Immunopathogenesis of multiple sclerosis: molecular and cellular mechanisms and new immunotherapeutic approaches

References

• Lassmann H, Bradl M. Multiple sclerosis: experimental models and reality. Acta Neuropathol. 2017;133(2):223–244. doi: 10.1007/s00401-016-1631-4.
   PubMed Web of Science ®Google Scholar
• Walton C, King R, Rechtman L, et al. Rising prevalence of multiple sclerosis worldwide: insights from the atlas of MS, third edition. Mult Scler. 2020;26(14):1816–1821. doi: 10.1177/1352458520970841.
   PubMed Web of Science ®Google Scholar
• Kokas Z, Járdánházy A, Sandi D, et al. Real-world operation of multiple sclerosis centres in Central-Eastern European countries covering 107 million inhabitants. Mult Scler Relat Disord. 2023;69:104406. doi: 10.1016/j.msard.2022.104406.
   PubMed Web of Science ®Google Scholar
• Ascherio A. Environmental factors in multiple sclerosis. Expert Rev Neurother. 2013;13(12 Suppl):3–9. doi: 10.1586/14737175.2013.865866.
   PubMed Web of Science ®Google Scholar
• Vong V, Simpson-Yap S, Phaiju S, et al. The association between tobacco smoking and depression and anxiety in people with multiple sclerosis: a systematic review. Mult Scler Relat Disord. 2023;70:104501. doi: 10.1016/j.msard.2023.104501.
   PubMed Web of Science ®Google Scholar
• Plantone D, Primiano G, Manco C, et al. Vitamin D in neurological diseases. Int J Mol Sci. 2023;24(1):87. doi: 10.3390/ijms24010087.
   Web of Science ®Google Scholar
• Ridaura VK, Faith JJ, Rey FE, et al. Gut microbiota from twins discordant for obesity modulate metabolism in mice. Science. 2013;341(6150):1241214. doi: 10.1126/science.1241214.
   PubMed Web of Science ®Google Scholar
• Wang X, Liang Z, Wang S, et al. Role of gut microbiota in multiple sclerosis and potential therapeutic implications. Curr Neuropharmacol. 2022;20(7):1413–1426. doi: 10.2174/1570159X19666210629145351.
   PubMed Web of Science ®Google Scholar
• Lublin FD, Reingold SC, Cohen JA, et al. Defining the clinical course of multiple sclerosis: the 2013 revisions. Neurology. 2014;83(3):278–286. doi: 10.1212/WNL.0000000000000560.
   PubMed Web of Science ®Google Scholar
• Polman CH, Reingold SC, Banwell B, et al. Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol. 2011;69(2):292–302. doi: 10.1002/ana.22366.
   PubMed Web of Science ®Google Scholar
• Dobson R, Giovannoni G. Multiple sclerosis – a review. Eur J Neurol. 2019;26(1):27–40. doi: 10.1111/ene.13819.
   PubMed Web of Science ®Google Scholar
• Yamasaki R, Kira JI. Multiple sclerosis. Adv Exp Med Biol. 2019;1190:217–247. doi: 10.1007/978-981-32-9636-7_14.
   PubMed Web of Science ®Google Scholar
• Nociti V. What is the role of brain derived neurotrophic factor in multiple sclerosis neuroinflammation? Neurosciences. 2020;7(3):291–299. doi: 10.20517/2347-8659.2020.25.
   Google Scholar
• Caprariello AV, Rogers JA, Morgan ML, et al. Biochemically altered myelin triggers autoimmune demyelination. Proc Natl Acad Sci U S A. 2018;115(21):5528–5533. doi: 10.1073/pnas.1721115115.
   PubMed Web of Science ®Google Scholar
• Guo MH, Sama P, LaBarre BA, et al. Dissection of multiple sclerosis genetics identifies B and CD4+ T cells as driver cell subsets. Genome Biol. 2022;23(1):127. doi: 10.1186/s13059-022-02694-y.
