{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T06:12:01Z","timestamp":1791267121436,"version":"4.1.0"},"reference-count":132,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T00:00:00Z","timestamp":1707955200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"BrightFocus Foundation"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glaucoma is a progressive neurodegenerative disease characterized by damage to the optic nerve that results in irreversible vision loss. While the exact pathology of glaucoma is not well understood, emerging evidence suggests that dysregulation of the complement system, a key component of innate immunity, plays a crucial role. In glaucoma, dysregulation of the complement cascade and impaired regulation of complement factors contribute to chronic inflammation and neurodegeneration. Complement components such as C1Q, C3, and the membrane attack complex have been implicated in glaucomatous neuroinflammation and retinal ganglion cell death. This review will provide a summary of human and experimental studies that document the dysregulation of the complement system observed in glaucoma patients and animal models of glaucoma driving chronic inflammation and neurodegeneration. Understanding how complement-mediated damage contributes to glaucoma will provide opportunities for new therapies.<\/jats:p>","DOI":"10.3390\/ijms25042307","type":"journal-article","created":{"date-parts":[[2024,2,15]],"date-time":"2024-02-15T05:55:59Z","timestamp":1707976559000},"page":"2307","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":34,"title":["The Role of Complement Dysregulation in Glaucoma"],"prefix":"10.3390","volume":"25","author":[{"given":"Cindy","family":"Hoppe","sequence":"first","affiliation":[{"name":"Schepens Eye Research Institute of Mass Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"},{"name":"Animal Physiology\/Neurobiology, Department of Biology, Friedrich-Alexander-Universit\u00e4t Erlangen-N\u00fcrnberg, 91058 Erlangen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meredith","family":"Gregory-Ksander","sequence":"additional","affiliation":[{"name":"Schepens Eye Research Institute of Mass Eye and Ear, Department of Ophthalmology, Harvard Medical School, Boston, MA 02114, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,2,15]]},"reference":[{"key":"ref_1","first-page":"e11686","article-title":"Epidemiology of Glaucoma: The Past, Present, and Predictions for the Future","volume":"12","author":"Allison","year":"2020","journal-title":"Cureus"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"979","DOI":"10.1016\/j.ophtha.2011.11.003","article-title":"Glaucoma 2.0: Neuroprotection, neuroregeneration, neuroenhancement","volume":"119","author":"Chang","year":"2012","journal-title":"Ophthalmology"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.phrs.2012.03.002","article-title":"Protecting the retinal neurons from glaucoma: Lowering ocular pressure is not enough","volume":"66","author":"Pascale","year":"2012","journal-title":"Pharmacol. Res."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"270","DOI":"10.5935\/0004-2749.20160077","article-title":"Normal-tension glaucoma: An update","volume":"79","author":"Esporcatte","year":"2016","journal-title":"Arq. Bras. Oftalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1016\/j.optom.2016.02.003","article-title":"Glaucoma history and risk factors","volume":"10","author":"McMonnies","year":"2017","journal-title":"J. Optom."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1016\/j.exer.2018.11.005","article-title":"All roads lead to glaucoma: Induced retinal injury cascades contribute to a common neurodegenerative outcome","volume":"183","author":"Alqawlaq","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1186\/s12974-014-0194-3","article-title":"Tumor necrosis factor alpha has an early protective effect on retinal ganglion cells after optic nerve crush","volume":"11","author":"Fernandes","year":"2014","journal-title":"J. Neuroinflamm."},{"key":"ref_8","first-page":"779","article-title":"Polymorphism in the TNF-alpha(-863) locus associated with reduced risk of primary open angle glaucoma","volume":"18","author":"Wang","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"e156-162","DOI":"10.1111\/j.1442-9071.2011.02595.x","article-title":"Association of tumour necrosis factor-alpha-308 G\/A polymorphism with primary open-angle glaucoma","volume":"40","author":"Bozkurt","year":"2012","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"8442","DOI":"10.1167\/iovs.11-8152","article-title":"Neurodegenerative and inflammatory pathway components linked to TNF-alpha\/TNFR1 signaling in the glaucomatous human retina","volume":"52","author":"Yang","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1002\/1098-1136(200010)32:1<42::AID-GLIA40>3.0.CO;2-3","article-title":"Tumor necrosis