I型干扰素在系统性红斑狼疮中的研究进展
Research Progress of Type I Interferon in Systemic Lupus Erythematosus
DOI: 10.12677/jcpm.2024.34226, PDF, HTML, XML,    科研立项经费支持
作者: 孙颖颖：济宁医学院临床医学院，山东 济宁；宋 芹*：济宁医学院附属医院风湿免疫科，山东 济宁
关键词: 系统性狼疮狼疮；I型干扰素；干扰素-α；干扰素-β；干扰素-κ；治疗靶点；Systemic Lupus Erythematosus； Type I Interferons； Interferon-α； Interferon-β； Interferon-κ； Therapeutic Targets
摘要: 系统性红斑狼疮(SLE)是一种慢性、多系统、炎症性自身免疫性疾病，具有复杂的发病机制和遗传易感性。随着对这种疾病的不断了解，发现SLE与干扰素基因特征有关，尤其I型干扰素对先天免疫系统和适应性免疫系统都有影响，本文就I型干扰素在系统性红斑狼疮中的研究进展进行综述。
Abstract: Systemic lupus erythematosus (SLE) is a chronic, multisystem, inflammatory autoimmune disease with complex pathogenesis and genetic susceptibility. With the increasing understanding of this disease, it has been found that SLE is associated with interferon gene characterization, especially type I interferon, which has an effect on both the innate and adaptive immune systems, and this article provides a review of the progress of type I interferon research in SLE.
文章引用：孙颖颖, 宋芹. I型干扰素在系统性红斑狼疮中的研究进展[J]. 临床个性化医学, 2024, 3(4): 1573-1579. https://doi.org/10.12677/jcpm.2024.34226

1. 引言

系统性红斑狼疮(SLE)是一种典型的自身免疫性疾病，可影响全身的各种组织和器官。系统性红斑狼疮的特征是免疫系统过度激活，导致自身抗体和免疫复合物增加以及器官功能障碍[1]。随着测序技术的不断发展，SLE患者高度的I型IFN上调基因，称为干扰素刺激基因(ISG)。这些基因最初被测量为外周血细胞中的mRNA转录表达，具有独特的干扰素(IFN)基因特征[2]，50%的SLE患者血液中I型干扰素(IFN)水平长期持续升高[3]。IFN特征已被提议作为SLE特定发病率的标志物[4]。此外，I型干扰素阻断疗法为SLE新的治疗靶点提供支持，现综述如下。

2. I型干扰素的概述

IFN-I家族由IFN-α、IFN-β、IFN-ɛ、IFN-κ和IFN-ω组成[5]。IFN-α和IFN-β都会触发信号级联反应，通过激活JAK1、TYK2、STAT1和STAT2，启动IFN刺激基因(ISG)的基因转录。值得注意的是，其他STAT家族成员和IFN反应因子(IRF)也有助于激活IFN反应[6]。一项针对SLE患者的转录组分析研究确定了STAT1和STAT2等位基因相关的长链非编码RNA (lncRNA) linc00513的过表达，这种升高的linc00513通过促进STAT1和STAT2的磷酸化增加，是I型IFN信号通路的正调节因子[7]。影响I型IFN通路上游事件的基因中的SNP的分析揭示了IRF转录因子家族中许多遗传风险多态性，这些多态性与狼疮患者的高I型IFN水平相关。IRF1、IRF5、IRF7和IRF8被认为是I型IFN产生的主要诱导剂，介导主要模式识别受体(PRR)的信号通路，两种主要的PRR信号通路可识别DNA：Toll样受体和环GMP-AMP合酶(cGAS)-干扰素基因刺激因子(STING) [8]。当通过PRR激活时，I型IFN主要由浆细胞样树突状细胞(pDC)产生，每个pDC可以在12小时内产生多达109IFN-α分子[9]，pDC中I型IFN产生的早期阶段由Toll样受体(主要是TLR7和TLR9)产生内源性核酸[10]。在机制上，pDCs通过内体膜中TLR7或TLR9的表达，通过受体介导的内吞作用感知病原体的RNA或DNA，并启动涉及髓系分化因子和下游转录因子的激活链，最终诱导I型IFNs的表达[11] [12]。IRF5在IFN-α和IFN-β的产生中起着关键作用，IRF5表达水平升高与SLE患者的抗RNA结合蛋白(抗RBP)或抗双链DNA (抗dsDNA)自身抗体阳性相关[13]。患者的双链DNA (dsDNA)和免疫复合物(IC)刺激TLR9会导致IFN-I过量产生[14]。事实上，IRF5和STAT4的SLE相关风险变异中的许多SNP被发现与抗dsDNA自身抗体的水平相关，因此表明这些基因和增强的I型IFN反应可能通过促进自身抗体的产生来增加SLE的风险。IRF5的相同风险等位基因在健康供体中存在时，与先天免疫细胞(如pDC和中性粒细胞)的激活增加、可检测的自身抗体和I型IFN通路富集有关，因此表现为症状前SLE [15]。小鼠中TLR7的过度表达和男性SLE患者中TLR7转录增加的遗传变体，易患SLE [16]。外周血单核细胞(PBMC)中环状GMP-AMP合酶(cGAS)和干扰素-I诱导蛋白16 (IFI16)的高表达水平与疾病活动度密切相关。cGAS识别胞质双链DNA可诱导cGAMP的产生并激活IFN基因刺激因子(STING)。cGAS在DNA刺激的IFN-β产生中起关键作用，并导致与ISG高表达相关的疾病，尤其是SLE [17]。IFI16不仅作为促炎分子和内皮细胞凋亡的诱导剂，而且通过与STING相互作用导致IFN-I的产生，作为病毒感染和全身性自身免疫性疾病炎症的重要介质[18]，外周血单核细胞(PBMC)中环状GMP-AMP合酶(cGAS)和干扰素-I诱导蛋白16 (IFI16)的高表达水平与疾病活动度密切相关。cGAS-STING轴的阻断代表了SLE的一个有前途的治疗靶点。内源性逆转录元件(如LINE-1)也可以激活SLE中的I型IFN系统[19]，作为额外的核酸刺激。

