上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2022 , Vol. 42 >Issue 1: 107 - 112

DOI: https://doi.org/10.3969/j.issn.1674-8115.2022.01.016

综述

PD-1/PD-L1通路在自身免疫性眼病中作用的研究进展

  • 杨辰玲 ,
  • 周慧芳
展开
  • 上海交通大学医学院附属第九人民医院眼科，上海市眼眶病眼肿瘤重点实验室，上海 200011
杨辰玲（1996—），女，博士生；电子信箱：ycl.0315@qq.com。
周慧芳，电子信箱：fangzzfang@163.com。

收稿日期: 2021-06-08

  网络出版日期: 2022-01-28

基金资助

国家自然科学基金(82071003)

收起

Research progress on the role of PD-1/PD-L1 pathway in autoimmune eye diseases

  • Chenling YANG ,
  • Huifang ZHOU
Expand
  • Department of Ophthalmology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine; Shanghai Key Laboratory of Orbital Diseases and Ocular Oncology, Shanghai 200011, China
ZHOU Huifang, E-mail: fangzzfang@163.com.

Received date: 2021-06-08

  Online published: 2022-01-28

Supported by

National Natural Science Foundation of China(82071003)

Fold

摘要

自身免疫性眼病是一类由自身免疫反应引起的炎症性眼病，主要包括自身免疫性葡萄膜炎、甲状腺相关眼病、干燥综合征相关型干眼症、视神经脊髓炎谱系障碍等。这类疾病发病机制复杂，可累及眼表、眼内和眼眶。传统治疗方法主要包括糖皮质激素治疗和免疫抑制剂治疗，其有效率低且不良反应较大，因此需要对自身免疫性眼病发病机制做更加深入的研究以期寻找到治疗靶点进行对因治疗。程序性死亡蛋白-1（programmed death 1，PD-1）已被证实与许多自身免疫性疾病相关，它与程序性死亡蛋白配体1（programmed death ligand 1，PD-L1）组成的信号通路对于调节免疫反应起关键作用。PD-1/PD-L1通路的失活可能导致自身免疫性T细胞的异常活化，从而导致自身免疫性疾病的发生发展。该综述系统总结了现阶段已研究发现的PD-1/PD-L1通路的免疫调节机制，以及其在自身免疫性眼病中的作用，并对未来靶向治疗的潜在可能提出展望。

关键词： 自身免疫性眼病; 程序性死亡蛋白-1; 程序性死亡蛋白配体1; 自身免疫性葡萄膜炎; 甲状腺相关眼病; 干燥综合征; 视神经脊髓炎谱系障碍

本文引用格式

杨辰玲 , 周慧芳 . PD-1/PD-L1通路在自身免疫性眼病中作用的研究进展[J]. 上海交通大学学报（医学版）, 2022 , 42(1) : 107 -112 . DOI: 10.3969/j.issn.1674-8115.2022.01.016

Abstract

Autoimmune eye diseases are a kind of inflammatory eye disease caused by autoimmune reaction, mainly including autoimmune uveitis, thyroid-associated ophthalmopathy, Sj?gren's syndrome-related ophthalmoxerosis, neuromyelitis optica spectrum disorder and so on. The pathogenesis of these diseases is complex, involving the ocular surface, intraocular and orbital lesions. Traditional treatment methods mainly include corticosteroids and immune inhibitors, which have low efficiency and many side effects. Therefore, more in-depth research on the pathogenesis of autoimmune eye diseases is needed in order to find therapeutic targets for the etiological treatment. Programmed death 1 (PD-1) has been confirmed to be associated with many autoimmune diseases, and PD-1/programmed death ligand 1 (PD-L1) pathway plays a key role in the regulation of immune responses. Inactivation of the PD-1/PD-L1 pathway may lead to abnormal activation of autoimmune T cells, leading to the occurrence and development of autoimmune diseases. In this review, the immune regulation mechanism of PD-1/PD-L1 pathway that has been discovered at the present stage, as well as its role in autoimmune ophthalmopathy, is systematically summarized, and the potential of targeted treatment of autoimmune eye diseases in the future is prospected.

