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      The eye as a complement dysregulation hotspot

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          Abstract

          Complement turnover is tightly regulated throughout the human body in order to prevent over-activation and subsequent damage from inflammation. In the eye, low-level complement activation is maintained to provide immune tolerance in this immune privileged organ. Conversely, the complement system is suppressed in the cornea to protect it from continuous immunological insult. Over-activation of the complement cascade has been implicated in the disease progression of glaucoma and diabetic retinopathy and is now known to be a central driver in the pathogenesis of age-related macular degeneration (AMD). Indeed, it is with AMD where the most recent and exciting work has been carried out with complement-based therapies entering into clinical trials. However, the success of these trials will depend upon delivering the therapeutics to the correct anatomical sites within the eye, so a full understanding of how complement regulation is compartmentalized in the eye is required, a topic that will be highlighted in this review.

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          The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited.

          Don H Anderson, Monte Radeke, Natasha Gallo … (2010)
          During the past ten years, dramatic advances have been made in unraveling the biological bases of age-related macular degeneration (AMD), the most common cause of irreversible blindness in western populations. In that timeframe, two distinct lines of evidence emerged which implicated chronic local inflammation and activation of the complement cascade in AMD pathogenesis. First, a number of complement system proteins, complement activators, and complement regulatory proteins were identified as molecular constituents of drusen, the hallmark extracellular deposits associated with early AMD. Subsequently, genetic studies revealed highly significant statistical associations between AMD and variants of several complement pathway-associated genes including: Complement factor H (CFH), complement factor H-related 1 and 3 (CFHR1 and CFHR3), complement factor B (CFB), complement component 2 (C2), and complement component 3 (C3). In this article, we revisit our original hypothesis that chronic local inflammatory and immune-mediated events at the level of Bruch's membrane play critical roles in drusen biogenesis and, by extension, in the pathobiology of AMD. Secondly, we report the results of a new screening for additional AMD-associated polymorphisms in a battery of 63 complement-related genes. Third, we identify and characterize the local complement system in the RPE-choroid complex - thus adding a new dimension of biological complexity to the role of the complement system in ocular aging and AMD. Finally, we evaluate the most salient, recent evidence that bears directly on the role of complement in AMD pathogenesis and progression. Collectively, these recent findings strongly re-affirm the importance of the complement system in AMD. They lay the groundwork for further studies that may lead to the identification of a transcriptional disease signature of AMD, and hasten the development of new therapeutic approaches that will restore the complement-modulating activity that appears to be compromised in genetically susceptible individuals. Copyright 2009 Elsevier Ltd. All rights reserved.
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            The dynamic nature of Bruch's membrane.

            J.C. Booij, D.C. Baas, J Beisekeeva … (2010)
            Bruch's membrane (BM) is a unique pentalaminar structure, which is strategically located between the retinal pigment epithelium (RPE) and the fenestrated choroidal capillaries of the eye. BM is an elastin- and collagen-rich extracellular matrix that acts as a molecular sieve. BM partly regulates the reciprocal exchange of biomolecules, nutrients, oxygen, fluids and metabolic waste products between the retina and the general circulation. Accumulating evidence suggests that the molecular, structural and functional properties of BM are dependent on age, genetic constitution, environmental factors, retinal location and disease state. As a result, part of the properties of BM are unique to each human individual at a given age, and therefore uniquely affect the development of normal vision and ocular disease. The changes occurring in BM with age include increased calcification of elastic fibres, increased cross-linkage of collagen fibres and increased turnover of glycosaminoglycans. In addition, advanced glycation end products (AGEs) and fat accumulate in BM. These age-related changes may not only influence the normal age-related health of photoreceptor cells, but also the onset and progression of diseases like retinitis pigmentosa (RP) and age-related macular degeneration (AMD). Undoubtedly, BM is the site of drusen development. Confluent drusen and uncontrolled activation of the complement cascade are most likely the first signs of AMD. Furthermore, the nature of adhesive interactions between the RPE and BM are instrumental in the development of retinal detachments and proliferative retinal disease. Finally, BM is passively or actively involved in a range of other retinal disorders such as Pseudoxanthoma elasticum (PXE), Sorsby's Fundus Dystrophy and Malattia Leventinese. Here, we review the dynamic nature of Bruch's membrane, from molecule to man, during development, aging and disease. We propose a simple and straightforward nomenclature for BM deposits. Finally, we attempt to correlate recently published mRNA expression profiles of the RPE and choroid with molecular, structural and functional properties of BM. Our review may shed light on the complex involvement of BM in retinal pathology, notably age-related macular degeneration.
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              Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration

