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

基本信息

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
项目类别：
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

项目摘要

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一种慢性且常常致残的疾病，影响着数百万美国人。治疗有助于预防自身免疫性疾病的症状，但无法治愈自身免疫性疾病。被认为是遗传倾向和环境因素共同作用的结果，但其病因是为了开发新的和改进的治疗方法，并潜在地找到一种更好的治疗方法。了解自身免疫性疾病的潜在分子机制至关重要。在建立的突变小鼠品系中，我们发现编码基因中的一个小目标缺失转录因子 Ikaros，导致免疫耐受的严重缺陷，具有高水平的自身反应幼小小鼠血清中的抗体抗体是由 B 细胞产生的，并且存在。自身反应性抗体表明 Ikaros 对于控制 B 细胞如何响应抗原和确保 Ikaros 在人类自身免疫性疾病中的作用得到了最近全基因组的支持。关联研究 (GWAS)，其中 Ikaros 基因位点 (IKZF1) 的遗传变异与此外，最近的研究报告了患有自身免疫性疾病的患者。我们建议使用携带 IKZF1 突变的 Ikaros 突变小鼠作为新的自身免疫模型。研究 Ikaros 突变 B 细胞耐受性破坏的分子机制。初步数据表明 Ikaros 调节 B 细胞成熟的两个不同阶段，这对于适当的耐受性：中央耐受性检查点和 Ag 共刺激信号的要求我们将使用这个小鼠模型来直接检验伊卡罗斯限制的假设。通过强制中央耐受性并建立对“第二信号”的要求来增强自身反应性 B 细胞（表明危险）通过表观遗传机制。因此，我们的研究设计侧重于结合体内和离体了解中枢耐受性和 B 细胞自身反应性直接评估与适当相关的基因表达、表观遗传和信号传导途径。具体来说，我们将研究 Ikaros 在 BCR 信号传导和异常 B 细胞激活中的作用。建立中心耐受性（目标 1）。我们将采用 Ikaros 突变模型来研究的作用。 Ikaros 参与调节成熟 B 细胞对抗原反应的分子机制（目标 2）。检查 B 细胞内在以及不同免疫细胞的相对外在贡献和作用观察到的 B 细胞耐受性破坏中的谱系（目标 3）。