Key words： autoimmune eye disease; programmed death 1 (PD-1); programmed death ligand 1 (PD-L1); autoimmune uveitis; thyroid-associated ophthalmopathy; Sj?gren's syndrome; neuromyelitis optica spectrum disorder

参考文献

1 LOHMANN T, LESLIE R D, LONDEI M. T cell clones to epitopes of glutamic acid decarboxylase 65 raised from normal subjects and patients with insulin-dependent diabetes[J]. J Autoimmun, 1996, 9(3): 385-389.
2 SCHWARTZ R H, MUELLER D L, JENKINS M K, et al. T-cell clonal anergy[J]. Cold Spring Harb Symp Quant Biol, 1989, 54 Pt 2: 605-610.
3 SHARPE A H. Mechanisms of costimulation[J]. Immunol Rev, 2009, 229(1): 5-11.
4 LAFFERTY K J, CUNNINGHAM A J. A new analysis of allogeneic interactions[J]. Aust J Exp Biol Med Sci, 1975, 53(1): 27-42.
5 EDNER N M, CARLESSO G, RUSH J S, et al. Targeting co-stimulatory molecules in autoimmune disease[J]. Nat Rev Drug Discov, 2020, 19(12): 860-883.
6 KEIR M E, BUTTE M J, FREEMAN G J, et al. PD-1 and its ligands in tolerance and immunity[J]. Annu Rev Immunol, 2008, 26: 677-704.
7 DONG H, STROME S E, SALOMAO D R, et al. Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion[J]. Nat Med, 2002, 8(8): 793-800.
8 YU J X, HODGE J P, OLIVA C, et al. Trends in clinical development for PD-1/PD-L1 inhibitors[J]. Nat Rev Drug Discov, 2020, 19(3): 163-164.
9 DAI S, JIA R, ZHANG X, et al. The PD-1/PD-Ls pathway and autoimmune diseases[J]. Cell Immunol, 2014, 290(1): 72-79.
10 KOBAYASHI M, KAWANO S, HATACHI S, et al. Enhanced expression of programmed death-1 (PD-1)/PD-L1 in salivary glands of patients with Sj?gren's syndrome[J]. J Rheumatol, 2005, 32(11): 2156-2163.
11 RILEY J L. PD-1 signaling in primary T cells[J]. Immunol Rev, 2009, 229(1): 114-125.
12 SUN C, MEZZADRA R, SCHUNACHER T N. Regulation and function of the PD-L1 checkpoint[J]. Immunity, 2018, 48(3): 434-452.
13 BUTTE M J, KEIR M E, PHAMDUY T B, et al. Programmed death-1 ligand 1 interacts specifically with the B7-1 costimulatory molecule to inhibit T cell responses[J]. Immunity, 2007, 27(1): 111-122.
14 SALMANINEJAD A, KHORAMSHIHI V, AZANI A, et al. PD-1 and cancer: molecular mechanisms and polymorphisms[J]. Immunogenetics, 2018, 70(2): 73-86.
15 FRANCISCO L M, SALINAS V H, BROWN K E, et al. PD-L1 regulates the development, maintenance, and function of induced regulatory T cells[J]. J Exp Med, 2009, 206(13): 3015-3029.
16 CHEN J, JIANG C C, JIN L, et al. Regulation of PD-L1: a novel role of pro-survival signalling in cancer[J]. Ann Oncol, 2016, 27(3): 409-416.
17 PRADHAN R, SINGHVI G, DUBEY SK, et al. MAPK pathway: a potential target for the treatment of non-small-cell lung carcinoma[J]. Future Med Chem, 2019, 11(8): 793-795.
18 DHILLON A S, HAGAN S, RATH O, et al. MAP kinase signalling pathways in cancer[J]. Oncogene, 2007, 26(22): 3279-3290.
19 LIU S, CHEN S, YUAN W, et al. PD-1/PD-L1 interaction up-regulates MDR1/P-gp expression in breast cancer cells via PI3K/AKT and MAPK/ERK pathways[J]. Oncotarget, 2017, 8(59): 99901-99912.
20 STUTVOET T S, KOL A, DE VRIES E G, et al. MAPK pathway activity plays a key role in PD-L1 expression of lung adenocarcinoma cells[J]. J Pathol, 2019, 249(1): 52-64.
21 FREEMAN G J, LONG A J, IWAI Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation[J]. J Exp Med, 2000, 192(7): 1027-1034.
22 CARTER L, FOUSER L A, JUSSIF J, et al. PD-1:PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2[J]. Eur J Immunol, 2002, 32(3): 634-643.
23 杨培增. 临床葡萄膜炎[M]. 北京: 人民卫生出版社, 2004.
24 CHONG W P, HORAI R, MATTAPALLIL M J, et al. IL-27p28 inhibits central nervous system autoimmunity by concurrently antagonizing Th1 and Th17 responses[J]. J Autoimmun, 2014, 50: 12-22.
25 HORAI R, ZáRATE-BLADéS C R, DILLENBURG-PILLA P, et al. Microbiota-dependent activation of an autoreactive T cell receptor provokes autoimmunity in an immunologically privileged site[J]. Immunity, 2015, 43(2): 343-353.
