自身免疫性疾病中程序性细胞死亡因子1及其配体的研究进展

徐力; 聂柳燕; 汪胡燕; 杜燕; 薛静

doi:10.16766/j.cnki.issn.1674-4152.002466

自身免疫性疾病中程序性细胞死亡因子1及其配体的研究进展

doi: 10.16766/j.cnki.issn.1674-4152.002466

徐力^{1, 2},
聂柳燕¹,
汪胡燕¹,
杜燕¹,
薛静^1, ,

1.
浙江大学医学院附属第二医院风湿免疫科，浙江杭州 310009
2.
嘉兴学院附属妇儿医院内科，浙江嘉兴 314000

基金项目:

浙江省医药卫生科技项目 2018KY422

浙江省自然科学基金项目 LY22H100004

详细信息

通讯作者:
薛静，E-mail: jingxue@zju.edu.cn

中图分类号: R593.2
计量
- 文章访问数: 201
- HTML全文浏览量: 81
- PDF下载量: 11
- 被引次数: 0
出版历程
- 收稿日期: 2021-12-16
- 网络出版日期: 2022-09-05

Research progress of programmed cell death-1 and its ligand in autoimmune diseases

XU Li^{1, 2},
NIE Liu-yan¹,
WANG Hu-yan¹,
DU Yan¹,
XUE Jing^{1
, ,}

1.
Department of Rheumatology, the Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, Zhejiang 310009, China

摘要

摘要: 自身免疫性疾病是机体对自身抗原发生免疫反应，出现自身组织受到攻击损害的一类疾病，这种现象主要是由T细胞活化引起，同时其他如B细胞、树突状细胞等免疫细胞也参与了疾病的进程。程序性细胞死亡因子1(PD-1)是一种负性共刺激分子，由2号染色体上的程序性细胞死亡基因编码而来，分子量为50~55 kDa的跨膜蛋白，是从凋亡细胞中利用消减法分离出的免疫球蛋白基因超家族新成员。它与诱导性共刺激分子、CD28和细胞毒性T淋巴细胞相关蛋白4都隶属于免疫球蛋白超家族。PD-1有2个配体：程序性细胞死亡因子配体1(PD-L1)、PD-L2，通过与其配体相结合来抑制T细胞的活化和细胞因子的产生，在维持机体外周免疫耐受中发挥极其重要的作用。PD-1具有2种表达形式，膜结合型蛋白和可溶性蛋白。其中膜型PD-1通过直接与配体结合介导信号通路发挥负向免疫调节作用；可溶性PD-1则具有与PD-Ls结合的功能，阻断膜型PD-1与PD-Ls结合，干扰PD-1/PD-Ls介导的T细胞增殖抑制功能。近年来，抗PD-1抗体在恶性肿瘤靶向治疗中表现出卓越的疗效，同时也观察到这类患者出现关节炎、肌痛、继发性干燥综合征、血管炎等风湿性并发症的表现。伴随PD-1基因缺陷小鼠模型建立，越来越多的研究开始关注PD-1信号通路在自身免疫性疾病中的作用，本文就PD-1及其配体在自身免疫性疾病中的研究进展作总结概述。
- 自身免疫性疾病 /
- 程序性细胞死亡因子1 /
- 程序性细胞死亡因子配体1 /
- 程序性细胞死亡因子配体2
Abstract: Autoimmune disease is a disease wherein the body reacts to its own antigen and then attacks and damages tissues. This phenomenon is mainly caused by the activation of T cells. However, other immune cells such as B cells and dendritic cells also participate in the process of the disease. As a negative costimulatory molecule, programmed cell death-1(PD-1) is a 50-55 kDa transmembrane protein encoded by programmed cell death-1, gene on chromosome 2. It is a new member of the immunoglobulin gene superfamily isolated from apoptotic cells by subtractive method. It belongs to the immunoglobulin superfamily with inducible costimulator, CD28 and cytotoxic T-lymphocyte-associated protein 4. PD-1 has two ligands: programmed cell death-ligand 1(PD-L1) and PD-L2. By combining with their ligands, PD-1 can inhibit the activation of T cells and the production of cytokines, which plays an extremely important role in maintaining peripheral immune tolerance. PD-1 has two expression forms: membrane binding protein and soluble protein. Amongst them, membrane PD-1 plays a negative immunoregulation role by directly binding with ligands, whereas soluble PD-1 has the function of binding with PD-Ls, blocking the binding between membrane PD-1 and PD-Ls and interfering with PD-1/PD-Ls-mediated T cell proliferation inhibition. In recent years, PD-1 antibody has shown excellent efficacy in the targeted treatment of malignant tumours. Rheumatic complications such as arthritis, myalgia, secondary Sjogren's syndrome and vasculitis have also been observed in patients with autoimmune disease. With the establishment of PD-1 gene deficient mouse model, more and more research institutions are paying attention to the role of the PD-1 signalling pathway in autoimmune diseases. This paper summarises the research progress of PD-1 and its ligand in autoimmune diseases.
- Autoimmune diseases /
- Programmed cell death-1 /
- Programmed cell death-ligand 1 /
- Programmed cell death-ligand 2

