AGE-RELATED MACULAR DEGENERATION CURRENT INVESTIGATIONS AND TREATMENTS

agerelatedmaculardeg774enerationkapak

THE ROLE OF THE COMPLEMENT SYSTEM, INFLAMMATION AND OXIDATIVE STRESS IN AGE-RELATED MACULAR DEGENERATION

Demet İyidoğan

Antalya City Hospital, Department of Ophthalmology, Antalya, Türkiye

İyidoğan D. The Role of The Complement System, Inflammation and Oxidative Stress in Age-Related Macular Degeneration. In: Çıtırık M, Şekeryapan Gediz B, editors. AgeRelated Macular Degeneration: Current Investigations and Treatments. 1st ed. Ankara: Türkiye Klinikleri; 2025.

ABSTRACT

Age-related macular degeneration (AMD) is a progressive and neurodegenerative eye disease that is closely related to aging and leads to central vision loss. Due to the aging world population, the number of patients with AMD is expected to be 288 million by 2040. Although it poses a serious threat due to its increasing frequency and the permanent visual damage it can cause, no treatment has been found that prevents the development of the disease and is consistently effective in its progression. AMD is a multifactorial disease caused by a combination of genetic predisposition, age-related changes and lifestyle factors (such as smoking or diet). The pathophysiology of AMD is complex due to the structural and cellular complexity of the retina and molecular mechanisms. A lack of understanding regarding the etiopathogenesis of this complex and multifactorial disease hinders the development of effective treatment options. Therefore, research has focused on elucidating the etiopathogenesis. Recent studies have highlighted the fundamental roles of oxidative stress, inflammation, and the complement system in the initiation and progression of this disease. As we age, the levels of intracellular oxidizing products increase while the body’s antioxidant capacity decreases. The retina is particularly susceptible to photooxidation and oxidation due to its prolonged exposure to light and high metabolic activity. Therefore, oxidative stress has been considered to have an important role in the pathophysiology of AMD. On the other hand, it is known that drusen have components such as acute phase reactants and complement cascade. Histopathological examination of CNV also shows inflammatory cells. This knowledge highlights the significant role of local inflammation in the pathogenesis of the condition. Among several studies, a specific variant of the complement factor H (CFH) gene is recognized as the most wellknown genetic risk factor for AMD. Oxidative stress can activate the alternative complement pathway and impair the secretion and function of CFH, one of the main regulators of this pathway. Disruption of the complement cascade has been shown to be strongly associated with AMD and targeted therapeutic studies have been conducted. In this part of the book, the effects of oxidative stress, inflammation and complement system on RPE and their role in the pathogenesis of AMD are reviewed.

Keywords: AMD; Age-related macular degeneration; Oxidative stress; Inflammation; Complement system

Referanslar

  1. Al-Zamil WM, Yassin SA. Recent developments in age-related macular degeneration: a review. Clin Interv Aging. 2017;12:131330. [Crossref]  [PubMed]  [PMC]
