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

• 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
• 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

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.

项目摘要/摘要 1型糖尿病（T1D）是一种自身免疫性疾病，其特征是破坏胰腺β 细胞，导致胰岛素和高血糖的产生减少。尽管环境因素有贡献，但 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 针对T1D的风险增加等位基因。对于大多数情况，这些机制的确切机制 基因及其基因产物有助于自身免疫的发展尚待阐明。然而， 鉴于T1D需要激活通常被免疫沉默的自身抗原特异性T和B细胞 公差，它可能是HLA和非HLA等位基因的组合，以破坏正常公差 机制，可以激活这些自动反应性细胞。 尽管T细胞是T1D中β细胞破坏的主要效应因子，但认为自动反应性B细胞是 主要充当抗原呈现细胞。在健康的个体中，自动反应性B细胞通常会沉默 三种机制之一：受体编辑，克隆删除或消极。在我们最近的出版物中，我们确定了 B细胞携带具有高亲和力对胰岛素的抗原受体的细胞仅在厌氧B细胞室中发现， 被称为健康个体。重要的是，这些细胞以一级一级离开该隔室 亲戚（FDR），以及所有自身抗体阳性糖尿病患者和新发作糖尿病患者。我们假设人们 T1D发育风险携带自身免疫风险等位基因，会损害自动反应性B细胞的适当沉默 通过反对，使这些细胞被激活并导致疾病。在此应用程序中，我们建议 研究分析厌氧B细胞丧失与高风险基因型等位基因的损失的关联 维护B细胞消极。 AIM 1将在T1D患者的FDR中探索BND损失之间的关联 和风险等位基因基因型。 AIM 2将检查衰竭B细胞丧失与高风险T1D的关系 基因型等位基因PTPN22，使用鼠标模型。这些研究的潜在影响在于理解 风险等位基因如何共同破坏T1D中对自动抗原的免疫耐受性的维持。