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

• 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
• 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

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）是染色体畸变 在17号染色​​体的长臂上删除1.4兆座（MB） - 跨跨DNA序列。 17q12ds的特征是肾脏，尿和女性生殖器的结构和/或功能异常 年轻5型（Mody5）的成熟度糖尿病和神经发育障碍。十五人已知 在17q12ds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 Homenobox 1（LHX1）基因已广泛地与肾脏和 泌尿生殖器畸形，Mody5，近视残疾和神经精神病疾病在17q12ds中。然而， 我们对其他临床特征如何发展的知识差距存在差距 基因，尤其是那些鲜为人知的功能的基因，为17q12ds。值得注意的是，在我们的17q12ds患者队列中， 我们已经观察到免疫相关疾病，包括严重的特应性疾病，例如过敏反应 需要长时间的抗生素治疗和/或住院的食物和感染，表明 17q12ds可能的免疫失调，该点未解决。我们的初步数据暗示 17q12ds患者的CD4+和CD8+ T细胞的频率大大降低 与年龄匹配的健康对照相比 （HCS）尽管两组具有相似的Th2细胞因子产生T细胞的频率。这些发现可以 部分原因是我们观察到17q12ds的严重感染。新颖的microRNA（miRNA）2909，它 据报道调节包括IFNG在内的基因，由凋亡的转录因子编码 （AATF）在17q12ds中删除的基因。这增加了杂合的可能的机械意义 miR-2909的删除（以下miR-2909删除表示此）在改变T细胞免疫反应中 17q12ds。因此，我们提案的目的是检验17q12ds患者的总体假设 MiR-2909的缺失驱动的T细胞免疫反应改变了T细胞免疫反应。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了特应性疾病和感染。目标 该提案将通过以下方面实现：AIM 1。阐明患者CD4+和CD8+ T细胞的特征 使用常规和高维分析的17q12缺失综合征。 {作为探索性 方法，我们将介绍单核细胞，天然杀手（NK）细胞和B细胞子集，以评估可能的全局 17q12ds的免疫缺陷。这些发现与临床特征的关系将被评估。} AIM 2。阐明miR-2909在17q12缺失中改变CD4+和CD8+ T细胞免疫反应中的作用 综合征。拟议的研究将提高我们对免疫系统及其对此的影响 在17q12ds患者中发展临床表现。