factor-alpha: A potentially neurodestructive cytokine produced by glia in the human glaucomatous optic nerve head","volume":"32","author":"Yuan","year":"2000","journal-title":"Glia"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"4626","DOI":"10.4049\/jimmunol.1601488","article-title":"Overexpression of Soluble Fas Ligand following Adeno-Associated Virus Gene Therapy Prevents Retinal Ganglion Cell Death in Chronic and Acute Murine Models of Glaucoma","volume":"197","author":"Krishnan","year":"2016","journal-title":"J. Immunol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"184","DOI":"10.1186\/s12974-019-1576-3","article-title":"A small peptide antagonist of the Fas receptor inhibits neuroinflammation and prevents axon degeneration and retinal ganglion cell death in an inducible mouse model of glaucoma","volume":"16","author":"Krishnan","year":"2019","journal-title":"J. Neuroinflamm."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"300","DOI":"10.12659\/MSM.902081","article-title":"Toll-Like Receptor 4 Signaling in High Mobility Group Box-1 Protein 1 Mediated the Suppression of Regulatory T-Cells","volume":"23","author":"Luo","year":"2017","journal-title":"Med. Sci. Monit."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"825","DOI":"10.1016\/j.ajo.2012.03.050","article-title":"Association of Toll-like receptor 4 gene polymorphisms in Japanese subjects with primary open-angle, normal-tension, and exfoliation glaucoma","volume":"154","author":"Takano","year":"2012","journal-title":"Am. J. Ophthalmol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"4453","DOI":"10.1167\/iovs.07-1575","article-title":"Association of Toll-like receptor 4 gene polymorphisms with normal tension glaucoma","volume":"49","author":"Shibuya","year":"2008","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"409","DOI":"10.1016\/S0079-6123(08)01128-X","article-title":"TNF-alpha signaling in glaucomatous neurodegeneration","volume":"173","author":"Tezel","year":"2008","journal-title":"Prog. Brain Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s12177-009-9026-6","article-title":"The two sides of cytokine signaling and glaucomatous optic neuropathy","volume":"2","author":"Huang","year":"2009","journal-title":"J. Ocul. Biol. Dis. Inform."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"105","DOI":"10.3109\/02713683.2013.836541","article-title":"From mechanosensitivity to inflammatory responses: New players in the pathology of glaucoma","volume":"39","author":"Krizaj","year":"2014","journal-title":"Curr. Eye Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5071","DOI":"10.1167\/iovs.10-5289","article-title":"Oxidative stress and the regulation of complement activation in human glaucoma","volume":"51","author":"Tezel","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"620","DOI":"10.1016\/j.exer.2006.03.002","article-title":"Retinal synthesis and deposition of complement components induced by ocular hypertension","volume":"83","author":"Kuehn","year":"2006","journal-title":"Exp. Eye Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1167\/iovs.05-0830","article-title":"Complement component 1Q (C1Q) upregulation in retina of murine, primate, and human glaucomatous eyes","volume":"47","author":"Stasi","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1164","DOI":"10.1016\/j.cell.2007.10.036","article-title":"The classical complement cascade mediates CNS synapse elimination","volume":"131","author":"Stevens","year":"2007","journal-title":"Cell"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1429","DOI":"10.1172\/JCI44646","article-title":"Molecular clustering identifies complement and endothelin induction as early events in a mouse model of glaucoma","volume":"121","author":"Howell","year":"2011","journal-title":"J. Clin. Investig."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2379","DOI":"10.1016\/j.ymthe.2018.08.017","article-title":"Complement C3-Targeted Gene Therapy Restricts Onset and Progression of Neurodegeneration in Chronic Mouse Glaucoma","volume":"26","author":"Bosco","year":"2018","journal-title":"Mol. Ther."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1186\/s13024-016-0091-6","article-title":"Inhibition of the classical pathway of the complement cascade prevents early dendritic and synaptic degeneration in glaucoma","volume":"11","author":"Williams","year":"2016","journal-title":"Mol. Neurodegener."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2151","DOI":"10.1016\/j.molimm.2011.07.012","article-title":"Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma","volume":"48","author":"Jha","year":"2011","journal-title":"Mol. