T cells promoting transitions toward autoimmunity

总结 自身免疫性疾病是由涉及多个基因、细胞类型和免疫缺陷的组合引起的。 和环境因素。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（一种疾病）风险个体， 具有明确的亚临床自身免疫自然史的患者，以及唐氏综合征（DS）患者， 具有极高的发展自身免疫性疾病的风险的条件。核心假设是，天真的T 处于危险中的个体的细胞隔室富含潜在致病前体，“准备”过渡到 自身反应性效应T细胞，以及调控机制的失败，以抑制这一过程最终导致 自身免疫性疾病该方法利用了高风险的横截面和纵向队列的访问 或已知进展为自身免疫;背景下的遗传学和自身抗原特异性T细胞的专业知识 自身免疫和单细胞多模态分析的专业知识。这些专业知识将使我们能够探索 T细胞状态的方式尚未适用于自身免疫。在我们的前两个目标中，我们将深入描述T 从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，我们讨论 使用纵向队列前瞻性跟踪触发事件的外部触发因素的作用，并确定是否 自身免疫性特征在获得第二种自身免疫性疾病的受试者中被夸大 致病前体是否存在于有自身免疫风险的个体的幼稚T细胞区室中 与非高危人群相比。目标2将确定具有疾病遗传风险的细胞类型 转换和识别支持致病性前体T细胞的潜在途径。目标3将确定外部 有助于致病前体向效应物转变的因素，包括前瞻性纵向研究 在家中进行密集样本采集以追踪免疫变异桥接触发事件高风险队列。目标4 将确定在过渡到T1 D的个体中观察到的特征是否在以下个体中被夸大： 发展出其他的自身免疫性疾病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志物，以确定进展和缓解风险 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.