Research progress on the complement system in wet age-related macular degeneration_Chinese Journal of Ocular Fundus Diseases

Authors：

Liu Guina ^1,2 , Jiang Xiaoshuang ¹ , Yang Tingting ¹ ,  Lu Fang ¹

1. Department of Ophthalmology, West China Hospital of Sichuan University, Chengdu 610041, China;
2. Department of Ophthalmology, West China Second University Hospital, Sichuan University, Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu 610041, China;

Corresponding?author：

Lu Fang, Email: lufang@wchscu.cn

Keywords：

Complement system; Wet age-related macular degeneration; Choroidal neovascularization; Complement inhibitors; Review

DOI：

10.3760/cma.j.cn511434-20250220-00062

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Age-related macular degeneration (AMD) is the third leading cause of irreversible blindness worldwide. Wet AMD (wAMD) is the primary type of AMD leading to blindness, characterized by rapid vision loss due to neovascularization. Currently, the primary treatment for wAMD relies on anti-vascular endothelial growth factor (VEGF) drugs. However, some patients respond poorly to this therapy, suggesting a complex pathogenesis that necessitates the exploration of multi-target therapeutic strategies. Recent studies have revealed that aberrant activation of the complement system plays a crucial role in the development of wAMD. Specifically, molecules such as C3, C5, C3a, C5a, and the membrane attack complex (MAC) are involved in the formation of choroidal neovascularization (CNV) by modulating VEGF and other inflammatory factors. Genetic studies have confirmed a strong association between mutations in complement-related genes and wAMD, such as CFH and C3. Furthermore, animal experiments support the therapeutic potential of complement inhibitors in treating CNV. Currently, clinical trials targeting complement components like C3, C5, and MAC are underway, with some drugs having advanced to phase Ⅱ/Ⅲ clinical studies. However, their efficacy requires further validation. In the future, complement-targeted therapy, particularly in combination with anti-VEGF treatment, is poised to become a new direction in wAMD management, potentially offering superior therapeutic options for patients.

Citation： Liu Guina, Jiang Xiaoshuang, Yang Tingting, Lu Fang. Research progress on the complement system in wet age-related macular degeneration. Chinese Journal of Ocular Fundus Diseases, 2025, 41(12): 989-994. doi: 10.3760/cma.j.cn511434-20250220-00062 Copy