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"E3839","DOI":"10.1073\/pnas.1608769114","article-title":"Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective","volume":"114","author":"Harder","year":"2017","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"380","DOI":"10.3389\/fncel.2014.00380","article-title":"Versatility of the complement system in neuroinflammation, neurodegeneration and brain homeostasis","volume":"8","author":"Orsini","year":"2014","journal-title":"Front. Cell. Neurosci."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"7227","DOI":"10.1073\/pnas.0501536102","article-title":"A common haplotype in the complement regulatory gene factor H (HF1\/CFH) predisposes individuals to age-related macular degeneration","volume":"102","author":"Hageman","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/ng1750","article-title":"Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration","volume":"38","author":"Gold","year":"2006","journal-title":"Nat. Genet."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"553","DOI":"10.1056\/NEJMoa072618","article-title":"Complement C3 variant and the risk of age-related macular degeneration","volume":"357","author":"Yates","year":"2007","journal-title":"N. Engl. J. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"970486","DOI":"10.3389\/fimmu.2022.970486","article-title":"The role of the complement system in Multiple Sclerosis: A review","volume":"13","author":"Stuve","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1742-2094-3-29","article-title":"Complement activation in the Parkinson\u2019s disease substantia nigra: An immunocytochemical study","volume":"3","author":"Loeffler","year":"2006","journal-title":"J. Neuroinflamm."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"5532","DOI":"10.1038\/s41380-019-0536-8","article-title":"The complement cascade in Alzheimer\u2019s disease: A systematic review and meta-analysis","volume":"26","author":"Krance","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"867","DOI":"10.1038\/sj.eye.6702176","article-title":"The complement system and age-related macular degeneration","volume":"20","author":"Sivaprasad","year":"2006","journal-title":"Eye"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"154","DOI":"10.3389\/fimmu.2020.00154","article-title":"A Systematic Investigation on Complement Pathway Activation in Diabetic Retinopathy","volume":"11","author":"Shahulhameed","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1038\/ni.1923","article-title":"Complement: A key system for immune surveillance and homeostasis","volume":"11","author":"Ricklin","year":"2010","journal-title":"Nat. Immunol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1016\/j.pharmthera.2016.11.014","article-title":"Complement: A primer for the coming therapeutic revolution","volume":"172","author":"Barnum","year":"2017","journal-title":"Pharmacol. Ther."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"2835","DOI":"10.1016\/j.celrep.2019.10.084","article-title":"Cell-Type-Specific Complement Expression in the Healthy and Diseased Retina","volume":"29","author":"Pauly","year":"2019","journal-title":"Cell Rep."},{"key":"ref_41","unstructured":"Janeway, C. (2001). Immunobiology 5: The Immune System in Health and Disease, Garland Pub. [5th ed.]."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1038\/cr.2009.139","article-title":"Complement and its role in innate and adaptive immune responses","volume":"20","author":"Dunkelberger","year":"2010","journal-title":"Cell Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1058","DOI":"10.1056\/NEJM200104053441406","article-title":"Complement. First of two parts","volume":"344","author":"Walport","year":"2001","journal-title":"N. Engl. J. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"262","DOI":"10.3389\/fimmu.2015.00262","article-title":"Complement System Part I\u2014Molecular Mechanisms of Activation and Regulation","volume":"6","author":"Merle","year":"2015","journal-title":"Front. Immunol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.molimm.2005.06.025","article-title":"Complement deficiency and disease: An update","volume":"43","author":"Sjoholm","year":"2006","journal-title":"Mol. Immunol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"301","DOI":"10.1016\/j.imbio.2006.12.004","article-title":"New perspectives on mannan-binding lectin-mediated complement activation","volume":"212","author":"Degn","year":"2007","journal-title":"Immunobiology"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1016\/S0161-5890(03)00155-X","article-title":"The role of mannose-binding lectin in health and disease","volume":"40","author":"Turner","year":"2003","journal-title":"Mol. