The Blood-ocular Barriers and their Dysfunction: Anatomy, Physiology, Pathology

Abstract

Complex barriers comprise the blood-aqueous (BAB) and the blood-retinal barrier (BRB), and separate anterior and posterior eye chambers, vitreous body, and sensory retina from the circulation. They prevent pathogens and toxins from entering the eye, control movement of fluid, proteins, and metabolites, and contribute to the maintenance of the ocular immune status. Morphological correlates of blood-ocular barriers are tight junctions between neighboring endothelial and epithelial cells, which function as gatekeepers of the paracellular transport of molecules, thereby limiting their uncontrolled access to ocular chambers and tissues. The BAB is composed of tight junctions between endothelial cells of the iris vasculature, endothelial cells of Schlemmʼs canal inner wall, and cells of the nonpigmented ciliary epithelium. The BRB consists of tight junctions between endothelial cells of the retinal vessels (inner BRB) and epithelial cells of the retinal pigment epithelium (outer BRB). These junctional complexes respond rapidly to pathophysiological changes, thus enabling vascular leakage of blood-derived molecules and inflammatory cells into ocular tissues and chambers. Blood-ocular barrier function, which can be clinically measured by laser flare photometry or fluorophotometry, is compromised in traumatic, inflammatory, or infectious processes, but also frequently contributes to the pathophysiology of chronic diseases of the anterior eye segment and the retina, as exemplified by diabetic retinopathy and age-related macular degeneration.

Key words

blood-ocular barriers - blood-aqueous barrier - blood-retinal barrier - tight junctions - diabetic retinopathy - age-related macular degeneration