  2. Buitendijk GHS, Rochtchina E, Myers C, Cornelia MD, Lee K, Klein BEK, et al. Prediction of age-related macular degeneration in the general population: the Three Continent AMD Consortium. Ophthalmology. 2013;120:2644-55. [PubMed]
  3. Wong WL, Su X, Li X, Cheung CMG, Klein R, Cheng CY, et al. Global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis. Lancet Glob Health. 2014;2:e106-16. [Crossref]  [PubMed]
  4. Khandhadia S,Cherry J, Lotery AJ. Age-related macular degeneration. Adv. Exp. Med. Biol. 2012;724:15-36. [Crossref]  [PubMed]
  5. Mitchell P, Liew, G, Gopinath B, Wong TY. Age-related macular degeneration. Lancet 2018;392:1147-1159. [Crossref]  [PubMed]
  6. Horner F, Lip PL, Mohammed BR, Fusi-Rubiano W, Gokhale E, Mushtaq B, et al. Comparing Effectiveness of Three Different Anti-VEGF Treatment Regimens for Neovascular Age-Related Macular Degeneration: Two Years' Real-World Clinical Outcomes. Clin. Ophthalmol. 2021;15:1703-1713. [Crossref]  [PubMed]  [PMC]
  7. Arrigo A, Saladino A, Aragona E, Mercuri S, Introini U, Bandello F, et al. Different Outcomes of Anti-VEGF Treatment for Neovascular AMD according to Neovascular Sutypes and Baseline Features: 2-Year Real-Life Clinical Outcomes. BioMed Res. Int. 2021;2021:5516981. [Crossref]  [PubMed]  [PMC]
  8. Age-Related Eye Disease Study 2 Research G et al. Secondary analyses of the effects of lutein/zeaxanthin on age-related macular degeneration progression: AREDS2 report No 3. JAMA Ophthalmol. 2014;132(2):142-149. [PubMed]
  9. A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol. 2001;119(10): 1417-36. [Crossref]  [PubMed]  [PMC]
  10. Brown GC, Brown MM, Rapuano S, Boyer D. Cost-Utility Analysis of VEGF Inhibitors for Treating Neovascular Age-Related Macular Degeneration. Am.J.Ophthalmol.2020;218:225-241. [Crossref]  [PubMed]
  11. Comparison of Age-Related Macular Degeneration Treatments Trials (CATT) Research Group. Martin OF, Maguire MG. Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: Two-year results. Ophthalmology 2012;119:1388-98. [Crossref]  [PubMed]  [PMC]
  12. Chakravarthy U, Harding SP, Rogers CA, Downes SM, Lotery AJ, Culliford LA, et al. IVAN study investigators Alternative treatments to inhibit VEGF in age-related choroidal neovascularisation:2-year findings of the IVAN randomised controlled trial. Lancet 2013;382:1258-67. [Crossref]  [PubMed]
  13. Priya RR, Chew EY, Swaroop A. Genetic studies of age-related macular degeneration: lessons, challenges, and opportunities for disease management. Ophthalmology. 2012;119(12):2526-2536. [Crossref]  [PubMed]  [PMC]
  14. Ajana S., Cougnard-Gregoire A., Colijn JM., Merle BMJ., Verzijeden T., Jong PTV. et al. Predicting progression to advanced age-related macular degeneration from clinical, genetic and lifestyle factors using machine learning. Ophthalmology. 2021;128(4):587-597. [Crossref]  [PubMed]
  15. Lambert NG, El Shelmani H, Singh MK, Mansergh FC, Wride MA, Padilla M, et al. Risk factors and biomarkers of age-related macular degeneration. Prog. Retin. Eye Res. 2016;54:64-102. [Crossref]  [PubMed]  [PMC]
  16. Van de Ven JPH, Nilsson SC, Tan PL, Buitendijk GHS, Ristau T, Mohlin FC. et al. Campochiaro P.A., et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat. Genet. 2013;45:813-817. [Crossref]  [PubMed]
