{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,16]],"date-time":"2026-05-16T01:40:45Z","timestamp":1778895645697,"version":"3.51.4"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T00:00:00Z","timestamp":1742947200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Neurol."],"abstract":"<jats:p>Optic neuritis (ON) is an inflammatory condition of the optic nerve associated with demyelinating diseases like multiple sclerosis, neuromyelitis optica spectrum disorder, and myelin oligodendrocyte glycoprotein antibody-associated disease. The complement system is crucial in ON pathogenesis, driving blood-optic nerve barrier disruption, inflammation, and tissue damage. This review explores the complement activation pathways\u2014classical, alternative, and lectin\u2014and their roles in ON progression. Key proteins such as C3, C5, and terminal pathway components are highlighted as central to disease mechanisms. Recent advances in complement-targeted therapies, including C1q blockers, C3 and C5 inhibitors, show promising results in clinical and preclinical studies. Novel therapies, like anaphylatoxin receptor blockers and recombinant factor H, expand the treatment landscape, while plasma exchange remains vital for severe, corticosteroid-resistant cases. Challenges remain, such as ON heterogeneity, the long-term safety of complement inhibition, and the need for personalized approaches. Future studies should focus on unraveling complement-mediated mechanisms, identifying biomarkers, and refining therapeutic strategies. This review highlights the critical role of complement in ON and the latest therapeutic advances to improve patient outcomes.<\/jats:p>","DOI":"10.3389\/fneur.2025.1566771","type":"journal-article","created":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T05:20:38Z","timestamp":1742966438000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":2,"title":["Complement updates in optic neuritis"],"prefix":"10.3389","volume":"16","author":[{"given":"Yuhong","family":"He","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Guo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jifu","family":"Xin","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,3,26]]},"reference":[{"key":"ref1","doi-asserted-by":"publisher","first-page":"770","DOI":"10.1016\/j.survophthal.2019.06.001","article-title":"Critical review: typical and atypical optic neuritis","volume":"64","author":"Abel","year":"2019","journal-title":"Surv Ophthalmol"},{"key":"ref2","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1016\/j.ajo.2018.07.020","article-title":"Myelin oligodendrocyte glycoprotein antibody\u2013positive optic neuritis: clinical characteristics, radiologic clues, and outcome","volume":"195","author":"Chen","year":"2018","journal-title":"Am J Ophthalmol"},{"key":"ref3","doi-asserted-by":"publisher","first-page":"439","DOI":"10.1007\/s10384-021-00840-w","article-title":"Current understanding of the epidemiologic and clinical characteristics of optic neuritis","volume":"65","author":"Nakazawa","year":"2021","journal-title":"Jpn J Ophthalmol"},{"key":"ref4","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/j.exer.2008.05.017","article-title":"Inflammatory demyelination induces axonal injury and retinal ganglion cell apoptosis in experimental optic neuritis","volume":"87","author":"Shindler","year":"2008","journal-title":"Exp Eye Res"},{"key":"ref5","doi-asserted-by":"publisher","first-page":"2192","DOI":"10.3390\/genes14122192","article-title":"Uncovering the genetics and physiology behind optic neuritis","volume":"14","author":"Del Negro","year":"2023","journal-title":"Genes"},{"key":"ref6","doi-asserted-by":"publisher","first-page":"638473","DOI":"10.3389\/fneur.2021.638473","article-title":"Association of circulating T follicular helper cells with idiopathic optic neuritis and neuromyelitis optica spectrum disorders","volume":"12","author":"Wu","year":"2021","journal-title":"Front Neurol"},{"key":"ref7","doi-asserted-by":"publisher","first-page":"309","DOI":"10.1146\/annurev-immunol-042617-053245","article-title":"Complement and the regulation of T cell responses","volume":"36","author":"West","year":"2018","journal-title":"Annu Rev Immunol"},{"key":"ref8","doi-asserted-by":"publisher","first-page":"257","DOI":"10.3389\/fimmu.2015.00257","article-title":"Complement system part II: role in