Lv Ge, Sun Gan, Wu Peilin, Du Xiao, Zeng Ting, Wen Wen, Zhou Lina, An Yunfei, Tang Xuemei, He Tingyan, Zhao Xiaodong, Du Hongqiang
National Clinical Research Center for Child Health and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Ministry of Education Key Laboratory of Child Development and Disorders, Children's Hospital of Chongqing Medical University, Chongqing, China.
Pediatr Allergy Immunol. 2022 Jan;33(1):e13671. doi: 10.1111/pai.13671. Epub 2021 Oct 7.
TYK2 deficiency is a rare primary immunodeficiency disease caused by loss-of-function mutations of TYK2 gene, which is initially proposed as a subset of hyper-IgE syndrome (HIES). However, accumulating evidence suggests TYK2-deficient patients do not necessarily present with HIES characteristics, indicating a vacuum of knowledge on the exact roles of TYK2 in human immune system.
Pathogenic effects of patients were confirmed by qRT-PCR, Western blot, and protein stability assays. The responses to cytokines including IFN-α/β/γ, IL-6, IL-10, IL-12, and IL-23 of peripheral blood mononuclear cells (PBMCs) from these patients were detected by Western blot, qRT-PCR, and flow cytometry. The differentiation of T and B cells was detected by flow cytometry.
We described five more TYK2-deficient cases presenting with or without hyper-IgE levels, atopy, and distinct pathogen infection profile, which are caused by novel TYK2 mutations. These mutations were all found by high-throughput sequencing and confirmed by Sanger sequencing. The patients showed heterogeneous responses to various cytokine treatments, including IFN-α/β/γ, IL-6, IL-10, IL-12, and IL-23. The homeostasis of lymphocytes is also disrupted.
Based on our findings, we propose that TYK2 works as a multi-tasker in orchestrating various cytokine signaling pathways, differentially combined defects which account for the expressed clinical manifestations.
酪氨酸激酶2（TYK2）缺乏症是一种由TYK2基因功能丧失突变引起的罕见原发性免疫缺陷病，最初被认为是高免疫球蛋白E综合征（HIES）的一个亚型。然而，越来越多的证据表明，TYK2缺乏症患者不一定具有HIES的特征，这表明人们对TYK2在人类免疫系统中的确切作用缺乏了解。
通过定量逆转录聚合酶链反应（qRT-PCR）、蛋白质免疫印迹法和蛋白质稳定性测定来证实患者的致病效应。通过蛋白质免疫印迹法、qRT-PCR和流式细胞术检测这些患者外周血单个核细胞（PBMC）对包括干扰素-α/β/γ、白细胞介素-6、白细胞介素-10、白细胞介素-12和白细胞介素-23在内的细胞因子的反应。通过流式细胞术检测T细胞和B细胞的分化。
我们描述了另外5例TYK2缺乏症病例，这些病例有或没有高免疫球蛋白E水平、特应性和不同的病原体感染谱，由新的TYK2突变引起。这些突变均通过高通量测序发现，并经桑格测序证实。患者对各种细胞因子治疗（包括干扰素-α/β/γ、白细胞介素-6、白细胞介素-10、白细胞介素-12和白细胞介素-23）表现出异质性反应。淋巴细胞稳态也受到破坏。
基于我们的研究结果，我们提出TYK2在协调各种细胞因子信号通路中起多任务作用，不同的联合缺陷导致了所表现出的临床表现。
