[1]刘自强,接传红,王建伟,等.糖尿病视网膜病变免疫机制的研究进展[J].眼科新进展,2022,42(2):150-154.[doi:10.13389/j.cnki.rao.2022.0031]
　LIU Ziqiang,JIE Chuanhong,WANG Jianwei,et al.Research progress in immune mechanisms against diabetic retinopathy[J].Recent Advances in Ophthalmology,2022,42(2):150-154.[doi:10.13389/j.cnki.rao.2022.0031]
点击复制

糖尿病视网膜病变免疫机制的研究进展/HTML
分享到：

《眼科新进展》[ISSN:1003-5141/CN:41-1105/R]

卷:
42卷
期数:
2022年2期
页码:
150-154
栏目:
文献综述
出版日期:
2022-02-05

文章信息/Info

Title:
Research progress in immune mechanisms against diabetic retinopathy
作者:
刘自强; 接传红; 王建伟; 邓宇; 李媛媛
100040　北京市，中国中医科学院眼科医院
Author(s):
LIU Ziqiang; JIE Chuanhong; WANG Jianwei; DENG Yu;  LI Yuanyuan
Eye Hospital,China Academy of Chinese Medical Sciences,Beijing 100040,China
关键词:
糖尿病视网膜病变; 免疫机制; 血-视网膜屏障; 小胶质细胞; 补体系统; 细胞因子
Keywords:
diabetic retinopathy;  immune mechanism;  blood-retinal barrier;  microglia;  complement system;  cytokines
分类号:
R774
DOI:
10.13389/j.cnki.rao.2022.0031
文献标志码:
A
摘要:
糖尿病视网膜病变（DR）是我国工作年龄人群中发病率位居第一的视网膜血管性疾病，其治疗呈复杂性和难治性，且周期长，是近年来国内外眼科临床治疗较为棘手的疾病之一。目前，DR的发病机制尚未完全明确，有学者提出免疫系统失调和炎症是DR发病的重要因素。因此，本文从血-视网膜屏障、小胶质细胞、补体系统、细胞因子等方面进行综述，探讨免疫机制在DR发病中的作用。
Abstract:
Diabetic retinopathy (DR) is the most common retinal vascular disease in the working-age population in China. Its treatment is complicated within a long duration. DR is one of the most hard-to-treat ophthalmic diseases at home and abroad in recent years. At present, the pathogenesis of this disease is not completely clear. Some scholars have proposed that immune system disorders and inflammations are important factors inducing DR. Therefore, this paper reviews the blood-retinal barrier, microglia, complement system, and cytokines to explore the role of immune mechanisms in DR.

参考文献/References:

