Genetic risk alleles as drivers of loss of anergic B cells in autoimmunity

遗传风险等位基因是自身免疫中无能 B 细胞丧失的驱动因素

基本信息

批准号：
9305774
负责人：
Mia Smith
金额：
$ 4.4万
依托单位：
COLORADO STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9305774
关键词：
Acute Affect Affinity Alleles Antigen Receptors Antigen-Presenting Cells Autoantibodies Autoantigens Autoimmune Diseases Autoimmune Process Autoimmunity B cell repertoire B-Lymphocytes Beta Cell Binding Biological Assay Blood Cell Compartmentation Cells Clonal Deletion DNA Development Diabetes Mellitus Disease Disease Progression Disease Resistance Environmental Risk Factor Experimental Models First Degree Relative Gene Expression Genes Genetic Genetic Risk Genotype Goals Human Hyperglycemia Immune Tolerance Impairment Individual Insulin Insulin-Dependent Diabetes Mellitus Lupus Lymphocyte Maintenance Modeling Mus Orthologous Gene Patients Production Publications Risk SNP genotyping Site Structure of beta Cell of islet T-Lymphocyte To autoantigen Work anergy autoreactive B cell autoreactivity diabetes risk diabetic gene product genome wide association study high risk mouse model receptor risk variant

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 environmental factors contribute, genetic factors are likely the primary determinants of risk. With recent advances in GWAS studies, hundreds of risk-conferring alleles have been discovered for T1D. For most cases the exact mechanisms by which these genes and their gene products contribute to development of autoimmunity remains to be elucidated. However, given that T1D requires the activation of autoantigen-specific T and B cells that are normally silenced by immune tolerance, it is likely a combination of HLA and non-HLA alleles act in concert to undermine normal tolerance mechanisms, allowing activation of these autoreactive cells. Although T cells are the primary effectors of beta cell destruction in T1D, autoreactive B cells are thought to act primarily as antigen presenting cells. In a healthy individual, autoreactive B cells are normally silenced by one of three mechanisms: receptor editing, clonal deletion, or anergy. In our recent publication, we determined B cells bearing antigen receptors with high affinity for insulin are found only in the anergic B cell compartment, termed BND, of healthy individuals. Importantly, these cells leave this compartment in a proportion of first-degree relatives (FDRs), and in all autoantibody positive pre-diabetics and new onset diabetics. We hypothesize people at risk for development of T1D carry autoimmune risk alleles that impair proper silencing of autoreactive B cells by anergy, allowing these cells to become activated and contribute to disease. In this application we propose studies to analyze the association of loss of anergic B cells with high risk genotype alleles known to contribute to maintenance of B cell anergy. Aim 1 will explore in FDRs of T1D patients the association between loss of BNDs and risk allele genotype. Aim 2 will examine the relationship of loss of anergic B cells with the high risk T1D genotype allele, Ptpn22, using a mouse model. The potential impact of these studies will lie in understanding how risk alleles conspire to undermine maintenance of immune tolerance to autoantigens in T1D.

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。尽管环境因素有所贡献，遗传因素可能是风险的主要决定因素。随着 GWAS 研究的最新进展，数百个已发现 T1D 的风险等位基因。在大多数情况下，这些的确切机制基因及其基因产物对自身免疫发展的贡献仍有待阐明。然而，鉴于 T1D 需要激活自身抗原特异性 T 细胞和 B 细胞，而这些细胞通常会被免疫沉默耐受性，很可能是 HLA 和非 HLA 等位基因的组合协同作用，破坏了正常的耐受性机制，允许激活这些自身反应细胞。尽管 T 细胞是 T1D 中 β 细胞破坏的主要效应器，但自身反应性 B 细胞被认为主要充当抗原呈递细胞。在健康个体中，自身反应性 B 细胞通常会被以下因素沉默：三种机制之一：受体编辑、克隆删除或无反应。在我们最近的出版物中，我们确定携带对胰岛素具有高亲和力的抗原受体的 B 细胞仅存在于无反应性 B 细胞区室中，称为 BND，健康个体。重要的是，这些细胞以一级比例离开该隔室。亲属（FDR），以及所有自身抗体阳性的糖尿病前期患者和新发糖尿病患者。我们假设人们有患 T1D 风险的人携带自身免疫风险等位基因，会损害自身反应性 B 细胞的正常沉默通过无能，使这些细胞被激活并导致疾病。在此应用中，我们建议研究分析无反应性 B 细胞损失与已知造成的高风险基因型等位基因之间的关系维持B细胞无反应性。目标 1 将探讨 T1D 患者的 FDR 中 BND 丢失之间的关联和风险等位基因基因型。目标 2 将检查无反应性 B 细胞损失与高风险 T1D 的关系使用小鼠模型对等位基因 Ptpn22 进行基因分型。这些研究的潜在影响将在于理解风险等位基因如何共同破坏 T1D 患者对自身抗原的免疫耐受的维持。