   PubMed Web of Science ®Google Scholar
• Goris A, Vandebergh M, McCauley JL, et al. Genetics of multiple sclerosis: lessons from polygenicity. Lancet Neurol. 2022;21(9):830–842. doi: 10.1016/S1474-4422(22)00255-1.
   PubMed Web of Science ®Google Scholar
• Attfield KE, Jensen LT, Kaufmann M, et al. The immunology of multiple sclerosis. Nat Rev Immunol. 2022;22(12):734–750. doi: 10.1038/s41577-022-00718-z.
   PubMed Web of Science ®Google Scholar
• Trend S, Leffler J, Jones AP, et al. Associations of serum short-chain fatty acids with circulating immune cells and serum biomarkers in patients with multiple sclerosis. Sci Rep. 2021;11(1):5244. doi: 10.1038/s41598-021-84881-8.
   PubMed Web of Science ®Google Scholar
• Calahorra L, Camacho-Toledano C, Serrano-Regal MP, et al. Regulatory cells in multiple sclerosis: from blood to brain. Biomedicines. 2022;10(2):335. doi: 10.3390/biomedicines10020335.
   PubMed Web of Science ®Google Scholar
• Mazzitelli JA, Smyth LC, Cross KA, et al. Cerebrospinal fluid regulates skull bone marrow niches via direct access through dural channels. Nat Neurosci. 2022;25(5):555–560. doi: 10.1038/s41593-022-01029-1.
   PubMed Web of Science ®Google Scholar
• Shi K, Li H, Chang T, et al. Bone marrow hematopoiesis drives multiple sclerosis progression. Cell. 2022;185(13):2234.e17–2247.e17. doi: 10.1016/j.cell.2022.05.020.
   Web of Science ®Google Scholar
• Cui LY, Chu SF, Chen NH. The role of chemokines and chemokine receptors in multiple sclerosis. Int Immunopharmacol. 2020;83:106314. doi: 10.1016/j.intimp.2020.106314.
   PubMed Web of Science ®Google Scholar
• Sferruzza G, Clarelli F, Mascia E, et al. Transcriptomic analysis of peripheral monocytes upon fingolimod treatment in relapsing remitting multiple sclerosis patients. Mol Neurobiol. 2021;58(10):4816–4827. doi: 10.1007/s12035-021-02465-z.
   PubMed Web of Science ®Google Scholar
• Saravia J, Chapman NM, Chi H. Helper T cell differentiation. Cell Mol Immunol. 2019;16(7):634–643. doi: 10.1038/s41423-019-0220-6.
   PubMed Web of Science ®Google Scholar
• Ahmadi L, Eskandari N, Ghanadian M, et al. The immunomodulatory aspect of quercetin penta acetate on Th17 cells proliferation and gene expression in multiple sclerosis. Cell J. 2023;25(2):110–117.
   PubMed Web of Science ®Google Scholar
• Moser T, Akgün K, Proschmann U, et al. The role of TH17 cells in multiple sclerosis: therapeutic implications. Autoimmun Rev. 2020;19(10):102647. doi: 10.1016/j.autrev.2020.102647.
   PubMed Web of Science ®Google Scholar
• Ferber IA, Brocke S, Taylor-Edwards C, et al. Mice with a disrupted IFN-gamma gene are susceptible to the induction of experimental autoimmune encephalomyelitis (EAE). J Immunol. 1996;156(1):5–7. doi: 10.4049/jimmunol.156.1.5.
   PubMed Web of Science ®Google Scholar
• Sosa RA, Murphey C, Robinson RR, et al. IFN-γ ameliorates autoimmune encephalomyelitis by limiting myelin lipid peroxidation. Proc Natl Acad Sci U S A. 2015;112(36):E5038–E5047. doi: 10.1073/pnas.1505955112.
   PubMed Web of Science ®Google Scholar
• Espejo C, Penkowa M, Sáez-Torres I, et al. Treatment with anti-interferon-γ monoclonal antibodies modifies experimental autoimmune encephalomyelitis in interferon-γ receptor knockout mice. Exp Neurol. 2001;172(2):460–468. doi: 10.1006/exnr.2001.7815.