1.	Han X, Gharahkhani P, Mitchell P, et al. Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration[J]. J Hum Genet, 2020, 65(8): 657-665. DOI: 10.1038/s10038-020-0750-x.
2.	Song P, Du Y, Chan KY, et al. The national and subnational prevalence and burden of age-related macular degeneration in China[J/OL]. J Glob Health, 2017, 7(2): 020703[2017-12-01]. https://pubmed.ncbi.nlm.nih.gov/29302323/. DOI: 10.7189/jogh.07.020703.
3.	中華醫學會眼科學分會眼底病學組, 中國醫師協會眼科醫師分會眼底病學組. 中國年齡相關性黃斑變性臨床診療指南(2023年)[J]. 中華眼科雜志, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.Retinal Disease Group, Ophthalmology Branch of Chinese Medical Association, Retinal Disease Group, Ophthalmology Branch of Chinese Medical Doctor Association. Evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China (2023)[J]. Chin J Ophthalmol, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.
4.	Sarks S, Cherepanoff S, Killingsworth M, et al. Relationship of Basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2007, 48(3): 968-977. DOI: 10.1167/iovs.06-0443.
5.	Flaxel CJ, Adelman RA, Bailey ST, et al. Age-related macular degeneration preferred practice pattern^?[J]. Ophthalmology, 2020, 127(1): 1-65. DOI: 10.1016/j.ophtha.2019.09.024.
6.	Mettu PS, Allingham MJ, Cousins SW. Incomplete response to anti-VEGF therapy in neovascular AMD: exploring disease mechanisms and therapeutic opportunities[J/OL]. Prog Retin Eye Res, 2021, 82: 100906[2021-10-03]. https://pubmed.ncbi.nlm.nih.gov/33022379/. DOI: 10.1016/j.preteyeres.2020.100906.
7.	Thomas CJ, Mirza RG, Gill MK. Age-related macular degeneration[J]. Med Clin North Am, 2021, 105(3): 473-491. DOI: 10.1016/j.mcna.2021.01.003.
8.	Spaide RF, Jaffe GJ, Sarraf D, et al. Consensus nomenclature for reporting neovascular age-related macular degeneration data: consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group[J]. Ophthalmology, 2020, 127(5): 616-636. DOI: 10.1016/j.ophtha.2019.11.004.
9.	Elsheikh RH, Chauhan MZ, Sallam AB. Current and novel therapeutic approaches for treatment of neovascular age-related macular degeneration[J/OL]. Biomolecules, 2022, 12(11): 1629[2022-11-03]. https://pubmed.ncbi.nlm.nih.gov/36358978/. DOI: 10.3390/biom12111629.
10.	Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis[J]. Nat Immunol, 2010, 11(9): 785-797. DOI: 10.1038/ni.1923.
11.	Menny A, Serna M, Boyd C M, et al. CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers[J/OL]. Nat Commun, 2018, 9(1): 5316[2018-12-14]. https://pubmed.ncbi.nlm.nih.gov/30552328/. DOI: 10.1038/s41467-018-07653-5.
12.	Black JR, Clark SJ. Age-related macular degeneration: genome-wide association studies to translation[J]. Genet Med, 2016, 18(4): 283-289. DOI: 10.1038/gim.2015.70.
13.	Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration[J]. Nat Genet, 2013, 45(4): 433-439. DOI: 10.1038/ng.2578.
14.	Yanagisawa S, Kondo N, Miki A, et al. A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population[J/OL]. PLoS One, 2011, 6(12): e28847[2011-12-12]. https://pubmed.ncbi.nlm.nih.gov/22174912/. DOI: 10.1371/journal.pone.0028847.
15.	Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration[J]. N Engl J Med, 2007, 357(6): 553-561. DOI: 10.1056/NEJMoa072618.
16.	Sofat R, Casas JP, Webster AR, et al. Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype[J]. Int J Epidemiol, 2012, 41(1): 250-262. DOI: 10.1093/ije/dyr204.
17.	Wang Q, Zhao HS, Li L. Association between complement factor Ⅰ gene polymorphisms and the risk of age-related macular degeneration: a meta-analysis of literature[J]. Int J Ophthalmol, 2016, 9(2): 298-305. DOI: 10.18240/ijo.2016.02.23.
18.	Nishiguchi KM, Yasuma TR, Tomida D, et al. C9-R95X polymorphism in patients with neovascular age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2012, 53(1): 508-512. DOI: 10.1167/iovs.11-8425.
19.	Jensen EG, Jakobsen TS, Thiel S, et al. Associations between the complement system and choroidal neovascularization in wet age-related macular degeneration[J/OL]. Int J Mol Sci, 2020, 21(24): 9752[2020-12-21]. https://pubmed.ncbi.nlm.nih.gov/33371261/. DOI: 10.3390/ijms21249752.
20.	Altay L, Sitnilska V, Schick T, et al. Early local activation of complement in aqueous humour of patients with age-related macular degeneration[J]. Eye (Lond), 2019, 33(12): 1859-1864. DOI: 10.1038/s41433-019-0501-4.
21.	Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization[J]. Proc Natl Acad Sci USA, 2006, 103(7): 2328-2333. DOI: 10.1073/pnas.0408835103.
22.	Park YG, Park YS, Kim IB. Complement system and potential therapeutics in age-related macular degeneration[J]. Int J Mol Sci, 2021, 22(13): 6851. DOI: 10.3390/ijms22136851.