I型干扰素(IFN)是系统性红斑狼疮(SLE)的主要致病因素。IFN-I通过对内皮细胞的作用直接促进内皮功能障碍，即过量IFN-I引起的EPC耗竭可能与SLE患者的内皮功能障碍和心血管风险增加有关[20]。Tie2是血管稳定所必需的受体，I型IFN通过抑制Tie2信号传导在内皮细胞(EC)的稳定性中发挥重要作用[21]。I型干扰素还促进NK细胞和细胞毒性T细胞的细胞溶解活性，可增加组织损伤和抗原过载，这是SLE发展的主要因素之一[22]。虽然I.型干扰素被认为是SLE发病机制中的关键干扰素，但不同类别的I型干扰素似乎在SLE的调控中具有不同的功能。

3. I型干扰素在系统性红斑狼疮中的作用

1) 干扰素-α (IFN-α)：IFN-α是自身免疫反应的关键调节因子，IFN-α可能由所有白细胞产生，但浆细胞样树突状细胞(pDC)是主要来源。NK细胞在含RNA的免疫复合物刺激下可诱导pDCs分泌IFN-α，而单核细胞则起抑制作用[23]。此外，重组IFN-α作为恶性肿瘤或肝炎感染患者的治疗药物时，可诱发SLE。中性粒细胞胞外陷阱(NETs)提供内源性I型IFN通路刺激，从而能够分泌高水平IFN-α [24]。IFN-α可加速内皮细胞(EC)凋亡和破坏内皮祖细胞(EPC) [25]，也可改变内皮祖细胞(EPC)和髓样循环血管生成细胞(CAC)介导的血管修复之间的平衡，IFN-α对狼疮血管生成的有害影响通过抑制IL-1依赖性途径来干扰SLE的血管修复[26]。IFN-α也可使平滑肌祖细胞(SMPC)维持未成熟状态，从而产生巨噬细胞并最终产生泡沫细胞[27]，这会导致SLE患者的内皮功能障碍和过早心血管风险(CVD)的显著增加。血清IFN-α水平升高与SLE疾病活动性和发热、关节痛、皮疹和白细胞减少等特定临床表现相关[28]。高剂量IFN-α治疗可诱导多种神经精神不良反应，脑脊液中检测到较高水平的IFN-α，但当狼疮精神病的表现消退时，IFN-α水平下降[29]。在最近比较SLE患者与健康对照的微阵列研究中，IFN-α诱导基因的过度表达是SLE患者外周血单核细胞中最主要的发现之一[30] [31]。SLE家族队列中年轻个体的血清IFN-α活性较高，这种与年龄相关的IFN-α活性模式可能导致成年早期SLE发病率的增加[32]。IFN-α是自身免疫反应的关键调节因子。

