Local dysregulation of the alternative complement pathway in retinal pigment epithelium as a model for age-related macular degeneration
Final Report Abstract
Several polymorphisms in complement genes are associated with an increased risk to develop age related macular degeneration (AMD), one of the most common causes for blindness in the elderly. This suggests that dysregulation of the complement system may be an important pathogenic mechanism in AMD. To investigate the consequences of altered complement regulation in the RPE/choroid and retina we focused on three main chapters: The dysregulation by subretinal injection of lentivirus, an analysis of Cd59a complement regulator knockout mice between 4-15 months and the establishment and analysis of a intermediate (7day) light exposure model. We have established new ways for a precise read out of subretinal administered lentivirus. Especially in vivo techniques have proven a useful tool to monitor retinal changes in injected animals over time. However, complement dysregulation and damage occurs also in control injected eyes. We have observed increased autofluorescent spots in the fundus of aged Cd59a-/- mice.This process was significantly elevated in Cd59a-/- mice at 9 and 15 months, despite a grossly normal retinal histology. Immunohistochemistry with anti- CD45 and anti-Iba1 showed corresponding subretinal macrophages as a source of the autofluorescent spots. Relative qRT-PCR for main components of the alternative complement pathway showed a significant increase in the RPE/Choroid of 9 and 15 months old Cd59a-/- mice while levels in retina and 4 month old animals were not significantly altered. We used 7 day light exposure to assess the effects of photooxidative stress on the retina RPE/choroid of three different mouse strains. On the structural level, there was a large variation between the different strains. The main response was retinal thinning which correlated with reduced ERG responses on a functional level. On the molecular level we showed the effect on the dysregulation of complement expression which also varies between the strains and established a baseline characterisation of local complement expression in different mouse strains in the eye. In this project we could gather relevant insights into the local complement expression and structural changes of the eye, in particular after subretinal injection, complement regulator knockout and light exposure. Thus, this dataset helps to understand the undelaying mechanisms of AMD and can be used as a future tool for further analysis of the complex interplay between RPE/retina and the innate immune system.
Publications
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(2012) Age related macular degeneration - causes and current treatment. Retina Patient Day, University College London, UK
Herrmann P
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(2013) CD59a deficiency leads to increased age-related subretinal macrophage accumulation and elevated local C3 expression in the RPE/choroid complex of aged mice. ARVO meeting, Seattle, USA
Herrmann P, Cowing JA, Carvalho LS, Luhmann UFO, Ali RR
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(2013) Etiology and pathogenesis of age related macular degeneration. Ophthalmologe 110(4):377-89
Herrmann P, Holz FG, Charbel Issa P
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(2013) Knockout of complement regulator Cd59a in mice leads to dysregulation of complement factors and increased subretinal macrophage accumulation. Poster presentation - PRO RETINA 8th International Research Colloquium, Potsdam, Germany
Herrmann P, Cowing JA, Carvalho LS, Luhmann UFO, Ali RR
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(2013) Optical coherence tomography based in vivo assessment and scoring of murine experimental autoimmune uveoretinitis. PLoS ONE 8(5):e63002
Chu CJ, Herrmann P, Carvalho LS, Liyanage S, Bainbridge JWB, Ali RR, Dick AD, Luhmann UFO
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(2013) Ätiologie und Pathogenese der altersabhängigen Makuladegeneration. Der Ophthalmologe, April 2013, Volume 110, Issue 4, pp 377–389
Herrmann P, Holz FG, Charbel Issa P
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(2014)The role of the complement system in age-related macular degeneration. Dtsch Arztebl 111 (8):133-138
Weber HF, Charbel Issa P, Pauly D, Herrmann P, Grassmann F, Holz FG
