Decoding the B cell endotype in early onset type 1 diabetes

解读早发 1 型糖尿病中的 B 细胞内型

• 批准号: 10294155
• 负责人: Mia Smith
• 金额: $ 14.72万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10294155
• 关键词: 10 year old; 18 year old; Affinity; Age; Age of Onset; Antibodies; Antigen-Presenting Cells; Antigens; Autoantibodies; Autoimmune Diseases; Autoimmunity; B-Lymphocyte Subsets; B-Lymphocytes; Bar Codes; Beta Cell; Binding; Blood; CD86 gene; Cell Compartmentation; Cells; Cytometry; Development; Diabetes autoantibodies; Diagnosis; Disease; Disease Progression; Exhibits; Frequencies; Future; Goals; Hyperglycemia; Individual; Inflammation; Insulin; Insulin-Dependent Diabetes Mellitus; Left; Mediating; Memory; Molecular; Organ Donor; Pancreas; Pathogenesis; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Plasmablast; Play; Population; Prediabetes syndrome; Production; Reporting; Risk; Role; Sampling; Signal Transduction; Site; Spleen; Stains; Structure of beta Cell of islet; Study Subject; T-Lymphocyte; TNFRSF6 gene; Therapeutic; Work; age group; age related; autoreactive B cell; autoreactive T cell; early onset; functional status; genetic signature; high dimensionality; high risk; insight; insulin dependent diabetes mellitus onset; islet; lymph nodes; offender; peripheral blood; prevent; response; rituximab; therapeutic target; transcriptome sequencing; type I diabetic

Project Summary/Abstract Type 1 diabetes (T1D) is an autoimmune disorder characterized by destruction of the pancreatic beta cells, leading to decreased production of insulin and hyperglycemia. Although T cells are the primary effectors of beta cell destruction in T1D, autoreactive B cells are thought to be essential contributors as antigen presenting cells. Moreover, recent findings indicate that B cells appear to play a more pathogenic role in individuals who develop T1D at an earlier age. Studies have shown that young onset T1D subjects have increased B cells in their blood and an increased frequency of B cells in their pancreas compared to later onset T1D subjects. Importantly, this age-specific B cell signature is also associated with rapid progression of disease. Despite the recent evidence for B cell participation in a more aggressive form of disease, little is known regarding the phenotype and function of B cells in subjects at different ages of onset. Recently we developed a robust 38+ B cell panel for high dimensional single-cell mass cytometry to simultaneously identify total and insulin-reactive B cells, the various B cell subpopulations, and their activation and functional status, allowing for a more granular characterization of B cells. Using this comprehensive B cell panel, in aim 1 we will determine whether a specific B cell subset / phenotype exists in the peripheral blood of young onset T1D subjects and a portion of at-risk autoantibody positive prediabetics, which could explain their rapid progression of disease. In aim 2 we will compare the B cell population in paired spleen and pancreatic lymph node samples from early onset, late onset, and control organ donors to determine whether a specific B cell subset has migrated from the periphery (spleen) to the site of inflammation (pancreatic lymph node). The potential impact of these studies lies in identification of the pathogenic B cell(s) responsible for the rapid progression of disease, which will inform our understanding of the aggressiveness of early onset T1D and increase the precision of future age appropriate therapeutics.

项目摘要/摘要 1型糖尿病（T1D）是一种自身免疫性疾病，其特征是破坏胰腺β 细胞，导致胰岛素和高血糖的产生减少。尽管T细胞是主要效应子 T1D中β细胞破坏的β细胞破坏，自动反应性B细胞被认为是必不可少的抗原贡献者 呈现细胞。此外，最近的发现表明，B细胞在 早年发展T1D的个人。研究表明，年轻的发作T1D受试者具有 与以后的发作相比 T1D主题。重要的是，这种特定年龄的B细胞特征也与 疾病。尽管最近有B细胞参与更具侵略性的疾病的证据，但很少 关于B细胞在不同年龄发作年龄的受试者中B细胞的表型和功能已知。最近我们 开发了一个可靠的38+ B细胞面板，用于高维单细胞质量细胞术，以同时识别 总和胰岛素反应B细胞，各种B细胞亚群及其激活和功能状态， 允许对B细胞的更颗粒状的表征。使用这个全面的B细胞面板，在AIM 1中，我们将 确定特定的B细胞子集 /表型是否存在于年轻发作T1D的外围血液中 受试者和一部分高危自身抗体阳性前糖尿病，这可以解释其快速发展 疾病。在AIM 2中，我们将比较成对的脾和胰淋巴结样品中的B细胞种群 从早期发作，晚发和控制器官供体来确定特定的B细胞子集是否具有 从周围（脾）迁移到炎症部位（胰腺淋巴结）。潜在影响 这些研究在于鉴定导致的致病性B细胞快速进展 疾病，这将使我们对早期发作的侵略性的理解，并增加 未来年龄适当的治疗学的精度。