   PubMed Web of Science ®Google Scholar
• Wagner CA, Roqué PJ, Goverman JM. Pathogenic T cell cytokines in multiple sclerosis. J Exp Med. 2020;217(1):jem.20190460. doi: 10.1084/jem.20190460.
   Web of Science ®Google Scholar
• Bedoya SK, Lam B, Lau K, et al. Th17 cells in immunity and autoimmunity. Clin Dev Immunol. 2013;2013:986716–986789. doi: 10.1155/2013/986789.
   Google Scholar
• Babaloo Z, Aliparasti MR, Babaiea F, et al. The role of Th17 cells in patients with relapsing-remitting multiple sclerosis: interleukin-17A and interleukin-17F serum levels. Immunol Lett. 2015;164(2):76–80. doi: 10.1016/j.imlet.2015.01.001.
   PubMed Web of Science ®Google Scholar
• Nelson KM, Dahlin JL, Bisson J, et al. The essential medicinal chemistry of curcumin. J Med Chem. 2017;60(5):1620–1637. doi: 10.1021/acs.jmedchem.6b00975.
   PubMed Web of Science ®Google Scholar
• Kleinschek MA, Owyang AM, Joyce-Shaikh B, et al. IL-25 regulates Th17 function in autoimmune inflammation. J Exp Med. 2007;204(1):161–170. doi: 10.1084/jem.20061738.
   PubMed Web of Science ®Google Scholar
• Maeda K, Tanioka T, Iwamoto S. Regulatory effect of IL-4 on early Th17 differentiation from naive T cells into stem cell memory Th17 precursors via modulation of CD31 and CCR6 expression. Showa Univ J Med Sci. 2020;32(2):135–145. doi: 10.15369/sujms.32.135.
   Google Scholar
• Khan D, Ansar Ahmed S. Regulation of IL-17 in autoimmune diseases by transcriptional factors and microRNAs. Front Genet. 2015;6:236. doi: 10.3389/fgene.2015.00236.
   PubMed Web of Science ®Google Scholar
• Miyashita Y, Kouwaki T, Tsukamoto H, et al. TICAM-1/TRIF associates with Act1 and suppresses IL-17 receptor–mediated inflammatory responses. Life Sci Alliance. 2022;5(2):e202101181. doi: 10.26508/lsa.202101181.
   PubMed Web of Science ®Google Scholar
• Regen T, Isaac S, Amorim A, et al. IL-17 controls Central nervous system autoimmunity through the intestinal microbiome. Sci Immunol. 2021;6(56):eaaz6563. doi: 10.1126/sciimmunol.aaz6563.
   PubMed Web of Science ®Google Scholar
• Matsuzaki G, Teruya N, Kiyohara Kohama H, et al. Mycobacterium bovis BCG-mediated suppression of Th17 response in mouse experimental autoimmune encephalomyelitis. Immunopharmacol Immunotoxicol. 2021;43(2):203–211. doi: 10.1080/08923973.2021.1878215.
   PubMed Web of Science ®Google Scholar
• Pilipović I, Vujnović I, Stojić-Vukanić Z, et al. Noradrenaline modulates CD4+ T cell priming in rat experimental autoimmune encephalomyelitis: a role for the α1-adrenoceptor. Immunol Res. 2019;67(2-3):223–240. doi: 10.1007/s12026-019-09082-y.
   PubMed Web of Science ®Google Scholar
• Melnikov M, Rogovskii V, Sviridova A, et al. The dual role of the β 2-Adrenoreceptor in the modulation of IL-17 and IFN-γ production by T cells in multiple sclerosis. Int J Mol Sci. 2022;23(2):668. doi: 10.3390/ijms23020668.
   PubMed Web of Science ®Google Scholar
• Carvajal Gonczi CM, Tabatabaei Shafiei M, East A, et al. Reciprocal modulation of helper Th1 and Th17 cells by the β2‐adrenergic receptor agonist drug terbutaline. FEBS J. 2017;284(18):3018–3028. doi: 10.1111/febs.14166.
   PubMed Web of Science ®Google Scholar
• Lorton D, Bellinger DL. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. Int J Mol Sci. 2015;16(3):5635–5665. doi: 10.3390/ijms16035635.