23.	Trakkides TO, Sch?fer N, Reichenthaler M, et al. Oxidative stress increases endogenous complement-dependent inflammatory and angiogenic responses in retinal pigment epithelial cells independently of exogenous complement sources[J]. Antioxidants (Basel), 2019, 8(11): 548. DOI: 10.3390/antiox8110548.
24.	Long Q, Cao X, Bian A, et al. C3a increases VEGF and decreases PEDF mRNA levels in human retinal pigment epithelial cells[J/OL]. Biomed Res Int, 2016, 2016: 6958752[2016-09-22]. https://pubmed.ncbi.nlm.nih.gov/27747237/. DOI: 10.1155/2016/6958752.
25.	Tan X, Fujiu K, Manabe I, et al. Choroidal neovascularization is inhibited via an intraocular decrease of inflammatory cells in mice lacking complement component C3[J/OL]. Sci Rep, 2015, 5: 15702[2015-10-28]. https://pubmed.ncbi.nlm.nih.gov/26507897/. DOI: 10.1038/srep15702.
26.	Llorián-Salvador M, Byrne EM, Szczepan M, et al. Complement activation contributes to subretinal fibrosis through the induction of epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial cells[J/OL]. J Neuroinflammation, 2022, 19(1): 182[2022-07-14]. https://pubmed.ncbi.nlm.nih.gov/35831910/. DOI: 10.1186/s12974-022-02546-3.
27.	Jo DH, Kim JH, Yang W, et al. Anti-complement component 5 antibody targeting MG4 domain inhibits choroidal neovascularization[J]. Oncotarget, 2017, 8(28): 45506-45516. DOI: 10.18632/oncotarget.17221.
28.	Bora NS, Kaliappan S, Jha P, et al. Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H[J]. J Immunol, 2006, 177(3): 1872-1878. DOI: 10.4049/jimmunol.177.3.1872.
29.	Rohrer B. Anaphylatoxin signaling in retinal pigment and choroidal endothelial cells: characteristics and relevance to age-related macular degeneration[J]. Adv Exp Med Biol, 2018, 1074: 45-51. DOI: 10.1007/978-3-319-75402-4_6.
30.	Cortright DN, Meade R, Waters SM, et al. C5a, but not C3a, increases VEGF secretion in ARPE-19 human retinal pigment epithelial cells[J]. Curr Eye Res, 2009, 34(1): 57-61. DOI: 10.1080/02713680802546658.
31.	Kunchithapautham K, Atkinson C, Rohrer B. Smoke exposure causes endoplasmic reticulum stress and lipid accumulation in retinal pigment epithelium through oxidative stress and complement activation[J]. J Biol Chem, 2014, 289(21): 14534-14546. DOI: 10.1074/jbc.M114.564674.
32.	Coughlin B, Schnabolk G, Joseph K, et al. Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells[J/OL]. Sci Rep, 2016, 6: 23794[2016-04-31]. https://pubmed.ncbi.nlm.nih.gov/27029558/. DOI: 10.1038/srep23794.
33.	Brockmann C, Brockmann T, Dege S, et al. Intravitreal inhibition of complement C5a reduces choroidal neovascularization in mice[J]. Graefe's Arch Clin Exp Ophthalmol, 2015, 253(10): 1695-1704. DOI: 10.1007/s00417-015-3041-z.
34.	Xiong Z, Wang Q, Li W, et al. Platelet-derived growth factor-D activates complement system to propagate macrophage polarization and neovascularization[J/OL]. Front Cell Dev Biol, 2021, 9: 686886[2021-06-02]. https://pubmed.ncbi.nlm.nih.gov/34150781/. DOI: 10.3389/fcell.2021.686886.
35.	Kunchithapautham K, Bandyopadhyay M, Dahrouj M, et al. Sublytic membrane-attack-complex activation and VEGF secretion in retinal pigment epithelial cells[J]. Adv Exp Med Biol, 2012, 723: 23-30. DOI: 10.1007/978-1-4614-0631-0_4.
36.	Fosbrink M, Niculescu F, Rus V, et al. C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1[J]. J Biol Chem, 2006, 281(28): 19009-19018. DOI: 10.1074/jbc.M602055200.
37.	Lueck K, Wasmuth S, Williams J, et al. Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration[J]. Eye (Lond), 2011, 25(8): 1074-1082. DOI: 10.1038/eye.2011.109.
38.	Kunchithapautham K, Rohrer B. Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelium monolayers[J]. J Biol Chem, 2011, 286(27): 23717-23724. DOI: 10.1074/jbc.M110.214593.
39.	Bora PS, Sohn JH, Cruz JM, et al. Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization[J]. J Immunol, 2005, 174(1): 491-497. DOI: 10.4049/jimmunol.174.1.491.
40.	Lipo E, Cashman SM, Kumar-Singh R. Aurintricarboxylic acid inhibits complement activation, membrane attack complex, and choroidal neovascularization in a model of macular degeneration[J]. Invest Ophthalmol Vis Sci, 2013, 54(10): 7107-7114. DOI: 10.1167/iovs.13-12923.
41.	Liu J, Jha P, Lyzogubov VV, et al. Relationship between complement membrane attack complex, chemokine (C-C motif) ligand 2 (CCL₂) and vascular endothelial growth factor in mouse model of laser-induced choroidal neovascularization[J]. J Biol Chem, 2011, 286(23): 20991-21001. DOI: 10.1074/jbc.M111.226266.
42.	Wickham SE, Hotze EM, Farrand AJ, et al. Mapping the intermedilysin-human CD59 receptor interface reveals a deep correspondence with the binding site on CD59 for complement binding proteins C8alpha and C9[J]. J Biol Chem, 2011, 286(23): 20952-20962. DOI: 10.1074/jbc.M111.237446.
