Retinal Microglia in Glaucoma

Wang, Jiawei; Chen, Shida; Zhang, Xiulan; Jonas, Jost B.

doi:10.1097/ijg.0000000000000200

Cited by 57 publications

(43 citation statements)

References 94 publications

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“…The inner retinal surface is a complex environment, consisting of: a robust vasculature with endothelial cells and pericytes, astrocytes, microglia, axons of the nerve fiber layer, a variety of phagocytic cells (Koeberle, Gauldie et al 2004, Kezic, Chrysostomou et al 2013, Wang, Chen et al 2015), and the ganglion cell layer itself, which contains up to 30 different sub-types of RGCs (Badea and Nathans 2004, Kong, Fish et al 2005, Coombs, van der List et al 2006, Volgyi, Chheda et al 2009, Kim, Zhang et al 2010, Sanes and Masland 2015), and 10 different types of DAC (Perez De Sevilla Muller, Shelley et al 2007). As is the case for many other CNS tissues, this cellular diversity can be a challenge in carrying out experiments.…”

Section: Discussionmentioning

confidence: 99%

Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification

Hedberg-Buenz

Christopher

Lewis

et al. 2016

Experimental Eye Research

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The inner surface of the retina contains a complex mixture of neurons, glia, and vasculature, including retinal ganglion cells (RGCs), the final output neurons of the retina and primary neurons that are damaged in several blinding diseases. The goal of the current work was two-fold: to assess the feasibility of using computer-assisted detection of nuclei and random forest classification to automate the quantification of RGCs in hematoxylin/eosin (H&E)-stained retinal whole-mounts; and if possible, to use the approach to examine how nuclear size influences disease susceptibility among RGC populations. To achieve this, data from RetFM-J, a semi-automated ImageJ-based module that detects, counts, and collects quantitative data on nuclei of H&E-stained whole-mounted retinas, were used in conjunction with a manually curated set of images to train a random forest classifier. To test performance, computer-derived outputs were compared to previously published features of several well-characterized mouse models of ophthalmic disease and their controls: normal C57BL/6J mice; Jun-sufficient and Jun-deficient mice subjected to controlled optic nerve crush (CONC); and DBA/2J mice with naturally occurring glaucoma. The result of these efforts was development of RetFM-Class, a command-line-based tool that uses data output from RetFM-J to perform random forest classification of cell type. Comparative testing revealed that manual and automated classifications by RetFM-Class correlated well, with 83.2% classification accuracy for RGCs. Automated characterization of C57BL/6J retinas predicted 54,642 RGCs per normal retina, and identified a 48.3% Jun-dependent loss of cells at 35 days post CONC and a 71.2% loss of RGCs among 16-month-old DBA/2J mice with glaucoma. Output from automated analyses was used to compare nuclear area among large numbers of RGCs from DBA/2J mice (n=127,361). In aged DBA/2J mice with glaucoma, RetFM-Class detected a decrease in median and mean nucleus size of cells classified into the RGC category, as did an independent confirmation study using manual measurements of nuclear area demarcated by BRN3A-immunoreactivity. In conclusion, we have demonstrated that histology-based random forest classification is feasible and can be utilized to study RGCs in a high-throughput fashion. Despite having some limitations, this approach demonstrated a significant association between the size of the RGC nucleus and the DBA/2J form of glaucoma.

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Section: Discussionmentioning

confidence: 99%

Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification

Hedberg-Buenz

Christopher

Lewis

et al. 2016

Experimental Eye Research

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“…The possible mechanisms may be related to upregulation of complement system and toll-like receptor 4 signaling activity along with microglial activation in the optic nerve, 11 which occur early in the glaucomatous process. 28 …”