              Johanna M. Seddon, Yi Yu, Mary-Elizabeth C Miller … (2013)
              To define the role of rare variants in advanced age-related macular degeneration (AMD) risk, we sequenced the exons of 681 genes within AMD-associated loci and pathways in 2,493 cases and controls. We first tested each gene for increased or decreased burden of rare variants in cases compared to controls. We found that 7.8% of AMD cases compared to 2.3% of controls are carriers of rare missense CFI variants (OR=3.6, p=2×10−8). There was a predominance of dysfunctional variants in cases compared to controls. We then tested individual variants for association to disease. We observed significant association with rare missense alleles outside CFI. Genotyping in 5,115 independent samples confirmed associations to AMD with a K155Q allele in C3 (replication p=3.5×10−5, OR=2.8; joint p=5.2×10−9, OR=3.8) and a P167S allele in C9 (replication p=2.4×10−5, OR=2.2; joint p=6.5×10−7, OR=2.2). Finally, we show that the 155Q allele in C3 results in resistance to proteolytic inactivation by CFH and CFI. These results implicate loss of C3 protein regulation and excessive alternative complement activation in AMD pathogenesis, thus informing both the direction of effect and mechanistic underpinnings of this disorder.
              Article 0 comments Cited 139 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Simon J. Clark:
                ORCID: http://orcid.org/0000-0001-8394-8355
                +44 161 2757775 , simon.clark-3@manchester.ac.uk
                Journal
                Journal ID (nlm-ta): Semin Immunopathol
                Journal ID (iso-abbrev): Semin Immunopathol
                Title: Seminars in Immunopathology
                Publisher: Springer Berlin Heidelberg (Berlin/Heidelberg )
                ISSN (Print): 1863-2297
                ISSN (Electronic): 1863-2300
                Publication date (Electronic): 25 September 2017
                Publication date PMC-release: 25 September 2017
                Publication date (Print): 2018
                Volume: 40
                Issue: 1
                Pages: 65-74
                Affiliations
                [1 ]ISNI 0000000121662407, GRID grid.5379.8, Division of Evolution and Genomic Medicine, School of Biological Sciences, Faculty of Biology Medicine and Health, , University of Manchester, ; Oxford Road, Manchester, M13 9PT UK
                [2 ]ISNI 0000 0004 0430 9101, GRID grid.411037.0, Manchester Royal Eye Hospital, Manchester Academic Health Science Centre, , Central Manchester University Hospitals NHS Foundation Trust, ; Manchester, UK
                Author notes

                This article is a contribution to the special issue on Complement in Health and Disease: Novel Aspects and Insights - Guest Editors: Paul Morgan and David Kavanagh

                Author information
                http://orcid.org/0000-0001-8394-8355
                Article
                Publisher ID: 649
                DOI: 10.1007/s00281-017-0649-6
                PMC ID: 5794836
                PubMed ID: 28948331
                SO-VID: 84218475-3f9e-469f-9df0-e3490c6f73cc
                Copyright © © The Author(s) 2017
                License:

                Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.

                History
                Date received : 26 August 2017
                Date accepted : 30 August 2017
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100000265, Medical Research Council;
                Award ID: MR/K024418/1
                Award ID: MR/P025838/1
                Award ID: MR/P025838/1
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100000615, Fight for Sight UK;
                Award ID: 1852/53
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/100011718, Macular Society;
                Award ID: 12928
                Award Recipient :
                Categories
                Subject: Review
                Custom metadata
                issue-copyright-statement © Springer-Verlag GmbH Germany, part of Springer Nature 2018

                ScienceOpen disciplines: Pathology
                Keywords: age-related macular degeneration,complement dysregulation,retinal disease,inflammation,immune tolerance,clinical trials,complement therapies
                Data availability:
                ScienceOpen disciplines: Pathology
                Keywords: age-related macular degeneration, complement dysregulation, retinal disease, inflammation, immune tolerance, clinical trials, complement therapies

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