  17. Maugeri A, Barchitta M, Agodi A. The association between complement factor H rs1061170 polymorphism and age-related macular degeneration: A comprehensive meta-analysis stratified by stage of disease and ethnicity. Acta Ophthalmol. 2019;97:e8-e21. [Crossref]  [PubMed]
  18. Nussenblatt RB, Lee RW, Chew E, Wei L, Liu B, Sen HN, et al. Immune Responses in Age-Related Macular Degeneration and a Possible Long-term Therapeutic Strategy for Prevention. Am. J. Ophthalmol. 2014;158:5-11. [Crossref]  [PubMed]  [PMC]
  19. Shaw AC, Goldstein DR, Montgomery R. Age-dependent dysregulation of innate immunity. Nat. Rev. Immunol. 2013;13:875-887. [Crossref]  [PubMed]  [PMC]
  20. Hogan MJ. Role of the retinal pigment epithelium in macular disease. Trans Am Acad Ophthalmol Otolaryngol. 1972;76:64-80. [PubMed]
  21. Chen M, Xu H. Parainflammation, chronic inflammation, and age-related macular degeneration. J. Leukoc. Biol. 2015;98:713-725. [Crossref]  [PubMed]  [PMC]
  22. Bhutto I, Lutty G. Understanding age-related macular degeneration (AMD): Relationships between the photoreceptor/retinal pigment epithelium/Bruch's membrane/choriocapillaris complex. Mol Aspects Med. 2012;33:295-317. [Crossref]  [PubMed]  [PMC]
  23. Armento A, Ueffing M, Clark SJ. The complement system in age-related macular degeneration. Cell. Mol. Life Sci. 2021;78:4487-4505. [Crossref]  [PubMed]  [PMC]
  24. Feher J, Kovacs I, Artico M, Cavallotti C, Papale A, Balacco Gabrieli C. Mitochondrial alterations of retinal pigment epithelium in age-related macular degeneration. Neurobiol. Aging. 2006;27:983-993. [Crossref]  [PubMed]
  25. Deng, Y, Qiao, L, DU M, Qu CH Wan L, Li J, Huang L. Age-related macular degeneration: Epidemiology, genetics, pathophysiology, diagnosis, and targeted therapy. Genes Dis. 2022;9,6279. [Crossref]  [PubMed]  [PMC]
  26. Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF. An integrated hypothesis that considers Durban as biomarkers of immune-mediated processes at the RPE-Bruch's membrane interface in aging and age-related macular degeneration. Prog. Retin. Eye Res. 2001;20:705-732. [Crossref]  [PubMed]
  27. Ham WT, Ruffolo JJ, Mueller HA, Clarke AM, Moon ME. Histologic analysis of photochemical lesions produced in rhesus retina by short-wave-length light. Invest Ophthalmol Vis Sci. 1978;17:1029-1035. [PubMed]
  28. Nishimura Y, Hara H, Kondo M, Hong S. Matsugi T. Oxidative stress in retinal diseases. Oxid. Med. Cell. Longev.2017;2017:38. [Crossref]  [PubMed]  [PMC]
  29. Winkler BS, Boulton ME, Gottsch JD, Sternberg P. Oxidative damage and age-related macular degeneration. Mol Vis.1999;5:32. [PubMed]
  30. Zhang SM, Fan B, Li YL1, Zuo ZY, Li GY. Oxidative Stress-Involved Mitophagy of Retinal Pigment Epithelium and Retinal Degenerative Diseases. Cell Mol Neurobiol. 2023 Jul 1;43(7):3265-3276. [Crossref]  [PubMed]  [PMC]
  31. Chen A, Raule N, Chomyn A, Attardi G. Decreased reactive oxygen species production in cells with mitochondrial haplogroups associated with longevity. PLoS One. 2012;7:464-73. [Crossref]  [PubMed]  [PMC]
  32. Korshunov SS, Skulachev VP, Starkov AA. High protonic potential actuates a mechanism of production of reactive oxygen species in mitochondria. FEBS letters. 1997;416:15-18. [Crossref]  [PubMed]
