修回日期: 2019-05-06
接受日期: 2019-05-20
在线出版日期: 2019-06-08
在乙型肝炎病毒(hepatitis B virus, HBV)感染期间可见到广泛的免疫介导的肝损伤. HBV免疫清除的失败从而导致慢性乙型肝炎(chronic hepatitis B, CHB), 并大大增加肝硬化和肝细胞癌的风险. T淋巴细胞在HBV感染中的免疫反应起重要作用, 尤其是调节性T细胞(regulatory T cell, Treg)和辅助性T细胞17(helper T cell 17, Th17)失衡的问题, 二者的平衡失调是HBV持续感染与肝脏炎性损伤的重要机制. 为了更好地揭示潜在的机制, 在本综述中, 我们系统地回顾了Treg和Th17, 讨论了在HBV感染后Treg与Th17两者之间的关系, 并对特异性转录因子维甲酸相关核孤儿受体γt(retinoid-related orphan nuclear receptor γt, RORγt)和叉头/翅膀状螺旋转录因子3(forkhead/winged helix family transcription factor 3, Foxp3)两者之间的变化, 随着近几年对HBV免疫靶向治疗研究的不断深入, Foxp3/Treg与RORγt/Th17的平衡似乎对HBV的感染至关重要, 以此为契机可以为CHB的治疗提供新的思路.
核心提要: 乙型肝炎病毒(hepatitis B virus, HBV)感染期间可见到广泛的免疫介导的肝损伤,随着近几年对HBV免疫靶向治疗研究的不断深入, 叉头/翅膀状螺旋转录因子3/调节性T细胞与维甲酸相关核孤儿受体γt/辅助性T细胞17的平衡似乎对HBV的感染至关重要, 以此为契机可以为慢性乙型肝炎的治疗提供新的思路.
引文著录: 贾冠华, 游晶, 李静, 范晶华. Foxp3/Treg与RORγt/Th17失衡在慢性乙型肝炎病毒感染中的作用. 世界华人消化杂志 2019; 27(11): 709-714
Revised: May 6, 2019
Accepted: May 20, 2019
Published online: June 8, 2019
A wide range of immune-mediated liver damage can be seen during infection with hepatitis B virus (HBV). Failure of HBV immune clearance leads to chronic hepatitis and greatly increases the risk of liver cirrhosis and hepatocellular carcinoma. Recently, there have been many studies on the relationship between the outcome of HBV infection and the immune status of patients. The immune response of T lymphocytes in HBV infection plays an important role, especially the imbalance of regulatory T cells (Treg)/Helper T cell 17 (Th17). The imbalance between the Treg and Th17 is an important mechanism of persistent HBV infection and inflammatory injury of the liver. To better reveal the underlying mechanisms, we systematically review the roles of Treg and Th17 and discuss the relationship between Treg and Th17 during HBV infection as well as the changes in the two related specific transcription factors, retinoid-related orphan nuclear receptor γt (RORγt) and forkhead/winged helix family transcription factor 3 (Foxp3). The research on HBV immunotargeting therapy in recent years has suggested the role of Foxp3/Treg and RORγt/Th17 imbalance in HBV infection. Such findings provide new ideas for the treatment of chronic hepatitis B.
- Citation: Jia GH, You J, Li J, Fan JH. Role of Foxp3/Treg and RORγt/Th17 imbalance in chronic hepatitis B virus infection. Shijie Huaren Xiaohua Zazhi 2019; 27(11): 709-714
- URL: https://www.wjgnet.com/1009-3079/full/v27/i11/709.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v27.i11.709
乙型肝炎病毒(hepatitis B virus, HBV)感染是对人类的健康构成严重的威胁. 当今全球大约有20亿人感染了HBV, 全世界有超过3.7亿患者为慢性感染者. HBV是慢性肝炎、肝硬化和肝细胞癌的主要原因, 每年有约100万人因肝硬化、肝细胞癌死亡[1]. HBV感染后的临床结果是多变的. 成人中大多数HBV感染(急性或隐性)最终会自发恢复. 大约5%的HBV感染者成为慢性感染, 是肝硬化和肝细胞癌的重要危险因素. HBV感染结局是由于不同的CD4+T细胞反应, 这是目前被认为在抗HBV治疗中免疫调节起关键作用[2].
