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Klin Monbl Augenheilkd 2023; 240(05): 650-661
DOI: 10.1055/a-2063-8957
Review/Übersicht

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

Artikel in mehreren Sprachen: English | deutsch
Barbara M. Braunger
1   Institut für Anatomie und Zellbiologie, Julius-Maximilians-Universität Würzburg, Medizinische Fakultät, Deutschland
,
Andreas Gießl
2   Augenklinik, Friedrich-Alexander-Universität Erlangen-Nürnberg, Medizinische Fakultät, Erlangen, Deutschland
,
Ursula Schlötzer-Schrehardt
2   Augenklinik, Friedrich-Alexander-Universität Erlangen-Nürnberg, Medizinische Fakultät, Erlangen, Deutschland
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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

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References/Literatur

  • 1 Kellner U. Physiologie und Pathophysiologie der Retina und des Glaskörpers. In: Kellner U, Wachtlin J. Hrsg. Retina. Stuttgart: Thieme; 2008
    Suche in Google Scholar
  • 2 Cunha-Vaz J. The blood-ocular barriers. Surv Ophthalmol 1979; 23: 279-296
    Suche in Google Scholar
  • 3 Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol 2003; 3: 879-889
    Suche in Google Scholar
  • 4 Joachim S, Schmid H. Die Immunologie des Auges. Allergo J 2014; 23: 14-15
    Suche in Google Scholar
  • 5 Raviola G. The structural basis of the blood-ocular barriers. Exp Eye Res 1977; 25 (Suppl.) S27-S63
    Suche in Google Scholar
  • 6 Otani T, Furuse M. Tight Junction Structure and Function Revisited. Trends Cell Biol 2020; 30: 805-817
    Suche in Google Scholar
  • 7 Krug SM, Schulzke JD, Fromm M. Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol 2014; 36: 166-176
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 10 Schrems W, Grosskopf P. Fluorophotometrie als Methode zum Nachweis von Permeabilitätsänderungen der Blut-Kammerwasser-Schranke. Klin Monbl Augenheilkd 1986; 188: 122-127
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 12 Sawa M. Laser flare-cell photometer: principle and significance in clinical and basic ophthalmology. Jpn J Ophthalmol 2017; 61: 21-42
    Suche in Google Scholar
  • 13 Schaub F, Fauser S, Kirchhof B. et al. Laser Flare Photometrie zur Identifizierung von Hochrisikopatienten für proliferative Vitreoretinopathie. Ophthalmologe 2018; 115: 1079-1083
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 19 Freddo TF. A contemporary concept of the blood-aqueous barrier. Prog Retin Eye Res 2013; 32: 181-195
    Suche in Google Scholar
  • 20 Coca-Prados M. The blood-aqueous barrier in health and disease. J Glaucoma 2014; 23 (8 Suppl. 1): S36-S38
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 22 Küchle M. Laser tyndallometry in anterior segment diseases. Curr Opin Ophthalmol 1994; 5: 110-116
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 30 Küchle M, Naumann GOH. Intraokulare Entzündungen. In: Naumann GOH. Hrsg. Pathologie des Auges. Berlin, Heidelberg: Springer; 1997: 143-300
    Suche in Google Scholar
  • 31 Vestweber D. How leukocytes cross the vascular endothelium. Nat Rev Immunol 2015; 15: 692-704
    Suche in Google Scholar
  • 32 Labib BA, Chigbu DI. Pathogenesis and Manifestations of Zika Virus-Associated Ocular Diseases. Trop Med Infect Dis 2022; 7: 106
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 37 Naumann GO, Schlötzer-Schrehardt U, Küchle M. Pseudoexfoliation syndrome for the comprehensive ophthalmologist. Intraocular and systemic manifestations. Ophthalmology 1998; 105: 951-968
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 41 Parodi MB, Liberali T, Iacono P. et al. The spectrum of iris angiography abnormalities in pseudoexfoliation syndrome. Eye (Lond) 2008; 22: 49-54
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 43 Mayro EL, Ritch R, Pasquale LR. Early-onset Exfoliation Syndrome: A Literature Synthesis. J Glaucoma 2021; 30: e164-e168
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 51 Provis JM. Development of the primate retinal vasculature. Prog Retin Eye Res 2001; 20: 799-821
    Suche in Google Scholar
  • 52 Cunha-Vaz J, Bernardes R, Lobo C. Blood-retinal barrier. Eur J Ophthalmol 2011; 21 (Suppl. 06) S3-S9
    Suche in Google Scholar
  • 53 Chen M, Luo C, Zhao J. et al. Immune regulation in the aging retina. Prog Retin Eye Res 2019; 69: 159-172
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 55 Diaz-Coranguez M, Ramos C, Antonetti DA. The inner blood-retinal barrier: Cellular basis and development. Vision Res 2017; 139: 123-137
    Suche in Google Scholar
  • 56 Dejana E. Endothelial cell-cell junctions: happy together. Nat Rev Mol Cell Biol 2004; 5: 261-270
    Suche in Google Scholar
  • 57 Gonçalves A, Ambrósio AF, Fernandes R. Regulation of claudins in blood-tissue barriers under physiological and pathological states. Tissue Barriers 2013; 1: e24782
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 60 Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res 2005; 97: 512-523
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 62 Naumann GOH. Glaukome und Hypotonie-Syndrome. In: Naumann GOH. Hrsg. Pathologie des Auges. Berlin, Heidelberg: Springer; 1997: 1245-1371
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 68 OʼLeary F, Campbell M. The blood-retina barrier in health and disease. FEBS J 2023; 290: 878-891
    Suche in Google Scholar
  • 69 Antonetti DA, Klein R, Gardner TW. Diabetic retinopathy. N Engl J Med 2012; 366: 1227-1239
    Suche in Google Scholar
  • 70 Pan WW, Lin F, Fort PE. The Innate Immune System in Diabetic Retinopathy. Prog Retin Eye Res 2021; 84: 100940
    Suche in Google Scholar
  • 71 Daruich A, Matet A, Moulin A. et al. Mechanisms of macular edema: Beyond the surface. Prog Retin Eye Res 2018; 63: 20-68
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 73 Weinberger D, Fink-Cohen S, Gaton DD. et al. Non-retinovascular leakage in diabetic maculopathy. Br J Ophthalmol 1995; 79: 728-731
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 76 Holz FG, Strauss EC, Schmitz-Valckenberg S. et al. Geographic atrophy: clinical features and potential therapeutic approaches. Ophthalmology 2014; 121: 1079-1091
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 79 Usui-Ouchi A, Usui Y, Kurihara T. et al. Retinal microglia are critical for subretinal neovascular formation. JCI Insight 2020; 5: e137317
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar
  • 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
    Suche in Google Scholar