Publikationsverlauf

Eingereicht: 05. Januar 2023

Angenommen: 21. März 2023

Artikel online veröffentlicht:
19. Mai 2023

• References/Literatur

• 1 Kellner U. Physiologie und Pathophysiologie der Retina und des Glaskörpers. In: Kellner U, Wachtlin J. Hrsg. Retina. Stuttgart: Thieme; 2008
• 2 Cunha-Vaz J. The blood-ocular barriers. Surv Ophthalmol 1979; 23: 279-296
• 3 Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 2003; 3: 879-889
• 4 Joachim S, Schmid H. Die Immunologie des Auges. Allergo J 2014; 23: 14-15
• 5 Raviola G. The structural basis of the blood-ocular barriers. Exp Eye Res 1977; 25 (Suppl.) S27-S63
• 6 Otani T, Furuse M. Tight Junction Structure and Function Revisited. Trends Cell Biol 2020; 30: 805-817
• 7 Krug SM, Schulzke JD, Fromm M. Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol 2014; 36: 166-176
• 8 Vellonen KS, Hellinen L, Mannermaa E. et al. Expression, activity and pharmacokinetic impact of ocular transporters. Adv Drug Deliv Rev 2018; 126: 3-22
• 9 Liu P, Thomson BR, Khalatyan N. et al. Selective permeability of mouse blood-aqueous barrier as determined by ¹⁵N-heavy isotope tracing and mass spectrometry. Proc Natl Acad Sci U S A 2018; 115: 9032-9037
• 10 Schrems W, Grosskopf P. Fluorophotometrie als Methode zum Nachweis von Permeabilitätsänderungen der Blut-Kammerwasser-Schranke. Klin Monbl Augenheilkd 1986; 188: 122-127
• 11 Van Schaik HJ, Heintz B, Larsen M. et al. Permeability of the blood-retinal barrier in healthy humans. European Concerted Action on Ocular Fluorometry. Graefes Arch Clin Exp Ophthalmol 1997; 235: 639-646
• 12 Sawa M. Laser flare-cell photometer: principle and significance in clinical and basic ophthalmology. Jpn J Ophthalmol 2017; 61: 21-42
• 13 Schaub F, Fauser S, Kirchhof B. et al. Laser Flare Photometrie zur Identifizierung von Hochrisikopatienten für proliferative Vitreoretinopathie. Ophthalmologe 2018; 115: 1079-1083
• 14 Küchle M, Hannappel E, Nguyen NX. et al. Korrelation zwischen Tyndallometrie mit dem, „Laser Flare-Cell Meter“ in vivo und biochemischer Proteinbestimmung im Kammerwasser. KIin Monbl Augenheilkd 1993; 202: 14-18
• 15 De Maria M, Iannetta D, Cimino L. et al. Measuring Anterior Chamber Inflammation After Cataract Surgery: A Review of the Literature Focusing on the Correlation with Cystoid Macular Edema. Clin Ophthalmol 2020; 14: 41-52
• 16 Liu X, McNally TW, Beese S. et al. Non-invasive Instrument-Based Tests for Quantifying Anterior Chamber Flare in Uveitis: A Systematic Review. Ocul Immunol Inflamm 2021; 29: 982-990
• 17 Ragg S, Key M, Rankin F. et al. The Effect of Molecular Weight on Passage of Proteins Through the Blood-Aqueous Barrier. Invest Ophthalmol Vis Sci 2019; 60: 1461-1469
• 18 Shechter R, London A, Schwartz M. Orchestrated leukocyte recruitment to immune-privileged sites: absolute barriers versus educational gates. Nat Rev Immunol 2013; 13: 206-218
• 19 Freddo TF. A contemporary concept of the blood-aqueous barrier. Prog Retin Eye Res 2013; 32: 181-195
• 20 Coca-Prados M. The blood-aqueous barrier in health and disease. J Glaucoma 2014; 23 (8 Suppl. 1): S36-S38
• 21 Braakman ST, Moore jr. JE, Ethier CR. et al. Transport across Schlemmʼs canal endothelium and the blood-aqueous barrier. Exp Eye Res 2016; 146: 17-21
• 22 Küchle M. Laser tyndallometry in anterior segment diseases. Curr Opin Ophthalmol 1994; 5: 110-116
• 23 Mao Z, Chen XB, Zhong YM. et al. Damage to the Blood-Aqueous Barrier in Ocular Blunt Trauma and Its Association with Intraocular Pressure Elevation. Ophthalmic Res 2016; 56: 92-97
• 24 Schauersberger J, Kruger A, Müllner-Eidenböck A. et al. Long-term disorders of the blood-aqueous barrier after small-incision cataract surgery. Eye (Lond) 2000; 14: 61-63
• 25 Liu Y, Luo L, He M, Liu X. Disorders of the blood-aqueous barrier after phacoemulsification in diabetic patients. Eye (Lond) 2004; 18: 900-904
• 26 Schumacher S, Nguyen NX, Küchle M. et al. Quantification of aqueous flare after phacoemulsification with intraocular lens implantation in eyes with pseudoexfoliation syndrome. Arch Ophthalmol 1999; 117: 733-735
• 27 Eter N, Spitznas M, Sbeity Z. et al. Evaluation of the blood-aqueous barrier by laser flare cell photometry following retinal cryocoagulation. Graefes Arch Clin Exp Ophthalmol 2004; 242: 120-124
• 28 Toris CB, Camras CB, Yablonski ME. et al. Effects of exogenous prostaglandins on aqueous humor dynamics and blood-aqueous barrier function. Surv Ophthalmol 1997; 41 (Suppl. 02) S69-S75
