Decoding the B cell endotype in early onset type 1 diabetes

项目概要/摘要 1型糖尿病（T1 D）是一种自身免疫性疾病，其特征是胰腺β-淀粉样蛋白（β-淀粉样蛋白）的破坏。 细胞，导致胰岛素产生减少和高血糖症。虽然T细胞是主要的效应器 T1 D中β细胞破坏的主要原因，自身反应性B细胞被认为是抗原 呈递细胞此外，最近的研究结果表明，B细胞似乎发挥了更多的致病作用， 在较早的年龄发展T1 D的人。研究表明，年轻发病的T1 D受试者 与晚发型相比，血液中的B细胞增加，胰腺中的B细胞频率增加 T1 D受试者重要的是，这种年龄特异性的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， 关于不同发病年龄的受试者中B细胞的表型和功能的已知文献。最近我们 开发了一种稳健的38+ B细胞组，用于高维单细胞团细胞术， 总的和胰岛素反应性B细胞，各种B细胞亚群，及其活化和功能状态， 允许B细胞的更颗粒化的表征。使用这种全面的B细胞面板，在目标1中，我们将 确定在年轻发病的T1 D的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前驱糖尿病患者，这可以解释他们的快速进展 疾病。在目标2中，我们将比较配对的脾和胰腺淋巴结样本中的B细胞群 从早发性、迟发性和对照器官供体中检测，以确定特定的B细胞亚群是否具有 从外周（脾）迁移到炎症部位（胰腺淋巴结）。的潜在影响 这些研究的重点在于鉴定致病性B细胞，这些细胞是导致急性淋巴细胞白血病快速进展的原因。 疾病，这将告知我们对早发性T1 D侵袭性的理解，并增加 未来适合年龄的治疗方法的精确性。

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.