Minegishi Yoshiyuki, Saito Masako, Morio Tomohiro, Watanabe Ken, Agematsu Kazunaga, Tsuchiya Shigeru, Takada Hidetoshi, Hara Toshiro, Kawamura Nobuaki, Ariga Tadashi, Kaneko Hideo, Kondo Naomi, Tsuge Ikuya, Yachie Akihiro, Sakiyama Yukio, Iwata Tsutomu, Bessho Fumio, Ohishi Tsutomu, Joh Kosuke, Imai Kohsuke, Kogawa Kazuhiro, Shinohara Miwa, Fujieda Mikiya, Wakiguchi Hiroshi, Pasic Srdjan, Abinun Mario, Ochs Hans D, Renner Eleonore D, Jansson Annette, Belohradsky Bernd H, Metin Ayse, Shimizu Norio, Mizutani Shuki, Miyawaki Toshio, Nonoyama Shigeaki, Karasuyama Hajime
Department of Immune Regulation, Graduate School, Tokyo Medical and Dental University, Yushima, Tokyo, Japan.
Immunity. 2006 Nov;25(5):745-55. doi: 10.1016/j.immuni.2006.09.009.
Tyrosine kinase 2 (Tyk2) is a nonreceptor tyrosine kinase that belongs to the Janus kinase (Jak) family. Here we identified a homozygous Tyk2 mutation in a patient who had been clinically diagnosed with hyper-IgE syndrome. This patient showed unusual susceptibility to various microorganisms including virus, fungi, and mycobacteria and suffered from atopic dermatitis with elevated serum IgE. The patient's cells displayed defects in multiple cytokine signaling pathways including those for type I interferon (IFN), interleukin (IL)-6, IL-10, IL-12, and IL-23. The cytokine signals were successfully restored by transducing the intact Tyk2 gene. Thus, the Tyk2 deficiency is likely to account for the patient's complex clinical manifestations, including the phenotype of impaired T helper 1 (Th1) differentiation and accelerated Th2 differentiation. This study identifies human Tyk2 deficiency and demonstrates that Tyk2 plays obligatory roles in multiple cytokine signals involved in innate and acquired immunity of humans, which differs substantially from Tyk2 function in mice.
酪氨酸激酶2（Tyk2）是一种非受体酪氨酸激酶，属于Janus激酶（Jak）家族。在此，我们在一名临床诊断为高IgE综合征的患者中鉴定出纯合Tyk2突变。该患者对包括病毒、真菌和分枝杆菌在内的多种微生物表现出异常易感性，并患有特应性皮炎，血清IgE升高。患者的细胞在多种细胞因子信号通路中存在缺陷，包括I型干扰素（IFN）、白细胞介素（IL）-6、IL-10、IL-12和IL-23的信号通路。通过转导完整的Tyk2基因，细胞因子信号得以成功恢复。因此，Tyk2缺陷可能是导致该患者复杂临床表现的原因，包括辅助性T细胞1（Th1）分化受损和Th2分化加速的表型。本研究鉴定出人类Tyk2缺陷，并证明Tyk2在人类先天和后天免疫所涉及的多种细胞因子信号中起关键作用，这与Tyk2在小鼠中的功能有很大不同。