［1］　中华医学会眼科学会眼底病学组.我国糖尿病视网膜病变临床诊疗指南(2014年)［J］.中华眼科杂志,2014,50(11):851-865.
Department of Ophthalmology,Chinese Medical Association.Clinical guidelines for diagnosis and treatment of diabetic retinopathy in China (2014)［J］.Chin J Ophthalmol,2014,50(11):851-865.
［2］　LECHNER J,O’LEARY O E,STITT A W.The pathology associated with diabetic retinopathy［J］.Vision Res,2017,139:7-14.
［3］　SCOTT I U,JACKSON G R,QUILLEN D A,LARSEN M,KLEIN R,LIAO J,et al.Effect of doxycycline vs placebo on retinal function and diabetic retinopathy progression in patients with severe nonproliferative or non-high-risk proliferative diabetic retinopathy:a randomized clinical trial［J］.JAMA Ophthalmol,2014,132(9):535-543.
［4］　OLGA S S,RAFAEL S,CRISTINA H.Circulating biomarkers of diabetic retinopathy:an overview based on physiopathology［J］.J Diabetes Res,2016,2016:1-13.
［5］　WHITEHEAD M,WICKREMASINGHE S,OSBORNE A,VAN WIJNGAARDEN P,MARTIN K R.Diabetic retinopathy:a complex pathophysiology requiring novel therapeutic strategies［J］.Expert Opin Biol Ther,2018,18(12):1257-1270.
［6］　TAWFIK A,SAMRA Y A,ELSHERBINY N M,AL-SHABRAWEY M.Implication of hyperhomocysteinemia in blood retinal barrier (BRB) dysfunction［J］.Biomolecules,2020,10(8):1119.
［7］　CHEN M,LUO C,ZHAO J,DEVARAJAN G,XU H.Immune regulation in the aging retina［J］.Prog Retin Eye Res,2019,69:159-172.
［8］　XU H,CHEN M.Diabetic retinopathy and dysregulated innate immunity［J］.Vision Res,2017,139:39-46.
［9］　ZHANG L,LI Y,PAYNE J,SRIVASTAVA S,FAN X,FUNG J,et al.Presence of retinal pericyte-reactive autoantibodies in diabetic retinopathy patients［J］.Sci Rep,2016,6:20341.
［10］　IKEDA T,NAKAMURA K,KIDA T,OKU H.Possible roles of anti-type II collagen antibody and innate immunity in the development and progression of diabetic retinopathy［J］.Graefes Arch Clin Exp Ophthalmol,2021.［Online ahead of print］.
［11］　NAKAIZUMI A,FUKUMOTO M,KIDA T,SUZUKI H,MORISHITA S,SATOU T,et al.Measurement of serum and vitreous concentrations of anti-type II collagen antibody in diabetic retinopathy［J］.Clin Ophthalmol,2015,9:543-547.
［12］　BALASHOVA L M,ZATSEVA N S,TEPLINSKAIA L E,KOVAL’CHUK L V,GANKOVSKAIA L V,OBRAZTSOVA E N,et al.Antibodies to types II and IV collagens,tumor necrosis factor-alpha and circulating immune complexes in lacrimal fluid and serum of patients with diabetic retinopathy and different stages［J］.Vestn Oftalmol,2000,116(3):31.
［13］　MADORE C,YIN Z,LEIBOWITZ J,BUTOVSKY O.Microglia,lifestyle stress,and neurodegeneration［J］.Immunity,2020,52(2):222-240.
［14］　KARLSTETTER M,SCHOLZ R,RUTAR M,WONG W T,PROVIS J M,LANGMANN T.Retinal microglia:just by stander or target for therapy［J］.Prog Retinal Eye Res,2015,45:30-57.
［15］　KINUTHIA U M,WOLF A,LANGMANN T.Microglia and inflammatory responses in diabetic retinopathy［J］.Front Immunol,2020,11:564077.
［16］　ZENG X X,NG Y K,LING E A.Neuronal and microglial response in the retina of streptozotocin-induced diabetic rats［J］.Vis Neurosci,2000,17(3):463-471.
［17］　CHEN X,ZHOU H,GONG Y,WEI S,ZHANG M.Early spatiotemporal characterization of microglial activation in the retinas of rats with streptozotocin-induced diabetes［J］.Graefes Arch Clin Exp Ophthalmol,2015,253(4):519-525.
［18］　ARROBA A I,ALCALDE-ESTEVEZ E,GARCA-RAMREZ M,CAZZONI D,DE LA VILLA P,SNCHEZ-FERNNDEZ E M,et al.Modulation of microglia polarization dynamics during diabetic retinopathy in db/db mice［J］.Biochim Biophys Acta,2016,1862(9):1663-1674.
［19］　ZENG H Y,GREEN W R,TSO M.Microglial activation in human diabetic retinopathy［J］.Arch Ophthalmol,2008,126(2):227.
［20］　CUKRAS C A,PETROU P,CHEW E Y,MEYERLE C B,WONG W T.Oral minocycline for the treatment of diabetic macular edema (DME):results of a phase I/II clinical study［J］.Invest Ophthalmol Vis Sci,2012,53(7):3865-3867.
［21］　BROWN G C,NEHER J J.Microglial phagocytosis of live neurons［J］.Nat Rev Neurosci,2014,15(4):209-216.
［22］　ANDERSON S R,ZHANG J,STEELE M R,ROMERO C O,KAUTZMAN A G,SCHAFER D P,et al.Complement targets newborn retinal ganglion cells for phagocytic elimination by microglia［J］.J Neurosci,2019,39(11):2025-2040.
［23］　BAI Q,WANG X,MAO X,HU D.Aldo-ketoreductase 1 member B1 (AKR1B1) inhibits retinal ganglion cell activity via activating NF-κB pathway and inducing mouse BV-2 microglia activation［J］.Chin J Cell Mol Immunol,2020,36(12):1063-1068.
