免疫共刺激分子与自身免疫性疾病的研究进展

冉庆森; 李琦; 刘丽; 孙立东; 杨庆; 李玉洁; 陈颖; 王娅杰; 翁小刚; 蔡维艳; 朱晓新

doi:10.13422/j.cnki.syfjx.20201901

您当前的位置：

首页 >

文章列表页 >

免疫共刺激分子与自身免疫性疾病的研究进展

综述 | 更新时间：2020-09-09

- 免疫共刺激分子与自身免疫性疾病的研究进展
- Relationship Between Immune Checkpoint and Autoimmune Disease
- 中国实验方剂学杂志 2020年26卷第18期页码：188-195
- 作者机构：
  
  中国中医科学院中药研究所，北京100700
- 作者简介：
  
  冉庆森，在读博士，从事中药药理学研究，E-mail：17801085606@163.com
  朱晓新，博士，研究员，博士生导师，从事中药药理学研究，E-mail：zhuxx@icmm.ac.cn
- 基金信息：
  
  国家“重大新药创制”科技重大专项(2017ZX09101002-002-002);中国中医科学院“一带一路”国际合作专项(GH201914);中国中医科学院院内课题(ZXKT17010;Z20107019-03;ZZ13-YQ-044)
- DOI：10.13422/j.cnki.syfjx.20201901
  中图分类号： R2-0;R22;R285.5;R284
- 收稿日期：2020-01-16，
  
  网络出版日期：2020-06-29，
  
  纸质出版日期：2020-09-20
- 稿件说明：
移动端阅览
冉庆森,李琦,刘丽等.免疫共刺激分子与自身免疫性疾病的研究进展[J].中国实验方剂学杂志,2020,26(18):188-195.

RAN Qing-sen,LI Qi,LIU Li,et al.Relationship Between Immune Checkpoint and Autoimmune Disease[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(18):188-195.
冉庆森,李琦,刘丽等.免疫共刺激分子与自身免疫性疾病的研究进展[J].中国实验方剂学杂志,2020,26(18):188-195. DOI： 10.13422/j.cnki.syfjx.20201901.

RAN Qing-sen,LI Qi,LIU Li,et al.Relationship Between Immune Checkpoint and Autoimmune Disease[J].Chinese Journal of Experimental Traditional Medical Formulae,2020,26(18):188-195. DOI： 10.13422/j.cnki.syfjx.20201901.

摘要

正常机体的免疫系统具有区别“自己”和“非己”的能力，对非己抗原能够发生免疫应答，对自身抗原则是处于无应答或微弱应答状态，时刻处于“免疫激活-免疫耐受”的动态平衡状态。然而，如果正常的免疫耐受被打破，将“自己”识别成“非己”，处于非正常免疫激活状态的T细胞就会持续迁延的对自身抗原产生异常的免疫应答，结果会导致自身免疫性疾病（ADS）的发生。因此，“无效”的免疫识别和免疫应答成为自身免疫性疾病的发病的主要致病机制。免疫共刺激分子（co-stimulatory molecule）作为连接抗原递呈细胞（APC）和免疫细胞（T细胞，B细胞）的重要纽带，有研究已经证实，正性免疫共刺激分子的高表达和负性免疫共刺激分子的低表达都会导致自身免疫耐受的缺陷，进而引发自身免疫性疾病。依据中医药“纠偏”，“扶正”的治疗特色。本文通过对4种典型性的自身免疫性疾病：系统性则是以红斑狼疮（SLE）和类风湿性关节炎（RA）为代表；器官特异性则是以多发性硬化症（MS）和Ⅰ型糖尿病（T1DM）发病机制进行探讨，依赖于这4种疾病发病过程中免疫共刺激分子对免疫识别与免疫应答的重要影响，并且依托于中医药对自身免疫平衡调节的作用，结合近十年来的相关文献，对免疫共刺激分子与自身免疫性疾病之间的关系进行论述，探寻不同的免疫共刺激分子在不同的自身免疫病中的共性，并初探中药以PD1-PDL1为药物靶点治疗自身免疫病的可行性。

