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Shyamanga Borooah, Bal Dhillon, James Ironside, Siddharthan Chandran, Alan F. Wright; Localized dysregulation of complement is involved in the pathogenesis of Late-Onset Retinal Macular Degeneration (LORMD). Invest. Ophthalmol. Vis. Sci. 2012;53(14):1643.
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LORMD is a fully penetrant, autosomal dominant retinal degeneration resulting from mutation in the protein C1QTNF5. Clinically, LORMD replicates many of the key features of AMD. Disease pathogenesis is currently incompletely understood. This study aims to identify whether disease mechanisms already identified in AMD are relevant to LORMD.
A LORMD donor eye was fixed in 4% formalin and paraffin embedded. 4µm sections were cut. Antigen retrieval was performed using a decloaking chamber. Slides were heated to 90 centigrade for 20 minutes before cooling to 80 centigrade. Immuno-staining was performed for C1QTNF5, CFH, C3d, C5b-9 and CD68. Perl’s stain was used to detect iron. Similarly prepared and stained control aged donor eyes were also stained.
Staining revealed prominent C3d localization to the sub RPE deposit and perivascularly in the choroid. Significant C5b-9 staining was noted to run linearly along the deposit centre and CFH was localized to deposit surfaces. C1QTNF5 was also found on deposit surfaces and on the RPE. Occasional enlarged CD68 positive macrophages and iron deposits were noted.
Previous studies have revealed that immunohistochemical staining of sub-retinal deposits in LORMD resembles drusen. In this study, the presence of C3d and C5b-9 provides strong evidence for complement activation in disease pathogenesis in LORMD. Localization of C1QTNF5 and CFH together on deposit surfaces supports evidence for an interaction between mutant C1QTNF5 and CFH resulting in local complement dysregulation. This study suggests that similar pathways are involved in the etiologies of both AMD and LORMD.
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