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，其特征是胰岛β细胞受损 细胞，导致胰岛素分泌减少和高血糖。尽管T细胞是主要的效应者 在T1D的β细胞破坏中，自身反应性B细胞被认为是作为抗原的主要贡献者 呈现细胞。此外，最近的发现表明，B细胞似乎在疾病中扮演着更具致病性的角色 较早发展为T1D的个体。研究表明，年轻的T1D受试者有 与发病较晚的患者相比，他们血液中的B细胞增加，胰腺中B细胞的频率增加 T1D受试者。重要的是，这种年龄特异的B细胞特征也与快速进展的 疾病。尽管最近有证据表明B细胞参与了一种更具侵袭性的疾病，但几乎没有 已知不同发病年龄受试者的B细胞表型和功能。最近我们 开发了用于高维单细胞质量细胞术的坚固的38+B细胞板，以同时识别 总B细胞和胰岛素反应性B细胞、各种B细胞亚群及其激活和功能状态， 从而可以对B细胞进行更细粒度的表征。使用这个全面的B细胞面板，在目标1中，我们将 年轻发病的T1D患者外周血中是否存在特定的B细胞亚群/表型 受试者和一部分高危自身抗体阳性的糖尿病前期患者，这可以解释他们的快速进展 疾病的威胁。在目标2中，我们将比较成对的脾和胰腺淋巴结样本中的B细胞数量 从早发、晚发和对照器官捐赠者中确定特定的B细胞亚群是否具有 从外周(脾)转移到炎症部位(胰腺淋巴结)。潜在的影响 这些研究的其中之一在于确定致病的B细胞(S)负责的快速进展 疾病，这将使我们了解早发性T1D的侵袭性，并增加 未来适龄疗法的精确度。