  33. Molday RS, Moritz OL. Photoreceptors at a glance. J. Cell Sci. 2015;128:4039-4045. [Crossref]  [PubMed]  [PMC]
  34. Ershov AV, Bazan NG. Photoreceptor phagocytosis selectively activates PPAR gamma expression in retinal pigment epithelial cells. J Neurosci Res. 2000;60:328-337. [Crossref]  [PubMed]
  35. Wu L, Ueda K, Nagasaki T, Sparrow JR. Light Damage in Abca4 and Rpe65rd12Mice. Investig. Opthalmol. Vis. Sci. 2014;55:1910-1918. [Crossref]  [PubMed]  [PMC]
  36. Schutt F, Bergmann M, Holz FG, Kopitz J. Proteins Modified by Malondialdehyde, 4-Hydroxynonenal, or Advanced Glycation End Products in Lipofuscin of Human Retinal Pigment Epithelium. Investig. Opthalmol. Vis. Sci. 2003;44:3663- 3668. [Crossref]  [PubMed]
  37. Sparrow JR, Nakanishi K, Parish CA. The lipofuscin fluorophore A2E mediates blue light-induced damage to retinal pigmented epithelial cells. Investig Ophthalmol Vis Sci. 2000;41:1981-1989. [PubMed]
  38. Rahman I, MacNee W. Role of oxidants/antioxidants in smoking-induced lung diseases. Free Radic Biol Med. 1996;21:669-681. [Crossref]  [PubMed]
  39. Shaw PX, Zhang L, Zhang M, Du H, Zhao L, Lee C, et al. Complement factor H genotypes impact risk of age-related macular degeneration by interaction with oxidized phospholipids. Proc. Natl. Acad. Sci. USA. 2012;109:13757-13762. [Crossref]  [PubMed]  [PMC]
  40. Dick AD. Intraocular health and the many faces of inflammation. Eye. 2017;31:87-96. [Crossref]  [PubMed]  [PMC]
  41. Nowak JZ. Age-related macular degeneration (AMD): pathogenesis and therapy. Pharmacol Rep. 2006;58: 353-63. [PubMed]
  42. Nassar K, Grisanti S, Elfar E, Lüke J, Lüke M, Grisanti S. Serum cytokines as biomarkers for age-related macular degeneration. Graefes Arch Clin Exp Ophthalmol 2015;253:699-704. [Crossref]  [PubMed]
  43. Scholl HP, Charbel Issa P, Walier M, Janzer S, Pollok Kopp B, Börncke F, et al. Systemic complement activation in age-related macular degeneration. PLoS One 2008;3:2593. [Crossref]  [PubMed]  [PMC]
  44. Fletcher EL. Contribution of microglia and monocytes to the development and progression of age related macular degeneration. Ophthalmic Physiol Opt. 2020;40:128-39. [Crossref]  [PubMed]
  45. Ambati J, Atkinson JP, Gelfand BD. Immunology of age-related macular degeneration. Nat Rev Immunol. 2013;13:438-51. [Crossref]  [PubMed]  [PMC]
  46. Wooff Y, Man SM, Aggio-Bruce R, Natoli R, Fernando N. IL-1 Family Members Mediate Cell Death, Inflammation and Angiogenesis in Retinal Degenerative Diseases. Front Immunol. 2019;10:1618. [Crossref]  [PubMed]  [PMC]
  47. Coughlin B, Schnabolk G, Joseph K, Raikwar H, Kunchithapautham K, Johnson K. Connecting the innate and adaptive immune responses in mouse choroidal neovascularization via the anaphylatoxin C5a and γδT-cells. Sci Rep. 2016;6:23794. [Crossref]  [PubMed]  [PMC]
  48. Celkova L, Doyle SL, Campbell M. NLRP3 Inflammasome and Pathobiology in AMD. J Clin Med. 2015;4:172-92. [Crossref]  [PubMed]  [PMC]
  49. Lavalette S, Raoul W, Houssier M, Camelo S, Levy O, Clippe B, et al. Interleukin-1beta inhibition prevents choroidal neovascularization and does not exacerbate photoreceptor degeneration. Am J Pathol. 2011;178:241623. [Crossref]  [PubMed]  [PMC]
