Studying alterations of T cell immune responses in the 17q12 deletion syndrome

研究 17q12 缺失综合征中 T 细胞免疫反应的变化

基本信息

批准号：
10518405
负责人：
Insoo Kang
金额：
$ 20.94万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-11-02 至 2024-10-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10518405
关键词：
17q 17q12 Age Anaphylaxis Antibiotic Therapy Apoptosis B-Lymphocyte Subsets CD8-Positive T-Lymphocytes CISH gene CTLA4 gene Cell Proliferation Cells Characteristics Chromosome abnormality Chromosomes Clinical Clinical Data Code Copy Number Polymorphism Cytometry DNA Sequence DNA copy number Data Defect Developmental Delay Disorders Disease Female genitalia Food Frequencies GKLF protein Gender Gene Deletion Gene Dosage Gene Expression Regulation Genes Genetic Diseases Genitourinary system Genotype Goals Heterozygote Homeobox Hospitalization Host Defense IL17 gene Immune Immune response Immune system Immunity Immunoglobulin G Immunoglobulins Infection Inflammatory Inherited Intellectual functioning disability Interferon Type II Interferons Interleukin-10 Kidney Knowledge Kruppel-like transcription factors LHX1 gene Memory MicroRNAs Microarray Analysis Natural Killer Cells Neurodevelopmental Disorder Neurons Parents Patients Pattern Phenotype Play Positioning Attribute Production Proliferating Reporting Role STAT1 gene Secondary to Serum Surface Syndrome T cell response T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets TNF gene Testing autism spectrum disorder autosome clinical development cohort cytokine dimensional analysis hepatic nuclear factor 1 high dimensionality interest malformation maturity onset diabetes of the young monocyte neuropsychiatry novel peripheral blood reference genome reproductive tract response transcription factor urinary

项目摘要

Project Summary/Abstract: The 17q12 deletion syndrome (17q12DS) is a chromosomal aberration with the deletion of a 1.4 megabases (Mb)‒spanning DNA sequence on the long arm of chromosome 17. Clinically, the 17q12DS is characterized by structural and/or functional abnormalities of the kidney, urinary and female genital tracts, maturity-onset diabetes of the young type 5 (MODY5), and neurodevelopmental disorders. Fifteen known genes are detected in the deleted 1.4 Mb of the 17q12DS; among these genes, the hepatocyte nuclear factor 1- beta (HNF1B) and LIM Homeobox 1 (LHX1) genes have been extensively characterized in relation to renal and urogenital malformations, MODY5, intellectual disability, and neuropsychiatric conditions in 17q12DS. However, there is a knowledge gap in our understanding of how other clinical features develop in relation to the deleted genes, especially those with less known functions, of 17q12DS. Of note, in our cohort of patients with 17q12DS, we have observed immune related disorders including severe atopic diseases like anaphylactic reactions to foods and infections requiring prolonged-course antibiotic therapy and/or hospitalizations, suggesting the possible immune dysregulation in 17q12DS, the point not addressed previously. Our preliminary data suggest that patients with 17q12DS have a substantially decreased frequency of CD4+ and CD8+ T cells producing the T helper (Th) 1 cytokine IFN-γ, the Th17 cytokine IL-17, and TNF-α compared to age-matched healthy controls (HCs) although both groups had similar frequencies of Th2 cytokine-producing T cells. These findings could account in part for our observations of severe infections in 17q12DS. The novel microRNA (miRNA) 2909, which is reported to regulate genes including IFNG, is encoded by the apoptosis-antagonizing transcription factor (AATF) gene that is deleted in 17q12DS. This raises the possible mechanistic implication of a heterozygous deletion of miR-2909 (hereafter miR-2909 deletion indicates this) in altering T cell immune responses in 17q12DS. The goal of our proposal is thus to test the overarching hypothesis that patients with 17q12DS have altered T cell immune responses driven in part by the deletion of miR-2909. Our study is the first one investigating the immune system in patients with 17q12DS who may have increased atopic diseases and infections. The goal of the proposal will be achieved with: Aim 1. Elucidate the characteristics of CD4+ and CD8+ T cells in patients with the 17q12 deletion syndrome using conventional and high-dimensional analyses. {As an exploratory approach, we will profile monocytes, natural killer (NK) cells, and B cell subsets to evaluate the possible global immune defect in 17q12DS. The relationship of these findings with clinical characteristics will be assessed.} Aim 2. Elucidate the role of miR-2909 in altering CD4+ and CD8+ T cell immune responses in the 17q12 deletion syndrome. The proposed study will advance our understanding on the immune system and its implication in developing clinical manifestations in patients with 17q12DS.

项目摘要/摘要：17q12 缺失综合征 (17q12DS) 是一种染色体畸变， 17 号染色体长臂上 1.4 兆碱基 (Mb) 跨度 DNA 序列的缺失。临床上， 17q12DS 的特点是肾脏、泌尿系统和女性生殖器的结构和/或功能异常神经束、青少年发病的 5 型糖尿病 (MODY5) 和神经发育障碍 15 种已知疾病。在 17q12DS 删除的 1.4 Mb 中检测到基因；在这些基因中，肝细胞核因子 1- beta (HNF1B) 和 LIM 同源框 1 (LHX1) 基因的特征主要与肾和然而，17q12DS 中存在泌尿生殖畸形、MODY5、智力障碍和神经精神疾病。我们对与删除相关的其他临床特征如何发展的理解存在知识差距值得注意的是，在我们的 17q12DS 患者队列中，我们观察到与免疫相关的疾病，包括严重的特应性疾病，例如过敏反应需要长期抗生素治疗和/或住院治疗的食物和感染，表明 17q12DS 可能存在免疫失调，我们的初步数据表明这一点。 17q12DS 患者产生 T 细胞的 CD4+ 和 CD8+ T 细胞的频率显着降低与年龄匹配的健康对照相比，辅助 (Th)1 细胞因子 IFN-γ、Th17 细胞因子 IL-17 和 TNF-α (HC) 尽管两组产生 Th2 细胞因子的 T 细胞的频率相似，但这些发现可能是这样的。部分解释了我们观察到的 17q12DS 严重感染，该新型 microRNA (miRNA) 2909。据报道可调节包括 IFNG 在内的基因，由凋亡拮抗转录因子编码 (AATF) 基因在 17q12DS 中被删除，这提出了杂合子的可能机制含义。 miR-2909 的删除（以下简称 miR-2909 删除表明这一点）在改变 T 细胞免疫反应中因此，我们提案的目标是检验 17q12DS 患者具有的总体假设。 T 细胞免疫反应的改变部分是由 miR-2909 的删除引起的，我们的研究是第一个调查的研究。 17q12DS 患者的免疫系统可能增加特应性疾病和感染。该提案的目标将通过以下方式实现：目标 1. 阐明患者 CD4+ 和 CD8+ T 细胞的特征使用常规和高维分析来分析 17q12 缺失综合征{作为探索性分析。方法，我们将分析单核细胞、自然杀伤 (NK) 细胞和 B 细胞亚群，以评估可能的全局 17q12DS 中的免疫缺陷将评估这些发现与临床特征的关系。} 目的 2. 阐明miR-2909在改变17q12缺失中CD4+和CD8+ T细胞免疫反应中的作用拟议的研究将增进我们对免疫系统及其在疾病中的影响的理解。 17q12DS 患者出现临床表现。