immunity","volume":"6","author":"Merle","year":"2015","journal-title":"Front Immunol"},{"key":"ref9","doi-asserted-by":"publisher","first-page":"178","DOI":"10.1016\/j.jneuroim.2012.09.002","article-title":"Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica","volume":"254","author":"Kuroda","year":"2013","journal-title":"J Neuroimmunol"},{"key":"ref10","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1186\/s12974-021-02249-1","article-title":"Neuromyelitis optica spectrum disorders: from pathophysiology to therapeutic strategies","volume":"18","author":"Carnero Contentti","year":"2021","journal-title":"J Neuroinflammation"},{"key":"ref11","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1073\/pnas.1616998114","article-title":"Structure and activation of C1, the complex initiating the classical pathway of the complement cascade","volume":"114","author":"Mortensen","year":"2017","journal-title":"Proc Natl Acad Sci"},{"key":"ref12","doi-asserted-by":"publisher","first-page":"151","DOI":"10.1016\/S0065-2776(08)60340-5","article-title":"The classical complement pathway: activation and regulation of the first complement component","volume":"37","author":"Cooper","year":"1985","journal-title":"Adv Immunol"},{"key":"ref13","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1172\/JCI110898","article-title":"Mechanisms of activation of the classical pathway of complement by Hageman factor fragment","volume":"71","author":"Ghebrehiwet","year":"1983","journal-title":"J Clin Invest"},{"key":"ref14","doi-asserted-by":"publisher","first-page":"158","DOI":"10.1111\/j.1600-065X.2012.01146.x","article-title":"PAMP s and DAMP s: signal 0s that spur autophagy and immunity","volume":"249","author":"Tang","year":"2012","journal-title":"Immunol Rev"},{"key":"ref15","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/S0140-6736(73)91886-2","article-title":"Reaction mechanism of the alternative pathway of complement fixation","volume":"301","author":"Lachmann","year":"1973","journal-title":"Lancet"},{"key":"ref16","doi-asserted-by":"publisher","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":"ref17","doi-asserted-by":"publisher","first-page":"12904","DOI":"10.1038\/s41598-017-11410-x","article-title":"Complement protein C3 suppresses axon growth and promotes neuron loss","volume":"7","author":"Peterson","year":"2017","journal-title":"Sci Rep"},{"key":"ref18","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1007\/s00401-021-02366-4","article-title":"Complement component 3 from astrocytes mediates retinal ganglion cell loss during neuroinflammation","volume":"142","author":"Gharagozloo","year":"2021","journal-title":"Acta Neuropathol"},{"key":"ref19","doi-asserted-by":"publisher","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":"ref20","doi-asserted-by":"publisher","first-page":"1603","DOI":"10.1681\/ASN.2016030343","article-title":"Anti-factor B and anti-C3b autoantibodies in C3 glomerulopathy and Ig-associated membranoproliferative GN","volume":"28","author":"Marinozzi","year":"2017","journal-title":"J Am Soc Nephrol"},{"key":"ref21","doi-asserted-by":"publisher","first-page":"1073","DOI":"10.1080\/14712598.2021.1884223","article-title":"Targeting the complement system in neuromyelitis optica spectrum disorder","volume":"21","author":"Asavapanumas","year":"2021","journal-title":"Expert Opin Biol Ther"},{"key":"ref22","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1155\/2022\/4997393","article-title":"Effects of C5a and receptor CD88 on glutamate and N-methyl-D-aspartic acid receptor expression in the mouse model of optic Neuromyelitis","volume":"2022","author":"Li","year":"2022","journal-title":"Comput Math Methods Med"},{"key":"ref23","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1111\/sji.12132","article-title":"Increased soluble C 5b-9 in CSF of Neuromyelitis Optica","volume":"79","author":"Wang","year":"2014","journal-title":"Scand J Immunol"},{"key":"ref24","doi-asserted-by":"publisher","first-page":"2859","DOI":"10.2147\/NDT.S322789","article-title":"Effect of low complement C4 on clinical characteristics of patients with first-episode Neuromyelitis Optica Spectrum disorder","volume":"17","author":"Pan","year":"2021","journal-title":"Neuropsychiatr Dis