T cells promoting transitions toward autoimmunity

T 细胞促进向自身免疫的转变

基本信息

批准号：
10658696
负责人：
Jane Hoyt Buckner
金额：
$ 131.63万
依托单位：
BENAROYA RESEARCH INST AT VIRGINIA MASON
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-18 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658696
关键词：
Address Autoantigens Autoimmune Autoimmune Diseases Autoimmune Process Autoimmunity Biological Assay Biological Markers Cell Compartmentation Cells Chromatin Clinical Collaborations Collection Data Diagnosis Disease Down Syndrome Effector Cell Environmental Risk Factor Epigenetic Process Event Failure Fingers Funding Genes Genetic Genetic Diseases Genetic Risk Goals Health Hazards Home Immune Immune Tolerance Immunologics In Vitro Individual Insulin-Dependent Diabetes Mellitus Knowledge Leadership Longitudinal Studies Longitudinal cohort Memory Natural History Nucleic Acid Regulatory Sequences Pathogenicity Pathway interactions Population Process Prospective cohort Publishing Research Design Risk Role Sampling Staging Surface T memory cell T-Lymphocyte Testing Variant Work autoimmune inflammation autoreactivity biobank cell type cohort cost disorder risk effector T cell genetic variant high risk in vitro Assay in vivo individual patient multimodality novel pre-clinical precursor cell prevent progression risk prospective restraint risk variant sample collection transcriptome treatment response

项目摘要

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.

概括自身免疫性疾病是由涉及多种基因、细胞类型的免疫失误组合导致的在拟议的研究中，我们将研究这些因素如何促进转变。通过比较患有 1 型糖尿病（一种疾病）风险的个体来研究自身免疫性疾病的亚临床自身免疫具有明确的亚临床自身免疫自然史，以及患有唐氏综合症（DS）的个体，发生自身免疫性疾病的风险极高。核心假设是幼稚 T。高危个体的细胞区室富含潜在致病前体，“准备”转变为自身反应性效应T细胞，以及抑制这一过程的调节机制的失败最终导致该方法利用了高风险的横截面和纵向队列。或已知会发展为自身免疫；自身免疫和单细胞多模式分析方面的专业知识相结合，这些专业知识将使我们能够进行探索。 T 细胞状态的方式尚未应用于自身免疫在我们的前两个目标中，我们将深入描述 T 细胞的特征。在目标 3 和 4 中，我们解决了来自高危受试者的跨平台细胞的问题。使用纵向队列前瞻性地跟踪外部触发事件的作用并确定是否患有第二种自身免疫性疾病的受试者的自身免疫特征被夸大，目标 1 将确定具有自身免疫风险的个体的初始 T 细胞区室中是否存在致病前体目标 2 将识别具有疾病遗传风险的细胞类型。转变并识别支持致病性前体 T 细胞的潜在途径。目标 3 将识别外部。导致致病前体向效应物转变的因素，包括前瞻性纵向高风险队列，在家中进行大量样本收集，以跟踪免疫变异桥接触发事件。将确定过渡到 T1D 的个体中所见的特征是否在以下个体中被夸大：最终，从这项工作中获得的知识将有助于发展其他自身免疫性疾病。疾病分期、选择性治疗并建立生物标志物以确定进展和反应的风险来治疗。