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

项目总结/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。虽然环境因素也有影响， 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， 已经发现了T1 D的风险赋予等位基因。在大多数情况下， 基因和它们的基因产物对自身免疫发展的贡献仍有待阐明。然而，在这方面， 考虑到T1 D需要激活自身抗原特异性T和B细胞，这些细胞通常被免疫抑制， 在正常的免疫耐受中，可能是HLA和非HLA等位基因的组合共同作用破坏了正常的免疫耐受。 机制，允许激活这些自身反应细胞。 尽管T细胞是T1 D中β细胞破坏的主要效应物，但认为自身反应性B细胞是T1 D中β细胞破坏的主要效应物。 主要作为抗原呈递细胞。在健康个体中，自身反应性B细胞通常被以下抑制： 三种机制之一：受体编辑、克隆缺失或无反应性。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细胞仅在无反应性B细胞区室中发现， 被称为BND，健康个体。重要的是，这些细胞以一级细胞的比例离开这个区室。 亲属（FDR），以及所有自身抗体阳性的前驱糖尿病患者和新发糖尿病患者。我们假设人们 具有发生T1 D风险的患者携带自身免疫风险等位基因，这些等位基因损害自身反应性B细胞的适当沉默 通过无反应性，使这些细胞被激活，并有助于疾病。在本申请中，我们提出 分析无反应性B细胞丢失与已知导致无反应性的高风险基因型等位基因的相关性的研究 维持B细胞无反应性。目的1将在T1 D患者的FDR中探索BND丢失与 和危险等位基因基因型。目的2将检查无反应性B细胞的丢失与高风险T1 D的关系 基因型等位基因Ptpn 22。这些研究的潜在影响将在于理解 风险等位基因如何合谋破坏T1 D患者对自身抗原免疫耐受性的维持。

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.