The Role of RFX6 in Type 1 Diabetes

RFX6 在 1 型糖尿病中的作用

• 批准号: 9908956
• 负责人: Sara Vazquez
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-05 至 2023-09-04
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908956
• 关键词: Adoptive Transfer; Affect; Antibodies; Antibody Affinity; Antigens; Autoantibodies; Autoantigens; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Biological Assay; Biological Markers; Blood Glucose; Cells; Computing Methodologies; Data; Data Set; Development; Diabetes Mellitus; Diagnostic; Endocrinology; Enteroendocrine Cell; Epithelium; Exhibits; Future; Genes; Genetic; Genetic Transcription; Goals; Gold; Health Care Costs; Human; Immune Tolerance; Immune response; Immunization; Immunobiology; Immunotherapy; Incidence; Insulin; Insulin-Dependent Diabetes Mellitus; Intestines; Investigation; Islets of Langerhans; Knowledge; Learning; Maps; Mediator of activation protein; Molecular Target; Morbidity - disease rate; Mus; Pancreas; Pathogenesis; Pathology; Patients; Pattern; Peptides; Phage Display; Physicians; Polyglandular Autoimmune Syndrome Type I; Population; Prevalence; Proteins; Proteome; Public Health; Regulation; Resolution; Role; Scientist; Serum; Specificity; Testing; Therapeutic; Thymic epithelial cell; Thymus Gland; Time; Tissues; Work; career; central tolerance; chronic autoimmune disease; clinical biomarkers; clinical diagnostics; clinical predictors; clinically actionable; cohort; cost; glucose monitor; improved; mortality; mouse model; novel; patient subsets; programs; response; single cell sequencing; skills; transcription factor

PROJECT SUMMARY/ABSTRACT Type 1 diabetes (T1D) is a devastating and chronic autoimmune disease that affects 0.5% of the US population. Strategies for targeted induction of immune tolerance promise to produce a durable cure for T1D. However, these approaches rely on knowledge of specific molecular targets of autoimmunity. INS, GAD2, and other known autoantigens are the current gold-standard biomarkers for T1D, but the prevalence of ‘autoantibody-negative’ sporadic and immunotherapy-associated cases suggests that there are additional, unknown causal antigens in T1D. Thus, high-throughput antigen discovery represents a critical next step to enable antigen-specific re- establishment of immune tolerance in T1D. In preliminary work, I adapted a proteome-wide phage display assay to identify antigenic targets of human serum autoantibodies. I applied this approach to sera from a cohort of patients with Autoimmune Polyendocrine Syndrome Type 1 (APS1), with the rationale that (i) APS1 patients have a high incidence of T1D and (ii) APS1 patients make high affinity antibodies, increasing the sensitivity of my assay to discover novel autoantigens. Strikingly, I found that many APS1 patients exhibited a strong autoantibody response to RFX6. As RFX6 is expressed specifically in pancreatic islets and has been implicated in congenital cases of diabetes and intestinal pathology, this discovery motivates a mechanistic investigation of the role of RFX6 in pancreatic autoimmunity. My central hypothesis is that RFX6 autoimmunity is sufficient to cause diabetes and that RFX6 is a previously unknown autoantigen in sporadic T1D. In my first aim, I will use mouse models to test the causal relationship between anti-RFX6 immune response and pancreatic pathology, including overt diabetes. In my second aim, I will determine whether T1D patients mount an immune response to RFX6. Specifically, I will test for RFX6 autoantibodies in sporadic T1D patients, as well as in autoantibody- negative and immunotherapy-induced diabetes where there is a pressing need for antigen discovery. Finally, I found in preliminary analyses that RFX6 may exhibit non-canonical regulation in the thymus: the pattern of RFX6 expression does not match that of classic tissue-specific autoantigens in the thymic epithelium. Therefore, in my third aim, I will dissect the pattern and regulation of thymic RFX6 expression. Results from this aim will have broad implications for the immunobiology of central tolerance, and more specifically, may elucidate mechanisms of loss of immune tolerance in the setting of autoimmune diabetes. Together, these aims will definitively determine the role and spectrum of immune response to RFX6. In the longer term, the goals of this project are to establish an actionable clinical biomarker, as well as to expand the autoantigen spectrum in T1D to enable improved specificity of future antigen-specific therapeutic approaches.

项目摘要/摘要 1型糖尿病（T1D）是一种毁灭性和慢性自身免疫性疾病，影响美国人群的0.5％。 有针对性诱导免疫耐受性的策略有望产生耐用的T1D治疗方法。然而， 这些方法取决于了解自身免疫的特定分子靶标。 ins，gad2和其他已知的 自动抗原是当前T1D的金标准生物标记物，但“自动抗体阴性”的流行率 零星和免疫疗法相关的病例表明，还有其他未知的因果抗原 T1D。这是，高通量抗原发现代表了实现抗原特异性重新的关键下一步 在T1D中建立免疫公差。在初步工作中，我改编了全蛋白质组的噬菌体显示器 分析以鉴定人血清自身抗体的抗原靶标。我从队列中应用了这种方法 1型自身免疫性多发性分泌综合征（APS1）的患者的理由是（i）APS1患者 具有很高的T1D和（II）APS1患者的高度亲和力抗体，从而提高了敏感性 我的评估是发现新颖的自动抗原。令人惊讶的是，我发现许多APS1患者暴露了强大 对RFX6的自身抗体反应。由于rfx6在胰岛中特别表达，并已牵连 在先天性的糖尿病和肠道病理病例中，这一发现激发了对 RFX6在胰腺自身免疫中的作用。我的中心假设是RFX6自身免疫足以 导致糖尿病，RFX6是零星T1D中先前未知的自身抗原。在我的第一个目标中，我会使用 小鼠模型测试抗RFX6免疫反应与胰腺病理学之间的因果关系， 包括明显的糖尿病。在我的第二个目标中，我将确定T1D患者是否会安装免疫反应 对于rfx6。特别是，我将测试偶发的T1D患者的RFX6自身抗体，以及自身抗体 - 阴性和免疫疗法诱导的糖尿病在迫切需要抗原发现。最后，我 在初步分析中发现，RFX6可能在胸腺中表现出非典型调节：RFX6的模式 表达与胸腺上皮中经典组织特异性自身抗原的表达不符。因此，在我的 第三目的，我将剖析胸腺RFX6表达的模式和调节。这个目标的结果将有 对中央耐受性的免疫生物学的广泛影响，更具体地说明了机制 自身免疫性糖尿病中免疫耐受性丧失。这些目标将共同确定 确定免疫反应对RFX6的作用和光谱。从长远来看，该项目的目标是 建立可操作的临床生物标志物，并扩展T1D中的自动抗原光谱 提高了未来抗原特异性治疗方法的特异性。