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"373","DOI":"10.1016\/j.molimm.2009.09.005","article-title":"The down-stream effects of mannan-induced lectin complement pathway activation depend quantitatively on alternative pathway amplification","volume":"47","author":"Harboe","year":"2009","journal-title":"Mol. Immunol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"158","DOI":"10.2174\/138945008783502458","article-title":"Properdin and complement activation: A fresh perspective","volume":"9","author":"Hourcade","year":"2008","journal-title":"Curr. Drug Targets"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1025","DOI":"10.4049\/jimmunol.121.3.1025","article-title":"Binding of desoxycholate, phosphatidylcholine vesicles, lipoprotein and of the S-protein to complexes of terminal complement components","volume":"121","author":"Podack","year":"1978","journal-title":"J. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1007\/s12026-011-8239-5","article-title":"Membrane attack by complement: The assembly and biology of terminal complement complexes","volume":"51","author":"Tegla","year":"2011","journal-title":"Immunol. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2187","DOI":"10.1016\/j.molimm.2010.05.007","article-title":"Complement control protein factor H: The good, the bad, and the inadequate","volume":"47","author":"Ferreira","year":"2010","journal-title":"Mol. Immunol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1074","DOI":"10.3389\/fimmu.2019.01074","article-title":"The Role of Membrane Bound Complement Regulatory Proteins in Tumor Development and Cancer Immunotherapy","volume":"10","author":"Geller","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"65","DOI":"10.3389\/fimmu.2020.00065","article-title":"Adaptive Immunity: New Aspects of Pathogenesis Underlying Neurodegeneration in Glaucoma and Optic Neuropathy","volume":"11","author":"Jiang","year":"2020","journal-title":"Front. Immunol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1038\/nature07201","article-title":"Origin and physiological roles of inflammation","volume":"454","author":"Medzhitov","year":"2008","journal-title":"Nature"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"348","DOI":"10.1016\/j.preteyeres.2009.06.001","article-title":"Para-inflammation in the aging retina","volume":"28","author":"Xu","year":"2009","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"5888","DOI":"10.1167\/iovs.09-5103","article-title":"Immune activation in retinal aging: A gene expression study","volume":"51","author":"Chen","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"336","DOI":"10.1186\/s12974-020-02011-z","article-title":"Complement peptide C3a receptor 1 promotes optic nerve degeneration in DBA\/2J mice","volume":"17","author":"Harder","year":"2020","journal-title":"J. Neuroinflamm."},{"key":"ref_59","unstructured":"Kastin, A.J. (2013). Handbook of Biologically Active Peptides, Academic Press. [2nd ed.]."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3455","DOI":"10.4049\/jimmunol.156.9.3455","article-title":"A new biologic role for C3a and C3a desArg: Regulation of TNF-alpha and IL-1 beta synthesis","volume":"156","author":"Takabayashi","year":"1996","journal-title":"J. Immunol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1096\/fj.02-0737com","article-title":"Regulation by complement C3a and C5a anaphylatoxins of cytokine production in human umbilical vein endothelial cells","volume":"17","author":"Monsinjon","year":"2003","journal-title":"FASEB J."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1159\/000235517","article-title":"Induction of mediator release from human glomerular mesangial cells by the terminal complement components C5b-9","volume":"96","author":"Schonermark","year":"1991","journal-title":"Int. Arch. Allergy Appl. Immunol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"20991","DOI":"10.1074\/jbc.M111.226266","article-title":"Relationship between complement membrane attack complex, chemokine (C-C motif) ligand 2 (CCL2) and vascular endothelial growth factor in mouse model of laser-induced choroidal neovascularization","volume":"286","author":"Liu","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1161\/CIRCRESAHA.119.314845","article-title":"Complement Membrane Attack Complexes Assemble NLRP3 Inflammasomes Triggering IL-1 Activation of IFN-gamma-Primed Human Endothelium","volume":"124","author":"Xie","year":"2019","journal-title":"Circ. Res."},{"key":"ref_65","first-page":"2903","article-title":"The complement membrane attack complex triggers intracellular Ca2+ fluxes leading to NLRP3 inflammasome activation","volume":"126","author":"Triantafilou","year":"2013","journal-title":"J. Cell Sci."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"1006","DOI":"10.4049\/jimmunol.1300489","article-title":"Cutting edge: The NLRP3 inflammasome links complement-mediated inflammation and IL-1beta release","volume":"191","author":"Laudisi","year":"2013","journal-title":"J. Immunol."