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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：
10408036
负责人：
Seth E Frietze
金额：
$ 39.54万
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/10408036
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).

摘要自身免疫性疾病是一种慢性疾病，通常会导致残疾，影响着数百万美国人。当前治疗有助于预防自身免疫性疾病的症状，但没有治愈方法。自身免疫性疾病被认为是由于遗传易感性和环境因素的共同作用，但其病因是没有完全理解。为了开发新的和改进的治疗方法，并有可能找到治愈方法，更好的了解自身免疫性疾病的潜在分子机制是至关重要的。使用新的在已建立的突变小鼠品系中，我们发现编码该基因的一个小的靶向缺失转录因子Ikaros导致免疫耐受性的严重缺陷，具有高水平的自身反应幼鼠血清中的抗体。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细胞对抗原的反应和确保对自己的宽容。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基因座位(IKZF1)的遗传变异已与几种自身免疫性疾病。此外，最近的研究报告了患有自身免疫性疾病的患者。携带IKZF1突变的病毒。我们建议使用我们的Ikaros突变小鼠作为一种新的自身免疫模型研究伊卡洛斯突变B细胞耐受性破坏的分子机制。我们有初步数据表明，Ikaros调节B细胞成熟的两个不同阶段，这两个阶段对适当的耐受性：中心耐受性检查点和对银的共刺激信号的要求在外围相遇。我们将使用这个小鼠模型来直接测试伊卡洛斯限制自身反应性B细胞通过加强中枢耐受和建立“第二信号”的要求 (表示危险)通过表观遗传机制。因此，我们的研究设计集中在一个用体内和体外相结合的方法了解中枢耐受和B细胞自身反应接近了。直接评估与适当的基因表达、表观遗传和信号通路相关的而不是异常的B细胞激活。具体地说，我们将研究Ikaros在BCR信号和建立中心耐受性(目标1)。我们将使用我们的伊卡洛斯突变模型来研究伊卡洛斯在调节成熟B细胞对抗原的反应的分子机制中(目标2)。最后，我们将检查B细胞的内在，以及不同免疫细胞的相对外在贡献和作用观察到的B细胞耐受打破的谱系(目标3)。