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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要/摘要 1 型糖尿病 (T1D) 是一种自身免疫性疾病，其特征是胰腺 β 细胞破坏细胞，导致胰岛素产生减少和高血糖。尽管T细胞是主要效应器自身反应性 B 细胞被认为是 T1D 中 β 细胞破坏的重要贡献者呈现细胞。此外，最近的研究结果表明，B 细胞似乎在较早患上 T1D 的人。研究表明年轻发病的 T1D 受试者与发病较晚的患者相比，血液中的 B 细胞增多，胰腺中 B 细胞的频率增加 T1D 科目。重要的是，这种年龄特异性 B 细胞特征还与疾病的快速进展相关。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，但很少有证据表明 B 细胞参与了一种更具侵袭性的疾病。已知不同发病年龄受试者的 B 细胞表型和功能。最近我们开发了强大的 38+ B 细胞面板，用于高维单细胞质谱流式分析，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，允许对 B 细胞进行更精细的表征。使用这个全面的 B 细胞组，在目标 1 中，我们将确定年轻发病 T1D 的外周血中是否存在特定的 B 细胞亚群/表型受试者和部分高危自身抗体阳性前驱糖尿病患者，这可以解释他们的快速进展的疾病。在目标 2 中，我们将比较配对的脾脏和胰腺淋巴结样本中的 B 细胞群从早发、晚发和对照器官捐献者中确定特定 B 细胞亚群是否具有从外周（脾脏）迁移到炎症部位（胰腺淋巴结）。潜在影响这些研究的重点在于鉴定导致疾病快速进展的致病性 B 细胞。疾病，这将有助于我们了解早发型 T1D 的侵袭性，并增加适合未来年龄的治疗的精确度。