HTML全文

参考文献(40)

[1]	HE W W, WANG B, LI Q, et al. Aberrant Expressions of co-stimulatory and co-inhibitory molecules in autoimmune diseases[J]. Front Immunol, 2019, 10: 261. doi: 10.3389/fimmu.2019.00261
[2]	PATEL H, MANSURI M S, SINGH M, et al. Association of cytotoxic t-lymphocyte antigen 4(CTLA4) and thyroglobulin (TG) genetic variants with autoimmune hypothyroidism[J]. PLoS One, 2016, 11(3): e0149441. DOI: 10.1371/journal.pone.0149441.
[3]	ASANO T, MATSUOKA N, FUJITA Y, et al. Serum levels of T cell immunoglobulin and mucin-domain containing molecule 3 in patients with systemic lupus erythematosus[J]. J Clin Med, 2020, 9(11): 3563. doi: 10.3390/jcm9113563
[4]	LI Y Y, LIANG Z D, TIAN Y, et al. High-affinity PD-1 molecules deliver improved interaction with PD-L1 and PD-L2[J]. Cancer Sci, 2018, 109(8): 2435-2445. doi: 10.1111/cas.13666
[5]	GAO J, GAI N, WANG L, et al. Meta-analysis of programmed cell death 1 polymorphisms with systemic lupus erythematosus risk[J]. Oncotarget, 2017, 8(22): 36885-36897. doi: 10.18632/oncotarget.16378
[6]	XU-MONETTE M Z Y, ZHOU J F, YOUNG K H. PD-1 expression and clinical PD-1 blockade in B-cell lymphomas[J]. Blood, 2018, 131(1): 68-83. doi: 10.1182/blood-2017-07-740993
[7]	ASANO T, MEGURI Y, YOSHIOKA T, et al. PD-1 modulates regulatory T-cell homeostasis during low-dose interleukin-2 therapy[J]. Blood, 2017, 129(15): 2186-2197. doi: 10.1182/blood-2016-09-741629
[8]	FABRIZIO F P, TROMBETTA D, ROSSI A, et al. Gene code CD274/PD-L1: From molecular basis toward cancer immunotherapy[J]. Ther Adv Med Oncol, 2018, 10: 1758835918815598. DOI: 10.1177/1758835918815598.
[9]	ZHAO Y L, HARRISON D L, SONG Y R, et al. Antigen-presenting cell-intrinsic PD-1 neutralizes PD-L1 in cis to attenuate PD-1 signaling in T cells[J]. Cell reports, 2018, 24(2): 379-390. doi: 10.1016/j.celrep.2018.06.054
[10]	CHATTERJEE A, RODGER E J, AHN A, et al. Marked global DNA hypomethylation is associated with constitutive PD-L1 expression in Melanoma[J]. Science, 2018, 4: 312-325.
[11]	TIAN M, ZHANG Y H, LIU Z Z, et al. The PD-1/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats[J]. Sci Rep, 2016, 6: 27683. DOI: 10.1038/srep27683.
[12]	LIU S C, QIN T T, LIU Z J, et al. Anlotinib alters tumor immune microenvironment by downregulating PD-L1 expression on vascular endothelial cells[J]. Cell Death Dis, 2020, 11(5): 309. doi: 10.1038/s41419-020-2511-3
[13]	ZAMANI M R, ASLANI S, SALMANINEJAD A, et al. PD-1/PD-L and autoimmunity: A growing relationship[J]. Cell Immunol, 2016, 310: 27-41. doi: 10.1016/j.cellimm.2016.09.009
[14]	GARCIA A, SHIN D S, MORENO B H, et al. Interferon receptor signaling pathways regulating PD-L1 and PD-L2 expression[J]. Cell Reports, 2019, 29(11): 3766. doi: 10.1016/j.celrep.2019.11.113
[15]	BAI J, GAO Z T, LI X, et al. Regulation of PD-1/PD-L1 pathway and resistance to PD-1/PD-L1 blockade[J]. Oncotarget, 2017, 8(66): 110693-110707. doi: 10.18632/oncotarget.22690
