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Jane Coffman, Gayle J T Pauer, Stephanie A Hagstrom, Mary E Rayborn, Joe G Hollyfield, Dean Bok, Vera L Bonilha, Roxana A Radu; Complement reactivity in Stargardt macular degeneration. Invest. Ophthalmol. Vis. Sci. 2016;57(12):6592.
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© ARVO (1962-2015); The Authors (2016-present)
Stargardt macular degeneration (STGD) is a central blinding disease of children and young adults caused mostly by mutations in the ABCA4 gene. The proposed role of ABCA4 is to facilitating the clearance of all-trans-retinaldehyde from photoreceptor outer-segment disc membranes following a photobleach. The pathological hallmark of STGD is deposition of fluorescent vitamin A-containing pigments in cells of the retinal pigment epithelium (RPE). Phenotypic features of the Abca4-/- mouse, the STGD model, include RPE lipofuscin-bisretinoid accumulation, followed by complement dysregulation, and loss of photoreceptor cells. Bisretinoid-dependent complement activation was previously reported in cultured fetal human RPE cells but has never been studied in the context of the RPE of a STGD patient. Here, we evaluate the complement system in the donor eyes of STGD patients.
Eyes were obtained through the FFB eye donor program. The patients were clinically diagnosed as STGD based on the symptoms and ocular changes. STGD donor #1 (66 y.o) had two ABCA4 mutations; ABCA4 genotype for STGD donor #2 (69 y.o) is unknown. Fixed perimacular and peripheral tissue samples of STGD and normal eyes (84 y.o.) were processed for immunohistochemistry using specific antibodies to C5b-9 (membrane attack complex, MAC), C3b/iC3b, and complement factor H (CFH).
STGD eyes showed increased thickness of Bruch’s membrane (BM) in the perimacular region in comparison to the control eyes. The deposition of MAC was indicated by significant C5b-9 immunoreactivity between BM and broken RPE basolateral membranes and also in the RPE cells. In contrast, the control eye showed C5b-9 immunoreactivity primarily in the choriocapillaris endothelium beneath an intact BM and little to none in the RPE. Pixel intensity quantification of MAC deposition was about 1.8-fold higher in STGD eye #2 compared to the control eye. C3 breakdown fragments were also observed within the RPE cells. We measured about 1.3-fold increase of C3b/iC3b level in the STGD eye compared to the control. However, CFH immunoreactivity appears similar between STGD and control eyes.
Preliminary data suggest that, like the RPE of the Abca4-/- mouse, STGD human RPE cells are also dysfunctional as they lose their ability to suppress chronic insult by the complement system. Further analyses are directed toward characterization of complement reactivity using STGD patient-derived RPE cells.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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