Abstract

The normal immune system has the ability to distinguish between "self" and "non-self". Because of its dynamic balance of "immune activity-immune tolerance"

it will produce immune response to the non-self antigen

but with no response or weak response to the self-antigen. However

if the balance was broken

T cell in the abnormal immune activation state will respond continually to the self-antigen

with an abnormal immune response

which caused autoimmune disease. Pathologically

"invalid" immune recognition and immune response become the main causes for autoimmune diseases. Co-stimulatory molecule is an important link between Attach antigen presenting cells（APC） and immune cells (T cell and B cell). Studies have proved that excessive co-stimulation and/or insufficient co-inhibition could cause detect of self-tolerance and induce autoimmunity. Although co-stimulatory and co-inhibitory pathways have a significant impact on all ADS

this paper focuses on their effect on two systemic autoimmune diseases [systemic lupus erythematosus （SLE） and rheumatoid arthritis（RA）] and two organ-specific autoimmune diseases [multiple sclerosis （MS） and type 1 diabetes （T1DM）]

in order to discuss the pathogenesis and relationship between co-stimulatory molecules and autoimmune diseases.

关键词

Keywords

references

ZHANG Q , VIGNALI D A . Co-stimulatory and co-inhibitory pathways in Autoimmunity [J]. Immunity , 2016 , 44 ( 5 ): 1034 - 1051 .

ADAMS A B , FORD M L , LARSEN C P . Costimulation blockade in autoimmunity and transplantation:the CD28 pathway [J]. J Immunol , 2016 , 197 ( 6 ): 2045 - 2050 .

XIAO X , SHI X , FAN Y , et al . The costimulatory receptor OX40 inhibits interleukin-17 expression through activation of repressive chromatin remodeling pathways [J]. Immunity , 2016 , 44 ( 6 ): 1271 - 1283 .

ESENSTEN J H , HELOU Y A , CHOPRA G , et al . CD28 costimulation:from mechanism to therapy [J]. Immunity , 2016 , 44 ( 5 ): 973 - 988 .

HAQUE A , BEST S E , AMANTE F H , et al . CD4 + natural regulatory T cells prevent experimental cerebral malaria via CTLA-4 when expanded in vivo [J]. PLoS Pathogens , 2017 , 6 ( 12 ): e1001221 .

O'SULLIVAN B J , PAI S , STREET S , et al . Immunotherapy with costimulatory dendritic cells to control autoimmune inflammation [J]. J Immunol , 2015 , 187 ( 8 ): 4018 - 4030 .

JONES J C , FREEMAN G J . Costimulatory genes:hotspots of conflict between host defense and autoimmunity [J]. Immunity , 2017 , 38 ( 6 ): 1083 - 1085 .

JANAKIRAM M , SHAH U A , LIU W , et al . The third group of the B7-CD28 immune checkpoint family:HHLA2,TMIGD2,B7x,and B7-H3 [J]. Immunol Rev , 2017 , 276 ( 1 ): 26 - 39 .

王汉萍 , 周佳鑫 , 郭潇潇 , 等 . 免疫检查点抑制剂相关毒副作用管理之激素的使用 [J]. 中国肺癌杂志 , 2019 , 10 : 615 - 620 .

AKINRINMADE O A , CHETTY S , DARAMOLA A K , et al . CD64:an attractive immunotherapeutic target for M1-type macrophage mediated chronic inflammatory diseases [J]. Biomedicines , 2017 , doi: 10.3390/biomedicines5030056 http://dx.doi.org/10.3390/biomedicines5030056 .

邱艳 , 赵凌杰 , 蔡辉 . 姜黄素治疗自身免疫性疾病的研究进展 [J]. 现代医学 , 2014 , 42 ( 2 ): 216 - 218 .

杨念生 . 系统性红斑狼疮药物治疗发展趋势 [J]. 协和医学杂志 , 2020 , 11 ( 3 ): 247 - 251 .

CHATTERJEE M , KIS-TOTH K , THAI T H , et al . SLAMF6-driven co-stimulation of human peripheral T cells is defective in SLE T cells [J]. Autoimmunity , 2018 , 44 ( 3 ): 211 - 218 .

