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C. Luo, X. Yang, H. J. Kaplan, Gü. Tezel; Complement Activation During Glaucomatous Neurodegeneration. Invest. Ophthalmol. Vis. Sci. 2007;48(13):3284.
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The complement system is an essential effector of the humoral and cellular immunity. Based on the growing evidence of aberrant immune activity during glaucomatous neurodegeneration, this study aimed to determine the association of complement activation with the neurodegenerative process.
Proteomic analysis was performed using the chronic pressure-induced rat model of glaucoma induced by hypertonic saline injections into episcleral veins. Protein expression was determined in tryptic digests of retinal proteins using LC-MS/MS analysis. In addition, the extent and cellular localization of tissue immunolabeling for different complement components were determined in ocular hypertensive versus normotensive rat eyes (n:15), as well as in human donor eyes with glaucoma (n:34) in comparison to age-matched control eyes without glaucoma (n:20).
Proteomic analysis and tissue immunolabeling detected an up-regulation of several complement components in ocular hypertensive rat retinas, which included C1q and C3. Complement immunolabeling also exhibited an increase in the glaucomatous human retina. There was a prominent increase in C1q and C3 immunolabeling in inner retinal layers of glaucomatous donor eyes. Immunolabeling for C1 and C3 receptors on microglia also exhibited an increase in these eyes. Furthermore, immunolabeling for C5b-9 (membrane attack complex) was prominently detectable in retinal ganglion cell and nerve fiber layers of the glaucomatous human retina. Despite the evidence of complement activation, no increase was detectable in immunolabeling of glaucomatous tissues for complement regulatory proteins, CD35, CD55, and CD59. However, immunohistochemistry in rat and human eyes as well as proteomic analysis in ocular hypertensive rat retinas detected up-regulated expression of macrophage migration inhibitory factor, which could be an intrinsic effort against destructive consequences of complement activation.
These findings support that complement activation occurs during glaucomatous neurodegeneration, which can initially participate in healing of the injured tissue by eliminating cell debris and potentially toxic protein aggregates. However, findings of this study also suggest that a potential deficiency in intrinsic complement regulation may also exist facilitating the progression of tissue injury in glaucomatous eyes. Ongoing studies should determine how the immune response can be manipulated towards tissue repair while avoiding the initiation of an autoimmune neurodegenerative process.
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