• 29 Pleyer U, Ruokonen P. Kammerwasseranalyse in der Diagnostik intraokularer Entzündungen. In: Lang GK, Lang GE. Hrsg. Schlaglicht Augenheilkunde: Entzündliche Augenerkrankungen. Stuttgart: Thieme; 2016: 389-396
• 30 Küchle M, Naumann GOH. Intraokulare Entzündungen. In: Naumann GOH. Hrsg. Pathologie des Auges. Berlin, Heidelberg: Springer; 1997: 143-300
• 31 Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 2015; 15: 692-704
• 32 Labib BA, Chigbu DI. Pathogenesis and Manifestations of Zika Virus-Associated Ocular Diseases. Trop Med Infect Dis 2022; 7: 106
• 33 Koo EH, Eghrari AO, Dzhaber D. et al. Presence of SARS-CoV-2 Viral RNA in Aqueous Humor of Asymptomatic Individuals. Am J Ophthalmol 2021; 230: 151-155
• 34 Araujo-Silva CA, Marcos AAA, Marinho PM. et al. Presumed SARS-CoV-2 Viral Particles in the Human Retina of Patients With COVID-19. JAMA Ophthalmol 2021; 139: 1015-1021
• 35 Kong X, Liu X, Huang X. et al. Damage to the blood-aqueous barrier in eyes with primary angle closure glaucoma. Mol Vis 2010; 16: 2026-2032
• 36 Lee MC, Shei W, Chan AS. et al. Primary angle closure glaucoma (PACG) susceptibility gene PLEKHA7 encodes a novel Rac1/Cdc42 GAP that modulates cell migration and blood-aqueous barrier function. Hum Mol Genet 2017; 26: 4011-4027
• 37 Naumann GO, Schlötzer-Schrehardt U, Küchle M. Pseudoexfoliation syndrome for the comprehensive ophthalmologist. Intraocular and systemic manifestations. Ophthalmology 1998; 105: 951-968
• 38 Arcieri ES, Santana A, Rocha FN. et al. Blood-aqueous barrier changes after the use of prostaglandin analogues in patients with pseudophakia and aphakia: a 6-month randomized trial. Arch Ophthalmol 2005; 123: 186-192
• 39 Cellini M, Caramazza R, Bonsanto D. et al. Prostaglandin analogs and blood-aqueous barrier integrity: a flare cell meter study. Ophthalmologica 2004; 218: 312-317
• 40 Miyake K, Ota I, Ibaraki N. et al. Enhanced disruption of the blood-aqueous barrier and the incidence of angiographic cystoid macular edema by topical timolol and its preservative in early postoperative pseudophakia. Arch Ophthalmol 2001; 119: 387-394
• 41 Parodi MB, Liberali T, Iacono P. et al. The spectrum of iris angiography abnormalities in pseudoexfoliation syndrome. Eye (Lond) 2008; 22: 49-54
• 42 Nguyen NX, Küchle M, Martus P. et al. Quantification of blood–aqueous barrier breakdown after trabeculectomy: pseudoexfoliation versus primary open-angle glaucoma. J Glaucoma 1999; 8: 18-23
• 43 Mayro EL, Ritch R, Pasquale LR. Early-onset Exfoliation Syndrome: A Literature Synthesis. J Glaucoma 2021; 30: e164-e168
• 44 Wiggs JL, Pawlyk B, Connolly E. et al. Disruption of the blood-aqueous barrier and lens abnormalities in mice lacking lysyl oxidase-like 1 (LOXL1). Invest Ophthalmol Vis Sci 2014; 55: 856-864
• 45 Küchle M, Schönherr LI, Nguyen NX. et al. Quantitative measurement of aqueous flare and aqueous “cells” in eyes with diabetic retinopathy. Ger J Ophthalmol 1992; 1: 164-169
• 46 Schalnus R, Ohrloff C. Blut-Retina-Schranke und Blut-Kammerwasser-Schranke bei Typ I-Diabetikern ohne Retinopathie. Bestimmung der Permeabilität mittels Fluorophotometrie und Laser Flare Messung. Klin Monbl Augenheilkd 1993; 202: 281-287
• 47 Schoeneberger V, Eberhardt S, Menghesha L. et al. Association between blood-aqueous barrier disruption and extent of retinal detachment. Eur J Ophthalmol 2023; 33: 421-427
• 48 Schröder S, Muether PS, Caramoy A. et al. Anterior chamber aqueous flare is a strong predictor for proliferative vitreoretinopathy in patients with rhegmatogenous retinal detachment. Retina 2012; 32: 38-42
• 49 Mulder VC, van Dijk EHC, van Meurs IA. et al. Postoperative aqueous humour flare as a surrogate marker for proliferative vitreoretinopathy development. Acta Ophthalmol 2018; 96: 192-196
• 50 Hoerster R, Hermann MM, Rosentreter A. et al. Profibrotic cytokines in aqueous humour correlate with aqueous flare in patients with rhegmatogenous retinal detachment. Br J Ophthalmol 2013; 97: 450-453
• 51 Provis JM. Development of the primate retinal vasculature. Prog Retin Eye Res 2001; 20: 799-821
• 52 Cunha-Vaz J, Bernardes R, Lobo C. Blood-retinal barrier. Eur J Ophthalmol 2011; 21 (Suppl. 06) S3-S9
• 53 Chen M, Luo C, Zhao J. et al. Immune regulation in the aging retina. Prog Retin Eye Res 2019; 69: 159-172
• 54 Gardner TW, Antonetti DA, Barber AJ. et al. The molecular structure and function of the inner blood-retinal barrier. Doc Ophthalmol 1999; 97: 229-237
• 55 Diaz-Coranguez M, Ramos C, Antonetti DA. The inner blood-retinal barrier: Cellular basis and development. Vision Res 2017; 139: 123-137
• 56 Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 2004; 5: 261-270