［24］　ALTMANN C,SCHMIDT M H H.The role of microglia in diabetic retinopathy:inflammation,microvasculature defects and neurodegeneration［J］.Int J Mol Sci,2018,19(1):110.
［25］　李秀,罗蓉,李健,刘畅.小胶质细胞在糖尿病视网膜病变中的作用［J］.中华糖尿病杂志,2021,13(3):277-281.
LI X,LUO R,LI J,LIU C.Role of microglia in diabetic retinopathy［J］.Chin J Diabetes,2021,13(3):277-281.
［26］　YUN J H,PARK S W,KIM K J,BAE J S,LEE E H,PAEK S H.Endothelial STAT3 activation increases vascular leakage through downregulating tight junction proteins:implications for diabetic retinopathy［J］.J Cell Physiol,2017,232(5):1123-1134.
［27］　JO D H,YUN J H,CHO C S,KIM J H,KIM J H,CHO C H.Interaction between microglia and retinal pigment epithelial cells determines the integrity of outer blood-retinal barrier in diabetic retinopathy［J］.Glia,2019,67(2):321-331.
［28］　BOECK M,THIEN A,WOLF J,HAGEMEYER N,LAICH Y,YUSUF D,et al.Temporospatial distribution and transcriptional profile of retinal microglia in the oxygen-induced retinopathy mouse model［J］.Glia,2020,68(9):1859-1873.
［29］　XU W,HU Z,LV Y,DOU G,ZHANG Z,WANG H,et al.Microglial density determines the appearance of pathological neovascular tufts in oxygen-induced retinopathy［J］.Cell Tissue Res,2018,374(1):25-38.
［30］　LING M,MURALI M.Analysis of the complement system in the clinical immunology laboratory［J］.Clin Lab Med,2019,39(4):579-590.
［31］　GERL V B,BOHL J,PITZ S,STOFFELNS B,PFEIFFER N,BHAKDI S.Extensive deposits of complement C3d and C5b-9 in the choriocapillaris of eyes of patients with diabetic retinopathy［J］.Invest Ophthalmol Vis Sci,2002,43(4):1104-1108.
［32］　LAURA R K,GRNNE N B,FALLGAARD N S.Complement C3 and risk of diabetic microvascular disease:a cohort study of 95202 individuals from the general population［J］.Clin Chem,2018，64(7):1113-1124.
［33］　XU D,YI H,YU S,LI X,QIAO Y,DENG W.Association of complement C5 gene polymorphisms with proliferative diabetic retinopathy of type 2 diabetes in a Chinese Han population［J］.PLoS One,2016,11(3):e0149704.
［34］　GARCA-RAMREZ M,CANALS F,HERNNDEZ C,COLOM N,FERRER C,CARRASCO E,et al.Proteomic analysis of human vitreous fluid by fluorescence-based difference gel electrophoresis (DIGE):a new strategy for identifying potential candidates in the pathogenesis of proliferative diabetic retinopathy［J］.Diabetologia,2007,50(6):1294-1303.
［35］　孙洪岩,马瑞瑞,陈加玉,于旭辉,杨明明.糖尿病视网膜病变患者血清补体因子含量变化［J］.中华实验眼科杂志,2020,38(9):754-759.
SUN H Y,MA R R,CHEN J Y,YU X H,YANG M M.Changes of serum complement factors in diabetic retinopathy［J］.Chin J Exp Ophthalmol,2020,38(9):754-759.
［36］　HUANG C,FISHER K P,HAMMER S S,NAVITSKAYA S,BLANCHARD G J,BUSIK J V.Plasma exosomes contribute to microvascular damage in diabetic retinopathy by activating the classical complement pathway［J］.Diabetes,2018,67(8):db171587.
［37］　ZHANG J,GERHARDINGER C,LORENZI M.Early complement activation and decreased levels of glycosylphosphatidylinositol-anchored complement inhibitors in human and experimental diabetic retinopathy［J］.Diabetes,2002,51(12):3499.
［38］　XU H,CHEN M.Targeting the complement system for the management of retinal inflammatory and degenerative diseases［J］.Eur J Pharmacol,2016,787:94-104.
［39］　MANDAVA N,TIRADO-GONZALEZ V,GEIGER M D,PATNAIK J L,FRAZER-ABEL A,LYNCH A M,et al.Complement activation in the vitreous of patients with proliferative diabetic retinopathy［J］.Invest Ophthalmol Vis Sci,2020,61(11):39.
［40］　GENG P,DING Y,QIU L,LU Y.Serum mannose-binding lectin is a strong biomarker of diabetic retinopathy in Chinese patients with diabetes［J］.Diabetes Care,2015,38(5):868-875.
［41］　HOLT C B,HOFFMANN-PETERSEN I T,HANSEN T K,PARVING H H,THIEL S,HOVIND P,et al.Association between severe diabetic retinopathy and lectin pathway proteins-an 18-year follow-up study with newly diagnosed type 1 diabetes patients［J］.Immunobiology,2020,225(3):151939.
［42］　王玉亮,王峰,耿洁.细胞因子与细胞因子风暴［J］.天津医药,2020,48(6):494-499.
WANG Y L,WANG F,GENG J.Cytokine and cytokine storm［J］.Tianjin Med J,2020,48(6):494-499.
［43］　MESQUIDA M,DRAWNEL F,FAUSER S.The role of inflammation in diabetic eye disease［J］.Semin Immunopathol,2019,41(4):427-445.
［44］　PU L J,CHEN W,LIU Q H,HUANG A P,ZHAO Q,GU H H,et al.Relationship between miR-375 regulating Ndrg2/IL-6/STAT3 signaling pathway and diabetic retinopathy in rats［J］.Eur Rev Med Pharmacol Sci,2020,24(5):2189-2195.