  50. Sato K, Tacked A, Hasegawa E, Jo YJ, Arima M, Oshima Y, et al. Interleukin-6 plays a crucial role in the development of subretinal fibrosis in a mouse model. Immunol Med. 2018;41:23-29. [Crossref]  [PubMed]
  51. Qin T, Gao S. Inhibition of Proteasome Activity Upregulates IL-6 Expression in RPE Cells through the Activation of P38 MAPKs. J Ophthalmol. 2018;2018:5392432. [Crossref]  [PubMed]  [PMC]
  52. Ardeljan D, Wang Y, Park S, Shen D, Chu XK, Yu CR, et al. Interleukin-17 retinotoxicity is prevented by gene transfer of a soluble interleukin-17 receptor acting as a cytokine blocker: implications for age-related macular degeneration. PLoS One. 2014;9:e95900. [Crossref]  [PubMed]  [PMC]
  53. Tan W, Zou J, Yoshida S, Jiang B, Zhou Y. The Role of Inflammation in Age-Related Macular Degeneration. Int J Biol Sci. 2020 Sep 23;16(15):2989-3001. [Crossref]  [PubMed]  [PMC]
  54. Jiang K, Cao S, Cui JZ, Matsubara JA. Immuno-modulatory Effect of IFN-gamma in AMD and its Role as a Possible Target for Therapy. J Clin Exp Ophthalmol. 2013;(Suppl2):0071-76. [Crossref]  [PubMed]  [PMC]
  55. Schwarzer P, Kokona D, Ebneter A, Zinkernagel MS. Effect of Inhibition of Colony-Stimulating Factor 1 Receptor on Choroidal Neovascularization in Mice. Am J Pathol. 2020;190:412-25. [Crossref]  [PubMed]
  56. Cherepanoff S, McMenamin P, Gillies MC, Kettle E, Sarks SH. Bruch's membrane and choroidal macrophages in early and advanced age-related macular degeneration. Br J Ophthalmol. 2010;94:918-25. [Crossref]  [PubMed]
  57. McLeod DS, Bhutto I, Edwards MM, Silver RE, Seddon JM, Lutty GA. Distribution and Quantification of Choroidal Macrophages in Human Eyes With Age-Related Macular Degeneration. Invest Ophthalmol Vis Sci. 2016;57:5843-55. [Crossref]  [PubMed]  [PMC]
  58. Cruz-Guilloty F, Saeed AM, Duffort S, Cano M, Ebrahimi KB, Ballmick A, et al. T cells and macrophages responding to oxidative damage cooperate in pathogenesis of a mouse model of age-related macular degeneration. PLoS One.2014;9:e88201. [Crossref]  [PubMed]  [PMC]
  59. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74:5-17. [Crossref]  [PubMed]  [PMC]
  60. Singh A, Subhi Y, Krogh Nielsen M, Falk MK, Huldig Matzen SM, Sellebjerg F, et al. Systemic frequencies of T helper 1 and T helper 17 cells in patients with age-related macular degeneration: A case-control study. Sci Rep. 2017;7:605. PMC free article [Crossref]  [PubMed]  [PMC]
  61. Lechner J, Chen M, Hogg RE, Toth L, Silvestri G, Chacravarthy U, et al. Alterations in Circulating Immune Cells in Neovascular Age-Related Macular Degeneration. Sci Rep. 2015;5:16754. [Crossref]  [PubMed]  [PMC]
  62. Mousavi M, Armstrong RA. Genetic risk factors and age-related macular degeneration (AMD) J Optom. 2013;6:176-184. [Crossref]  [PubMed]  [PMC]
  63. Edwards AO, Ritter R, Abel KJ, Manning A, Panhuysen C, Farrer LA. Complement factor H polymorphism and age-related macular degeneration. Science. 2005;308:421-424. [Crossref]  [PubMed]
  64. Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, et al. Complement factor H polymorphism in age-related macular degeneration. Science. 2005;308:385-389. [Crossref]  [PubMed]  [PMC]
  65. Carroll MC. The complement system in B cell regulation. Mol. Immunol. 2004;41:141-146. [Crossref]  [PubMed]