• 57 Gonçalves A, Ambrósio AF, Fernandes R. Regulation of claudins in blood-tissue barriers under physiological and pathological states. Tissue Barriers 2013; 1: e24782
• 58 Joussen AM, Murata T, Tsujikawa A. et al. Leukocyte-mediated endothelial cell injury and death in the diabetic retina. Am J Pathol 2001; 158: 147-152
• 59 Nakahara T, Mori A, Kurauchi Y. et al. Neurovascular interactions in the retina: physiological and pathological roles. J Pharmacol Sci 2013; 123: 79-84
• 60 Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res 2005; 97: 512-523
• 61 Braunger BM, Leimbeck SV, Schlecht A. et al. Deletion of ocular transforming growth factor beta signaling mimics essential characteristics of diabetic retinopathy. Am J Pathol 2015; 185: 1749-1768
• 62 Naumann GOH. Glaukome und Hypotonie-Syndrome. In: Naumann GOH. Hrsg. Pathologie des Auges. Berlin, Heidelberg: Springer; 1997: 1245-1371
• 63 Vighi E, Trifunović D, Veiga-Crespo P. et al. Combination of cGMP analogue and drug delivery system provides functional protection in hereditary retinal degeneration. Proc Natl Acad Sci U S A 2018; 115: E2997-E3006
• 64 Campbell M, Cassidy PS, OʼCallaghan J. et al. Manipulating ocular endothelial tight junctions: Applications in treatment of retinal disease pathology and ocular hypertension. Prog Retin Eye Res 2018; 62: 120-133
• 65 Klaassen I, Van Noorden CJ, Schlingemann RO. Molecular basis of the inner blood-retinal barrier and its breakdown in diabetic macular edema and other pathological conditions. Prog Retin Eye Res 2013; 34: 19-48
• 66 Hudson N, Cahill M, Campbell M. Inner blood-retina barrier involvement in dry age-related macular degeneration (AMD) pathology. Neural Regen Res 2020; 15: 1656-1657
• 67 Messmer EP, Ruggli GH, Apple DJ, Naumann GOH. Spezielle Pathologie der Retina. In: Naumann GOH. Pathologie des Auges. Berlin, Heidelberg: Springer; 1997: 995-1152
• 68 OʼLeary F, Campbell M. The blood-retina barrier in health and disease. FEBS J 2023; 290: 878-891
• 69 Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012; 366: 1227-1239
• 70 Pan WW, Lin F, Fort PE. The Innate Immune System in Diabetic Retinopathy. Prog Retin Eye Res 2021; 84: 100940
• 71 Daruich A, Matet A, Moulin A. et al. Mechanisms of macular edema: Beyond the surface. Prog Retin Eye Res 2018; 63: 20-68
• 72 Xu HZ, Song Z, Fu S. et al. RPE barrier breakdown in diabetic retinopathy: seeing is believing. J Ocul Biol Dis Infor 2011; 4: 83-92
• 73 Weinberger D, Fink-Cohen S, Gaton DD. et al. Non-retinovascular leakage in diabetic maculopathy. Br J Ophthalmol 1995; 79: 728-731
• 74 Curcio CA. Soft Drusen in Age-Related Macular Degeneration: Biology and Targeting Via the Oil Spill Strategies. Invest Ophthalmol Vis Sci 2018; 59: AMD160-AMD181
• 75 Shu DY, Butcher E, Saint-Geniez M. EMT and EndMT: Emerging Roles in Age-Related Macular Degeneration. Int J Mol Sci 2020; 21: 4271
• 76 Holz FG, Strauss EC, Schmitz-Valckenberg S. et al. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology 2014; 121: 1079-1091
• 77 Wong TY, Chakravarthy U, Klein R. et al. The natural history and prognosis of neovascular age-related macular degeneration: a systematic review of the literature and meta-analysis. Ophthalmology 2008; 115: 116-126
• 78 Mammadzada P, Corredoira PM, André H. The role of hypoxia-inducible factors in neovascular age-related macular degeneration: a gene therapy perspective. Cell Mol Life Sci 2020; 77: 819-833
• 79 Usui-Ouchi A, Usui Y, Kurihara T. et al. Retinal microglia are critical for subretinal neovascular formation. JCI Insight 2020; 5: e137317
• 80 Funk M, Karl D, Georgopoulos M. et al. Neovascular age-related macular degeneration: intraocular cytokines and growth factors and the influence of therapy with ranibizumab. Ophthalmology 2009; 116: 2393-2399
• 81 Wecker T, Ehlken C, Bühler A. et al. Five-year visual acuity outcomes and injection patterns in patients with pro-re-nata treatments for AMD, DME, RVO and myopic CNV. Br J Ophthalmol 2017; 101: 353-359
• 82 Marneros AG, Fan J, Yokoyama Y. et al. Vascular endothelial growth factor expression in the retinal pigment epithelium is essential for choriocapillaris development and visual function. Am J Pathol 2005; 167: 1451-1459
• 83 Kurihara T, Westenskow PD, Bravo S. et al. Targeted deletion of Vegfa in adult mice induces vision loss. J Clin Invest 2012; 122: 4213-4217
• 84 Schlecht A, Leimbeck SV, Jagle H. et al. Deletion of Endothelial Transforming Growth Factor-beta Signaling Leads to Choroidal Neovascularization. Am J Pathol 2017; 187: 2570-2589