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Kenneth J Katschke, Hongkang Xi, Christian Cox, Tom Truong, Yann Malato, Justin Elstrott, Jianhua Tao, Lauri Diehl, Menno Van Lookeren Campagne; Classical pathway complement activation contributes to photoreceptor degeneration. Invest. Ophthalmol. Vis. Sci. 2018;59(9):5563.
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© ARVO (1962-2015); The Authors (2016-present)
Polymorphisms in complement genes have been linked to age-related macular degeneration (AMD). We sought to further understand how classical complement activation contributes to photoreceptor loss using human donor eyes and a murine model of retinal degeneration.
Human eye samples from AMD and control patients were collected and stained for C4 deposition. Wildtype (C4+/+) and C4-deficient (C4-/-) mice were treated with sodium iodate (NaIO3) to induce retinal degeneration. Retina cell loss was measured in vivo by SD-OCT (Heidelberg) and ex vivo by flow cytometry and morphometry on H&E sections. Photoreceptor function was measured using electroretinogram (ERG) recordings.
C4 deposition on photoreceptor outer segments was detected in 12 out of 18 AMD donor eyes and in 1 out of 13 control donor eyes. C4-/- mice showed a 63% reduction of recruited macrophages as compared to C4+/+ mice 3 days following NaIO3 treatment. Retinas of C4-/- mice were protected from NaIO3-induced photoreceptor degeneration as demonstrated by 26% thicker retinas and 42% more photoreceptors compared to C4+/+ mice, 7 days following NaIO3. By morphometry peripheral photoreceptor outer segment length was increased 5.3-fold in C4-/- compared to C4+/+. ERG a wave amplitudes, but not b wave amplitudes, were improved 1.6-fold in C4-/- vs. C4+/+ mice.
In post-mortem eyes, C4 was activated on photoreceptor outer segments of donors with AMD. Activation of the classical/lectin complement pathway contributed to retinal degeneration secondary to NaIO3-induced RPE loss by increasing macrophage recruitment associated with progressive loss of photoreceptor function. Combined, these results suggest that classical pathway complement activation may contribute to photoreceptor loss in AMD.
This is an abstract that was submitted for the 2018 ARVO Annual Meeting, held in Honolulu, Hawaii, April 29 - May 3, 2018.
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