},{"key":"ref_67","first-page":"1588","article-title":"Complement gene expression and regulation in mouse retina and retinal pigment epithelium\/choroid","volume":"17","author":"Luo","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"895519","DOI":"10.3389\/fimmu.2022.895519","article-title":"As in Real Estate, Location Matters: Cellular Expression of Complement Varies Between Macular and Peripheral Regions of the Retina and Supporting Tissues","volume":"13","author":"Zauhar","year":"2022","journal-title":"Front. Immunol."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"543","DOI":"10.1016\/j.exer.2008.09.005","article-title":"Up-regulation of complement factor B in retinal pigment epithelial cells is accompanied by complement activation in the aged retina","volume":"87","author":"Chen","year":"2008","journal-title":"Exp. Eye Res."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.preteyeres.2009.11.003","article-title":"The pivotal role of the complement system in aging and age-related macular degeneration: Hypothesis re-visited","volume":"29","author":"Anderson","year":"2010","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"3142","DOI":"10.1016\/j.ajpath.2014.07.017","article-title":"The membrane attack complex in aging human choriocapillaris: Relationship to macular degeneration and choroidal thinning","volume":"184","author":"Mullins","year":"2014","journal-title":"Am. J. Pathol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/j.exer.2011.06.015","article-title":"Elevated membrane attack complex in human choroid with high risk complement factor H genotypes","volume":"93","author":"Mullins","year":"2011","journal-title":"Exp. Eye Res."},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"8936","DOI":"10.1523\/JNEUROSCI.18-21-08936.1998","article-title":"The major cell populations of the mouse retina","volume":"18","author":"Jeon","year":"1998","journal-title":"J. Neurosci."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1778","DOI":"10.3389\/fimmu.2017.01778","article-title":"Bruch\u2019s Membrane Compartmentalizes Complement Regulation in the Eye with Implications for Therapeutic Design in Age-Related Macular Degeneration","volume":"8","author":"Clark","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"15","DOI":"10.3389\/fnagi.2018.00015","article-title":"The Complement System Is Critical in Maintaining Retinal Integrity during Aging","volume":"10","author":"Mukai","year":"2018","journal-title":"Front. Aging Neurosci."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"532","DOI":"10.1001\/archopht.122.4.532","article-title":"Prevalence of open-angle glaucoma among adults in the United States","volume":"122","author":"Friedman","year":"2004","journal-title":"Arch. Ophthalmol."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"2310","DOI":"10.1016\/j.neurobiolaging.2013.03.022","article-title":"Gene expression changes in aging retinal microglia: Relationship to microglial support functions and regulation of activation","volume":"34","author":"Ma","year":"2013","journal-title":"Neurobiol. Aging"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"5816","DOI":"10.1167\/iovs.15-17294","article-title":"Proteomics Analysis of Molecular Risk Factors in the Ocular Hypertensive Human Retina","volume":"56","author":"Yang","year":"2015","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"2635","DOI":"10.1167\/iovs.17-23434","article-title":"Proteomic Alterations in Aqueous Humor From Patients With Primary Open Angle Glaucoma","volume":"59","author":"Sharma","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"4921","DOI":"10.1167\/iovs.10-5531","article-title":"Proteome analysis of human aqueous humor","volume":"51","author":"Chowdhury","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"1938","DOI":"10.1002\/pmic.201500423","article-title":"Human aqueous humor proteome in cataract, glaucoma, and pseudoexfoliation syndrome","volume":"16","author":"Kliuchnikova","year":"2016","journal-title":"Proteomics"},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1080\/14789450.2017.1298448","article-title":"The potential impact of recent insights into proteomic changes associated with glaucoma","volume":"14","author":"Funke","year":"2017","journal-title":"Expert. Rev. Proteom."},{"key":"ref_83","doi-asserted-by":"crossref","unstructured":"Kaeslin, M.A., Killer, H.E., Fuhrer, C.A., Zeleny, N., Huber, A.R., and Neutzner, A. (2016). Changes to the Aqueous Humor Proteome during Glaucoma. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0165314"},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"100117","DOI":"10.1016\/j.mcpro.2021.100117","article-title":"Proteome Characterization of Glaucoma Aqueous Humor","volume":"20","author":"Liu","year":"2021","journal-title":"Mol. Cell. Proteom."},{"key":"ref_85","doi-asserted-by":"crossref","first-page":"108460","DOI":"10.1016\/j.exer.2021.108460","article-title":"Increased ratios of complement factors C3a to C3 in aqueous humor and serum mark glaucoma progression","volume":"204","author":"Hubens","year":"2021","journal-title":"Exp. Eye Res."