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Impaired Binding of the Age-related Macular Degeneration-associated Complement Factor H 402H Allotype to Bruch's Membrane in Human Retina*

  • Simon J. Clark
    Affiliations
    Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT
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  • Rahat Perveen
    Affiliations
    School of Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester M13 9PT

    Manchester Academic Health Science Centre, Central Manchester Foundation Trust, Oxford Road, Manchester M13 9WL
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  • Svetlana Hakobyan
    Affiliations
    Complement Biology Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales
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  • B. Paul Morgan
    Affiliations
    Complement Biology Group, Department of Medical Biochemistry and Immunology, School of Medicine, Cardiff University, Cardiff CF14 4XN, Wales
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  • Robert B. Sim
    Affiliations
    Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT, United Kingdom
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  • Paul N. Bishop
    Correspondence
    To whom correspondence may be addressed. Tel.: 44-161-275-5755
    Affiliations
    Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT

    School of Biomedicine, Faculty of Medical and Human Sciences, University of Manchester, Oxford Road, Manchester M13 9PT

    Manchester Academic Health Science Centre, Central Manchester Foundation Trust, Oxford Road, Manchester M13 9WL
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  • Anthony J. Day
    Correspondence
    To whom correspondence may be addressed. Tel.: 44-161-275-1495
    Affiliations
    Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Oxford Road, Manchester M13 9PT
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  • Author Footnotes
    * This work was supported by the Macular Disease Society, Medical Research Council (Grant G0900592), University of Manchester Intellectual Property Ltd., and Manchester National Institute for Health Research Biomedical Research Centre.
    The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1–S9.
Open AccessPublished:July 26, 2010DOI:https://doi.org/10.1074/jbc.M110.103986
      Age-related macular degeneration (AMD) is the predominant cause of blindness in the industrialized world where destruction of the macula, i.e. the central region of the retina, results in loss of vision. AMD is preceded by the formation of deposits in the macula, which accumulate between the Bruch's membrane and the retinal pigment epithelium (RPE). These deposits are associated with complement-mediated inflammation and perturb retinal function. Recent genetic association studies have demonstrated that a common allele (402H) of the complement factor H (CFH) gene is a major risk factor for the development of AMD; CFH suppresses complement activation on host tissues where it is believed to bind via its interaction with polyanionic structures. We have shown previously that this coding change (Y402H; from a tyrosine to histidine residue) alters the binding of the CFH protein to sulfated polysaccharides. Here we demonstrate that the AMD-associated polymorphism profoundly affects CFH binding to sites within human macula. Notably, the AMD-associated 402H variant binds less well to heparan sulfate and dermatan sulfate glycosaminoglycans within Bruch's membrane when compared with the 402Y form; both allotypes exhibit a similar level of binding to the RPE. We propose that the impaired binding of the 402H variant to Bruch's membrane results in an overactivation of the complement pathway leading to local chronic inflammation and thus contributes directly to the development and/or progression of AMD. These studies therefore provide a putative disease mechanism and add weight to the genetic association studies that implicate the 402H allele as an important risk factor in AMD.

