17q12缺失综合征患者反复发生的鼻窦肺部感染的根本原因是辅助性T细胞1功能下降。
Decreased T helper 1 cell function underlies recurrent sinopulmonary infections in the 17q12 deletion syndrome.
作者信息
Shin Junghee J, Shin Hyeon Jun, Gutierrez Alan, Yoo Noelle, Par-Young Jennefer, Osmani Lais, Shin Min Sun, Sanchez-Lara Pedro A, Bucala Richard, Soffer Gary, Kang Insoo
机构信息
Section of Rheumatology, Allergy & Immunology, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA; Section of Pulmonary, Allergy, Immunology and Sleep Medicine, Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA.
Section of Pulmonary, Critical Care and Sleep Medicine, Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA.
出版信息
EBioMedicine. 2025 Feb;112:105578. doi: 10.1016/j.ebiom.2025.105578. Epub 2025 Feb 1.
BACKGROUND
The 17q12 deletion syndrome (17q12DS) is a heterozygous deletion of a 1.4 megabase‒spanning DNA sequence on chromosome 17. The clinical characteristics of 17q12DS include neurodevelopmental disorders, kidney and urinary tract abnormalities. In our cohort of 37 subjects with 17q12DS, we observed increased atopic disorders and recurrent sinopulmonary infections, raising the possibility of immune dysregulation in 17q12DS, a feature that has not been previously reported. We tested the hypothesis that individuals with 17q12DS have altered T-cell function, contributing to recurrent infections and atopy.
METHODS
Alteration of CD4 T-cell functions was assessed on FACS sorted CD4 T-cells using RNA-seq analysis, and flow cytometry and multiplex assays.
FINDINGS
We found that individuals with 17q12DS had a substantially decreased frequency of CD4 T-cells producing the T helper (Th) 1 cytokine IFN-γ but not Th2 and Th17 cytokines when compared to age-matched healthy controls (HCs). RNA-seq analysis of CD4 T-cells from subjects with 17q12DS, when compared to HCs, revealed decreased levels of TBX21 encoding the Th1 transcription factor T-bet, IFNG, and other Th1 chemokine genes. These findings were validated using flow cytometry and multiplex assay.
INTERPRETATION
Our study is the first to demonstrate immune alterations in 17q12DS characterized by decreased T-bet and its downstream effector cytokines such as IFN-γ. These findings warrant further investigation into underlying mechanisms, which would inform precision therapy for individuals with 17q12DS.
FUNDING
National Institutes of HealthKL2 TR001862 to JJS, T35DK104689 to AG, 5T32AR007107 to JPY and LO, 1R01AG056728 to IK, and 1R21AI161838 to IK and JJS.
背景
17q12缺失综合征（17q12DS）是17号染色体上一段1.4兆碱基的DNA序列杂合缺失。17q12DS的临床特征包括神经发育障碍、肾脏和泌尿系统异常。在我们的37名17q12DS患者队列中，我们观察到特应性疾病和反复的鼻窦肺部感染增加，这增加了17q12DS存在免疫失调的可能性，这一特征此前尚未见报道。我们检验了这样一个假设，即17q12DS个体的T细胞功能发生改变，导致反复感染和特应性。
方法
使用RNA测序分析、流式细胞术和多重检测，对通过荧光激活细胞分选术分选的CD4 T细胞的功能改变进行评估。
研究结果
我们发现，与年龄匹配的健康对照（HC）相比，17q12DS个体产生辅助性T细胞（Th）1细胞因子IFN-γ的CD4 T细胞频率大幅降低，但Th2和Th17细胞因子未见降低。与HC相比，对17q12DS患者的CD4 T细胞进行RNA测序分析，发现编码Th1转录因子T-bet的TBX21、IFNG和其他Th1趋化因子基因的水平降低。这些发现通过流式细胞术和多重检测得到验证。
阐释
我们的研究首次证明了17q12DS存在免疫改变，其特征为T-bet及其下游效应细胞因子如IFN-γ水平降低。这些发现值得对潜在机制进行进一步研究，这将为17q12DS个体的精准治疗提供依据。
资助
美国国立卫生研究院向JJS提供KL2 TR001862资助，向AG提供T35DK104689资助，向JPY和LO提供5T32AR007107资助，向IK提供1R01AG056728资助，向IK和JJS提供1R21AI161838资助。
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