},{"key":"ref_86","doi-asserted-by":"crossref","unstructured":"Vashishtha, A., Maina, S.W., Altman, J., Jones, G., Lee, T.J., Bollinger, K.E., Ulrich, L., Toteberg-Harms, M., Estes, A.J., and Zhi, W. (2023). Complement System Proteins in the Human Aqueous Humor and Their Association with Primary Open-Angle Glaucoma. J. Pers. Med., 13.","DOI":"10.3390\/jpm13091400"},{"key":"ref_87","doi-asserted-by":"crossref","first-page":"828","DOI":"10.1136\/bjophthalmol-2021-320541","article-title":"Serum complement component 3, complement component 4 and complement component 1q levels predict progressive visual field loss in older women with primary angle closure glaucoma","volume":"107","author":"Li","year":"2023","journal-title":"Br. J. Ophthalmol."},{"key":"ref_88","doi-asserted-by":"crossref","first-page":"188","DOI":"10.1016\/j.pneurobio.2015.12.008","article-title":"Estrogens as neuroprotectants: Estrogenic actions in the context of cognitive aging and brain injury","volume":"157","author":"Brown","year":"2017","journal-title":"Prog. Neurobiol."},{"key":"ref_89","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1016\/j.ajo.2020.04.033","article-title":"Association Between 17-beta-Estradiol and Interleukin-8 and Visual Field Progression in Postmenopausal Women with Primary Angle Closure Glaucoma","volume":"217","author":"Li","year":"2020","journal-title":"Am. J. Ophthalmol."},{"key":"ref_90","doi-asserted-by":"crossref","first-page":"108077","DOI":"10.1016\/j.exer.2020.108077","article-title":"The aqueous humor proteome of primary open angle glaucoma: An extensive review","volume":"197","author":"Hubens","year":"2020","journal-title":"Exp. Eye Res."},{"key":"ref_91","doi-asserted-by":"crossref","first-page":"176","DOI":"10.18240\/ijo.2020.01.24","article-title":"Proteome alterations in aqueous humour of primary open angle glaucoma patients","volume":"13","author":"Liu","year":"2020","journal-title":"Int. J. Ophthalmol."},{"key":"ref_92","doi-asserted-by":"crossref","first-page":"1221","DOI":"10.1038\/s41598-022-05273-0","article-title":"Proteome alterations in the aqueous humor reflect structural and functional phenotypes in patients with advanced normal-tension glaucoma","volume":"12","author":"Lee","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_93","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1016\/j.jprot.2013.12.006","article-title":"Comparative proteomic study in serum of patients with primary open-angle glaucoma and pseudoexfoliation glaucoma","volume":"98","author":"Alvarez","year":"2014","journal-title":"J. Proteom."},{"key":"ref_94","doi-asserted-by":"crossref","first-page":"761","DOI":"10.1097\/IJG.0000000000001014","article-title":"Decreased Serum Levels of Complement C3 Reflect Complement System Dysregulation in Patients With Primary Open-angle Glaucoma: Results From a Pilot Study","volume":"27","author":"Li","year":"2018","journal-title":"J. Glaucoma"},{"key":"ref_95","doi-asserted-by":"crossref","first-page":"1247","DOI":"10.1167\/iovs.03-1123","article-title":"Microarray analysis of changes in mRNA levels in the rat retina after experimental elevation of intraocular pressure","volume":"45","author":"Ahmed","year":"2004","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_96","doi-asserted-by":"crossref","first-page":"3161","DOI":"10.1167\/iovs.06-1282","article-title":"Global changes in optic nerve head gene expression after exposure to elevated intraocular pressure in a rat glaucoma model","volume":"48","author":"Johnson","year":"2007","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_97","doi-asserted-by":"crossref","first-page":"977","DOI":"10.1167\/iovs.05-0865","article-title":"Microarray analysis of retinal gene expression in the DBA\/2J model of glaucoma","volume":"47","author":"Steele","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_98","doi-asserted-by":"crossref","first-page":"718087","DOI":"10.3389\/fncel.2021.718087","article-title":"Cytokine and Complement Response in the Glaucomatous betaB1-CTGF Mouse Model","volume":"15","author":"Reinehr","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_99","doi-asserted-by":"crossref","unstructured":"Gramlich, O.W., Godwin, C.R., Wadkins, D., Elwood, B.W., and Kuehn, M.H. (2021). Early Functional Impairment in Experimental Glaucoma Is Accompanied by Disruption of the GABAergic System and Inceptive Neuroinflammation. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22147581"},{"key":"ref_100","doi-asserted-by":"crossref","first-page":"6370","DOI":"10.1167\/iovs.12-10442","article-title":"Lack of immunoglobulins does not prevent C1q binding to RGC and does not alter the progression of experimental glaucoma","volume":"53","author":"Ding","year":"2012","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_101","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.nbd.2014.07.016","article-title":"Combinatorial targeting of early pathways profoundly inhibits neurodegeneration in a mouse model of glaucoma","volume":"71","author":"Howell","year":"2014","journal-title":"Neurobiol. Dis."