Donders Institute for Brain, Cognition and Behaviour
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Thesis defense Sarah de Jong (Donders series 562)

26 August 2022

Promotors: prof. dr. A.I. den Hollander, prof. dr. L.P.W.J. van den Heuvel
Co-promotors: dr. E.B. Volokhina, dr. A. Garanto Iglesias

The complement system in age-related macular degeneration – Functional analyses of rare coding variants in complement components

Age-related macular degeneration (AMD) is a major cause of vision loss among the elderly in the Western world, and increasing numbers of patients are expected in the coming years. Risk factors for AMD are multifactorial, and next to age, diet and body weight influence the disease risk. But also genetic predisposition plays an important role, and genetic variants in the complement system have been strongly linked with AMD. The complement system is part of the innate immune system and plays a role in first line defense against pathogens and clearance of apoptotic cells. Overactivation of the complement system, however, can lead to host tissue damage. And while the exact mechanisms of AMD development are not yet known, AMD patients present with complement activation locally in the retina and choroid, but also on a systemic level.
In this thesis the effects of rare coding variants in the central complement regulators complement factor I (CFI) and complement factor H (CFH) were studied. Performing a screening of 126 rare coding variants in CFI, it could be shown that 54% of the variants lead to a significant reduction of Factor I (FI) protein secretion. In carriers with a rare variant in CFH it was shown that carriers present with reduced Factor H (FH) plasma levels and increased complement activation levels.
As mentioned, the exact mechanisms of AMD development are not yet known. In order to get better insight, induced pluripotent stem cells were generated from carriers with a rare variant in CFI. These cells were differentiated into retinal organoids and the secreted complement components measured. While these data are preliminary, they indicate that most complement components are secreted in retinal organoids, indicating that they might be a suitable model to test complement inhibitors in vitro.