[16]	BOMMARITO D, HALL C, TAAMS L S, et al. Inflammatory cytokines compromise programmed cell death-1(PD-1)-mediated T cell suppression in inflammatory arthritis through up-regulation of soluble PD-1[J]. Clin Exp Immunol, 2017, 188(3): 455-466. doi: 10.1111/cei.12949
[17]	ZHAO P, WANG P, DONG S Y, et al. Depletion of PD-1-positive cells ameliorates autoimmune disease[J]. Nature Biomedical Engineering, 2019, 3(4): 292-305. doi: 10.1038/s41551-019-0360-0
[18]	GIANCHECCHI E, FIERABRACCI A. Inhibitory receptors and pathways of lymphocytes: The role of PD-1 in Treg development and their involvement in autoimmunity onset and cancer progression[J]. Front Immunol, 2018, 9: 2374. doi: 10.3389/fimmu.2018.02374
[19]	CANAVAN M, FLOUDAS A, VEALE D J, et al. The PD-1: PD-L1 axis in Inflammatory Arthritis[J]. BMC Rheumatology, 2021, 5(1): 1. doi: 10.1186/s41927-020-00171-2
[20]	BARTOSIÑSKA J, ZAKRZEWSKA E, KRÓL A, et al. Differential expression of programmed death 1(PD-1) on CD4⁺ and CD8⁺ T cells in rheumatoid arthritis and psoriatic arthritis[J]. Pol Arch Intern Med, 2017, 127(12): 815-822.
[21]	LUO Q, YE J Q, ZENG L L, et al. Elevated expression of PD-1 on T cells correlates with disease activity in rheumatoid arthritis[J]. Mol Med Rep, 2018, 17(2): 3297-3305.
[22]	GUO Y X, WALSH A M, CANAVAN M, et al. Immune checkpoint inhibitor PD-1 pathway is down-regulated in synovium at various stages of rheumatoid arthritis disease progression[J]. PLoS One, 2018, 13(2): e0192704. DOI: 10.1371/journal.pone.0192704.
[23]	LIU C P, JIANG J A, GAO L, et al. A promoter region polymorphism in PDCD-1 gene is associated with risk of rheumatoid arthritis in the Han Chinese population of southeastern China[J]. Int J Genomics, 2014, 2014: 247637. DOI: 10.1155/2014/247637.
[24]	ZOU Y M, ZHANG Z T, LIU Y G, et al. Are programmed cell death 1 gene polymorphisms correlated with susceptibility to rheumatoid arthritis?A meta-analysis[J]. Medicine, 2017, 96(35): e7805. doi: 10.1097/MD.0000000000007805
[25]	KONG E K D, PROKUNINA-OLSSON L, WONG W H S, et al. A new haplotype of PDCD1 is associated with rheumatoid arthritis in Hong Kong Chinese[J]. Arthritis Rheum, 2005, 52(4): 1058-1062. doi: 10.1002/art.20966
[26]	WU X Y, XU L, CHENG Q, et al. Increased serum soluble programmed death ligand 1(sPD-L1) is associated with the presence of interstitial lung disease in rheumatoid arthritis: A monocentric cross-sectional study[J]. Respir Med, 2020, 166: 105948. doi: 10.1016/j.rmed.2020.105948
[27]	CURRAN C S, GUPTA S, SANZ I, et al. PD-1 immunobiology in systemic lupus erythematosus[J]. J Autoimmun, 2019, 97: 1-9. doi: 10.1016/j.jaut.2018.10.025
[28]	SHI H, YE J N, TENG J L, et al. Elevated serum autoantibodies against co-inhibitory PD-1 facilitate T cell proliferation and correlate with disease activity in new-onset systemic lupus erythematosus patients[J]. Arthritis Res Ther, 2017, 19(1): 52. doi: 10.1186/s13075-017-1258-4
[29]	JIA X Y, ZHU Q Q, WANG Y Y, et al. The role and clinical significance of programmed cell death-ligand 1 expressed on CD19B-cells and subsets in systemic lupus erythematosus[J]. Clin Immunol, 2019, 198: 89-99. doi: 10.1016/j.clim.2018.11.015