},{"key":"ref_102","doi-asserted-by":"crossref","first-page":"2025","DOI":"10.1523\/JNEUROSCI.1854-18.2018","article-title":"Complement Targets Newborn Retinal Ganglion Cells for Phagocytic Elimination by Microglia","volume":"39","author":"Anderson","year":"2019","journal-title":"J. Neurosci."},{"key":"ref_103","doi-asserted-by":"crossref","first-page":"2024","DOI":"10.1167\/iovs.09-3560","article-title":"Gene expression changes in areas of focal loss of retinal ganglion cells in the retina of DBA\/2J mice","volume":"51","author":"Panagis","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_104","doi-asserted-by":"crossref","first-page":"9821","DOI":"10.1038\/s41598-018-28183-6","article-title":"S100B immunization triggers NFkappaB and complement activation in an autoimmune glaucoma model","volume":"8","author":"Reinehr","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_105","doi-asserted-by":"crossref","first-page":"140","DOI":"10.3389\/fncel.2016.00140","article-title":"Simultaneous Complement Response via Lectin Pathway in Retina and Optic Nerve in an Experimental Autoimmune Glaucoma Model","volume":"10","author":"Reinehr","year":"2016","journal-title":"Front. Cell. Neurosci."},{"key":"ref_106","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1186\/s13024-018-0303-3","article-title":"Inhibition of monocyte-like cell extravasation protects from neurodegeneration in DBA\/2J glaucoma","volume":"14","author":"Williams","year":"2019","journal-title":"Mol. Neurodegener."},{"key":"ref_107","doi-asserted-by":"crossref","first-page":"310","DOI":"10.1159\/000079261","article-title":"A regulatory role for complement in innate immunity and autoimmunity","volume":"134","author":"Nauta","year":"2004","journal-title":"Int. Arch. Allergy Immunol."},{"key":"ref_108","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1073\/pnas.75.8.3943","article-title":"Demonstration of specific C5a receptor on intact human polymorphonuclear leukocytes","volume":"75","author":"Chenoweth","year":"1978","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_109","first-page":"321","article-title":"The structural basis for anaphylatoxin and chemotactic functions of C3a, C4a, and C5a","volume":"1","author":"Hugli","year":"1981","journal-title":"Crit. Rev. Immunol."},{"key":"ref_110","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1038\/349614a0","article-title":"The chemotactic receptor for human C5a anaphylatoxin","volume":"349","author":"Gerard","year":"1991","journal-title":"Nature"},{"key":"ref_111","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1172\/JCI61135","article-title":"Radiation treatment inhibits monocyte entry into the optic nerve head and prevents neuronal damage in a mouse model of glaucoma","volume":"122","author":"Howell","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_112","doi-asserted-by":"crossref","first-page":"800","DOI":"10.3181\/00379727-149-38902","article-title":"Experimental Toxoplasma gondii infection in mice: The role of the fifth component of complement","volume":"149","author":"Araujo","year":"1975","journal-title":"Proc. Soc. Exp. Biol. Med."},{"key":"ref_113","doi-asserted-by":"crossref","first-page":"2435","DOI":"10.1016\/S0021-9258(19)39817-5","article-title":"Deficiency of the murine fifth complement component (C5). A 2-base pair gene deletion in a 5\u2019-exon","volume":"265","author":"Wetsel","year":"1990","journal-title":"J. Biol. Chem."},{"key":"ref_114","doi-asserted-by":"crossref","first-page":"76","DOI":"10.1186\/1742-2094-10-76","article-title":"Deficiency of complement component 5 ameliorates glaucoma in DBA\/2J mice","volume":"10","author":"Howell","year":"2013","journal-title":"J. Neuroinflamm."},{"key":"ref_115","doi-asserted-by":"crossref","first-page":"1381","DOI":"10.3389\/fphar.2019.01381","article-title":"Intravitreal Therapy Against the Complement Factor C5 Prevents Retinal Degeneration in an Experimental Autoimmune Glaucoma Model","volume":"10","author":"Reinehr","year":"2019","journal-title":"Front. Pharmacol."},{"key":"ref_116","doi-asserted-by":"crossref","first-page":"293","DOI":"10.1007\/s00441-020-03240-7","article-title":"Preservation of optic nerve structure by complement inhibition in experimental glaucoma","volume":"382","author":"Gassel","year":"2020","journal-title":"Cell Tissue Res."},{"key":"ref_117","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1007\/s00347-014-3100-6","article-title":"Complement activation after induction of ocular hypertension in an animal model","volume":"112","author":"Becker","year":"2015","journal-title":"Ophthalmologe"},{"key":"ref_118","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1681\/ASN.V1061242","article-title":"The terminal sequence of complement plays an essential role in antibody-mediated renal cell apoptosis","volume":"10","author":"Sato","year":"1999","journal-title":"J. Am. Soc. Nephrol."