43.	Schnabolk G, Beon MK, Tomlinson S, et al. New insights on complement inhibitor CD59 in mouse laser-induced choroidal neovascularization: mislocalization after injury and targeted delivery for protein replacement[J]. J Ocul Pharmacol Ther, 2017, 33(5): 400-411. DOI: 10.1089/jop.2016.0101.
44.	Bora NS, Jha P, Lyzogubov VV, et al. Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice[J]. J Biol Chem, 2010, 285(44): 33826-33833. DOI: 10.1074/jbc.M110.153130.
45.	Chen G, Tzekov R, Li W, et al. Pharmacogenetics of complement factor H Y402H polymorphism and treatment of neovascular AMD with anti-VEGF agents: a meta-analysis[J/OL]. Sci Rep, 2015, 5: 14517[2015-09-28]. https://pubmed.ncbi.nlm.nih.gov/26411831/. DOI: 10.1038/srep14517.
46.	Marazita MC, Dugour A, Marquioni-Ramella MD, et al. Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: implications for age-related macular degeneration[J]. Redox Biol, 2016, 7: 78-87. DOI: 10.1016/j.redox.2015.11.011.
47.	Armento A, Schmidt TL, Sonntag I, et al. CFH Loss in human RPE cells leads to inflammation and complement system dysregulation via the NF-κB pathway[J/OL]. Int J Mol Sci, 2021, 22(16): 8727[2021-08-13]. https://pubmed.ncbi.nlm.nih.gov/34445430/. DOI: 10.3390/ijms22168727.
48.	Lundh Von Leithner P, Kam JH, Bainbridge J, et al. Complement factor h is critical in the maintenance of retinal perfusion[J]. Am J Pathol, 2009, 175(1): 412-421. DOI: 10.2353/ajpath.2009.080927.
49.	Lyzogubov VV, Tytarenko RG, Jha P, et al. Role of ocular complement factor H in a murine model of choroidal neovascularization[J]. Am J Pathol, 2010, 177(4): 1870-1880. DOI: 10.2353/ajpath.2010.091168.
50.	Borras C, Delaunay K, Slaoui Y, et al. Mechanisms of FH protection against neovascular AMD[J/OL]. Front Immunol, 2020, 11: 443[2020-04-03]. https://pubmed.ncbi.nlm.nih.gov/32318056/. DOI: 10.3389/fimmu.2020.00443.
51.	Rohrer B, Coughlin B, Kunchithapautham K, et al. The alternative pathway is required, but not alone sufficient, for retinal pathology in mouse laser-induced choroidal neovascularization[J/OL]. Mol Immunol, 2011, 48(6-7): e1-8[2011-01-22]. https://pubmed.ncbi.nlm.nih.gov/21257205/. DOI: 10.1016/j.molimm.2010.12.016.
52.	Schnabolk G, Coughlin B, Joseph K, et al. Local production of the alternative pathway component factor B is sufficient to promote laser-induced choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1850-1863. DOI: 10.1167/iovs.14-15910.
53.	Little K, Llorián-Salvador M, Tang M, et al. Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration[J/OL]. J Neuroinflammation, 2020, 17(1): 355[2020-11-25]. https://pubmed.ncbi.nlm.nih.gov/33239022/. DOI: 10.1186/s12974-020-02033-7.
54.	Pras E, Kristal D, Shoshany N, et al. Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration[J]. J Med Genet, 2015, 52(7): 484-492. DOI: 10.1136/jmedgenet-2015-103130.
55.	de Breuk A, Lechanteur YTE, Heesterbeek TJ, et al. Genetic risk in families with age-related macular degeneration[J/OL]. Ophthalmol Sci, 2021, 1(4): 100087[2021-12-06]. https://pubmed.ncbi.nlm.nih.gov/36246952/. DOI: 10.1016/j.xops.2021.100087.
56.	Yang F, Sun Y, Jin Z, et al. Complement factor I polymorphism is not associated with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in a Chinese population[J]. Ophthalmologica, 2014, 232(1): 37-45. DOI: 10.1159/000358241.
57.	Leveziel N, Yu Y, Reynolds R, et al. Genetic factors for choroidal neovascularization associated with high myopia[J]. Invest Ophthalmol Vis Sci, 2012, 53(8): 5004-5009. DOI: 10.1167/iovs.12-9538.
58.	Miyake M, Yamashiro K, Nakanishi H, et al. Evaluation of pigment epithelium-derived factor and complement factor I polymorphisms as a cause of choroidal neovascularization in highly myopic eyes[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 4208-4212. DOI: 10.1167/iovs.13-12280.
59.	van den Bos RM, Pearce NM, Granneman J, et al. Insights into enhanced complement activation by structures of properdin and its complex with the C-terminal domain of C3b[J/OL]. Front Immunol, 2019, 10: 2097[2019-09-04]. https://pubmed.ncbi.nlm.nih.gov/31552043/. DOI: 10.3389/fimmu.2019.02097.
60.	Wolf-Schnurrbusch UE, Stuck AK, Hess R, et al. Complement factor P in choroidal neovascular membranes of patients with age-related macular degeneration[J]. Retina, 2009, 29(7): 966-973. DOI: 10.1097/IAE.0b013e3181a2f40f.
61.	Sch?fer N, Wolf HN, Enzbrenner A, et al. Properdin modulates complement component production in stressed human primary retinal pigment epithelium cells[J/OL]. Antioxidants (Basel), 2020, 9(9): 793[2020-08-26]. https://pubmed.ncbi.nlm.nih.gov/32859013/. DOI: 10.3390/antiox9090793.