HBV是一种重要的人类病原体, 隶属于嗜肝DNA病毒科正嗜肝DNA病毒属, 通过逆转录的方式进行复制的核糖核酸, HBV包括一个包膜和一个含有部分双链的核衣壳. 从基因组结构及编码蛋白来看, HBV是由不完全的环状双链DNA组成, HBV基因组中有4个开放读码框均位于长链, 分别是S区、C区、P区、X区来表达; 当HBV进入肝细胞后, 包膜脱落, 核衣壳进入细胞核, 部分双链松弛的环状DNA被修复, 形成共价闭合的环状DNA(cccDNA); 之后cccDNA与染色质结合后被逆转录成前体RNA, 继续在细胞核中复制乙肝病毒, 因此就目前治疗手段HBV很难从肝脏内完全清除[3]. 但有研究发现[4]慢性乙型肝炎(chronic hepatitis B, CHB)的致病因素是免疫系统的紊乱或失衡引起的CD4+T细胞通过释放不同的细胞因子, 产生两个亚群即(regulatory T cell, Treg)和CD4+辅助性T细胞17(helper T cell 17, Th17), 近年来, Th17/Treg平衡在CHB患者中的研究越来越多, 有研究表明[5,6]Th17和Treg及其特异性转录因子维甲酸相关核孤儿受体γt(retinoid-related orphan nuclear receptor γt, RORγt)和叉头/翅膀状螺旋转录因子3(forkhead/winged helix family transcription factor 3, Foxp3)在炎症性疾病治疗中可作为免疫稳态的关键调节因子. RORγt是促进Th17分化的特异性转录因子, 而Foxp3是Treg特异性转录因子. 许多研究发现[7], 在Treg和Th17之间存在不平衡, 两者之间的失衡与慢性炎症、自身免疫性疾病和癌症的发展密切相关. Treg和Th17失衡可能是引起CHB发病的免疫因素.
Treg细胞以及其他T细胞亚群, 通过刺激胸腺自身抗原这些Treg被称为胸腺Treg细胞或天然Treg细胞. Sakaguchi等[8]和Takahashi等[9]发现了一个具有强效抑制活性的CD4+T细胞亚群可以表达CD25并将这些CD4+CD25+细胞称为Treg. 后来, 他们发现这些细胞表达了高水平的FOXP3CD4+CD25-T细胞可以转化为Treg表型并特异性表达FOXP3[10]. CD4+CD25+Treg细胞是CD4+T细胞的谱系, 其特征在于TGF-β的产生和转录因子FoxP3的表达. Treg细胞通过细胞接触和细胞分泌抑制细胞因子如IL-10, TGF-β和IL-35而表现出免疫抑制和自身免疫耐受功能[11]. 维持Treg抑制功能需要转录因子Foxp3的表达, 其功能本身是由多种翻译后调节修饰, Treg谱系稳定性也取决于Treg细胞特异性CPG低甲基化模式T细胞受体刺激诱导[12]. Treg细胞是免疫应答负调节的重要组成部分, 维持免疫平衡和免疫耐受[13]. 通过限制肝脏免疫应答或抑制保护性T细胞, 从而促进HBV复制和存活, Treg细胞反应可能是导致HBV持续感染的免疫机制[14].
Foxp3是一种转录因子, 属于该家族叉头盒(FOX)蛋白质. FOX蛋白首先是在果蝇胚胎中被发现[15], 将其定位于细胞核调节基因表达. 所有家庭成员有一个叉头(FKH)域, 作为转录激活因子或抑制因子. FOX的FKH结构域可以调节转录大约700个基因. Foxp3最初被发现是开发中的主要调节器和Treg的功能[16]. 已经在免疫环境中广泛发现了Foxp3的表观遗传修饰, 包括甲基化, 乙酰化和磷酸化. 在Treg稳定性中起到正面和负面作用Treg特异性去甲基化区域是高度保守的CpG基序和保守的非编码序列2[17], Foxp3的乙酰化, 可以准确定量通过邻近连接测定[18], 是一种稳定的Treg修饰[19]. 相反, 表观遗传修饰磷酸化, 介导了Treg的不稳定性, 在存在磷酸化诱导物Pim-2激酶的情况下, Treg减少了Foxp3的表达和抑制功能[20]. 翻译后修饰和Foxp3的外源调控共同决定了Treg的稳定性, 前者改变其质量, 而后者使其表达水平波动[21].
高迁移率族蛋白-1维持了CHB感染患者的Treg稳定性, 这降低了对HBV的免疫力, 通过减少Treg自噬来激活特异性抗HBV免疫[22].
