東京醫(yī)科齒科大學(xué)（Tokyo Medical and Dental University）Yoshiyuki Minegishi博士及其同事最近鑒別出一種罕見的人類Tyk2缺陷癥患者，并證明人類Tyk2分子與人類免疫反應(yīng)中多種關(guān)鍵細(xì)胞因子有關(guān),，強(qiáng)調(diào)Tyk2在人體中的重要地位,，并證明在人類和在小鼠中功能不同。文章刊登于10月電子版《Immunity》,。
Tyk2是一種非受體酪氨酸激酶，屬于Janus 激酶(Jak)家族成員之一,，是IL-12 和IFN-gamma信號途徑都需要的一種酶,。高IgE 綜合癥（hyper IgE syndrome ，HIES）是一種原發(fā)性免疫缺陷病(primary immunodeficiency,，PID) ,。Yoshiyuki Minegishi博士在對一名診斷為HIES的患者的免疫異常進(jìn)行研究,，發(fā)現(xiàn)這名患者還具有其它非HIES癥狀，患者體內(nèi)兩種不同的可溶性蛋白（細(xì)胞因子）IL-12和IFN-gamma缺失,。進(jìn)一步發(fā)現(xiàn)患者Tyk2基因的兩個拷貝都發(fā)生突變,。
奇怪的是，這名患者不僅IL-12 和IFN-gamma信號途徑發(fā)生缺陷,，IL-6,，IL-10 和IL-23細(xì)胞因子信號途徑也發(fā)生缺陷。這些與早期在研究Tyk2缺陷小鼠時得到的理論明顯矛盾,，小鼠實(shí)驗(yàn)只顯示INF信號部分削弱,，而IL-6和IL-10信號正常。
人類患者和小鼠模型所得到的結(jié)果差異似乎來源于物種差異,。向患者細(xì)胞中添加正常Tyk2后,，IL-12 和 I型 IFN 信號通路恢復(fù)正常；相反,，抑制人類正常細(xì)胞中Tyk2表達(dá)會破壞IFN-gamma信號通路,。因此，與在小鼠中觀察結(jié)果不同,，Tyk2似乎對于人類免疫系統(tǒng)中多種細(xì)胞因子信號都至關(guān)重要,。
研究人員總結(jié)到，Tyk2功能缺失會導(dǎo)致多種細(xì)胞因子信號通路發(fā)生缺陷,，就像在人類HIES患者中觀察到的一樣,；人類Tyk2突變作為原發(fā)性免疫缺陷的一種類型，特征與常染色體隱性HIES相似,。Minegishi說：“這是首次對人類Tyk2基因缺陷進(jìn)行研究,，證明Tyk2在人類先天性免疫反應(yīng)和獲得性免疫反應(yīng)中發(fā)揮無可替代的作用。”
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.
