科學(xué)家與美因茲約翰古騰堡大學(xué)醫(yī)學(xué)中心教授Bernd Kaina一起工作,，第一次表明人血液中的某些循環(huán)細(xì)胞--也稱為單核細(xì)胞--對(duì)活性氧（ROS）極敏感。他們也闡明了原因：ROS是氧的攻擊性形式，它們是在氧化應(yīng)激期間所產(chǎn)生,，在各種疾病中起重要作用,。
但是活性氧也是由免疫系統(tǒng)細(xì)胞在病原體的反應(yīng)中自然產(chǎn)生的，尤其是巨噬細(xì)胞,。巨噬細(xì)胞與樹(shù)突細(xì)胞相似,，由單核細(xì)胞產(chǎn)生，這發(fā)生在單核細(xì)胞離開(kāi)血液進(jìn)入組織之時(shí),?？茖W(xué)家們指出，巨噬細(xì)胞與樹(shù)突細(xì)胞均能抵抗ROS,，就如反對(duì)ROS的前體細(xì)胞一樣,，即單核細(xì)胞。美因茲研究小組將單核細(xì)胞的這種超敏屬性歸于明顯存在于這些細(xì)胞中的DNA修復(fù)的多種缺陷,。他們認(rèn)為,，這種現(xiàn)象背后存在一種調(diào)節(jié)免疫反應(yīng)并防止過(guò)多的活性氧生產(chǎn)的精確機(jī)制，這正是首次觀察到的,。他們的工作已發(fā)表在領(lǐng)先的科學(xué)雜志《國(guó)家科學(xué)研究院學(xué)報(bào)》（ Proceedings of the National Academy of Sciences）上,。
眾所周知，電離輻射和癌癥治療藥物的一種不良影響就是免疫系統(tǒng)損傷,，即免疫系統(tǒng)停止正常運(yùn)作,。然而，目前還不清楚,，免疫系統(tǒng)的哪一種細(xì)胞對(duì)輻射和化療最敏感,，哪一種細(xì)胞對(duì)對(duì)輻射和化療具有抗性。"這正是我們?cè)诋?dāng)前研究項(xiàng)目中解決的問(wèn)題",， Bernd Kaina博士說(shuō),，他是一名教授，也是美因茲大學(xué)醫(yī)學(xué)中心毒理學(xué)研究所的所長(zhǎng),，"我們能夠證明,，人類單核細(xì)胞對(duì)ROS超級(jí)敏感，而巨噬細(xì)胞和樹(shù)突狀細(xì)胞則對(duì)ROS具有抗性,，這兩種細(xì)胞通過(guò)細(xì)胞因子的成熟而衍生自單核細(xì)胞",。科學(xué)家們?cè)诒┞队谠趧?dòng)脈粥樣硬化中起作用的輻射,、化學(xué)藥物甚至是氧化低密度脂蛋白（oxLDL）后觀察到單核細(xì)胞的這種極端敏感性,。上面所有的因素導(dǎo)致細(xì)胞內(nèi)活性氧的形成，它們損傷DNA,，導(dǎo)致細(xì)胞死亡,，甚至惡性轉(zhuǎn)化,。特異性免疫系統(tǒng)細(xì)胞，尤其是巨噬細(xì)胞,，在對(duì)病原體入侵機(jī)體的反應(yīng)中產(chǎn)生活性氧,。理想情況下，一旦病原體被清除,，活性氧的生產(chǎn)應(yīng)該停止,。也有必要限制活性氧產(chǎn)生的數(shù)量，因?yàn)檫@些也會(huì)在發(fā)炎組織損害健康細(xì)胞,。事實(shí)上,，慢性感染，其中活性氧是不斷產(chǎn)生的,，通常與增加的癌癥易感性有關(guān),。
單核細(xì)胞為什么對(duì)活性氧反應(yīng)如此敏感？Kaina的研究團(tuán)隊(duì)已成功地確定了單核細(xì)胞對(duì)氧化應(yīng)激超級(jí)敏感的原因：?jiǎn)魏思?xì)胞對(duì)它們的遺傳物質(zhì)不能修復(fù)緊接于ROS誘導(dǎo)損傷的DNA,。這是因?yàn)檫@些細(xì)胞產(chǎn)生非常低水平的某些重要修復(fù)蛋白,，它們?cè)卺t(yī)學(xué)術(shù)語(yǔ)中也稱XRCC1、ligase III,、PARP-1和 DNA-PK,。并在醫(yī)學(xué)術(shù)語(yǔ)。"單核細(xì)胞實(shí)際上是有缺陷的,，就2個(gè)重要的DNA修復(fù)系統(tǒng)來(lái)看,，即堿基切除修復(fù)和DNA雙鏈斷裂修復(fù)"， Kaina解釋到,，"迄今為止，這種性質(zhì)的一般修復(fù)缺陷已經(jīng)觀察到,，它們既不在人體細(xì)胞內(nèi)也不在體外實(shí)驗(yàn)系統(tǒng)中,。"
Kaina教授推測(cè)，單核細(xì)胞中的修復(fù)缺陷在免疫反應(yīng)的調(diào)節(jié)中發(fā)揮著重要作用：為防止發(fā)炎組織中巨噬細(xì)胞過(guò)度產(chǎn)生活性氧和免疫反應(yīng)過(guò)度活動(dòng),，單核細(xì)胞正如產(chǎn)生ROS的巨噬細(xì)胞的前體細(xì)胞一樣,，由于它們對(duì)ROS的極度敏感而遭受增強(qiáng)的、選擇性的破壞,。反過(guò)來(lái),，越少的單核細(xì)胞意味著越少的巨噬細(xì)胞及因此更低水平的ROS--總的來(lái)說(shuō)是調(diào)節(jié)單核/巨噬細(xì)胞/樹(shù)突狀細(xì)胞系統(tǒng)的一個(gè)精確途徑。這很明顯有潛在的臨床意義：特別在慢性炎癥性疾病情況下,，機(jī)體處于不平衡狀態(tài)中,，過(guò)量活性氧被產(chǎn)生，這導(dǎo)致健康細(xì)胞遺傳物質(zhì)的損傷,，也是癌癥發(fā)生的一個(gè)起作用的因素,。這可能的,，這種惡性循環(huán)被炎癥組織中單核細(xì)胞的選擇性清除所中斷也是可能的。（生物谷bioon.com）