TADA T , KUMADA T , TOYODA H , et al . Long-term natural history of liver disease in patients with chronic hepatitis B virus infection:an analysis using the Markov chain model [J]. J Gastroenterol , 2018 , 53 (Supplement s 1 ): 1196 - 1205 .

BENOIST C . CD4 + CD25 + T regulatory cells dependent on ICOS promote regulation of effector cells in the prediabetic lesion [J]. J Exp Med , 2017 , 199 ( 11 ): 1479 - 1489 .

LIANG S C , LATCHMAN Y E , BUHLMANN J E , et al . Regulation of PD-1,PD-L1,and PD-L2 expression during normal and autoimmune responses [J]. Eur J Immunol , 2018 , 33 ( 10 ): 2706 - 2716 .

JACQUEMIN C , SCHMITT N , CONTIN-BORDES C , et al . OX40 ligand contributes to human lupus pathogenesis by promoting T follicular helper response [J]. Immunity , 2015 , 42 ( 6 ): 1159 - 1170 .

KASAGI S , KAWANO S , OKAZAKI T , et al . Anti-programmed cell death 1 antibody reduces CD4 + PD-1 + T cells and relieves the lupus-like nephritis of NZB/W F1 mice [J]. J Immunol , 2018 , 184 ( 5 ): 2337 - 2347 .

NISHIMURA H , NOSE M , HIAI H , et al . Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor [J]. Immunity , 2019 , 11 ( 2 ): 141 - 151 .

SAGE P T , FRANCISCO L M , CARMAN C V , et al . The receptor PD-1 controls follicular regulatory T cells in the lymph nodes and blood [J]. Nat Immunol , 2018 , 14 ( 2 ): 152 - 161 .

许砚秋 , 邓秀琴 , 何冠 . 系统性红斑狼疮在中医药治疗的进展 [J]. 临床医药文献电子杂志 , 2018 , 8 ( 51 ): 194 - 195 .

KONDO Y , YOKOSAWA M , KANEKO S , et al . Review:transcriptional regulation of CD4 + T cell differentiation in experimentally induced arthritis and rheumatoid arthritis [J]. Arthritis Rheumatol , 2018 , 70 ( 5 ): 128 - 132 .

CRIBBS A P , KENNEDY A , PENN H , et al . Treg cell function in rheumatoid arthritis is compromised by CTLA-4 promoter methylation resulting in a failure to activate the indoleamine 2,3-dioxygenase pathway [J]. Arthritis Rheumatol , 2018 , 66 ( 9 ): 2344 - 2354 .

TADA Y , NAGASAWA K , HO A , et al . CD28-deficient mice are highly resistant to collagen-induced arthritis [J]. J Immunol , 2016 , 162 ( 1 ): 203 - 208 .

KNOERZER D B , SCHWARTZ B D , MENGLE-GAW L J , et al . Collagen-induced arthritis in the BB rat.Prevention of disease by treatment with CTLA-4-Ig [J]. J Clin Invest , 2015 , 96 ( 2 ): 987 - 993 .

KO H J , CHO M L , LEE S Y , et al . CTLA4-Ig modifies dendritic cells from mice with collagen-induced arthritis to increase the CD4 + CD25 + Foxp3 + regulatory T cell population [J]. J Clin Invest , 2018 , 34 ( 2 ): 110 - 120 .

OFLAZOGLU E , BOURSALIAN T E , ZENG W , et al . Blocking of CD27-CD70 pathway by anti-CD70 antibody ameliorates joint disease in murine collagen-induced arthritis [J]. J Immunol , 2018 , 183 ( 6 ): 3770 - 777 .

GIANCHECCHI E , DELFINO DV , FIERABRACCI A . Recent insights into the role of the PD-1/PD-L1 pathway in immunological tolerance and autoimmunity [J]. Autoimmun Rev , 2017 , 12 ( 11 ): 1091 - 1100 .