1. Han X, Gharahkhani P, Mitchell P, et al. Genome-wide meta-analysis identifies novel loci associated with age-related macular degeneration[J]. J Hum Genet, 2020, 65(8): 657-665. DOI: 10.1038/s10038-020-0750-x.
2. Song P, Du Y, Chan KY, et al. The national and subnational prevalence and burden of age-related macular degeneration in China[J/OL]. J Glob Health, 2017, 7(2): 020703[2017-12-01]. https://pubmed.ncbi.nlm.nih.gov/29302323/. DOI: 10.7189/jogh.07.020703.
3. 中華醫學會眼科學分會眼底病學組, 中國醫師協會眼科醫師分會眼底病學組. 中國年齡相關性黃斑變性臨床診療指南(2023年)[J]. 中華眼科雜志, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.Retinal Disease Group, Ophthalmology Branch of Chinese Medical Association, Retinal Disease Group, Ophthalmology Branch of Chinese Medical Doctor Association. Evidence-based guidelines for diagnosis and treatment of age-related macular degeneration in China (2023)[J]. Chin J Ophthalmol, 2023, 59(5): 347-366. DOI: 10.3760/cma.j.cn112142-20221222-00649.
4. Sarks S, Cherepanoff S, Killingsworth M, et al. Relationship of Basal laminar deposit and membranous debris to the clinical presentation of early age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2007, 48(3): 968-977. DOI: 10.1167/iovs.06-0443.
5. Flaxel CJ, Adelman RA, Bailey ST, et al. Age-related macular degeneration preferred practice pattern^?[J]. Ophthalmology, 2020, 127(1): 1-65. DOI: 10.1016/j.ophtha.2019.09.024.
6. Mettu PS, Allingham MJ, Cousins SW. Incomplete response to anti-VEGF therapy in neovascular AMD: exploring disease mechanisms and therapeutic opportunities[J/OL]. Prog Retin Eye Res, 2021, 82: 100906[2021-10-03]. https://pubmed.ncbi.nlm.nih.gov/33022379/. DOI: 10.1016/j.preteyeres.2020.100906.
7. Thomas CJ, Mirza RG, Gill MK. Age-related macular degeneration[J]. Med Clin North Am, 2021, 105(3): 473-491. DOI: 10.1016/j.mcna.2021.01.003.
8. Spaide RF, Jaffe GJ, Sarraf D, et al. Consensus nomenclature for reporting neovascular age-related macular degeneration data: consensus on Neovascular Age-Related Macular Degeneration Nomenclature Study Group[J]. Ophthalmology, 2020, 127(5): 616-636. DOI: 10.1016/j.ophtha.2019.11.004.
9. Elsheikh RH, Chauhan MZ, Sallam AB. Current and novel therapeutic approaches for treatment of neovascular age-related macular degeneration[J/OL]. Biomolecules, 2022, 12(11): 1629[2022-11-03]. https://pubmed.ncbi.nlm.nih.gov/36358978/. DOI: 10.3390/biom12111629.
10. Ricklin D, Hajishengallis G, Yang K, et al. Complement: a key system for immune surveillance and homeostasis[J]. Nat Immunol, 2010, 11(9): 785-797. DOI: 10.1038/ni.1923.
11. Menny A, Serna M, Boyd C M, et al. CryoEM reveals how the complement membrane attack complex ruptures lipid bilayers[J/OL]. Nat Commun, 2018, 9(1): 5316[2018-12-14]. https://pubmed.ncbi.nlm.nih.gov/30552328/. DOI: 10.1038/s41467-018-07653-5.
12. Black JR, Clark SJ. Age-related macular degeneration: genome-wide association studies to translation[J]. Genet Med, 2016, 18(4): 283-289. DOI: 10.1038/gim.2015.70.
13. Fritsche LG, Chen W, Schu M, et al. Seven new loci associated with age-related macular degeneration[J]. Nat Genet, 2013, 45(4): 433-439. DOI: 10.1038/ng.2578.
14. Yanagisawa S, Kondo N, Miki A, et al. A common complement C3 variant is associated with protection against wet age-related macular degeneration in a Japanese population[J/OL]. PLoS One, 2011, 6(12): e28847[2011-12-12]. https://pubmed.ncbi.nlm.nih.gov/22174912/. DOI: 10.1371/journal.pone.0028847.
15. Yates JR, Sepp T, Matharu BK, et al. Complement C3 variant and the risk of age-related macular degeneration[J]. N Engl J Med, 2007, 357(6): 553-561. DOI: 10.1056/NEJMoa072618.
16. Sofat R, Casas JP, Webster AR, et al. Complement factor H genetic variant and age-related macular degeneration: effect size, modifiers and relationship to disease subtype[J]. Int J Epidemiol, 2012, 41(1): 250-262. DOI: 10.1093/ije/dyr204.