Section: Discussionmentioning

confidence: 99%

Prospective Study of Oral Health and Risk of Primary Open-Angle Glaucoma in Men

et al. 2016

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Purpose Tooth loss or periodontal disease is associated with systemic endothelial dysfunction, which has been implicated in primary open-angle glaucoma (POAG). The relationship between oral health and POAG has received limited attention. Thus, we evaluated the association between oral health history and risk of POAG and POAG subtypes. Design Prospective cohort study Participants Health Professionals Follow-up Study participants (40,536 men) followed biennially from 1986 to 2012. At each 2-year risk period, eligible participants were 40+ years old, free of POAG, and reported eye examinations. Methods Using validated questions, we updated participants' status on number of natural teeth, teeth lost, periodontal disease with bone loss and root canal treatments. Main Outcome Measures During follow-up, 485 incident cases of POAG were confirmed with medical records and classified into subtypes defined by intraocular pressure (IOP) (≥ or < 22 mm Hg) or by visual field (VF) loss pattern at diagnosis (peripheral loss only or early paracentral loss). Multivariable relative risks (MVRR) and 95% confidence intervals (CIs) were estimated. Results Number of natural teeth, periodontal disease or root canal treatment were not associated with POAG. However, compared to no report of tooth loss, a report of losing teeth within the past 2 years was associated with a 1.45 fold increased risk of POAG (95% CI=1.06, 1.97); in particular, a report within the past 2 years of both losing teeth and having a prevalent diagnosis of periodontal disease was associated with 1.85 fold increased risk of POAG (95% CI=1.07, 3.18). The associations with recent tooth loss was not significantly different for the POAG subtypes (p for heterogeneity ≥ 0.36), although associations were strongest in relation to the POAG subtypes with IOP < 22 mm Hg (MVRR = 1.93, 95% CI=1.09, 3.43) and with early paracentral VF loss (MVRR = 2.27, 95% CI=1.32, 3.88). Conclusion While the number of natural teeth was not associated with risk of POAG, recent tooth loss was associated with an increased risk of POAG. Because these findings may be due to chance, they need confirmation in larger studies.

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“…38 The precise method by which minocycline protects RGCs, and, by implication, the specific mechanism(s) by which the microglia are toxic to RGCs, remain unclear, but suggested pathways of microglial toxicity include release of proinflammatory mediators and activation of the immune system. 3,6,7 In this context, it is noteworthy that minocycline has been shown to downregulate MHC II RT1B expression within spinal cord microglia and macrophages and concurrently reduce the severity of EAE symptoms. 39 MHC II molecules expressed by activated microglia present antigenic fragments to the immune system for recognition and activation of CD4 + T cells.…”

Section: Discussionmentioning

confidence: 99%

“…3,5 It has indisputably been proven that microglia within the retina and optic nerve (ON) become reactive in response to RGC degeneration in animal models of glaucoma. 3,6,7 Of arguably greater interest, however, is the recent finding that alterations in microglial function may, in fact, precede RGC injury in glaucoma. 8,9 This result further focuses debate on whether microglial activation is detrimental or beneficial to RGC survival.…”

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confidence: 99%

Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

Chidlow

Ebneter

Wood

et al. 2016

Journal of Glaucoma

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Aim: We acquired age-matched and sex-matched Sprague-Dawley rats from 2 independent breeding establishments. Serendipitously, we observed that constitutive, and bacterial toxin-induced, expression of major histocompatibility complex (MHC) class II RT1B chain in the uveal tract was much lower in one of the cohorts. Activated microglia are known to upregulate MHC II RT1B expression during optic nerve (ON) degeneration induced by raised intraocular pressure (IOP). We investigated whether, in a model of experimental glaucoma, microglial upregulation of MHC II RT1B was less efficacious and ON degeneration correspondingly less severe in the cohort of rats with low MHC II RT1B expression.Methods: Experimental glaucoma was induced by lasering the trabecular meshwork using a standard protocol. After 2 weeks of elevated IOP, retinal ganglion cells (RGC) survival, ON degeneration, and microglial responses were determined in both cohorts of rats.Results: Raised IOP-induced expression of MHC II RT1B by microglia was muted in the "Low" cohort compared with the "High" cohort. Axonal degeneration, RGC loss, and microgliosis were all significantly lower in the cohort of rats with low basal and induced expression of MHC II RT1B, despite both cohorts displaying IOP responses that were indistinguishable in terms of peak IOP and IOP exposure.Conclusions: Expression of MHC II RT1B by activated microglia in the ON during experimental glaucoma was associated with more severe RGC degeneration. Further studies are needed to elucidate the role of MHC II during experimental glaucoma.

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Retinal Microglia in Glaucoma

Cited by 57 publications

References 94 publications

Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification

Quantitative measurement of retinal ganglion cell populations via histology-based random forest classification

Prospective Study of Oral Health and Risk of Primary Open-Angle Glaucoma in Men

Evidence Supporting an Association Between Expression of Major Histocompatibility Complex II by Microglia and Optic Nerve Degeneration During Experimental Glaucoma

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