      Introduction

      AMD
      The abbreviations used are: AMD
      age-related macula degeneration
      RPE
      retinal pigment epithelium
      CFH
      complement factor H
      flCFH
      full-length complement factor H
      CFHBS
      CFH-binding sites
      GAG
      glycosaminoglycans
      CCP
      complement control protein domain
      HS
      heparan sulfate
      DS
      dermatan sulfate
      ANOVA
      analysis of variance.
      affects ∼50 million people worldwide and can be subdivided into two types, neovascular (“wet”) and atrophic (“dry”), which have different disease characteristics (
      • Coleman H.R.
      • Chan C.C.
      • Ferris 3rd, F.L.
      • Chew E.Y.
      ). Both of these forms of AMD are preceded by the accumulation of extracellular deposits, including drusen, between the RPE and Bruch's membrane, a multilaminar extracellular matrix that separates the retina from the blood vessels in the choroid. These deposits, which lead to visual impairment, are associated with local chronic inflammation at the RPE-Bruch's membrane interface that results from an overactivation of the complement system (
      • Hageman G.S.
      • Luthert P.J.
      • Victor Chong N.H.
      • Johnson L.V.
      • Anderson D.H.
      • Mullins R.F.
      ), a major effector system in innate immunity that acts as a front line defense against microorganisms and also has an important role in the clearance of cellular debris from host tissues. A common polymorphism (Y402H) (
      • Day A.J.
      • Willis A.C.
      • Ripoche J.
      • Sim R.B.
      ) in the gene encoding the complement regulator factor H has been found to be strongly associated with the development of AMD (
      • Edwards A.O.
      • Ritter 3rd, R.
      • Abel K.J.
      • Manning A.
      • Panhuysen C.
      • Farrer L.A.
      ,
      • Klein R.J.
      • Zeiss C.
      • Chew E.Y.
      • Tsai J.Y.
      • Sackler R.S.
      • Haynes C.
      • Henning A.K.
      • SanGiovanni J.P.
      • Mane S.M.
      • Mayne S.T.
      • Bracken M.B.
      • Ferris F.L.
      • Ott J.
      • Barnstable C.
      • Hoh J.
      ,
      • Haines J.L.
      • Hauser M.A.
      • Schmidt S.
      • Scott W.K.
      • Olson L.M.
      • Gallins P.
      • Spencer K.L.
      • Kwan S.Y.
      • Noureddine M.
      • Gilbert J.R.
      • Schnetz-Boutaud N.
      • Agarwal A.
      • Postel E.A.
      • Pericak-Vance M.A.
      ,
      • Hageman G.S.
      • Anderson D.H.
      • Johnson L.V.
      • Hancox L.S.
      • Taiber A.J.
      • Hardisty L.I.
      • Hageman J.L.
      • Stockman H.A.
      • Borchardt J.D.
      • Gehrs K.M.
      • Smith R.J.
      • Silvestri G.
      • Russell S.R.
      • Klaver C.C.
      • Barbazetto I.
      • Chang S.
      • Yannuzzi L.A.
      • Barile G.R.
      • Merriam J.C.
      • Smith R.T.
      • Olsh A.K.
      • Bergeron J.
      • Zernant J.
      • Merriam J.E.
      • Gold B.
      • Dean M.
      • Allikmets R.
      ). About 35% of people of European descent carry the 402H disease allele in which a His residue substitutes for a Tyr at position 402 in the preprotein. However, other risk and protective CFH alleles have been identified (reviewed in Ref.
      • Barlow P.N.
      • Hageman G.S.
      • Lea S.M.
      ) along with polymorphisms in other complement components, e.g. in factor B (
      • Montes T.
      • Tortajada A.
      • Morgan B.P.
      • Rodríguez de Córdoba S.
      • Harris C.L.
      ).
      Factor H, a serum glycoprotein that is mainly produced in the liver, acts as a regulator of the alternative complement pathway. In this regard, it plays an important role in host recognition, preventing damage from the random deposition of C3b on host surfaces that, otherwise unchecked, would lead to opsonization and inflammation (
      • Barlow P.N.
      • Hageman G.S.
      • Lea S.M.
      ). CFH is believed to bind to polyanions on host tissues (supplemental Fig. S1), positioning it to act as a co-factor for the proteolytic deactivation of C3b by factor I (
      • Kazatchkine M.D.
      • Fearon D.T.
      • Silbert J.E.
      • Austen K.F.
      ,
      • Meri S.
      • Pangburn M.K.
      ). One such family of polyanionic molecules thought to be involved in this recognition pathway are the glycosaminoglycans (GAGs), i.e. ubiquitous polysaccharides found on the cell surface and in the extracellular matrix of mammalian tissues. Although it is well established that CFH interacts with heparin (
      • Meri S.
      • Pangburn M.K.
      ,
      • Clark S.J.
      • Higman V.A.
      • Mulloy B.
      • Perkins S.J.
      • Lea S.M.
      • Sim R.B.
      • Day A.J.
      ,