2) 干扰素-β (IFN-β)：成纤维细胞和上皮细胞及B细胞，会产生IFN-β [33]，在狼疮中，IFN-β在发育中的B细胞中的过度表达可能会促进自身反应性成熟B细胞的产生[34]。在SLE小鼠模型中，B细胞内在产生的IFN-β不依赖于环境，是TLR7信号增强和自身反应性B细胞发育的固定特征[35]。SLE患者PBMC中cGAS和IFI16的表达与IFN-β相结合可能作为早期诊断和监测SLE疾病活动的潜在生物标志物[36]。SLE患者循环B细胞中IFN-β水平升高，在非裔美国肾病患者和自身抗体患者中明显更高[37]，有肾脏疾病史的SLE受试者在过渡和幼稚B细胞中也表现出IFN-β的显著增加。系统性红斑狼疮骨髓间充质干细胞基于涉及先天信号分子线粒体抗病毒信号蛋白的正反馈回路产生更多的干扰素β，IFN-β信号转导抑制人SLE骨髓的成骨[38]。

3) 干扰素-κ (IFN-κ)：在SLE患者中，狼疮角质细胞产生IFN-κ，IFN-κ是一种多功能I型IFN，当在小鼠胰岛的β细胞中转基因表达时，可诱导自身免疫[39]，也会导致IL-6的过量产生[40]，因此，IFN-κ被认为是参与人类和小鼠模型SLE的光敏性和其他皮肤表现的关键介质，也是预防皮肤红斑狼疮(CLE)靶向治疗的潜在新靶点[41] [42]。在SLE皮肤病变中，I型IFN的产生增加，浆细胞样树突状细胞在皮肤狼疮病变中积聚[43]。

4) 干扰素-ɛ和干扰素-ω在系统性红斑狼疮的作用尚不明确。

4. IFN-I通路的靶向治疗

目前SLE的标准治疗包括使用皮质类固醇和免疫抑制剂[44]，I型IFN被认为是减少SLE慢性炎症和终末器官损伤的潜在靶点。两种最常用的系统性红斑狼疮药物羟氯喹(HCQ)和糖皮质激素会影响I型IFN系统并下调I型IFN特征。HCQ通过阻断核酸的TLR7/9结合表位[45]以及可能通过干扰内源性核酸来干扰TLR7和TLR9激活。最近，还表明HCQ抑制IFN-β诱导的DNA传感器cGAS [46]。糖皮质激素具有许多免疫抑制作用，包括高剂量使用时pDC的消耗[47]。

现已经开发出抗IFN-α抗体(rontalizumab、sifalimumab及AGS-009)、抗I型IFN受体抗体(anifrolumab)和诱导抗IFN-α抗体(IFN-α激酶)的疫苗制剂。罗他利珠单抗(Rontalizumab)是一种中和IFN-α的人源化IgG1单克隆抗体，在给予rontalizumab后，在3 mg/kg和10 mg/kg队列中观察到IRGs表达的快速下降，并且这种效果可以通过重复给药来维持[48]。西法木单抗(Sifalimumab)是一种全人源IgG1单克隆抗体，可中和IFN-α。但IFN特征的抑制程度是中度疾病患者高于疾病活动性更强的患者，西伐单抗I期研究的结果显示，与安慰剂相比，治疗后IFN信号具有显著的剂量依赖性抑制，并且未报告严重不良事件[49]。AGS-009是一种人源化IgG4单克隆抗IFN-α抗体，AGS-009已成功完成Ia期安全性试验。阿尼鲁单抗(Anifrolumab)是一种全人源IgG1κ单克隆抗体，可与IFNAR结合并阻止所有I型IFN的信号传导。Anifrolumab在中度至重度SLE患者的多个临床终点显著降低了疾病活动度[50]。免疫治疗疫苗干扰素α激肽(IFN-K)诱导中和抗IFN-α2b抗体，显著降低IFN基因特征，耐受性好，免疫原性好，安全性可接受[51]。

5. 小结与展望

综上所述，随着科研工作不断进展，IFN-I越来越被认为是SLE患者的一种中枢致病介质。不同类型的I型干扰素被人类发现，成为研究的热点。I型干扰素在狼疮的发生发展中占据着不可或缺的地位，针对IFN和IFN信号通路的新的治疗策略正在开发中，但进展有限，需要我们进一步的研究，提供更具体、更有效的靶向治疗，并最终为SLE提供个性化的治疗方法。

基金项目

基于转录组数据的系统性红斑狼疮疾病机制及治疗的研究(2021YXNS091)；ANCA相关性血管炎肺受累风险因素分析及预测模型建立(20230YXNS154)；白芍总苷治疗类风湿关节炎合并冠心病的疗效观察及作用机制研究(2022YXNS185)。

NOTES

*通讯作者。

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