title: Identification of factor H-like protein 1 as the predominant complement regulator in Bruch's membrane: implications for age-related macular degeneration.
abstract: The tight regulation of innate immunity on extracellular matrix (ECM) is a vital part of immune homeostasis throughout the human body, and disruption to this regulation in the eye is thought to contribute directly to the progression of age-related macular degeneration (AMD). The plasma complement regulator factor H (FH) is thought to be the main regulator that protects ECM against damaging complement activation. However, in the present study we demonstrate that a truncated form of FH, called FH-like protein 1 (FHL-1), is the main regulatory protein in the layer of ECM under human retina, called Bruch's membrane. Bruch's membrane is a major site of AMD disease pathogenesis and where drusen, the hallmark lesions of AMD, form. We show that FHL-1 can passively diffuse through Bruch's membrane, whereas the full sized, glycosylated, FH cannot. FHL-1 is largely bound to Bruch's membrane through interactions with heparan sulfate, and we show that the common Y402H polymorphism in the CFH gene, associated with an increased risk of AMD, reduces the binding of FHL-1 to this heparan sulfate. We also show that FHL-1 is retained in drusen whereas FH coats the periphery of the lesions, perhaps inhibiting their clearance. Our results identify a novel mechanism of complement regulation in the human eye, which highlights potential new avenues for therapeutic strategies.
authors.affiliation: Centre for Hearing and Vision Research, Institute of Human Development, University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom; simon.clark-3@manchester.ac.uk.
authors.forename: Simon J
authors.identifier: http://orcid.org/0000-0001-8394-8355
authors.initials: SJ
authors.lastname: Clark
authors.affiliation: Institute of Pharmacology of Natural Products and Clinical Pharmacology, Ulm University, 89081 Ulm, Germany;
authors.forename: Christoph Q
authors.initials: CQ
authors.lastname: Schmidt
authors.affiliation: Centre for Hearing and Vision Research, Institute of Human Development, University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom;
authors.forename: Anne M
authors.initials: AM
authors.lastname: White
authors.affiliation: Complement Biology Group, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; and.
authors.forename: Svetlana
authors.initials: S
authors.lastname: Hakobyan
authors.affiliation: Complement Biology Group, Institute of Infection and Immunity, School of Medicine, Cardiff University, Cardiff CF14 4XN, United Kingdom; and.
authors.forename: B Paul
authors.initials: BP
authors.lastname: Morgan
authors.affiliation: Centre for Hearing and Vision Research, Institute of Human Development, University of Manchester, Manchester M13 9PT, United Kingdom; Centre for Advanced Discovery and Experimental Therapeutics, University of Manchester and Central Manchester University Hospitals NHS Foundation Trust, Manchester Academic Health Science Centre, Manchester M13 9WL, United Kingdom; Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester M13 9WL, United Kingdom.
authors.forename: Paul N
authors.initials: PN
authors.lastname: Bishop
mesh_terms: D016570:Bruch Membrane / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D003167:Complement Activation; D003180:Complement C3b Inactivator Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D017242:Complement Factor H / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D005109:Extracellular Matrix / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006031:Glycosylation; D006497:Heparan Sulfate / Q000276:immunology / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007113:Immunity, Innate; D008268:Macular Degeneration / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D021381:Protein Transport; D012160:Retina / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015593:Retinal Drusen / Q000235:genetics / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D003180:Complement C3b Inactivator Proteins; D017242:Complement Factor H; D006497:Heparan Sulfate; C517621:CFHR1 protein, human