   PubMed Web of Science ®Google Scholar
• Wei Y, Braunstein Z, Chen J, et al. JAK2/STAT5 inhibition protects mice from experimental autoimmune encephalomyelitis by modulating T cell polarization. Int Immunopharmacol. 2023;120:110382. doi: 10.1016/j.intimp.2023.110382.
   PubMed Web of Science ®Google Scholar
• Al-Mazroua HA, Nadeem A, Ansari MA, et al. CCR1 antagonist ameliorates experimental autoimmune encephalomyelitis by inhibition of Th9/Th22-related markers in the brain and periphery. Mol Immunol. 2022;144:127–137. doi: 10.1016/j.molimm.2022.02.017.
   PubMed Web of Science ®Google Scholar
• Lv J, Han M, Liu G, et al. Carboplatin ameliorates the pathogenesis of experimental autoimmune encephalomyelitis by inducing T cell apoptosis. Int Immunopharmacol. 2023;121:110458. doi: 10.1016/j.intimp.2023.110458.
   PubMed Web of Science ®Google Scholar
• do Sacramento PM, Sales M, Kasahara T, et al. Major depression favors the expansion of Th17-like cells and decrease the proportion of CD39 + treg cell subsets in response to myelin antigen in multiple sclerosis patients. Cell Mol Life Sci. 2022;79(6):298. doi: 10.1007/s00018-022-04315-0.
   PubMed Web of Science ®Google Scholar
• Cruciani C, Puthenparampil M, Tomas-Ojer P, et al. T-cell specificity influences disease heterogeneity in multiple sclerosis. Neurol Neuroimmunol Neuroinflamm. 2021;8(6):e1075. doi: 10.1212/NXI.0000000000001075.
   PubMed Web of Science ®Google Scholar
• Luoqian J, Yang W, Ding X, et al. Ferroptosis promotes T-cell activation-induced neurodegeneration in multiple sclerosis. Cell Mol Immunol. 2022;19(8):913–924. doi: 10.1038/s41423-022-00883-0.
   PubMed Web of Science ®Google Scholar
• McIntyre LL, Greilach SA, Othy S, et al. Regulatory T cells promote remyelination in the murine experimental autoimmune encephalomyelitis model of multiple sclerosis following human neural stem cell transplant. Neurobiol Dis. 2020;140:104868. doi: 10.1016/j.nbd.2020.104868.
   PubMed Web of Science ®Google Scholar
• Li YF, Zhang SX, Ma XW, et al. The proportion of peripheral regulatory T cells in patients with multiple sclerosis: a meta-analysis. Mult Scler Relat Disord. 2019;28:75–80. doi: 10.1016/j.msard.2018.12.019.
   PubMed Web of Science ®Google Scholar
• Ozenci V, Kouwenhoven M, Huang YM, et al. Multiple sclerosis: levels of interleukin-10-secreting blood mononuclear cells are low in untreated patients but augmented during interferon-beta-1b treatment. Scand J Immunol. 1999;49(5):554–561. doi: 10.1046/j.1365-3083.1999.00546.x.
   PubMed Web of Science ®Google Scholar
• Seifert HA, Gerstner G, Kent G, et al. Estrogen-induced compensatory mechanisms protect IL-10-deficient mice from developing EAE. J Neuroinflammation. 2019;16(1):195. doi: 10.1186/s12974-019-1588-z.
   PubMed Web of Science ®Google Scholar
• Rasouli J, Ciric B, Imitola J, et al. Expression of GM-CSF in T cells is increased in multiple sclerosis and suppressed by IFN-β therapy. J Immunol. 2015;194(11):5085–5093. doi: 10.4049/jimmunol.1403243.
   PubMed Web of Science ®Google Scholar
• Komuczki J, Tuzlak S, Friebel E, et al. Fate-mapping of GM-CSF expression identifies a discrete subset of inflammation-driving T helper cells regulated by cytokines IL-23 and IL-1β. Immunity. 2019;50(5):1289.e6–1304.e6. doi: 10.1016/j.immuni.2019.04.006.
