title: Inhibition of the alternative complement pathway preserves photoreceptors after retinal injury.
abstract: Degeneration of photoreceptors is a primary cause of vision loss worldwide, making the underlying mechanisms surrounding photoreceptor cell death critical to developing new treatment strategies. Retinal detachment, characterized by the separation of photoreceptors from the underlying retinal pigment epithelium, is a sight-threatening event that can happen in a number of retinal diseases. The detached photoreceptors undergo apoptosis and programmed necrosis. Given that photoreceptors are nondividing cells, their loss leads to irreversible visual impairment even after successful retinal reattachment surgery. To better understand the underlying disease mechanisms, we analyzed innate immune system regulators in the vitreous of human patients with retinal detachment and correlated the results with findings in a mouse model of retinal detachment. We identified the alternative complement pathway as promoting early photoreceptor cell death during retinal detachment. Photoreceptors down-regulate membrane-bound inhibitors of complement, allowing for selective targeting by the alternative complement pathway. When photoreceptors in the detached retina were removed from the primary source of oxygen and nutrients (choroidal vascular bed), the retina became hypoxic, leading to an up-regulation of complement factor B, a key mediator of the alternative pathway. Inhibition of the alternative complement pathway in knockout mice or through pharmacological means ameliorated photoreceptor cell death during retinal detachment. Our current study begins to outline the mechanism by which the alternative complement pathway facilitates photoreceptor cell death in the damaged retina.
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: J Harry
authors.initials: JH
authors.lastname: Sweigard
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Hidetaka
authors.initials: H
authors.lastname: Matsumoto
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Kaylee E
authors.initials: KE
authors.lastname: Smith
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Leo A
authors.initials: LA
authors.lastname: Kim
authors.affiliation: Schepens Eye Research Institute, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA 02114, USA.
authors.forename: Eleftherios I
authors.initials: EI
authors.lastname: Paschalis
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Okonuki
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Castillejos
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Keiko
authors.initials: K
authors.lastname: Kataoka
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Eiichi
authors.initials: E
authors.lastname: Hasegawa
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Yanai
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Deeba
authors.initials: D
authors.lastname: Husain
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: John D
authors.initials: JD
authors.lastname: Lambris
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Demetrios
authors.initials: D
authors.lastname: Vavvas
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA.
authors.forename: Joan W
authors.initials: JW
authors.lastname: Miller
authors.affiliation: Angiogenesis Laboratory, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, 243 Charles Street, Boston, MA 02114, USA. kip_connor@meei.harvard.edu.
authors.forename: Kip M
authors.initials: KM
authors.lastname: Connor
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D016923:Cell Death; D003170:Complement Pathway, Alternative / Q000276:immunology*; D004195:Disease Models, Animal; D006801:Humans; D000860:Hypoxia / Q000473:pathology; D008810:Mice, Inbred C57BL; D020419:Photoreceptor Cells, Vertebrate / Q000276:immunology* / Q000473:pathology*; D012160:Retina / Q000473:pathology*; D012162:Retinal Degeneration / Q000276:immunology / Q000473:pathology
chemical_list: D015703:Antigens, CD