  66. Piri N, Kaplan HJ. Role of Complement in the Onset of Age-Related Macular Degeneration. Biomolecules. 2023 May 13;13(5):832. [Crossref]  [PubMed]  [PMC]
  67. Keenan TD, Toso M, Pappas C, Nichols L, Bishop PN, Hageman GS. Assessment of Proteins Associated With Complement Activation and Inflammation in Maculae of Human Donors Homozygous Risk at Chromosome 1 CFH-to-F13B. Invest. Ophthalmol. Vis. Sci. 2015;56:4870-4879. [Crossref]  [PubMed]
  68. Qin S, Dong N, Yang M, Wang J, Feng X, Wang Y. Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option. J. Immunol. Res. 2021;2021:9945725. [Crossref]  [PubMed]  [PMC]
  69. Harboe M, Ulvund G, Vien L, Fung M, Mollnes TE. The quantitative role of alternative pathway amplification in classical pathway induced terminal complement activation. Clin. Exp. Immunol. 2004;138:439-446. [Crossref]  [PubMed]  [PMC]
  70. Asgari E, Le Friec G, Yamamoto H, Perucha E, Sacks S, Koehl J, et al. C3a modulates IL-1β secretion in human monocytes by regulating ATP efflux and subsequent NLRP3 inflammasome activation. Blood. 2013;122:3473-3481. [Crossref]  [PubMed]
  71. Anderson OA, Finkelstein A, Shima DT. A2E induces IL-1β production in retinal pigment epithelial cells via the NLRP3 inflammasome. PLoS One. 2013;8:e67263. [Crossref]  [PubMed]  [PMC]
  72. Liu RT, Gao J, Cao S, Sandhu N, Cui JZ, Chou CL, Fang E, Matsubara JA. Inflammatory mediators induced by amyloid-beta in the retina and RPE in vivo: implications for inflammasome activation in age-related macular degeneration. Invest Ophthalmol Vis Sci. 2013;54:2225-2237. [Crossref]  [PubMed]  [PMC]
  73. Triantafilou K, Hughes TR, Triantafilou M, Morgan BP. The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation. J Cell Sci. 2013;126:2903-2913. [Crossref]  [PubMed]
  74. Kauppinen A, Niskanen H, Suuronen T, Kinnunen K, Salminen A, Kaarniranta K. Oxidative stress activates NLRP3 inflammasomes in ARPE-19 cells-implications for age-related macular degeneration (AMD) Immunol Lett. 2012;147:29-33. [Crossref]  [PubMed]
  75. Luo C, Zhao J, Madden A, Chen M, Xu H. Complement expression in retinal pigment epithelial cells is modulated by activated macrophages. Exp Eye Res. 2013;112:93-101. [Crossref]  [PubMed]
  76. Lueck K, Busch M, Moss SE, Greenwood J, Kasper M, Lommatzsch A, et al. Complement Stimulates Retinal Pigment Epithelial Cells to Undergo Pro-Inflammatory Changes. Ophthalmic Res. 2015;54:195-203. [Crossref]  [PubMed]
  77. Clark SJ, Ridge LA, Herbert AP, Hakobyan S, Mulloy B, Lennon R, et al. Tissue-specific host recognition by complement factor H is mediated by differential activities of its glycosaminoglycan-binding regions. J. Immunol. 2013;190:2049-2057. [Crossref]  [PubMed]  [PMC]
  78. Parente R, Clark S, Inforzato A, Day AJ. Complement factor H in host defense and immune evasion. Cell. Mol. Life Sci. 2017;74:1605-1624. [Crossref]  [PubMed]  [PMC]
  79. Ferrington DA, Kapphahn RJ, Leary MM, Atilano SR, Terluk MR, Karunadharma P, et al. Increased retinal mtDNA damage in the CFH variant associated with age-related macular degeneration. Exp. Eye Res. 2016;145:269-277. [Crossref]  [PubMed]  [PMC]
  80. Nozaki M, Raisler BJ, Sakurai E, Sarma JV, Barnum SR, Lambris JD, et al. Drusen complement components C3a and C5a promote choroidal neovascularization. Proc. Natl. Acad. Sci. USA. 2006;103:2328-2333. [Crossref]  [PubMed]  [PMC]
