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The Factor H gene cluster and complement homeostasis in the retina

Stampoulis, Dimitrios; (2022) The Factor H gene cluster and complement homeostasis in the retina. Doctoral thesis (Ph.D), UCL (University College London). Green open access

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Abstract

A common polymorphism in Complement factor H (FH) that switches a tyrosine at position 402 to a histidine is linked to susceptibility to developing age-related macular degeneration (AMD), and other less common variants of FH are associated with higher penetrance early onset forms of the disease. Deletion of the genes encoding complement Factor H related protein 1 and 3 (CFHR1 and CFHR3) decreases AMD risk but almost nothing is known about the regulation of these genes in the mouse retina, or the effects of retinal stress on their expression. This study addresses the role of the CFH gene cluster in complement homeostasis in the retina. Initial experiments confirmed that inflammatory cytokines affect the expression of complement genes in ARPE-19 cells. The role of hypoxia in gene expression of complement genes was assessed in ARPE-19 cells and co-culture experiments revealed the effect of C3 and C5 on the capacity of microglia cells to phagocytose ARPE-19 cells. The main focus of this study was to characterise the retinal phenotype of RPE-CFH knock-out mice. In vivo studies showed changes in the retinal phenotype of RPE-CFH knock-out mice. Initial studies of Cfh-/- Cfhr-/- mice showed significant downregulation in the expression of complement genes in the RPE, and increased C3b deposition in the RPE and the retinal vessels. Gene expression analysis in the RPE of Cfh+/+ Cfhr-/- mice showed that CFH mRNA levels were decreased 8-fold. Analysis of the retinal phenotype of aged Abca4-/- Rdh8-/- mice, which accumulate lipofuscin in the retina, showed excessive stress in the RPE, evidence of complement activation and changes in the expression of CRPs. Subcellular re-localisation of the C3aR in the RPE suggests that C3a/C3aR signaling plays an important role in complement homeostasis in the RPE. This study highlights the importance of RPE derived FH in maintaining retinal health and provides further evidence of complement dysregulation in AMD pathogenesis.

Type: Thesis (Doctoral)
Qualification: Ph.D
Title: The Factor H gene cluster and complement homeostasis in the retina
Open access status: An open access version is available from UCL Discovery
Language: English
Additional information: Copyright © The Author 2022. Original content in this thesis is licensed under the terms of the Creative Commons Attribution-NonCommercial 4.0 International (CC BY-NC 4.0) Licence (https://creativecommons.org/licenses/by-nc/4.0/). Any third-party copyright material present remains the property of its respective owner(s) and is licensed under its existing terms. Access may initially be restricted at the author’s request.
UCL classification: UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL
URI: https://discovery.ucl.ac.uk/id/eprint/10150145
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