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

项目摘要/摘要：17q12缺失综合征(17q12DS)是一种染色体异常 17号染色体长臂上一个1.4兆碱基(Mb)DNA序列的缺失。临床上， 17q12DS的特征是肾脏、尿路和女性生殖器的结构和/或功能异常 青少年5型成熟型糖尿病(MODY5)和神经发育障碍。已知的15个 在17q12DS缺失的1.4Mb中检测到基因，其中肝细胞核因子1- β(HNF1B)和LIM Homeobox 1(LHX1)基因已被广泛描述为与肾脏和 17q12ds中的泌尿生殖系统畸形、MODY5、智力残疾和神经精神疾病。然而， 在我们对其他临床特征如何发展与缺失的关系的理解上存在知识差距 17q12DS的基因，尤其是那些功能较少的基因。值得注意的是，在我们的17q12DS患者队列中， 我们观察到了免疫相关的疾病，包括严重的特应性疾病，如过敏反应 需要长疗程抗生素治疗和/或住院的食物和感染，表明 17q12DS可能存在免疫失调，这一点在前面没有提到。我们的初步数据显示 患有17q12DS的患者产生T细胞的CD4和CD8T细胞频率显著降低 Th1细胞因子干扰素-γ、Th17细胞因子IL-17和肿瘤坏死因子-α与年龄匹配的健康对照组的比较 (HCS)，尽管两组产生Th2细胞因子的T细胞频率相似。这些发现可能 这部分解释了我们在17q12ds中观察到的严重感染。新型微RNA(MiRNA)2909，它 据报道，包括IFNG在内的调控基因是由抗凋亡转录因子编码的 (AATF)基因在17q12DS中缺失。这提出了杂合子可能的机械学含义 MIR-2909缺失(此后miR-2909缺失表明这一点)在改变T细胞免疫反应中 17q12DS。因此，我们的建议的目标是检验17q12DS患者有 部分由miR-2909缺失驱动的T细胞免疫反应改变。我们的研究是第一个调查 17q12DS患者的免疫系统可能增加了特应性疾病和感染。目标是 目标1.阐明患者的CD4和CD8 T细胞的特征 使用常规和高维分析对17q12缺失综合征进行分析。{作为一个探索性的 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存在免疫缺陷。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缺失的CD4和CD8 T细胞免疫应答中的作用 综合症。这项拟议的研究将增进我们对免疫系统及其在 17q12DS患者临床表现的演变。

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.