Role of the transcription factor Ikaros in development of autoimmune disease

转录因子 Ikaros 在自身免疫性疾病发展中的作用

• 批准号: 10159202
• 负责人: Seth E Frietze
• 金额: $ 45.17万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-06-15 至 2023-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10159202
• 关键词: Affect; Age; American; Antibodies; Antigens; Antinuclear Antibodies; Autoantibodies; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Cell Activation; B-Lymphocytes; Biological Assay; Cell Lineage; Cell Maturation; Cells; Chronic; DNA Binding; Data; Defect; Development; Disease; Ensure; Environmental Risk Factor; Epigenetic Process; Etiology; Exons; Flow Cytometry; Future; Gene Expression; Genes; Genetic Predisposition to Disease; Genetic Transcription; Goals; Health; Human; Immune; Immune Tolerance; Investigation; Knowledge; Lead; Link; LoxP-flanked allele; Mature B-Lymphocyte; Mediating; Modeling; Molecular; Mus; Mutant Strains Mice; Mutate; Mutation; Pathogenesis; Patients; Phenotype; Proteins; Regulator Genes; Reporting; Research; Research Design; Role; Serum; Signal Pathway; Signal Transduction; Specificity; Symptoms; System; TNFSF5 gene; Testing; United States; Zinc Fingers; autoreactive B cell; autoreactivity; cell type; central tolerance; chronic autoimmune disease; clinically relevant; epigenetic regulation; gene repression; genetic variant; genome wide association study; genomic locus; improved; in vivo; insight; mouse model; mutant; mutant mouse model; novel; prevent; programs; public health relevance; response; targeted treatment; tool; transcription factor; transcriptomics

ABSTRACT Autoimmune diseases are chronic and often disabling illnesses that affect millions of Americans. Current treatments help to prevent the symptoms of autoimmune disease, but there are no cures. Autoimmune disease is thought to be due to a combination of genetic predispositions and environmental factors, but the etiology is not fully understood. In order to develop new and improved treatments, and to potentially find a cure, a better understanding of the underlying molecular mechanisms of autoimmune disease is essential. Using a newly established strain of mutant mice, we found that a small targeted deletion in the gene encoding the transcription factor Ikaros, resulted in a profound defect in immune tolerance, with high levels of autoreactive antibodies in the serum of very young mice. Antibodies are produced by B cells, and the presence of autoreactive antibodies indicates that Ikaros is necessary to control how B cells respond to antigen and to ensure tolerance to self. A role for Ikaros in human autoimmune disease is supported by recent genome-wide association studies (GWAS), where genetic variants in the Ikaros gene locus (IKZF1) have been linked to several autoimmune diseases. Furthermore, recent studies have reported patients with autoimmune disease that carry IKZF1 mutations. We propose to employ our Ikaros-mutant mice as a new model of autoimmunity to investigate the molecular mechanisms underlying the break of tolerance in Ikaros-mutated B cells. We have preliminary data suggesting that Ikaros regulates two distinct stages of B-cell maturation that are critical for proper tolerance: The central tolerance checkpoint and the requirement for costimulatory signal upon Ag encounter in the periphery. We will use this mouse model to directly test the hypothesis that Ikaros limits autoreactive B cells by enforcing central tolerance and establishing a requirement for the “second signal” (indicating danger) through epigenetic mechanisms. Accordingly, our study design is focused on an understanding of central tolerance and B-cell autoreactivity, using a combination of in vivo and ex vivo approaches. to directly assess the gene expression, epigenetic and signaling pathways associated with proper versus aberrant B cell activation. Specifically, we will investigate the role of Ikaros in BCR signaling and establishment of central tolerance (Aim 1). We will employ our Ikaros-mutant model to investigate the role of Ikaros in the molecular mechanisms regulating mature B-cell response to antigen (Aim 2). Lastly, we will examine the B-cell intrinsic, as well as the relative extrinsic contributions and roles of different immune cell lineages in the observed break of B-cell tolerance (Aim 3).

抽象的 自身免疫性疾病是慢性的，经常使影响数百万美国人的疾病致残。当前的 治疗有助于预防自身免疫性疾病的症状，但没有治疗方法。自身免疫性疾病 被认为是由于遗传易感性和环境因素的结合，但病因是 不完全理解。为了开发新的和改进的治疗方法，并有可能找到治疗方法 了解自身免疫性疾病的基本分子机制是必不可少的。使用新的 建立的突变小鼠菌株，我们发现编码该基因中的靶向缺失很小 转录因子ikaros，导致免疫耐受性有很大的缺陷，具有高水平的自动反应性 非常年轻的小鼠血清中的抗体。抗体是由B细胞产生的，并且存在 自动反应性抗体表明Ikaros是控制B细胞对抗原和对 确保宽容自我。 ikaros在人类自身免疫性疾病中的作用得到了近期全基因组的支持 协会研究（GWAS），其中Ikaros基因基因座（IKZF1）中的遗传变异已与 几种自身免疫性疾病。此外，最近的研究报告了自身免疫性疾病的患者 携带IKZF1突变。我们建议将我们的ikaros突变小鼠作为一种新的自身免疫模型 研究Ikaros突变B细胞中耐受性破裂的分子机制。我们有 初步数据表明，Ikaros调节了B细胞成熟的两个不同阶段，这对于 适当的容忍度：中央公差检查点和AG时对共刺激信号的要求 在外围遇到。我们将使用此鼠标模型直接测试Ikaros限制的假设 通过实施中央耐受性并建立对“第二信号”的要求，自动反应性B细胞 （表明危险）通过表观遗传机制。根据，我们的研究设计集中于 了解中央耐受性和B细胞自动反应性，结合体内和Ex vivo 方法。直接评估与适当相关的基因表达，表观遗传和信号通路 与异常B细胞激活相对于异常。具体而言，我们将研究Ikaros在BCR信号传导中的作用和 建立中央宽容（目标1）。我们将采用我们的ikaros-突动剂模型来调查 Ikaros在调节抗原成熟B细胞反应的分子机制中（AIM 2）。最后，我们会的 检查B细胞的内在以及不同免疫细胞的相对外部贡献和作用 在观察到的B细胞公差的断裂中谱系（AIM 3）。