［45］　YAO Y,LI R,DU J,LONG L,LI X,LUO N.Interleukin-6 and diabetic retinopathy:a systematic review and meta-analysis［J］.Curr Eye Res,2019,44(5):564-574.
［46］　YE E A,STEINLE J J.miR-146a suppresses STAT3/VEGF pathways and reduces apoptosis through IL-6 signaling in primary human retinal microvascular endothelial cells in high glucose conditions［J］.Vision Res,2017,139:15-22.
［47］　VALLE M L,DWORSHAK J,SHARMA A,IBRAHIM A S,AL-SHABRAWEY M,SHARMA S.Inhibition of interleukin-6 trans-signaling prevents inflammation and endothelial barrier disruption in retinal endothelial cells［J］.Exp Eye Res,2019,178:27-36.
［48］　YUN J H,PARK S W,KIM K J,BAE J S,LEE E H,PAEK S H,et al.Endothelial STAT3 activation increases vascular leakage through downregulating tight junction proteins:implications for diabetic retinopathy［J］.J Cell Physiol,2017,232(5):1123-1134.
［49］　ZHOU J,WANG S,XIA X.Role of intravitreal inflammatory cytokines and angiogenic factors in proliferative diabetic retinopathy［J］.Curr Eye Res,2012,37(5):416-420.
［50］　MENDIOLA A S,CARDONA A E.The IL-1β phenomena in neuroinflammatory diseases［J］.J Neural Transm (Vienna),2018,125(5):781-795.
［51］　SCUDERI S,D’AMICO A G,FEDERICO C,SACCONE S,MAGRO G,BUCOLO C,et al.Different retinal expression patterns of IL-1α,IL-1β,and their receptors in a rat model of type 1 STZ-induced diabetes［J］.J Mol Neurosci,2015,56(2):431-439.
［52］　KOWLURU R A,ODENBACH S.Role of interleukin-1beta in the development of retinopathy in rats:effect of antioxidants［J］.Invest Ophthalmol Vis Sci,2004,45(11):4161-4166.
［53］　STAHEL M,BECKER M,GRAF N,MICHELS S.Systemic interleukin 1β inhibition in proliferative diabetic retinopathy:a prospective open-label study using canakinumab［J］.Retina,2016,36(2):385-391.
［54］　FENG S,YU H,YU Y,GENG Y,LI D,YANG C,et al.Levels of inflammatory cytokines IL-1β,IL-6,IL-8,IL-17A,and TNF-α in aqueous humour of patients with diabetic retinopathy［J］.J Diabetes Res,2018,2018:8546423.
［55］　AMIL-BANGSA N H,MOHD-ALI B,ISHAK B,ABDUL-AZIZ C N N,NGAH N F,HASHIM H,et al.Total protein concentration and tumor necrosis factor α in tears of nonproliferative diabetic retinopathy［J］.Optom Vis Sci,2019,96(12):934-939.
［56］　AVELEIRA C A,LIN C M,ABCOUWER S F,AMBRSIO A F,ANTONETTI D A.TNF-α signals through PKCζ/NF-κB to alter the tight junction complex and increase retinal endothelial cell permeability［J］.Diabetes,2010,59(11):2872-2882.
［57］　GAO W,ZHU R,YANG L.Association of tumor necrosis factor-alpha -308 G/A and -238 G/A polymorphism with diabetic retinopathy:a systematic review and updated meta-analysis［J］.Ophthalmic Res,2020,Online ahead of print.
［58］　TAGHAVI Y,HASSANSHAHI G,KOUNIS N G,KONIARI I,KHORRAMDELAZAD H.Monocyte chemoattractant protein-1 (MCP-1/CCL2) in diabetic retinopathy:latest evidence and clinical considerations［J］.J Cell Commun Signal,2019,13(4):451-462.
［59］　JIANG Z,HENNEIN L,XU Y,BAO N,COH P,TAO L.Elevated serum monocyte chemoattractant protein-1 levels and its genetic polymorphism is associated with diabetic retinopathy in Chinese patients with type 2 diabetes［J］.Diabet Med,2016,33(1):84-90.
［60］　DONG N,XU B,CHU L,TANG X.Study of 27 aqueous humor cytokines in type 2 diabetic patients with or without macular edema［J］.PLoS One,2015,10(4):e0125329.
［61］　DONG N,LI X,XIAO L,YU W,WANG B,CHU L.Upregulation of retinal neuronal MCP-1 in the rodent model of diabetic retinopathy and its function in vitro［J］.Invest Ophthalmol Vis Sci,2012,53(12):7567-7575.
［62］　TONADE D,LIU H,PALCZEWSKI K,KERN T S.Photoreceptor cells produce inflammatory products that contribute to retinal vascular permeability in a mouse model of diabetes［J］.Diabetologia,2017,60(10):2111-2120.
［63］　WANG W,HE M,HUANG W.Association of monocyte chemoattractant protein-1 gene 2518A/G polymorphism with diabetic retinopathy in type 2 diabetes mellitus:a meta-analysis［J］.Diabetes Res Clin Pract,2016,120:40-46.
［64］　ZENG Y,CAO D,YU H,HU Y,HE M,YANG D,et al.Comprehensive analysis of vitreous humor chemokines in type 2 diabetic patients with and without diabetic retinopathy［J］.Acta Diabetol,2019,56(7):797-805.
［65］　EL-ASRAR A M A,NAWAZ M I,AHMAD A,DE ZUTTER A,SIDDIQUEI M M,BLANTER M,et al.Evaluation of proteoforms of the transmembrane chemokines CXCL16 and CX3CL1,their receptors,and their processing metalloproteinases ADAM10 and ADAM17 in proliferative diabetic retinopathy［J］.Front Immunol,2021,11:601639.