doi:10.1073/pnas.1111919109
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PMID:
Human monocytes are severely impaired in base and DNA double-strand break repair that renders them vulnerable to oxidative stress
M. Bauer, M. Goldstein, M. Christmann, H. Becker, D. Heylmann, B. Kaina
Abstract Monocytes are key players in the immune system. Crossing the blood barrier, they infiltrate tissues and differentiate into (i) macrophages that fight off pathogens and (ii) dendritic cells (DCs) that activate the immune response. A hallmark of monocyte/macrophage activation is the generation of reactive oxygen species (ROS) as a defense against invading microorganisms. How monocytes, macrophages, and DCs in particular respond to ROS is largely unknown. Here we studied the sensitivity of primary human monocytes isolated from peripheral blood and compared them with macrophages and DCs derived from them by cytokine maturation following DNA damage induced by ROS. We show that monocytes are hypersensitive to ROS, undergoing excessive apoptosis. These cells exhibited a high yield of ROS-induced DNA single- and double-strand breaks and activation of the ATR-Chk1-ATM-Chk2-p53 pathway that led to Fas and caspase-8, -3, and -7 activation, whereas macrophages and DCs derived from them were protected. Monocytes are also hypersensitive to ionizing radiation and oxidized low-density lipoprotein. The remarkable sensitivity of monocytes to oxidative stress is caused by a lack of expression of the DNA repair proteins XRCC1, ligase IIIα, poly(ADP-ribose) polymerase-1, and catalytic subunit of DNA-dependent protein kinase (DNA-PKcs), causing a severe DNA repair defect that impacts base excision repair and double-strand break repair by nonhomologous end-joining. During maturation of monocytes into macrophages and DCs triggered by the cytokines GM-CSF and IL-4, these proteins become up-regulated, making macrophages and DCs repair-competent and ROS-resistant. We propose that impaired DNA repair in monocytes plays a role in the regulation of the monocyte/macrophage/DC system following ROS exposure.
