在疾病中的活动。这里提出的研究将扩展我们最近发表的研究结果，表明胰岛素反应性 B 细胞在 T1D 发展中的作用。非肥胖糖尿病 (NOD) 小鼠模型的研究表明，胰岛抗原反应性 B 细胞是 T1D 发展所必需的，并进一步表明这些 B 细胞是胰腺中致糖尿病 T 细胞的激活和增殖所必需的。 B 细胞在人类疾病中的功能尚不清楚。然而，B 细胞耗竭疗法（利妥昔单抗）在 T1D 中的成功支持了这些细胞的作用。我们最近发现，在健康受试者中，携带高亲和力胰岛素结合抗原受体的 B 细胞驻留在无反应的、所谓的 BND 区室中，但在所有新发糖尿病和糖尿病前期患者中，以及也许最重要的是，在他们的一部分健康但“处于危险中”的一级亲属 (FDR) 中，都保留了该区室。这些发现表明，在与 1 型糖尿病患者具有相似环境暴露和基因型的健康个体中，B 细胞无反应性可能会丧失，因此可能是由这些因素驱动的 T1D 的诱发或起始事件。我们进一步证明 BND B 细胞表达的胰岛素反应性抗原受体与染色质和脂多糖发生交叉反应。因此，在疾病发展的背景下，BND 可能被携带共刺激 TLR 配体的染色质聚集体而不是胰岛素激活。在此 R21 应用中，我们建议将这些发现扩展到三个目标。在目标 1 中，我们将确定 BND 的逃逸是否仅发生在携带具有自身免疫风险的特定遗传等位基因的 FDR 中。某些风险等位基因可能会损害 B 细胞无反应性吗？在目标 2 中，我们将分析源自新发糖尿病患者胰岛的 B 细胞，确定它们是否被激活并表达高胰岛素亲和力、多反应性抗原受体，与 BND 起源一致。这些细胞是否可能是驻留在胰岛中的激活的 BND？在目标 3 中，我们将评估 BND 细胞的早期逃逸是否是 T1D 所特有的，或者是否也发生在其他自身免疫性疾病（即狼疮或自身免疫性甲状腺疾病）中。这是自身免疫的普遍事件吗？