二十年前发现了白介素17(Interleukin-17, IL-17)及其在免疫中的潜在作用[23], 然后Th17细胞在2005年被定义为T辅助细胞的独立谱系[24,25]. Th17细胞是分化簇CD4+Th细胞的子集, 其特征在于产生以下细胞因子: 白细胞介素IL-17, IL-21, IL-22, IL-26和肿瘤坏死因子. Th17细胞代表促炎细胞亚型, Th17细胞的形成, 发育和功能不同于Th1和Th2细胞[23,24]. 当幼稚CD4+T细胞在抗原活化过程中暴露于转化生长因子TGF-β和IL-6时, 在Th17细胞分化过程中起着至关重要的初始作用, Th17细胞特异性转录因子是RORγt[24].
Th17细胞和Th17相关细胞因子具有诱导肝细胞损伤或保肝作用[26]. Th17细胞已被证明在许多肝脏疾病中发挥作用, 包括酒精性肝病, 原发性胆汁性肝硬化和CHB[27,28]. CHB患者存在免疫紊乱或失衡, 辅助CD4+T细胞可通过释放Treg和Th17来协调宿主进行免疫应答[29].
Th17细胞主要基于IL-17的产生和RORγt转录因子的存在而区别于其他T细胞. Th17驱动的免疫反应被证明在急性HBV感染的发病机制中起重要作用, 并且加剧了CHB的炎症进展, 而且由Th17衍生的细胞因子的促炎活性导致肝细胞的持续损伤[30].
核激素受体的ROR家族通常包含三个不同的成员: RORα, RORβ和RORγ. 虽然RORγmRNA存在于各种外周组织中, 但其表达同型RORγt仅限于淋巴组织和某些类型的淋巴样细胞. RORγt被认为是Th17谱系的主转录因子, 已有一些研究开始对RORγt/Th17轴可以作为潜在抑制剂进行试验[31]. 有研究说明[32]TMP778和TMP920被鉴定为RORγt的反向激动剂. 两种分子都是通过分化的Th17细胞有效抑制Th17细胞的产生和IL-17的体外分泌.
RORγt的翻译后修饰机制, 包括乙酰化和泛素化[33]. RORγt是一种核受体和转录因子, 研究证明[34]氧固醇和时钟基因之间的联系使RORγt成为连接免疫的潜在节点来调控两者之间的新陈代谢和昼夜节律. 随着免疫学的不断扩展, RORγt可以作为一个调控靶点对HBV形成新的治疗思路.
如上所述, Treg和Th17细胞是重要的CD4+T细胞亚群, 其在炎症期间发育相关并且功能上相互作用. 最近的报道证明了他们的密切互动和过渡. 因此, Treg和Th17细胞之间存在平衡. 由于Treg和Th17细胞之间的平衡在HBV的发病机制中很重要.
许多研究[35-37]发现, Treg和Th17细胞之间的不平衡与慢性炎症, 自身免疫性疾病和癌症的发展密切相关. Su等[38]发现Treg的增加低于患有低至中度CHB的患者中的Th17细胞, 其导致Treg/Th17细胞比例降低. 严重CHB患者的Tregs频率显著增加, 而Th17细胞的频率略有增加, 导致Treg/Th17细胞比例增加. Treg/Th17的平衡在介导抗HBV治疗的免疫应答中起重要作用, 研究表明Th17细胞及其相关细胞因子与肝脏炎症程度呈正相关, 并参与肝损伤过程和HBV的清除[28]. 因此观察Treg/Th17比值的变化可为观察宿主和抗病毒治疗的免疫状态提供参考[1]. Th17和Treg细胞在免疫应答中是相互作用的. 在HBV感染期间, Treg细胞通过Treg细胞的细胞毒性或通过抑制性细胞因子如IL-10, TGF-β或IL-35来抑制Th17细胞. Treg细胞的消耗会增强Th17细胞反应, 导致更严重的肝损伤[39]. 越来越多的证据表明Treg细胞也会上调Th17细胞相关促炎细胞因子的产生, 主要是IL-17和IL-22[40,41]. HBV感染的患者存在Th17/Treg失衡, 并且Treg/Th17比值与炎症程度呈负相关, 因此Th17和Treg细胞之间的平衡可能是免疫稳态的关键指标, 其至少部分地反映了促炎症和抗炎过程之间的平衡. 总之, Th17/Treg比率可能是评估疾病严重程度的有用标志物.