},{"key":"ref_119","doi-asserted-by":"crossref","first-page":"F747-757","DOI":"10.1152\/ajprenal.2000.278.5.F747","article-title":"C5b-9 membrane attack complex mediates endothelial cell apoptosis in experimental glomerulonephritis","volume":"278","author":"Hughes","year":"2000","journal-title":"Am. J. Physiol. Ren. Physiol."},{"key":"ref_120","doi-asserted-by":"crossref","first-page":"48","DOI":"10.1016\/j.exer.2010.04.002","article-title":"Mechanisms of retinal ganglion cell injury and defense in glaucoma","volume":"91","author":"Qu","year":"2010","journal-title":"Exp. Eye Res."},{"key":"ref_121","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1016\/j.ajpath.2020.02.006","article-title":"Complement Membrane Attack Complex: New Roles, Mechanisms of Action, and Therapeutic Targets","volume":"190","author":"Xie","year":"2020","journal-title":"Am. J. Pathol."},{"key":"ref_122","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1016\/S0002-9440(10)64604-4","article-title":"Spontaneous classical pathway activation and deficiency of membrane regulators render human neurons susceptible to complement lysis","volume":"157","author":"Singhrao","year":"2000","journal-title":"Am. J. Pathol."},{"key":"ref_123","doi-asserted-by":"crossref","first-page":"362","DOI":"10.1006\/exnr.1999.7170","article-title":"Increased complement biosynthesis by microglia and complement activation on neurons in Huntington\u2019s disease","volume":"159","author":"Singhrao","year":"1999","journal-title":"Exp. Neurol."},{"key":"ref_124","doi-asserted-by":"crossref","first-page":"4347","DOI":"10.1167\/iovs.02-1032","article-title":"Gene microarray analysis of experimental glaucomatous retina from cynomologous monkey","volume":"44","author":"Miyahara","year":"2003","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_125","doi-asserted-by":"crossref","first-page":"3061","DOI":"10.2353\/ajpath.2010.100158","article-title":"The alternative and terminal pathways of complement mediate post-traumatic spinal cord inflammation and injury","volume":"177","author":"Qiao","year":"2010","journal-title":"Am. J. Pathol."},{"key":"ref_126","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1742-2094-4-13","article-title":"Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: A randomized placebo-controlled study in mice","volume":"4","author":"Leinhase","year":"2007","journal-title":"J. Neuroinflamm."},{"key":"ref_127","doi-asserted-by":"crossref","unstructured":"Fernandez-Vega Cueto, A., Alvarez, L., Garcia, M., Artime, E., Alvarez Barrios, A., Rodriguez-Una, I., Coca-Prados, M., and Gonzalez-Iglesias, H. (2020). Systemic Alterations of Immune Response-Related Proteins during Glaucoma Development in the Murine Model DBA\/2J. Diagnostics, 10.","DOI":"10.3390\/diagnostics10060425"},{"key":"ref_128","doi-asserted-by":"crossref","first-page":"9945725","DOI":"10.1155\/2021\/9945725","article-title":"Complement Inhibitors in Age-Related Macular Degeneration: A Potential Therapeutic Option","volume":"2021","author":"Qin","year":"2021","journal-title":"J. Immunol. Res."},{"key":"ref_129","doi-asserted-by":"crossref","first-page":"2166","DOI":"10.3389\/fimmu.2019.02166","article-title":"Complement Inhibitors in Clinical Trials for Glomerular Diseases","volume":"10","author":"Zipfel","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_130","doi-asserted-by":"crossref","first-page":"100290","DOI":"10.1016\/j.xops.2023.100290","article-title":"Safety and Target Engagement of Complement C1q Inhibitor ANX007 in Neurodegenerative Eye Disease: Results from Phase I Studies in Glaucoma","volume":"3","author":"Sun","year":"2023","journal-title":"Ophthalmol. Sci."},{"key":"ref_131","doi-asserted-by":"crossref","first-page":"124","DOI":"10.1038\/s41586-020-2975-4","article-title":"Reprogramming to recover youthful epigenetic information and restore vision","volume":"588","author":"Lu","year":"2020","journal-title":"Nature"},{"key":"ref_132","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1089\/cell.2023.0074","article-title":"Sustained Vision Recovery by OSK Gene Therapy in a Mouse Model of Glaucoma","volume":"25","author":"Karg","year":"2023","journal-title":"Cell Reprogram"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2307\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T14:00:08Z","timestamp":1760104808000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/4\/2307"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,2,15]]},"references-count":132,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2024,2]]}},"alternative-id":["ijms25042307"],"URL":"https:\/\/doi.org\/10.3390\/ijms25042307","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,2,15]]}}}