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      A Perspective of AMD Through the Eyes of Immunology

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          Origin and physiological roles of inflammation.

          Inflammation underlies a wide variety of physiological and pathological processes. Although the pathological aspects of many types of inflammation are well appreciated, their physiological functions are mostly unknown. The classic instigators of inflammation - infection and tissue injury - are at one end of a large range of adverse conditions that induce inflammation, and they trigger the recruitment of leukocytes and plasma proteins to the affected tissue site. Tissue stress or malfunction similarly induces an adaptive response, which is referred to here as para-inflammation. This response relies mainly on tissue-resident macrophages and is intermediate between the basal homeostatic state and a classic inflammatory response. Para-inflammation is probably responsible for the chronic inflammatory conditions that are associated with modern human diseases.
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            Local self-renewal can sustain CNS microglia maintenance and function throughout adult life.

            Microgliosis is a common response to multiple types of damage in the CNS. However, the origin of the cells involved in this process is still controversial and the relative importance of local expansion versus recruitment of microglia progenitors from the bloodstream is unclear. Here, we investigated the origin of microglia using chimeric animals obtained by parabiosis. We found no evidence of microglia progenitor recruitment from the circulation in denervation or CNS neurodegenerative disease, suggesting that maintenance and local expansion of microglia are solely dependent on the self-renewal of CNS resident cells in these models.
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              Drusen proteome analysis: an approach to the etiology of age-related macular degeneration.

              Drusen are extracellular deposits that accumulate below the retinal pigment epithelium on Bruch's membrane and are risk factors for developing age-related macular degeneration (AMD). The progression of AMD might be slowed or halted if the formation of drusen could be modulated. To work toward a molecular understanding of drusen formation, we have developed a method for isolating microgram quantities of drusen and Bruch's membrane for proteome analysis. Liquid chromatography tandem MS analyses of drusen preparations from 18 normal donors and five AMD donors identified 129 proteins. Immunocytochemical studies have thus far localized approximately 16% of these proteins in drusen. Tissue metalloproteinase inhibitor 3, clusterin, vitronectin, and serum albumin were the most common proteins observed in normal donor drusen whereas crystallin was detected more frequently in AMD donor drusen. Up to 65% of the proteins identified were found in drusen from both AMD and normal donors. However, oxidative protein modifications were also observed, including apparent crosslinked species of tissue metalloproteinase inhibitor 3 and vitronectin, and carboxyethyl pyrrole protein adducts. Carboxyethyl pyrrole adducts are uniquely generated from the oxidation of docosahexaenoate-containing lipids. By Western analysis they were found to be more abundant in AMD than in normal Bruch's membrane and were found associated with drusen proteins. Carboxymethyl lysine, another oxidative modification, was also detected in drusen. These data strongly support the hypothesis that oxidative injury contributes to the pathogenesis of AMD and suggest that oxidative protein modifications may have a critical role in drusen formation.
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                Author and article information

                Journal
                Investigative Opthalmology & Visual Science
                Invest. Ophthalmol. Vis. Sci.
                Association for Research in Vision and Ophthalmology (ARVO)
                1552-5783
                March 20 2018
                July 17 2018
                : 59
                : 4
                : AMD83
                Affiliations
                [1 ]Translational Health Sciences (Ophthalmology), University of Bristol, Bristol, United Kingdom
                [2 ]National Institute for Health Research Biomedical Research Centre of Ophthalmology, Moorfields Eye Hospital and University College London-Institute of Ophthalmology, London, United Kingdom
                [3 ]Bristol Eye Hospital, Bristol, United Kingdom
                [4 ]University College London–Institute of Ophthalmology, London, United Kingdom
                Article
                10.1167/iovs.18-23893
                30025105
                948311da-c309-4201-a066-4b4c7d3cc514
                © 2018

                http://creativecommons.org/licenses/by-nc-nd/4.0/

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