Treat"},{"key":"ref25","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1007\/s00401-017-1734-6","article-title":"Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica","volume":"134","author":"Tradtrantip","year":"2017","journal-title":"Acta Neuropathol"},{"key":"ref26","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1159\/000524587","article-title":"Development, characterization, and in vivo validation of a humanized C6 monoclonal antibody that inhibits the membrane attack complex","volume":"15","author":"Gytz Olesen","year":"2023","journal-title":"J Innate Immun"},{"key":"ref27","doi-asserted-by":"publisher","first-page":"703249","DOI":"10.3389\/fneur.2021.703249","article-title":"An experimental model of neuromyelitis optica spectrum disorder\u2013optic neuritis: insights into disease mechanisms","volume":"12","author":"Soerensen","year":"2021","journal-title":"Front Neurol"},{"key":"ref28","first-page":"1","article-title":"Human protectin (CD59), an 18,000-20,000 MW complement lysis restricting factor, inhibits C5b-8 catalysed insertion of C9 into lipid bilayers","volume":"71","author":"Meri","year":"1990","journal-title":"Immunology"},{"key":"ref29","doi-asserted-by":"publisher","first-page":"829","DOI":"10.1007\/s00401-013-1128-3","article-title":"C1q-targeted monoclonal antibody prevents complement-dependent cytotoxicity and neuropathology in in vitro and mouse models of neuromyelitis optica","volume":"125","author":"Phuan","year":"2013","journal-title":"Acta Neuropathol"},{"key":"ref30","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1167\/iovs.64.2.3","article-title":"Pharmacokinetic and target engagement measures of ANX007, an anti-C1q antibody fragment, following intravitreal administration in nonhuman primates","volume":"64","author":"Grover","year":"2023","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"ref31","doi-asserted-by":"publisher","first-page":"3459","DOI":"10.1523\/JNEUROSCI.3932-10.2011","article-title":"Complement protein C1q-mediated neuroprotection is correlated with regulation of neuronal gene and microRNA expression","volume":"31","author":"Benoit","year":"2011","journal-title":"J Neurosci"},{"key":"ref32","doi-asserted-by":"publisher","first-page":"3166","DOI":"10.1182\/blood-2021-153289","article-title":"Safety, tolerability, and clinical pharmacology of ANX009, an inhibitory antibody fab fragment against C1q, administered subcutaneously to healthy volunteers","volume":"138","author":"Grover","year":"2021","journal-title":"Blood"},{"key":"ref33","doi-asserted-by":"publisher","first-page":"1504","DOI":"10.3389\/fimmu.2020.01504","article-title":"Functional and structural characterization of a potent C1q inhibitor targeting the classical pathway of the complement system","volume":"11","author":"Laursen","year":"2020","journal-title":"Front Immunol"},{"key":"ref34","doi-asserted-by":"publisher","first-page":"7537","DOI":"10.1523\/JNEUROSCI.19-17-07537.1999","article-title":"Inactivation of rho signaling pathway promotes CNS axon regeneration","volume":"19","author":"Lehmann","year":"1999","journal-title":"J Neurosci"},{"key":"ref35","doi-asserted-by":"publisher","first-page":"1423","DOI":"10.1007\/s40265-021-01560-8","article-title":"Pegcetacoplan: first approval","volume":"81","author":"Hoy","year":"2021","journal-title":"Drugs"},{"key":"ref36","doi-asserted-by":"publisher","first-page":"1631","DOI":"10.1016\/j.molimm.2011.04.014","article-title":"Inhibiting the C5\u2013C5a receptor axis","volume":"48","author":"Woodruff","year":"2011","journal-title":"Mol Immunol"},{"key":"ref37","doi-asserted-by":"publisher","first-page":"1053","DOI":"10.1002\/ana.26626","article-title":"Ravulizumab in Aquaporin-4\u2013positive Neuromyelitis Optica Spectrum disorder","volume":"93","author":"Pittock","year":"2023","journal-title":"Ann Neurol"},{"key":"ref38","doi-asserted-by":"publisher","first-page":"1332890","DOI":"10.3389\/fneur.2024.1332890","article-title":"Immediate and sustained terminal complement inhibition with ravulizumab in patients with anti-aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder","volume":"15","author":"Ortiz","year":"2024","journal-title":"Front Neurol"},{"key":"ref39","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1080\/14712598.2024.2423002","article-title":"An evaluation of ravulizumab for the treatment of neuromyelitis optica spectrum disorder","volume":"24","author":"Balaban","year":"2024","journal-title":"Expert Opin Biol