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Scott McLeod, Imran Ahmed Bhutto, Malia Michelle Edwards, Manasee Gedam, Raj Baldeosingh, Gerard A Lutty; A Possible Role for Mast Cell-Derived Tryptase in the Pathogenesis of Geographic Atrophy. Invest. Ophthalmol. Vis. Sci. 2017;58(8):2267.
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We have previously shown that significant numbers of degranulating mast cells are found in choroids of eyes with age-related macular degeneration compared to aged controls. In this study, we examined the immunolocalization of tryptase, the most abundant mast cell secretory granule-derived serine protease, in aged control eyes and eyes with geographic atrophy (GA).
Postmortem human eyes with and without GA were obtained from the National Disease Research Interchange (NDRI). Tissue was fixed, cryopreserved, sectioned and immunostained with antibodies against tryptase, UEA lectin and DAPI. Additional sections were immunolabeled with antibodies against chymase, c-Kit, histamine and IgE. Sections were examined and imaged on a Zeiss 710 Confocal Microscope.
In the posterior pole region of all aged control eyes, tryptase immunoreactivity was confined to choroidal mast cells (MCs), which were located primarily in Sattlers layer. In eyes with GA, many MCs were located in the inner choroid near the choriocapillaris and Bruch’s membrane (BM). tryptase was found not only in MCs but also diffusely around them in choroidal stroma, suggesting they had degranulated. In sharp contrast to aged control eyes, eyes with GA also had strong tryptase staining in BM. Tryptase was observed within BM in the regions of retinal pigment epithelial atrophy, at the border of atrophy and extending well into the nonatrophic region. cKit and IgE were localized in all mast cells while chymase was present only in 2% of the MCs.
Our results demonstrate that tryptase, released during degranulation of choroidal mast cells, binds to BM in GA in advance of RPE atrophy. Tryptase activates MMPs which can degrade extracellular matrix (ECM) and basement membrane components found in BM. ECM modifications are likely to have a profound effect on the function, health and transport of RPE in GA.
This is an abstract that was submitted for the 2017 ARVO Annual Meeting, held in Baltimore, MD, May 7-11, 2017.
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