      • Prosser B.E.
      • Johnson S.
      • Roversi P.
      • Herbert A.P.
      • Blaum B.S.
      • Tyrrell J.
      • Jowitt T.A.
      • Clark S.J.
      • Tarelli E.
      • Uhrín D.
      • Barlow P.N.
      • Sim R.B.
      • Day A.J.
      • Lea S.M.
      ,
      • Pangburn M.K.
      • Atkinson M.A.
      • Meri S.
      ,
      • Blackmore T.K.
      • Sadlon T.A.
      • Ward H.M.
      • Lublin D.M.
      • Gordon D.L.
      ,
      • Blackmore T.K.
      • Hellwage J.
      • Sadlon T.A.
      • Higgs N.
      • Zipfel P.F.
      • Ward H.M.
      • Gordon D.L.
      ,
      • Giannakis E.
      • Jokiranta T.S.
      • Male D.A.
      • Ranganathan S.
      • Ormsby R.J.
      • Fischetti V.A.
      • Mold C.
      • Gordon D.L.
      ,
      • Herbert A.P.
      • Uhrín D.
      • Lyon M.
      • Pangburn M.K.
      • Barlow P.N.
      ) (a GAG only secreted by mast cells), there are few, if any, direct data demonstrating its binding to related GAGs in tissues (e.g. heparan sulfate (HS)), although this is often assumed. In this regard, CFH, which is composed of 20 contiguous complement control protein (CCP) modules (
      • Ripoche J.
      • Day A.J.
      • Harris T.J.
      • Sim R.B.
      ) (also referred to as short consensus repeats), has two major binding sites for heparin in CCPs 7 and 20 (
      • Clark S.J.
      • Higman V.A.
      • Mulloy B.
      • Perkins S.J.
      • Lea S.M.
      • Sim R.B.
      • Day A.J.
      ,
      • Prosser B.E.
      • Johnson S.
      • Roversi P.
      • Herbert A.P.
      • Blaum B.S.
      • Tyrrell J.
      • Jowitt T.A.
      • Clark S.J.
      • Tarelli E.
      • Uhrín D.
      • Barlow P.N.
      • Sim R.B.
      • Day A.J.
      • Lea S.M.
      ,
      • Blackmore T.K.
      • Sadlon T.A.
      • Ward H.M.
      • Lublin D.M.
      • Gordon D.L.
      ,
      • Blackmore T.K.
      • Hellwage J.
      • Sadlon T.A.
      • Higgs N.
      • Zipfel P.F.
      • Ward H.M.
      • Gordon D.L.
      ,
      • Giannakis E.
      • Jokiranta T.S.
      • Male D.A.
      • Ranganathan S.
      • Ormsby R.J.
      • Fischetti V.A.
      • Mold C.
      • Gordon D.L.
      ,
      • Herbert A.P.
      • Uhrín D.
      • Lyon M.
      • Pangburn M.K.
      • Barlow P.N.
      ). Importantly, the Tyr/His coding change at residue 402, located in CCP7, has a major effect on the heparin binding properties of CFH (
      • Clark S.J.
      • Higman V.A.
      • Mulloy B.
      • Perkins S.J.
      • Lea S.M.
      • Sim R.B.
      • Day A.J.
      ), and a structural explanation for this has been postulated (
      • Prosser B.E.
      • Johnson S.
      • Roversi P.
      • Herbert A.P.
      • Blaum B.S.
      • Tyrrell J.
      • Jowitt T.A.
      • Clark S.J.
      • Tarelli E.
      • Uhrín D.
      • Barlow P.N.
      • Sim R.B.
      • Day A.J.
      • Lea S.M.
      ). The Y402H polymorphism also affects the binding of CFH to DNA, necrotic cells, and host proteins (
      • Sjöberg A.P.
      • Trouw L.A.
      • Clark S.J.
      • Sjölander J.
      • Heinegård D.
      • Sim R.B.
      • Day A.J.
      • Blom A.M.
      ,
      • Laine M.
      • Jarva H.
      • Seitsonen S.
      • Haapasalo K.
      • Lehtinen M.J.
      • Lindeman N.
      • Anderson D.H.
      • Johnson P.T.
      • Järvelä I.
      • Jokiranta T.S.
      • Hageman G.S.
      • Immonen I.
      • Meri S.
      ), and in some cases, recognition of bacterial pathogens (
      • Schneider M.C.
      • Prosser B.E.
      • Caesar J.J.
      • Kugelberg E.
      • Li S.
      • Zhang Q.
      • Quoraishi S.
      • Lovett J.E.
      • Deane J.E.
      • Sim R.B.
      • Roversi P.
      • Johnson S.
      • Tang C.M.
      • Lea S.M.
      ,
      • Haapasalo K.
      • Jarva H.
      • Siljander T.
      • Tewodros W.
      • Vuopio-Varkila J.
      • Jokiranta T.S.
      ). At present, it is not known how these functional differences of the 402H and 402Y CFH variants contribute to AMD initiation/progression.

      Acknowledgments

      We thank Dr. I. Zambrano and colleagues at the Manchester Royal Eye Hospital Eye Bank for supplying donor eye tissue used in this study, Dr. Barbara Mulloy (National Institute for Biological Standards and Control) for supplying heparin and DS glycosaminoglycans and Jane Knott for help with the microscopy. We also thank Prof. John Gallagher for discussion and advice on technical aspects of the research project. The Bioimaging Facility microscopes used in this study were purchased with grants from the Biotechnology and Biological Sciences Research Council, Wellcome Trust, and University of Manchester Strategic Fund.

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