   Web of Science ®Google Scholar
• Imitola J, Rasouli J, Watanabe F, et al. Elevated expression of granulocyte-macrophage colony-stimulating factor receptor in multiple sclerosis lesions. J Neuroimmunol. 2018;317:45–54. doi: 10.1016/j.jneuroim.2017.12.017.
   PubMed Web of Science ®Google Scholar
• Rasouli J, Casella G, Yoshimura S, et al. A distinct GM-CSF + T helper cell subset requires T-bet to adopt a TH1 phenotype and promote neuroinflammation. Sci Immunol. 2020;5(52):eaba9953. doi: 10.1126/sciimmunol.aba9953.
   PubMed Web of Science ®Google Scholar
• Rasouli J, Casella G, Zhang W, et al. Transcription factor RUNX3 mediates plasticity of ThGM cells toward Th1 phenotype. Front Immunol. 2022;13:912583. doi: 10.3389/fimmu.2022.912583.
   PubMed Web of Science ®Google Scholar
• Yoshimura S, Thome R, Konno S, et al. IL-9 controls Central nervous system autoimmunity by suppressing GM-CSF production. J Immunol. 2020;204(3):531–539. doi: 10.4049/jimmunol.1801113.
   PubMed Web of Science ®Google Scholar
• Sheng W, Yang F, Zhou Y, et al. STAT5 programs a distinct subset of GM-CSF-producing T helper cells that is essential for autoimmune neuroinflammation. Cell Res. 2014;24(12):1387–1402. doi: 10.1038/cr.2014.154.
   PubMed Web of Science ®Google Scholar
• Plank MW, Kaiko GE, Maltby S, et al. Th22 cells form a distinct Th lineage from Th17 cells in vitro with unique transcriptional properties and tbet-dependent Th1 plasticity. J Immunol. 2017;198(5):2182–2190. doi: 10.4049/jimmunol.1601480.
   PubMed Web of Science ®Google Scholar
• Zhang L, Li Y-G, Li Y-h, et al. Increased frequencies of Th22 cells as well as Th17 cells in the peripheral blood of patients with ankylosing spondylitis and rheumatoid arthritis. PLOS One. 2012;7(4):e31000. doi: 10.1371/journal.pone.0031000.
   PubMed Web of Science ®Google Scholar
• Ouyang W, O’Garra A. IL-10 family cytokines IL-10 and IL-22: from basic science to clinical translation. Immunity. 2019;50(4):871–891. doi: 10.1016/j.immuni.2019.03.020.
   PubMed Web of Science ®Google Scholar
• Tahrali I, Kucuksezer UC, Akdeniz N, et al. CD3(-)CD56(+) NK cells display an inflammatory profile in RR-MS patients. Immunol Lett. 2019;216:63–69. doi: 10.1016/j.imlet.2019.10.006.
   PubMed Web of Science ®Google Scholar
• Mousset CM, Hobo W, Woestenenk R, et al. Comprehensive phenotyping of T cells using flow cytometry. Cytometry A. 2019;95(6):647–654. doi: 10.1002/cyto.a.23724.
   PubMedGoogle Scholar
• Jiang Q, Yang G, Xiao F, et al. Role of Th22 cells in the pathogenesis of autoimmune diseases. Acta Pharmacol Sin. 2021;12:688066.
   Google Scholar
• Lejeune D, Dumoutier L, Constantinescu S, et al. Interleukin-22 (IL-22) activates the JAK/STAT, ERK, JNK, and p38 MAP kinase pathways in a rat hepatoma cell line: pathways that are shared with and distinct from IL-10. J Biol Chem. 2002;277(37):33676–33682. doi: 10.1074/jbc.M204204200.
   PubMed Web of Science ®Google Scholar
• Zarobkiewicz MK, Kowalska W, Slawinski M, et al. The role of interleukin 22 in multiple sclerosis and its association with c-Maf and AHR. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2019;163(3):200–206. doi: 10.5507/bp.2019.024.