RAPTOPOULOU A P , BERTSIAS G , MAKRYGIANNAKIS D , et al . The programmed death 1/programmed death ligand 1 inhibitory pathway is up-regulated in rheumatoid synovium and regulates peripheral T cell responses in human and murine arthritis [J]. Arthritis Rheum , 2010 , 62 ( 7 ): 1870 - 1880 .

OKAZAKI T , HONJO T . PD-1 and PD-1 ligands:from discovery to clinical application [J]. Int Immunol , 2018 , 19 ( 7 ): 813 - 824 .

WAN B , NIE H , LIU A , et al . Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis [J]. J Immunol , 2018 , 177 ( 12 ): 8844 - 8850 .

CHEN D , JUEDES A E , TEMANN U A , et al . ICOS co-stimulatory receptor is essential for T-cell activation and function [J]. Nature , 2010 , 409 ( 6816 ): 97 - 101 .

俞小芬 . 中医药治疗类风湿性关节炎的研究进展 [J]. 辽宁中医药大学学报 , 2018 , 10 ( 2 ): 47 - 48 .

REICH D S , LUCCHINETTI C F , CALABRESI P A . Multiple sclerosis [J]. N Engl J Med , 2018 , 378 ( 2 ): 169 - 180 .

BITTNER S , AFZALI A M , WIENDL H , et al . Myelin oligodendrocyte glycoprotein(MOG35-55) induced experimental autoimmune encephalomyelitis(EAE) in C57BL/6 mice [J]. J Vis Exp , 2014 , doi: 10.3791/51275 http://dx.doi.org/10.3791/51275 .

OLIVEIRA-DOS-SANTOS A J , HO A , TADA Y , et al . CD28 costimulation is crucial for the development of spontaneous autoimmune encephalomyelitis [J]. J Immunol , 2018 , 162 ( 8 ): 4490 - 4495 .

HAANSTRA K G , DIJKMAN K , BASHIR N , et al . Selective blockade of CD28-mediated T cell costimulation protects rhesus monkeys against acute fatal experimental autoimmune encephalomyelitis [J]. J Immunol , 2015 , 195 ( 2 ): 1454 - 1466 .

CHENG X , ZHAO Z , VENTURA E , et al . The PD-1/PD-L pathway is up-regulated during IL-12-induced suppression of EAE mediated by IFN-gamma [J]. J Neuroimmunol , 2017 , 185 ( 1-2 ): 75 - 86 .

OLIVEIRA E M L , BAR-OR A , WALISZEWSKA A I , et al . CTLA-4 dysregulation in the activation of myelin basic protein reactive T cells may distinguish patients with multiple sclerosis from healthy controls [J]. J Autoimmun , 2018 , 20 ( 1 ): 71 - 81 .

HURWITZ A A , SULLIVAN T J , SOBEL R A , et al . Cytotoxic T lymphocyte antigen-4(CTLA-4) limits the expansion of encephalitogenic T cells in experimental autoimmune encephalomyelitis(EAE)-resistant BALB/c mice [J]. Proc Natl Acad Sci USA , 2002 , 99 ( 5 ): 3013 - 3017 .

KARANDIKAR N J , VANDERLUGT C L , EAGAR T , et . al.Tissue-specific up-regulation of B7-1 expression and function during the course of murine relapsing experimental autoimmune encephalomyelitis [J]. J Immunol , 2018 , 161 ( 1 ): 192 - 199 .

KOGUCHI K . Dysregulated T cell expression of TIM3 in multiple sclerosis .[J]. J Exp Med , 2013 , 23 ( 6 ): 1413 - 1418 .

CARTER L L , LEACH M W , AZOITEI M L , et al . PD-1/PD-L1,but not PD-1/PD-L2,interactions regulate the severity of experimental autoimmune encephalomyelitis [J]. Eur J Immunol , 2017 , 182 ( 1/2 ): 124 - 134 .

SCHREINER B , BAILEY S L , SHIN T , et . al.PD-1 ligands expressed on myeloid-derived APC in the CNS regulate T-cell responses in EAE [J]. Eur J Immunol , 2017 , 38 ( 10 ): 2706 - 2717 .

