T cells promoting transitions toward autoimmunity

摘要 自身免疫性疾病是涉及多个基因、细胞类型的免疫失误的组合 以及环境因素。在拟议的研究中，我们将研究这些因素如何促进从 通过比较1型糖尿病风险人群对自身免疫性疾病的亚临床自身免疫 有明确的亚临床自身免疫的自然病史，以及患有唐氏综合症(DS)的人， 罹患自身免疫性疾病风险极高的疾病。中心假设是天真的T 高危个体的细胞室富含潜在的致病前体，准备转移到 自身反应性效应T细胞，以及未能抑制这一过程的调节机制最终导致 在自身免疫性疾病中。该方法利用了对高风险的横断面和纵向队列的准入 或已知进展为自身免疫；在遗传学和自身抗原特异性T细胞方面的专业知识 自身免疫力和单细胞多模式分析方面的专业知识。总而言之，这些专业知识将使我们能够探索 T细胞状态，这种方式还不适用于自身免疫。在我们的前两个目标中，我们将深入描述T 来自高危受试者的跨平台细胞，并解决表观遗传学的作用。在目标3和4中，我们解决了 使用纵向队列的外部触发因素的作用前瞻性地跟踪触发事件并确定是否 获得第二种自身免疫性疾病的受试者自身免疫特征被夸大，目标1将确定 自身免疫高危个体的幼稚T细胞室中是否存在致病前体 与非风险个人相比，疾病的风险更大。目标2将确定具有致病遗传风险的细胞类型 并确定支持致病前体T细胞的潜在途径。目标3将确定外部 促进致病前体向效应者转变的因素，包括预期的纵向 高危队列与在家中密集采集样本以跟踪免疫变异桥接触发事件。目标4 将决定过渡到T1D的个体的特征是否在以下个体中被夸大 患上其他的自身免疫性疾病。最终，从这项工作中获得的知识将有助于 疾病分期、选择性治疗和建立生物标记物以确定进展和反应的风险 去接受治疗。

SUMMARY Autoimmune disease results from a combination of immunologic missteps involving multiple genes, cell types and environmental factors. In the proposed studies, we will study how these factors promote the transition from sub-clinical autoimmunity to autoimmune disease by comparing individuals at risk for type 1 diabetes, a disease with a well-defined natural history of sub-clinical autoimmunity, and individuals with Down syndrome (DS), a condition with extremely high risk of developing autoimmune disease. The central hypothesis is that the naïve T cell compartment of at-risk individuals is enriched for potentially pathogenic precursors “poised” to transition to autoreactive effector T cells, and the failure of regulatory mechanisms to restrain this process ultimately results in autoimmune disease. The approach leverages access to cross sectional and longitudinal cohorts at high risk or known to progress to autoimmunity; expertise in the genetics and autoantigen-specific T cells in the context of autoimmunity and expertise in single cell multi-modal analyses. Together, this expertise will allow us to probe T cell states in a manner not yet applied to autoimmunity. In our first two Aims, we will deeply characterize T cells across platforms from at risk subjects and address the role of epigenetics. In Aims 3 and 4 we address the role of external triggers using longitudinal cohorts prospectively tracking trigger events and determine whether autoimmune features are exaggerated in subjects acquiring a second autoimmune disease Aim 1 will determine whether pathogenic precursors are present in the naïve T cell compartment of individuals at risk for autoimmune disease compared to non-risk individuals. Aim 2 will identify cell types that harbor the genetic risk for disease transitions and identify underlying pathways that support pathogenic precursor T cells. Aim 3 will identify external factors that contribute to the transition of pathogenic precursors to effectors, including a prospective longitudinal high-risk cohort with intense at home sample collection to track immune variation bridging trigger events. Aim 4 will determine whether features seen in individuals who transition to T1D are exaggerated in individuals who develop additional autoimmune diseases. Ultimately, the knowledge gained from this work will contribute to staging of disease, selective therapies and establish biomarkers to determine risk of progression and response to therapy.