17. Wang Q, Zhao HS, Li L. Association between complement factor Ⅰ gene polymorphisms and the risk of age-related macular degeneration: a meta-analysis of literature[J]. Int J Ophthalmol, 2016, 9(2): 298-305. DOI: 10.18240/ijo.2016.02.23.
18. Nishiguchi KM, Yasuma TR, Tomida D, et al. C9-R95X polymorphism in patients with neovascular age-related macular degeneration[J]. Invest Ophthalmol Vis Sci, 2012, 53(1): 508-512. DOI: 10.1167/iovs.11-8425.
19. Jensen EG, Jakobsen TS, Thiel S, et al. Associations between the complement system and choroidal neovascularization in wet age-related macular degeneration[J/OL]. Int J Mol Sci, 2020, 21(24): 9752[2020-12-21]. https://pubmed.ncbi.nlm.nih.gov/33371261/. DOI: 10.3390/ijms21249752.
20. Altay L, Sitnilska V, Schick T, et al. Early local activation of complement in aqueous humour of patients with age-related macular degeneration[J]. Eye (Lond), 2019, 33(12): 1859-1864. DOI: 10.1038/s41433-019-0501-4.
21. Nozaki M, Raisler BJ, Sakurai E, et al. Drusen complement components C3a and C5a promote choroidal neovascularization[J]. Proc Natl Acad Sci USA, 2006, 103(7): 2328-2333. DOI: 10.1073/pnas.0408835103.
22. Park YG, Park YS, Kim IB. Complement system and potential therapeutics in age-related macular degeneration[J]. Int J Mol Sci, 2021, 22(13): 6851. DOI: 10.3390/ijms22136851.
23. Trakkides TO, Sch?fer N, Reichenthaler M, et al. Oxidative stress increases endogenous complement-dependent inflammatory and angiogenic responses in retinal pigment epithelial cells independently of exogenous complement sources[J]. Antioxidants (Basel), 2019, 8(11): 548. DOI: 10.3390/antiox8110548.
24. Long Q, Cao X, Bian A, et al. C3a increases VEGF and decreases PEDF mRNA levels in human retinal pigment epithelial cells[J/OL]. Biomed Res Int, 2016, 2016: 6958752[2016-09-22]. https://pubmed.ncbi.nlm.nih.gov/27747237/. DOI: 10.1155/2016/6958752.
25. Tan X, Fujiu K, Manabe I, et al. Choroidal neovascularization is inhibited via an intraocular decrease of inflammatory cells in mice lacking complement component C3[J/OL]. Sci Rep, 2015, 5: 15702[2015-10-28]. https://pubmed.ncbi.nlm.nih.gov/26507897/. DOI: 10.1038/srep15702.
26. Llorián-Salvador M, Byrne EM, Szczepan M, et al. Complement activation contributes to subretinal fibrosis through the induction of epithelial-to-mesenchymal transition (EMT) in retinal pigment epithelial cells[J/OL]. J Neuroinflammation, 2022, 19(1): 182[2022-07-14]. https://pubmed.ncbi.nlm.nih.gov/35831910/. DOI: 10.1186/s12974-022-02546-3.
27. Jo DH, Kim JH, Yang W, et al. Anti-complement component 5 antibody targeting MG4 domain inhibits choroidal neovascularization[J]. Oncotarget, 2017, 8(28): 45506-45516. DOI: 10.18632/oncotarget.17221.
28. Bora NS, Kaliappan S, Jha P, et al. Complement activation via alternative pathway is critical in the development of laser-induced choroidal neovascularization: role of factor B and factor H[J]. J Immunol, 2006, 177(3): 1872-1878. DOI: 10.4049/jimmunol.177.3.1872.
29. Rohrer B. Anaphylatoxin signaling in retinal pigment and choroidal endothelial cells: characteristics and relevance to age-related macular degeneration[J]. Adv Exp Med Biol, 2018, 1074: 45-51. DOI: 10.1007/978-3-319-75402-4_6.
30. Cortright DN, Meade R, Waters SM, et al. C5a, but not C3a, increases VEGF secretion in ARPE-19 human retinal pigment epithelial cells[J]. Curr Eye Res, 2009, 34(1): 57-61. DOI: 10.1080/02713680802546658.
31. Kunchithapautham K, Atkinson C, Rohrer B. Smoke exposure causes endoplasmic reticulum stress and lipid accumulation in retinal pigment epithelium through oxidative stress and complement activation[J]. J Biol Chem, 2014, 289(21): 14534-14546. DOI: 10.1074/jbc.M114.564674.
32. Coughlin B, Schnabolk G, Joseph K, et al. Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells[J/OL]. Sci Rep, 2016, 6: 23794[2016-04-31]. https://pubmed.ncbi.nlm.nih.gov/27029558/. DOI: 10.1038/srep23794.
