title: Cd59a deficiency in mice leads to preferential innate immune activation in the retinal pigment epithelium-choroid with age.
abstract: Dysregulation of the complement system has been implicated in the pathogenesis of age-related macular degeneration. To investigate consequences of altered complement regulation in the eye with age, we examined Cd59a complement regulator deficient (Cd59a(-/-)) mice between 4 and 15 months. In vivo imaging revealed an increased age-related accumulation of autofluorescent spots in Cd59a(-/-) mice, a feature that reflects accumulation of subretinal macrophages and/or microglia. Despite this activation of myeloid cells in the eye, Cd59a(-/-) mice showed normal retinal histology and function as well as normal choroidal microvasculature. With age, they revealed increased expression of activators of the alternative complement pathway (C3, Cfb, Cfd), in particular in the retinal pigment epithelium (RPE)-choroid but less in the retina. This molecular response was not altered by moderately-enhanced light exposure. Cd59a deficiency therefore leads to a preferential age-related dysregulation of the complement system in the RPE-choroid, that alone or in combination with light as a trigger, is not sufficient to cause choroidal vascular changes or retinal degeneration and dysfunction. This data emphasizes the particular vulnerability of the RPE-choroidal complex to dysregulation of the alternative complement pathway during aging.
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Philipp
authors.initials: P
authors.lastname: Herrmann
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Jill A
authors.initials: JA
authors.lastname: Cowing
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Enrico
authors.initials: E
authors.lastname: Cristante
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Sidath E
authors.initials: SE
authors.lastname: Liyanage
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Joana
authors.initials: J
authors.lastname: Ribeiro
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Yanai
authors.initials: Y
authors.lastname: Duran
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Abelleira Hervas
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK.
authors.forename: Livia S
authors.initials: LS
authors.lastname: Carvalho
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK; NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, UK.
authors.forename: James W B
authors.initials: JW
authors.lastname: Bainbridge
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK. Electronic address: u.luhmann@ucl.ac.uk.
authors.forename: Ulrich F O
authors.initials: UF
authors.lastname: Luhmann
authors.affiliation: Department of Genetics, UCL Institute of Ophthalmology, London, UK; NIHR Biomedical Research Centre for Ophthalmology, Moorfields Eye Hospital, London, UK.
authors.forename: Robin R
authors.initials: RR
authors.lastname: Ali
mesh_terms: D000375:Aging / Q000235:genetics*; D000704:Analysis of Variance; D000818:Animals; D018957:CD59 Antigens / Q000235:genetics / Q000378:metabolism*; D002829:Choroid / Q000378:metabolism* / Q000473:pathology; D003167:Complement Activation; D004195:Disease Models, Animal; D004596:Electroretinography; D005786:Gene Expression Regulation / Q000235:genetics; D007155:Immunologic Factors / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism / Q000473:pathology; D008268:Macular Degeneration / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D012160:Retina / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000378:metabolism* / Q000473:pathology
chemical_list: D018957:CD59 Antigens; C539311:CD59a protein, mouse; C453730:Crb1 protein, mouse; D007155:Immunologic Factors; D009419:Nerve Tissue Proteins; D012333:RNA, Messenger
keywords: AMD; Age-related retinal degeneration; Aging; Cd59a; Complement dysregulation; Complement regulator