RORγt、FoxP3分别作为Th17和Treg的特异性转录因子也可能是HBV感染和免疫反应的调节靶点. 高浓度的TGF-β在幼稚CD4+T细胞中诱导FoxP3表达, 促使其分化为Treg细胞[11]. 相反,TGF-β加IL-6或IL-21诱导表达RORγt的信号转导和转录激活因子3(signal transduction and activator of transcription 3, STAT3), 促进Th17细胞分化[42]. IL-21通过调节TGF-β信号传导抑制FoxP3表达并促进Th17细胞分化[43]. 维生素A代谢产物RORγt是TGF-β介导的Treg细胞分化的关键调节因子, 通过直接抵抗IL-6的活性来抑制Th17细胞分化. IL-2与TGF-β一起可以驱动Treg细胞分化, IL-2通过STAT5依赖性途径抑制Th17细胞分化[44]. 一些研究[2]还表明, Foxp3参与了CHB的发病机制, 而且CHB患者中Foxp3的mRNA表达水平增加. 表明Foxp3表达增加与疾病预后不良有关. 最近的一项研究表明[45], Th17/Treg细胞的相互分化也受TEAD转录因子TAZ和TEAD1的调节. 由Th17细胞表达的TAZ充当RORγt的辅因子, 并使Foxp3不稳定, 而由Treg细胞表达的TEAD1隔离TAZ .
由于Th17和Treg细胞的分化受共享和不同细胞因子的相互调节, 并且由于每个亚组在某些炎症条件下可以转化为另一种, 因此Th17/Treg平衡在许多自身免疫疾病中起着至关重要的作用[46]. 实际上, 患有类风湿性关节炎, 牛皮癣, 多发性硬化症和炎症性肠病的患者的Th17/Treg比率增加. 其中, 从Th17/Treg平衡的角度对类风湿性关节炎进行了广泛的研究. 类风湿性关节炎的特征在于关节滑膜的慢性炎症, 其导致骨和软骨的破坏. Th17细胞被认为是通过激活炎症关节内许多细胞类型(包括巨噬细胞, 树突状细胞和滑膜细胞)引发炎症的发病机制的主要驱动因素[33]. 累积的证据表明, Th17/Treg平衡是驱动自身免疫性疾病的致病机制的基础. 在纠正平衡的治疗方法已被证明是有效的, 并已被批准用于治疗类风湿性关节炎, 牛皮癣, 牛皮癣和银屑病关节炎, 强直性脊柱炎, 系统性红斑狼疮等自身免疫性疾病. 例如在使用单克隆抗体中和Th17相关细胞因子(包括IL-6, TNF-α, IL-17和IL-23)的治疗方法已经非常成功[43]. 还有抗人IL-6R的单克隆抗体通过降低Th17但增加类风湿性关节炎患者的Treg细胞水平来影响Th17/Treg细胞的比例[47]. 此外, 正在开发针对使用小分子靶向RORγt, STAT3, Foxp3和Foxo1的疗法. 地高辛是RORγt的抑制剂, 通过降低Th17/Treg比率, 改善了胶原诱导的关节炎[48]. 因此在CHB的治疗中开拓新的思路, 新的靶点, 通过抑制RORγt/FoxP3, 降低Th17/Treg比率使之达到免疫状态的平衡, RORγt/Foxp3比率可能代表潜在的预后标志物. Treg和Th17细胞之间的相互作用直接影响它们的平衡. 因此, Treg和Th17细胞之间的平衡不仅对指示肝损伤的严重程度具有重要意义, 而且具有潜在的治疗价值.
目前HBV感染仍是危害人类健康的重要因素, 使HBV感染者患肝硬化、肝癌的风险大大增加. Th17/Treg的失衡对许多慢性炎性和自身免疫性疾病的发生、发展和转归均具有重要影响, 而且Th17/Treg的平衡对人体正常的免疫应答、促炎和抗炎都具有重要作用. Th17/Treg平衡的靶向治疗性修饰以及功效方面取得了进展, RORγt/Foxp3比率也可能作为潜在的衡量治疗预后的标志物, 但目前的机制尚未研究清楚. 因此通过继续研究Treg和Th17细胞之间的相互作用实现对HBV的彻底清除, 以及CHB的完全治愈提供了新的思路.
学科分类: 胃肠病学和肝病学
手稿来源地: 云南省
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