33. Brockmann C, Brockmann T, Dege S, et al. Intravitreal inhibition of complement C5a reduces choroidal neovascularization in mice[J]. Graefe's Arch Clin Exp Ophthalmol, 2015, 253(10): 1695-1704. DOI: 10.1007/s00417-015-3041-z.
34. Xiong Z, Wang Q, Li W, et al. Platelet-derived growth factor-D activates complement system to propagate macrophage polarization and neovascularization[J/OL]. Front Cell Dev Biol, 2021, 9: 686886[2021-06-02]. https://pubmed.ncbi.nlm.nih.gov/34150781/. DOI: 10.3389/fcell.2021.686886.
35. Kunchithapautham K, Bandyopadhyay M, Dahrouj M, et al. Sublytic membrane-attack-complex activation and VEGF secretion in retinal pigment epithelial cells[J]. Adv Exp Med Biol, 2012, 723: 23-30. DOI: 10.1007/978-1-4614-0631-0_4.
36. Fosbrink M, Niculescu F, Rus V, et al. C5b-9-induced endothelial cell proliferation and migration are dependent on Akt inactivation of forkhead transcription factor FOXO1[J]. J Biol Chem, 2006, 281(28): 19009-19018. DOI: 10.1074/jbc.M602055200.
37. Lueck K, Wasmuth S, Williams J, et al. Sub-lytic C5b-9 induces functional changes in retinal pigment epithelial cells consistent with age-related macular degeneration[J]. Eye (Lond), 2011, 25(8): 1074-1082. DOI: 10.1038/eye.2011.109.
38. Kunchithapautham K, Rohrer B. Sublytic membrane-attack-complex (MAC) activation alters regulated rather than constitutive vascular endothelial growth factor (VEGF) secretion in retinal pigment epithelium monolayers[J]. J Biol Chem, 2011, 286(27): 23717-23724. DOI: 10.1074/jbc.M110.214593.
39. Bora PS, Sohn JH, Cruz JM, et al. Role of complement and complement membrane attack complex in laser-induced choroidal neovascularization[J]. J Immunol, 2005, 174(1): 491-497. DOI: 10.4049/jimmunol.174.1.491.
40. Lipo E, Cashman SM, Kumar-Singh R. Aurintricarboxylic acid inhibits complement activation, membrane attack complex, and choroidal neovascularization in a model of macular degeneration[J]. Invest Ophthalmol Vis Sci, 2013, 54(10): 7107-7114. DOI: 10.1167/iovs.13-12923.
41. Liu J, Jha P, Lyzogubov VV, et al. Relationship between complement membrane attack complex, chemokine (C-C motif) ligand 2 (CCL₂) and vascular endothelial growth factor in mouse model of laser-induced choroidal neovascularization[J]. J Biol Chem, 2011, 286(23): 20991-21001. DOI: 10.1074/jbc.M111.226266.
42. Wickham SE, Hotze EM, Farrand AJ, et al. Mapping the intermedilysin-human CD59 receptor interface reveals a deep correspondence with the binding site on CD59 for complement binding proteins C8alpha and C9[J]. J Biol Chem, 2011, 286(23): 20952-20962. DOI: 10.1074/jbc.M111.237446.
43. Schnabolk G, Beon MK, Tomlinson S, et al. New insights on complement inhibitor CD59 in mouse laser-induced choroidal neovascularization: mislocalization after injury and targeted delivery for protein replacement[J]. J Ocul Pharmacol Ther, 2017, 33(5): 400-411. DOI: 10.1089/jop.2016.0101.
44. Bora NS, Jha P, Lyzogubov VV, et al. Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice[J]. J Biol Chem, 2010, 285(44): 33826-33833. DOI: 10.1074/jbc.M110.153130.
45. Chen G, Tzekov R, Li W, et al. Pharmacogenetics of complement factor H Y402H polymorphism and treatment of neovascular AMD with anti-VEGF agents: a meta-analysis[J/OL]. Sci Rep, 2015, 5: 14517[2015-09-28]. https://pubmed.ncbi.nlm.nih.gov/26411831/. DOI: 10.1038/srep14517.
46. Marazita MC, Dugour A, Marquioni-Ramella MD, et al. Oxidative stress-induced premature senescence dysregulates VEGF and CFH expression in retinal pigment epithelial cells: implications for age-related macular degeneration[J]. Redox Biol, 2016, 7: 78-87. DOI: 10.1016/j.redox.2015.11.011.
47. Armento A, Schmidt TL, Sonntag I, et al. CFH Loss in human RPE cells leads to inflammation and complement system dysregulation via the NF-κB pathway[J/OL]. Int J Mol Sci, 2021, 22(16): 8727[2021-08-13]. https://pubmed.ncbi.nlm.nih.gov/34445430/. DOI: 10.3390/ijms22168727.
