东京医科齿科大学(Tokyo Medical and Dental University)Yoshiyuki Minegishi博士及其同事最近鉴别出一种罕见的人类Tyk2缺陷症患者,并证明人类Tyk2分子与人类免疫反应中多种关键细胞因子有关,强调Tyk2在人体中的重要地位,并证明在人类和在小鼠中功能不同。文章刊登于10月电子版《Immunity》。
Tyk2是一种非受体酪氨酸激酶,属于Janus 激酶(Jak)家族成员之一,是IL-12 和IFN-gamma信号途径都需要的一种酶。高IgE 综合症(hyper IgE syndrome ,HIES)是一种原发性免疫缺陷病(primary immunodeficiency,PID) 。Yoshiyuki Minegishi博士在对一名诊断为HIES的患者的免疫异常进行研究,发现这名患者还具有其它非HIES症状,患者体内两种不同的可溶性蛋白(细胞因子)IL-12和IFN-gamma缺失。进一步发现患者Tyk2基因的两个拷贝都发生突变。
奇怪的是,这名患者不仅IL-12 和IFN-gamma信号途径发生缺陷,IL-6,IL-10 和IL-23细胞因子信号途径也发生缺陷。这些与早期在研究Tyk2缺陷小鼠时得到的理论明显矛盾,小鼠实验只显示INF信号部分削弱,而IL-6和IL-10信号正常。
人类患者和小鼠模型所得到的结果差异似乎来源于物种差异。向患者细胞中添加正常Tyk2后,IL-12 和 I型 IFN 信号通路恢复正常;相反,抑制人类正常细胞中Tyk2表达会破坏IFN-gamma信号通路。因此,与在小鼠中观察结果不同,Tyk2似乎对于人类免疫系统中多种细胞因子信号都至关重要。
研究人员总结到,Tyk2功能缺失会导致多种细胞因子信号通路发生缺陷,就像在人类HIES患者中观察到的一样;人类Tyk2突变作为原发性免疫缺陷的一种类型,特征与常染色体隐性HIES相似。Minegishi说:“这是首次对人类Tyk2基因缺陷进行研究,证明Tyk2在人类先天性免疫反应和获得性免疫反应中发挥无可替代的作用。”
英文原文:
Mouse model underestimates the critical role of Tyk2 in human immune system
A new study identifies a human Tyk2 deficiency and definitively links this molecule with multiple cytokine signals that are critical for the human immune responses. The research, published online in October 2006 by the journal Immunity, highlights the importance of Tyk2 function in humans and its differences in mice.
Dr. Yoshiyuki Minegishi from Tokyo Medical and Dental University and colleagues investigated immunological abnormalities in a patient diagnosed with a unique primary immunodeficiency called hyper IgE syndrome (HIES). The researchers observed that the patient showed some symptoms not frequently associated with HIES and found that the signaling pathways of two different soluble proteins (cytokines), IL-12 and IFN-á, were defective in the patient.
The researchers subsequently discovered that the patient carried a mutation in both copies of the gene for Tyk2. Tyk2, a non-receptor tyrosine kinase that belongs to the Janus kinase (Jak) family, is an enzyme shared by both IL-12 and IFN-á signaling pathways.
Surprisingly, the patient's cells displayed severe defects in signaling pathways not only for IL-12 and IFN-á but also for other cytokines including IL-6, IL-10 and IL-23, an observation that is in stark contrast to earlier studies with Tyk2-deficient mice that exhibited partially impaired IFN signaling and normal IL-6 and IL-10 signaling. This discrepancy is most likely due to a species difference between humans and mice. When normal Tyk2 was given to the patient's cells, it restored IL-12 and type I IFN signaling. In contrast, inhibition of Tyk2 expression in a normal human cell line disrupted IFN-á signaling. Therefore, unlike what has been observed in mice, Tyk2 appears to be critical for the multiple cytokine signals involved in the immune system in humans.
The researchers conclude that the absence of functional Tyk2 caused the defects in the multiple cytokine signals that were observed in the patient and identify human Tyk2 mutation as a unique type of primary immunodeficiency with characteristics similar to autosomal recessive HIES. "This study is the first to identify human Tyk2 deficiency and demonstrates the unique and indispensable role played by Tyk2 in the innate and acquired immune response in human," says Dr. Minegishi.