[30]	LIAO W J, ZHENG H, WU S, et al. The systemic activation of programmed death 1-PD-L1 axis protects systemic lupus erythematosus model from nephritis[J]. Am J Nephrol, 2017, 46(5): 371-379. doi: 10.1159/000480641
[31]	李朝霞, 曾珊, 吴会霞, 等. 靶向调控T细胞免疫抑制受体在系统性红斑狼疮治疗中的作用[J]. 广东医学, 2019, 40(9): 1225-1230. https://www.cnki.com.cn/Article/CJFDTOTAL-GAYX201909008.htm LI C X, CEN S, WU H X, et al. The role of targeted regulation of Tcell immunosuppressive receptor in the trestment of systemic lupus erythematosus[J]. Guangdong Medical Journal, 2019, 40(9): 1225-1230. https://www.cnki.com.cn/Article/CJFDTOTAL-GAYX201909008.htm
[32]	DU Y, NIE L Y, XU L, et al. Serum levels of soluble programmed death-1(sPD-1) and soluble programmed death ligand 1(sPD-L1) in systemic lupus erythematosus: Association with activity and severity[J]. Scand J Immunol, 2020, 92(1): e12884.
[33]	杨月, 侯佳奇, 李国陵, 等. PD-1及其配体在原发性干燥综合征患者唇腺中的表达及临床意义[J]. 临床与病理杂志, 2017, 37(3): 456-461. https://www.cnki.com.cn/Article/CJFDTOTAL-WYSB201703002.htm YANG Y, HOU J Q, LI G L, et al. Expression and clinical significance of PD-1 and its ligands in salivary glands of patients with Sjogren's syndrome[J]. Journal of Clinical and Pathological Research, 2017, 37(3): 456-461. https://www.cnki.com.cn/Article/CJFDTOTAL-WYSB201703002.htm
[34]	WIENDL H, MITSDOERFFER M, SCHNEIDER D, et al. Human muscle cells express a B7-related molecule, B7-H1, with strong negative immune regulatory potential: A novel mechanism of counterbalancing the immune attack in idiopathic inflammatory myopathies[J]. FASEB J, 2003, 17(13): 1892-1894.
[35]	CHEN H, PENG Q L, YANG H B, et al. Increased levels of soluble programmed death ligand-1 associate with malignancy in patients with dermatomyositis[J]. J Rheumatol, 2018, 45(6): 835-840. doi: 10.3899/jrheum.170544
[36]	CHEN S, LI Y, DENG C W, et al. The associations between PD-1, CTLA-4 gene polymorphisms and susceptibility to ankylosing spondylitis: A meta-analysis and systemic review[J]. Rheumatol Int, 2016, 36(1): 33-44. doi: 10.1007/s00296-015-3327-9
[37]	CHEN M H, CHEN W S, LEE H T, et al. Inverse correlation of programmed death 1(PD-1) expression in T cells to the spinal radiologic changes in Taiwanese patients with ankylosing spondylitis[J]. Clin Rheumatol, 2011, 30(9): 1181-1187. doi: 10.1007/s10067-011-1721-6
[38]	YANABA K, HAYASHI M, YOSHIHARA Y, et al. Serum levels of soluble programmed death-1 and programmed death ligand-1 in systemic sclerosis: Association with extent of skin sclerosis[J]. J Dermatol, 2016, 43(8): 954-957. doi: 10.1111/1346-8138.13339
[39]	GARCÍA M, LEDEZMA IY, HERNÁNDEZ J, et al. Expression patterns of CD28 and CTLA-4 in early, chronic, and untreated rheumatoid arthritis[J]. J Clin Lab Anal, 2020, 34(5): e23188. DOI: 10.1002/jcla.23188.
[40]	WALKER L S K. PD-1 and CTLA4: Two checkpoints, one pathway?[J]. Sci Immunol, 2017, 2(11): eaan3864. DOI: 10.1126/sciimmunol.aan3864.