48. Lundh Von Leithner P, Kam JH, Bainbridge J, et al. Complement factor h is critical in the maintenance of retinal perfusion[J]. Am J Pathol, 2009, 175(1): 412-421. DOI: 10.2353/ajpath.2009.080927.
49. Lyzogubov VV, Tytarenko RG, Jha P, et al. Role of ocular complement factor H in a murine model of choroidal neovascularization[J]. Am J Pathol, 2010, 177(4): 1870-1880. DOI: 10.2353/ajpath.2010.091168.
50. Borras C, Delaunay K, Slaoui Y, et al. Mechanisms of FH protection against neovascular AMD[J/OL]. Front Immunol, 2020, 11: 443[2020-04-03]. https://pubmed.ncbi.nlm.nih.gov/32318056/. DOI: 10.3389/fimmu.2020.00443.
51. Rohrer B, Coughlin B, Kunchithapautham K, et al. The alternative pathway is required, but not alone sufficient, for retinal pathology in mouse laser-induced choroidal neovascularization[J/OL]. Mol Immunol, 2011, 48(6-7): e1-8[2011-01-22]. https://pubmed.ncbi.nlm.nih.gov/21257205/. DOI: 10.1016/j.molimm.2010.12.016.
52. Schnabolk G, Coughlin B, Joseph K, et al. Local production of the alternative pathway component factor B is sufficient to promote laser-induced choroidal neovascularization[J]. Invest Ophthalmol Vis Sci, 2015, 56(3): 1850-1863. DOI: 10.1167/iovs.14-15910.
53. Little K, Llorián-Salvador M, Tang M, et al. Macrophage to myofibroblast transition contributes to subretinal fibrosis secondary to neovascular age-related macular degeneration[J/OL]. J Neuroinflammation, 2020, 17(1): 355[2020-11-25]. https://pubmed.ncbi.nlm.nih.gov/33239022/. DOI: 10.1186/s12974-020-02033-7.
54. Pras E, Kristal D, Shoshany N, et al. Rare genetic variants in Tunisian Jewish patients suffering from age-related macular degeneration[J]. J Med Genet, 2015, 52(7): 484-492. DOI: 10.1136/jmedgenet-2015-103130.
55. de Breuk A, Lechanteur YTE, Heesterbeek TJ, et al. Genetic risk in families with age-related macular degeneration[J/OL]. Ophthalmol Sci, 2021, 1(4): 100087[2021-12-06]. https://pubmed.ncbi.nlm.nih.gov/36246952/. DOI: 10.1016/j.xops.2021.100087.
56. Yang F, Sun Y, Jin Z, et al. Complement factor I polymorphism is not associated with neovascular age-related macular degeneration and polypoidal choroidal vasculopathy in a Chinese population[J]. Ophthalmologica, 2014, 232(1): 37-45. DOI: 10.1159/000358241.
57. Leveziel N, Yu Y, Reynolds R, et al. Genetic factors for choroidal neovascularization associated with high myopia[J]. Invest Ophthalmol Vis Sci, 2012, 53(8): 5004-5009. DOI: 10.1167/iovs.12-9538.
58. Miyake M, Yamashiro K, Nakanishi H, et al. Evaluation of pigment epithelium-derived factor and complement factor I polymorphisms as a cause of choroidal neovascularization in highly myopic eyes[J]. Invest Ophthalmol Vis Sci, 2013, 54(6): 4208-4212. DOI: 10.1167/iovs.13-12280.
59. van den Bos RM, Pearce NM, Granneman J, et al. Insights into enhanced complement activation by structures of properdin and its complex with the C-terminal domain of C3b[J/OL]. Front Immunol, 2019, 10: 2097[2019-09-04]. https://pubmed.ncbi.nlm.nih.gov/31552043/. DOI: 10.3389/fimmu.2019.02097.
60. Wolf-Schnurrbusch UE, Stuck AK, Hess R, et al. Complement factor P in choroidal neovascular membranes of patients with age-related macular degeneration[J]. Retina, 2009, 29(7): 966-973. DOI: 10.1097/IAE.0b013e3181a2f40f.
61. Sch?fer N, Wolf HN, Enzbrenner A, et al. Properdin modulates complement component production in stressed human primary retinal pigment epithelium cells[J/OL]. Antioxidants (Basel), 2020, 9(9): 793[2020-08-26]. https://pubmed.ncbi.nlm.nih.gov/32859013/. DOI: 10.3390/antiox9090793.

Previous Article
Research progress on the role of CD4⁺ T cells and their subsets in retinal ischemia-reperfusion injury

Chinese Journal of Ocular Fundus Diseases

Research progress on the complement system in wet age-related macular degeneration

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Format

Content