相似文献/References:

[1]杜玮 刘子扬 周艳艳 雒雷鸣.糖尿病视网膜病变与血清胆红素水平的关系[J].眼科新进展,2012,32(5):000.
[2]范松涛 卢建民.阿司匹林与糖尿病患者玻璃体出血以及玻璃体切割术疗效的相关性研究[J].眼科新进展,2012,32(11):000.
[3]李艳 李筱荣 袁佳琴 潘斌.糖尿病大鼠视网膜中VEGF、PEDF的表达与血-视网膜屏障损伤[J].眼科新进展,2013,33(1):000.
[4]李朝晖 崔治华 胡晓英 孟丽珠 张敬维.糖尿病视网膜病变激光面积与疗效的分析[J].眼科新进展,2013,33(2):000.
[5]冯冬梅 朱鸿 施彩虹.CXC趋化因子及其受体在糖尿病视网膜病变中的作用[J].眼科新进展,2013,33(6):000.
[6]牛淑玲.糖尿病视网膜病变患者HbAlc、FPG与血小板参数的变化及危险因素分析[J].眼科新进展,2013,33(7):000.
[7]毕春潮 王睿 王建洲 雷春灵 董晓娟 王小莉 薛晓辉.Ad-PEDF对糖尿病视网膜病变大鼠视网膜新生血管的抑制作用[J].眼科新进展,2013,33(8):000.
[8]杨萍 孙书明 李晓鹏.辛伐他汀对糖尿病视网膜病变和炎症因子的影响[J].眼科新进展,2013,33(8):000.
[9]罗文婷 孙大卫.血管黏附蛋白-1在眼科疾病中的研究进展[J].眼科新进展,2013,33(8):000.
[10]李小璐 马雅玲.糖尿病视网膜病变大鼠视网膜VEGF和PEDF的动态表达[J].眼科新进展,2013,33(9):000.

备注/Memo

备注/Memo:
国家自然科学基金面上项目（编号：81874494）；首都卫生发展科研专项（编号：2020-2-4182，2020-3-4184）
更新日期/Last Update: 2022-02-05