系统性红斑狼疮治疗靶点相关研究进展

王欣; 张庆; 罗帅寒天; 张慧琳; 陆前进; 龙海

doi:10.11817/j.issn.1672-7347.2021.200056

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综述 | 更新时间：2022-04-02

系统性红斑狼疮治疗靶点相关研究进展
Advances in therapeutic targets-related study on systemic lupus erythematosus
中南大学学报(医学版) 中南大学学报(医学版) 2021年46卷第11期页码：1267-1275
作者机构：

1.中南大学湘雅二医院皮肤科，医学表观基因组学湖南省重点实验室，皮肤重大疾病与皮肤健康湖南省临床医学研究中心，长沙 410011
2.中南大学湘雅二医院护理部，长沙 410011
3.中国医学科学院皮肤病医院，中国医学科学院皮肤病研究所，南京 210042
作者简介：

王欣，Email: 178211068@csu.edu.cn, ORCID: 0000-0001-7216-2402
龙海，Email: dr.hailong@csu.edu.cn, ORCID: 0000-0001-6135-1486
基金信息：

国家自然科学基金(81773334;81703133;81872533);湖南省自然科学基金(2019JJ40427;2019JJ50855);湖南省科技计划项目“湖湘青年英才”支持计划(2018RS3031);长沙市杰出创新青年培养计划(kq1802002);中南大学中央高校基本科研业务费专项资金(502211904)
DOI：10.11817/j.issn.1672-7347.2021.200056
中图分类号：
CSTR：

王欣, 张庆, 罗帅寒天, 等. 系统性红斑狼疮治疗靶点相关研究进展[J]. 中南大学学报(医学版), 2021,46(11):1267-1275.

Xin WANG, Qing ZHANG, Shuaihantian LUO, et al. Advances in therapeutic targets-related study on systemic lupus erythematosus[J]. Journal of Central South University. Medical Science, 2021,46(11):1267-1275.
王欣, 张庆, 罗帅寒天, 等. 系统性红斑狼疮治疗靶点相关研究进展[J]. 中南大学学报(医学版), 2021,46(11):1267-1275. DOI： 10.11817/j.issn.1672-7347.2021.200056.

Xin WANG, Qing ZHANG, Shuaihantian LUO, et al. Advances in therapeutic targets-related study on systemic lupus erythematosus[J]. Journal of Central South University. Medical Science, 2021,46(11):1267-1275. DOI： 10.11817/j.issn.1672-7347.2021.200056.

摘要

系统性红斑狼疮(systemic lupus erythematosus，SLE)是一种自身免疫介导的慢性弥漫性结缔组织病。目前SLE的治疗主要依赖糖皮质激素及免疫抑制剂，但长期使用这些药物存在诸多难以避免的毒副作用。因此，寻找新型治疗靶点对于探索特异性更强、毒副作用更小的新疗法具有重要意义。目前对SLE治疗的研究，主要涉及B细胞/浆细胞相关靶点(如B淋巴细胞刺激因子、增殖诱导配体、CD20、CD22、CD19/FcγRIIb、Bruton酪氨酸激酶、蛋白酶体)、T细胞相关靶点(如钙调磷酸酶、哺乳动物雷帕霉素靶蛋白、调节因子X1、Rho激酶)、巨噬细胞相关靶点(如巨噬细胞游走抑制因子)、细胞内信号分子(如Cereblon、组蛋白去乙酰化酶6、Janus激酶/信号转导与转录激活因子等)、共刺激因子(如CD28/B7、CD40/CD154)、细胞因子(如IL-2、IL-12/23、IL-10、IL-6、干扰素)、IgE以及肠道菌群等方面。其中，针对B细胞/浆细胞相关靶点的贝利尤单抗(人源化抗B淋巴细胞刺激因子单克隆抗体)、泰它西普(重组人B淋巴细胞刺激因子受体-抗体融合蛋白)已在我国相继获批用于SLE的临床治疗。还有多种靶向治疗新药处在II期或III期临床试验阶段，其中，Anifrolumab(抗I型干扰素受体亚基1的全人单克隆抗体)已完成III期临床试验并取得良好应答，但其带状疱疹发生率高于对照组。近年来，这些针对不同靶点的基础研究和新药研发大大推动了医学界对SLE发病机制认识的深入，也反映出该病的复杂性和异质性。随着更多新疗法投入使用，未来有望迎来SLE个体化治疗的崭新局面。

Abstract

Systemic lupus erythematosus (SLE) is a chronic and autoimmunity-mediated diffuse connective tissue disease. The mainstay of treatments for SLE mainly relies on corticosteroids and immunosuppressants, which have a series of unavoidable side effects. Therefore, it is of fundamental importance to search novel therapeutic targets for better treatment with favorable efficacy and minor side effects. Recent studies shed light on potential therapeutic targets for SLE, mainly covering the followings: B-cell/plasmocyte-related targets [B cell activating factor (BAFF), a proliferation-inducing ligand (APRIL), CD20, CD22, CD19/FcγRIIb, Bruton tyrosine kinase (Btk), and proteasome], T cell-related targets [calcineurin, mammalian target of rapamycin (mTOR), regulatory factor X1 (RFX1), and Rho kinase], macrophage-related targets (macrophage migration inhibitory factor), intracellular signaling molecules, cytokines (cereblon, histone deacetylase 6, Janus activated kinase/signal transducer and activator of transcription), co-stimulating factors (CD28/B7, CD40/CD154), IgE autoantibody, and gut microbiome. Among them, belimumab (a humanized monoclonal antibody against B-lymphocyte stimulator) and telitacicept (a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein) have been sequentially approved for the clinical treatment of SLE in China. A variety of new targeted-therapy drugs are in the Phase 2 or Phase 3 clinical trials,among which anifrolumab (a human monoclonal antibody against type I interferon receptor subunit 1) has completed a Phase 3 clinical trial with good responses achieved, although its incidence of herpes zoster is higher than that in the control group. The research progress in both molecular mechanisms and new drug development for different therapeutic targets have greatly promoted our better and in-depth understanding of the pathogenesis of SLE, and have also reflected the complexity and heterogeneity of the disease. Successful development and clinical application of more novel therapies would no doubt usher in a new era of individualized treatment for SLE in the future.

关键词

红斑狼疮治疗靶点细胞因子IgE自身抗体肠道菌群

Keywords

systemic lupus erythematosustherapeutic targetscytokinesIgE autoantibodygut microbiota

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