Ther"},{"key":"ref40","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1080\/21505594.2019.1640035","article-title":"Distinct roles of the anaphylatoxin receptors C3aR, C5aR1 and C5aR2 in experimental meningococcal infections","volume":"10","author":"Muenstermann","year":"2019","journal-title":"Virulence"},{"key":"ref41","doi-asserted-by":"publisher","first-page":"576","DOI":"10.1016\/j.ophtha.2020.08.027","article-title":"C5 inhibitor avacincaptad pegol for geographic atrophy due to age-related macular degeneration: a randomized pivotal phase 2\/3 trial","volume":"128","author":"Jaffe","year":"2021","journal-title":"Ophthalmology"},{"key":"ref42","doi-asserted-by":"publisher","first-page":"888816","DOI":"10.3389\/fimmu.2022.888816","article-title":"Complement inhibition in ANCA-associated vasculitis","volume":"13","author":"Tesar","year":"2022","journal-title":"Front Immunol"},{"key":"ref43","doi-asserted-by":"publisher","first-page":"660382","DOI":"10.3389\/fimmu.2021.660382","article-title":"Autoantibodies against the complement regulator factor H in the serum of patients with neuromyelitis optica spectrum disorder","volume":"12","author":"Uzonyi","year":"2021","journal-title":"Front Immunol"},{"key":"ref44","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1016\/j.bbi.2017.04.023","article-title":"Low expression of complement inhibitory protein CD59 contributes to humoral autoimmunity against astrocytes","volume":"65","author":"Wang","year":"2017","journal-title":"Brain Behav Immun"},{"key":"ref45","doi-asserted-by":"publisher","first-page":"1644","DOI":"10.1177\/1352458515571446","article-title":"Role of membrane complement regulators in neuromyelitis optica","volume":"21","author":"Saadoun","year":"2015","journal-title":"Mult Scler J"},{"key":"ref46","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1007\/s00415-016-8073-8","article-title":"Plasma exchange response in 34 patients with severe optic neuritis","volume":"263","author":"Deschamps","year":"2016","journal-title":"J Neurol"},{"key":"ref47","doi-asserted-by":"publisher","first-page":"863","DOI":"10.3390\/diagnostics14090863","article-title":"Visual function improvement after plasma exchange therapy for acute optic neuritis in Neuromyelitis Optica Spectrum disorders: case series and review","volume":"14","author":"Iancu","year":"2024","journal-title":"Diagnostics"},{"key":"ref48","doi-asserted-by":"publisher","first-page":"7926","DOI":"10.1073\/pnas.1820892116","article-title":"Small-molecule factor B inhibitor for the treatment of complement-mediated diseases","volume":"116","author":"Schubart","year":"2019","journal-title":"Proc Natl Acad Sci"},{"key":"ref49","doi-asserted-by":"publisher","first-page":"4165","DOI":"10.2174\/0929867326666191001130342","article-title":"Discovery and Development of the Oral Complement Factor D InhibitorACH-4471","volume":"27","author":"Wiles","year":"2020","journal-title":"Curr Med Chem"},{"key":"ref50","doi-asserted-by":"publisher","first-page":"573","DOI":"10.11477\/mf.1416201318","article-title":"Current status and prospects of complement-targeting therapy for neuromyelitis optica","volume":"71","author":"Kuroda","year":"2019","journal-title":"Brain Nerve"},{"key":"ref51","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1097\/ICU.0000000000001007","article-title":"Evidence-based management of optic neuritis","volume":"35","author":"Bergeron","year":"2024","journal-title":"Curr Opin Ophthalmol"},{"key":"ref52","doi-asserted-by":"publisher","first-page":"1007","DOI":"10.3389\/fimmu.2019.01007","article-title":"The challenges and promise of complement therapeutics for ocular diseases","volume":"10","author":"Park","year":"2019","journal-title":"Front Immunol"}],"container-title":["Frontiers in Neurology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1566771\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,26]],"date-time":"2025-03-26T05:20:50Z","timestamp":1742966450000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fneur.2025.1566771\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,3,26]]},"references-count":52,"alternative-id":["10.3389\/fneur.2025.1566771"],"URL":"https:\/\/doi.org\/10.3389\/fneur.2025.1566771","relation":{},"ISSN":["1664-2295"],"issn-type":[{"value":"1664-2295","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,3,26]]},"article-number":"1566771"}}