26 HUANG Y, FANG S, LI D, et al. The involvement of T cell pathogenesis in thyroid-associated ophthalmopathy[J]. Eye (Lond), 2019, 33(2): 176-182.
27 ZHONG Z, SU G, KIJLSTRA A, et al. Activation of the interleukin-23/interleukin-17 signalling pathway in autoinflammatory and autoimmune uveitis[J]. Prog Retin Eye Res, 2021, 80: 100866.
28 MENG Q, YANG P, GUO H, et al. Characteristic expression of PD-1 and its ligands mRNAs in patients with noninfectious uveitis[J]. Int J Clin Exp Med, 2016, 9(1): 323-329.
29 CHEN J, QIAN H, HORAI R, et al. Mouse models of experimental autoimmune uveitis: comparative analysis of adjuvant-induced vs spontaneous models of uveitis[J]. Curr Mol Med, 2015, 15(6): 550-557.
30 LEE D J, TAYLOR A W. Recovery from experimental autoimmune uveitis promotes induction of antiuveitic inducible Tregs[J]. J Leukoc Biol, 2015, 97(6): 1101-1109.
31 ALGAZI A P, TSAI K K, SHOUSHTARI A N, et al. Clinical outcomes in metastatic uveal melanoma treated with PD-1 and PD-L1 antibodies[J]. Cancer, 2016, 122(21): 3344-3353.
32 MATSUO T, YAMASAKI O. Vogt-Koyanagi-Harada disease-like posterior uveitis in the course of nivolumab (anti-PD-1 antibody), interposed by vemurafenib (BRAF inhibitor), for metastatic cutaneous malignant melanoma[J]. Clin Case Rep, 2017, 5(5): 694-700.
33 SUN M M, LEVINSON R D, FILIPOWICZ A, et al. Uveitis in patients treated with CTLA-4 and PD-1 checkpoint blockade inhibition[J]. Ocul Immunol Inflamm, 2020, 28(2): 217-227.
34 HIROMATSU Y, EGUCHI H, TANI J, et al. Graves' ophthalmopathy: epidemiology and natural history[J]. Intern Med, 2014, 53(5): 353-360.
35 FANG S, LU Y, HUANG Y, et al. Mechanisms that underly T cell immunity in Graves' orbitopathy[J]. Front Endocrinol (Lausanne), 2021, 12: 648732.
36 夏晓玲. 甲状腺相关性眼病患者外周血CD4+、CD8+ T细胞表面PD-1表达水平的改变及其临床意义[D]. 上海: 第二军医大学, 2016.
37 BETTELLI E, CARRIER Y, GAO W, et al. Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells[J]. Nature, 2006, 441(7090): 235-238.
38 GONZáLEZ-AMARO R, MARAZUELA M. T regulatory (Treg) and T helper 17 (Th17) lymphocytes in thyroid autoimmunity[J]. Endocrine, 2016, 52(1): 30-38.
39 SYN N L, TENG M W L, MOK T S K, et al. De-novo and acquired resistance to immune checkpoint targeting[J]. Lancet Oncol, 2017, 18(12): e731-e741.
40 YAZICI B, YAZICI Z, YAL?INKAYA U. Aneurysmal bone cyst secondary to ossifying fibroma in the orbit[J]. Ophthalmic Plast Reconstr Surg, 2011, 27(4): e84-e85.
41 SAGIV O, KANDL T J, THAKAR S D, et al. Extraocular muscle enlargement and thyroid eye disease-like orbital inflammation associated with immune checkpoint inhibitor therapy in cancer patients[J]. Ophthalmic Plast Reconstr Surg, 2019, 35(1): 50-52.
42 王鑫, 刘苏. 干燥综合征相关型干眼症的临床诊疗进展[J]. 中华眼科医学杂志(电子版), 2018, 8(2): 82-86.
43 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.
44 CHIHARA N, ARANAMI T, SATO W, et al. Interleukin 6 signaling promotes anti-aquaporin 4 autoantibody production from plasmablasts in neuromyelitis optica[J]. Proc Natl Acad Sci U S A, 2011, 108(9): 3701-3706.
45 VARRIN-DOYER M, SPENCER C M, SCHULZE-TOPPHOFF U, et al. Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter[J]. Ann Neurol, 2012, 72(1): 53-64.
46 XUE Q, LI X, GU Y, et al. Unbalanced expression of ICOS and PD-1 in patients with neuromyelitis optica spectrum disorder[J]. Sci Rep, 2019, 9(1): 14130.
47 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, 2006, 177(12): 8844-8850.
48 FANG S, HUANG Y, ZHONG S, et al. Regulation of orbital fibrosis and adipogenesis by pathogenic Th17 cells in Graves orbitopathy[J]. J Clin Endocrinol Metab, 2017, 102(11): 4273-4283.
49 LI X, ZHONG T, TANG R, et al. PD-1 and PD-L1 expression in peripheral CD4/CD8+ T cells is restored in the partial remission phase in type 1 diabetes[J]. J Clin Endocrinol Metab, 2020, 105(6): 1947-1956.
50 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.
Options
文章导航

/

〈 〉