  81. Rohrer B, Long Q, Coughlin B, Wilson RB, Huang Y, Qiao F, et al. A targeted inhibitor of the alternative complement pathway reduces angiogenesis in a mouse model of age-related macular degeneration. Invest. Ophthalmol. Vis. Sci. 2009;50:3056-3064. [Crossref]  [PubMed]  [PMC]
  82. Bora NS, Jha P, Lyzogubov VV, Kaliappan S, Liu J, Tytarenko RG, et al. Recombinant membrane-targeted form of CD59 inhibits the growth of choroidal neovascular complex in mice. J. Biol. Chem. 2010;285:33826-33833. [Crossref]  [PubMed]  [PMC]
  83. Heesterbeek TJ, Lechanteur YTE, Lorés-Motta L, Schick T, Daha MR, Altay L, et al. Complement Activation Levels Are Related to Disease Stage in AMD. Invest. Ophthalmol. Vis. Sci. 2020;61:18. [Crossref]  [PubMed]  [PMC]
  84. Seddon JM, Gensler G, Milton RC, Klein ML, Rifai N. Association between C-reactive protein and age-related macular degeneration. JAMA. 2004;291(6):704-710. [Crossref]  [PubMed]
  85. Lauer N, Mihlan M, Hartmann A, Schlötzer-Schrehardt U, Keilhauer C, Scholl HPN, et al. Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk variant. J Immunol. 2011;187(8):4374-4383. [Crossref]  [PubMed]
  86. Okemefuna AI, Nan R, Miller A, Gor J, Perkins SJ. Complement factor H binds at two independent sites to C-reactive protein in acute phase concentrations. J Biol Chem. 2010;285:1053-1065. [Crossref]  [PubMed]  [PMC]
  87. Kaemmerer E, Schutt F, Krohne TU, Holz FG, Kopitz J. Effects of lipid peroxidation-related protein modifications on RPE lysosomal functions and POS phagocytosis. Invest Ophthalmol Vis Sci. 2007;48:1342-1347. [Crossref]  [PubMed]
  88. Weismann D, Hartvigsen K, Lauer N, Bennett KL, Scholl HP, Charbel Issa P, et al. Complement factor H binds malondialdehyde epitopes and protects from oxidative stress. Nature. 2011;478:76-81. [Crossref]  [PubMed]  [PMC]
  89. Chen M, Muckersie E, Robertson M, Forrester JV, Xu H. Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina. Exp Eye Res. 2008;87:543-550. [Crossref]  [PubMed]
  90. Thurman JM, Renner B, Kunchithapautham K, Ferreira VP, Pangburn MK, Ablonczy Z, et al. Oxidative stress renders retinal pigment epithelial cells susceptible to complement-mediated injury. J Biol Chem. 2009;284:16939-16947. [Crossref]  [PubMed]  [PMC]
  91. Kaarniranta K, Salminen A. Age-related macular degeneration: activation of innate immunity system via pattern recognition receptors. J Mol Med (Berl) 2009;87:117-123. [Crossref]  [PubMed]
  92. Borras C, Canonica J, Jorieux S, Abache T, El Sanharawi M, Klein C, et al. CFH exerts anti-oxidant effects on retinal pigment epithelial cells independently from protecting against membrane attack complex. Sci. Rep. 2019;9:1-12. [Crossref]  [PubMed]  [PMC]
  93. Armento A, Honisch S, Panagiotakopoulou V, Sonntag I, Jacob A, Bolz S, et al. Loss of Complement Factor H impairs antioxidant capacity and energy metabolism of human RPE cells. Sci. Rep. 2020;10:1-15. [Crossref]  [PubMed]  [PMC]
  94. Du H, Xiao X, Stiles T, Douglas C, Ho D, Shaw PX. Novel Mechanistic Interplay between Products of Oxidative Stress and Components of the Complement System in AMD Pathogenesis. Open J. Ophthalmol. 2016;06:43-50. [Crossref]  [PubMed]  [PMC]