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      Blood-retina barrier dysfunction in experimental autoimmune uveitis: the pathogenesis and therapeutic targets

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          Abstract

          Experimental autoimmune uveitis (EAU), an animal model of human uveitis, is characterized by infiltration of autoimmune T cells in the uvea as well as in the retina of susceptible animals. EAU is induced by the immunization of uveitogenic antigens, including either retinal soluble-antigen or interphotoreceptor retinoid-binding proteins, in Lewis rats. The pathogenesis of EAU in rats involves the proliferation of autoimmune T cells in peripheral lymphoid tissues and breakdown of the blood-retinal barrier, primarily in the uvea and retina, finally inducing visual dysfunction. In this review, we describe recent EAU studies to facilitate the design of a therapeutic strategy through the interruption of uveitogenic factors during the course of EAU, which will be helpful for controlling human uveitis.

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          Rodent models of experimental autoimmune uveitis.

          Pradeep K. Agarwal, P Silver, Rachel R. Caspi (2011)
          The model of experimental autoimmune uveitis (EAU) in mice and in rats is described. EAU targets immunologically privileged retinal antigens and serves as a model of autoimmune uveitis in humans as well as a model for autoimmunity in a more general sense. EAU is a well-characterized, robust, and reproducible model that is easily followed and quantitated. It is inducible with synthetic peptides derived from retinal autoantigens in commonly available strains of rats and mice. The ability to induce EAU in various gene-manipulated, including HLA-transgenic, mouse strains makes the EAU model suitable for the study of basic mechanisms as well as in clinically relevant interventions.
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            Understanding uveitis: the impact of research on visual outcomes.

            Graeme I Murray, D Smet, Talin Barisani-Asenbauer … (2011)
            The term uveitis encompasses a very diverse group of inflammatory ocular diseases that cause a significant burden of legal and economic blindness. Indeed, the socioeconomic impact of uveitis is at least as significant as that of diabetic retinopathy and, in the majority of cases, those affected are young individuals of working age. Significant progress has been made in our understanding of the mechanisms underlying the inflammatory process through the use of animal models, but correlation with human disease has proved elusive and many scientific approaches which appear highly effective in animal models prove to be less effective in patients. Nevertheless, effective, targeted treatments are needed in uveitis as current treatment is based on corticosteroids and immunosuppressive drugs whose usefulness is limited by their many side-effects. The aims of this review are to summarize the state of clinical research in uveitis, to identify gaps in our knowledge, and to propose new opportunities and methodologies for future developments in all aspects of uveitis research, including epidemiology, economic impact analysis, diagnosis, therapeutics, and clinical study design. Optimal patient management and efficient drug development depend on validated structured tools, such as those that have helped to drive a rapid acceleration in the means and methods available to assess and treat patients with rheumatoid arthritis and cancer. Uveitis care should witness a similar boom as the issues discussed are resolved. Copyright © 2011 Elsevier Ltd. All rights reserved.
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              Immunosuppression for the Uveitides

              Douglas A Jabs (2018)
              The uveitides are a collection of over 30 diseases, characterized by intraocular inflammation. Many cases of juvenile idiopathic arthritis-associated uveitis, many cases of intermediate uveitis, and most cases of posterior and panuveitides needing treatment are treated with corticosteroids and immunosuppression. Disease-specific, time-updated modelling of clinical data for several uveitides suggests superior prevention of ocular complications and of visual outcomes with immunosuppression. These studies also suggest that oral corticosteroids at doses low enough for safe long-term therapy (i.e. ≤ 7.5 mg/day) are ineffective, implying that immunosuppression should be part of the initial regimen. The Multicenter Uveitis Steroid Treatment (MUST) Trial and Follow-up Study was a randomized comparative effectiveness trial comparing systemic therapy with oral corticosteroids and immunosuppression to regional corticosteroid treatment. It demonstrated that, when used properly, oral corticosteroids and immunosuppression can be given safely for up to 7 years with no evident increased risk of systemic side effects compared to regional corticosteroid therapy, except for greater antibiotic use for infections. The Systemic Treatment for Eye Diseases (SITE) Cohort Study suggested long-term safety for this approach, when the immunosuppressive agents were either antimetabolites or calcineurin inhibitors. Hence, oral corticosteroids and immunosuppression may be a preferred initial therapy for many non-infectious, intermediate, posterior, and panuveitides. Non-alkylating-agent immunosuppression has a low rate of sustained, drug-free remissions, <10%/year. Non-alkylating-agent immunosuppression for ≥3 years with control of the inflammation for ≥2 years is associated with a decreased risk of relapse after discontinuing immunosuppression. Alkylating agents can induce sustained drug-free remissions but likely increase the lifetime risk of cancer. Biologics, which target specific cytokines and pathways, hold promise for the future. Monoclonal antibodies directed against tumor necrosis factor (TNF)-α, have been studied most often, and one, adalimumab, is United States Food and Drug Administration approved for the treatment of non-infectious, intermediate, posterior, and panuveitides.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Anat Cell Biol
                Journal ID (iso-abbrev): Anat Cell Biol
                Title: Anatomy & Cell Biology
                Publisher: Korean Association of Anatomists
                ISSN (Print): 2093-3665
                ISSN (Electronic): 2093-3673
                Publication date (Print): 31 March 2022
                Publication date (Electronic): 31 March 2022
                Publication date PMC-release: 31 March 2022
                Volume: 55
                Issue: 1
                Pages: 20-27
                Affiliations
                [1 ]Department of Anatomy, Kosin University College of Medicine, Busan, Korea
                [2 ]Department of Veterinary Anatomy, College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju, Korea
                [3 ]Department of Animal Science, College of Life Science, Sangji University, Wonju, Korea
                [4 ]Functional Biomaterials Research Center, Korea Research Institute of Bioscience and Biotechnology, Jeongeup, Korea
                [5 ]Department of Veterinary Anatomy, College of Veterinary Medicine and BK21 Plus Project Team, Chonnam National University, Gwangju, Korea
                Author notes
                Corresponding author: Taekyun Shin, Department of Veterinary Anatomy, College of Veterinary Medicine and Veterinary Medical Research Institute, Jeju National University, Jeju 63243, Korea, E-mail: shint@ 123456jejunu.ac.kr
                [*]

                These authors contributed equally to this work.

                Author information
                https://orcid.org/0000-0003-2238-1038
                https://orcid.org/0000-0002-6569-9487
                https://orcid.org/0000-0002-7302-9694
                https://orcid.org/0000-0002-0723-805X
                https://orcid.org/0000-0003-2451-0374
                https://orcid.org/0000-0002-9851-4354
                Article
                Publisher ID: acb-55-1-20
                DOI: 10.5115/acb.21.227
                PMC ID: 8968224
                PubMed ID: 35354673
                SO-VID: e931d913-f7f6-4115-9eaf-dcb42d77e192
                Copyright © Copyright © 2022. Anatomy & Cell Biology
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/4.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 12 November 2021
                Date revision received : 4 January 2022
                Date accepted : 6 January 2022
                Categories
                Subject: Review Article
                Subject: Disease-Oriented Research

                ScienceOpen disciplines: Cell biology
                Keywords: autoimmunity,blood-retina barrier,experimental autoimmune uveitis,interphotoreceptor retinoid-binding protein,retinal soluble antigen
                Data availability:
                ScienceOpen disciplines: Cell biology
                Keywords: autoimmunity, blood-retina barrier, experimental autoimmune uveitis, interphotoreceptor retinoid-binding protein, retinal soluble antigen

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