BODHANKAR S , GALIPEAU D , VANDENBARK A A , et . al.PD-1 Interaction with PD-L1 but not PD-L2 on B-cells mediates protective effects of estrogen against EAE [J]. J Cli Cel Immunol , 2018 , 4 ( 3 ): 143 .

石丽华 , 王庆武 . 中西医结合对防治多发性硬化症复发的疗效初探 [J]. 广西中医药 , 2017 , 24 ( 2 ): 14 - 17 .

ATKINSON M . Type 1 diabetes:new perspectives on disease pathogenesis and treatment [J]. Lancet , 2016 , 358 ( 9277 ): 221 - 229 .

BOZULIC L D , HUANG Y , XU H , et . al.Differential outcomes in prediabetic vs.overtly diabetic NOD mice nonmyeloablatively conditioned with costimulatory blockade [J]. Exp Hematol , 2011 , 39 ( 10 ): 977 - 985 .

BAKER R L , JR D H W , HASKINS K . CD40 on NOD CD4 T cells contributes to their activation and pathogenicity [J]. J Autoimmun , 2018 , 31 ( 4 ): 385 - 392 .

ARAKI M , CHUNG D , LIU S , et al . Genetic evidence that the differential expression of the ligand-independent Isoform of CTLA-4 Is the molecular basis of the Idd5.1 type 1 diabetes region in nonobese diabetic mice [J]. J Immunol , 2017 , 183 ( 8 ): 5146 - 5157 .

SAVERINO D , SIMONE R , BAGNASCO M , et . al.The soluble CTLA-4 receptor and its role in autoimmune diseases:an update [J]. Auto Immun Highlights , 2017 , 1 ( 2 ): 73 - 81 .

ANSARI M J , SALAMA A D , CHITNIS T , et al . The programmed death-1(PD-1) pathway regulates autoimmune diabetes in nonobese diabetic(NOD) mice [J]. J Exp Med , 2013 , 198 ( 1 ): 63 - 69 .

WANG J , YOSHIDA T , NAKAKI F , et . al.Establishment of NOD-Pdcd1(-/-) mice as an efficient animal model of type I diabetes [J]. Proc Natl Acad Sci USA , 2017 , 102 ( 33 ): 11823 - 11828 .

TIJANA M , SPANIER J A , PAUKEN K E , et . al.PD-1 pathway-mediated regulation of islet-specific CD4 + T cell subsets in autoimmune diabetes [J]. J Exp Med , 2016 , 198 ( 1 ): 63 - 69 .

王云卿 , 孙炜 , 赵延栋 . 中医药治疗糖尿病肾病临床与实验研究进展 [J]. 新中医 , 2019 , 18 ( 2 ): 161 - 169 .

PARRY R V , CHEMNITZ J M , FRAUWIRTH K A , et al . CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms [J]. Mol Cel Biol , 2015 , 25 ( 21 ): 9543 - 9553 .

POSTOW M A , SIDLOW R , HELLMANN M D . Immune-related adverse events associated with immune checkpoint blockade [J]. N Engl J Med , 2018 , 378 ( 2 ): 158 - 168 .

TOGNO-PEIRCE C , NAVA-CASTRO K , TERRAZAS L I , et al . Sex-associated expression of co-stimulatory molecules CD80,CD86,and accessory molecules,PDL-1,PDL-2 and MHC-II,in F480 + macrophages during murine cysticercosis [J]. Biomed Res Int , 2013 , 2013 : 570158 .

AARTS S , SEIJKENS T T P , VAN DORST K J F , et al . The CD40-CD40L dyad in experimental autoimmune encephalomyelitis and multiple sclerosis [J]. Front Immunol , 2017 , doi: 10.3389/fimmu.2017.01791 http://dx.doi.org/10.3389/fimmu.2017.01791 .

罗国安 , 王义明 , 范雪梅 , 等 . 从临床出发,以信号通路为靶标的复方新药研发策略、途径与实践——六论创建新医药学 [J]. 世界科学技术—中医药现代化 , 2017 , 20 ( 7 ): 11 - 32 .

浏览量

下载量

CSCD

文章被引用时，请邮件提醒。

提交

工具集

关联资源

暂无数据