   PubMed Web of Science ®Google Scholar
• Xu W, Li R, Dai Y, et al. IL-22 secreting CD4+ T cells in the patients with neuromyelitis optica and multiple sclerosis. J Neuroimmunol. 2013;261(1-2):87–91. doi: 10.1016/j.jneuroim.2013.04.021.
   PubMed Web of Science ®Google Scholar
• Perriard G, Mathias A, Enz L, et al. Interleukin-22 is increased in multiple sclerosis patients and targets astrocytes. J Neuroinflammation. 2015;12(1):119. doi: 10.1186/s12974-015-0335-3.
   PubMed Web of Science ®Google Scholar
• Lindahl H, Guerreiro-Cacais AO, Bedri SK, et al. IL-22 binding protein promotes the disease process in multiple sclerosis. J Immunol. 2019;203(4):888–898. doi: 10.4049/jimmunol.1900400.
   PubMed Web of Science ®Google Scholar
• Rolla S, Bardina V, De Mercanti S, et al. Th22 cells are expanded in multiple sclerosis and are resistant to IFN‐β. J Leukoc Biol. 2014;96(6):1155–1164. doi: 10.1189/jlb.5A0813-463RR.
   PubMed Web of Science ®Google Scholar
• Chihara N, Yamamura T. Immuno-pathogenesis of neuromyelitis optica and emerging therapies. Semin Immunopathol. 2022;44(5):599–610. doi: 10.1007/s00281-022-00941-9.
   PubMed Web of Science ®Google Scholar
• Kira J-I. Neuromyelitis optica and opticospinal multiple sclerosis: mechanisms and pathogenesis. Pathophysiology. 2011;18(1):69–79. doi: 10.1016/j.pathophys.2010.04.008.
   PubMedGoogle Scholar
• Babbe H, Roers A, Waisman A, et al. Clonal expansions of CD8+ T cells dominate the T cell infiltrate in active multiple sclerosis lesions as shown by micromanipulation and single cell polymerase chain reaction. J Exp Med. 2000;192(3):393–404. doi: 10.1084/jem.192.3.393.
   PubMed Web of Science ®Google Scholar
• Muraro PA, Robins H, Malhotra S, et al. T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest. 2014;124(3):1168–1172. doi: 10.1172/JCI71691.
   PubMed Web of Science ®Google Scholar
• Massey J, Jackson K, Singh M, et al. Haematopoietic stem cell transplantation results in extensive remodelling of the clonal T cell repertoire in multiple sclerosis. Front Immunol. 2022;13:798300. doi: 10.3389/fimmu.2022.798300.
   PubMed Web of Science ®Google Scholar
• van Nierop GP, van Luijn MM, Michels SS, et al. Phenotypic and functional characterization of T cells in white matter lesions of multiple sclerosis patients. Acta Neuropathol. 2017;134(3):383–401. doi: 10.1007/s00401-017-1744-4.
   PubMed Web of Science ®Google Scholar
• Schneider-Hohendorf T, Gerdes LA, Pignolet B, et al. Broader epstein–barr virus–specific T cell receptor repertoire in patients with multiple sclerosis. J Exp Med. 2022;219(11):e20220650.
   PubMed Web of Science ®Google Scholar
• Konjevic Sabolek M, Held K, Beltrán E, et al. Communication of CD8+ T cells with mononuclear phagocytes in multiple sclerosis. Ann Clin Transl Neurol. 2019;6(7):1151–1164. doi: 10.1002/acn3.783.
   PubMed Web of Science ®Google Scholar
• Page N, Lemeille S, Vincenti I, et al. Persistence of self-reactive CD8+ T cells in the CNS requires TOX-dependent chromatin remodeling. Nat Commun. 2021;12(1):1009. doi: 10.1038/s41467-021-21109-3.
   PubMed Web of Science ®Google Scholar
• Li R, Patterson KR, Bar-Or A. Reassessing B cell contributions in multiple sclerosis. Nat Immunol. 2018;19(7):696–707. doi: 10.1038/s41590-018-0135-x.
   PubMed Web of Science ®Google Scholar
• Ramesh A, Schubert RD, Greenfield AL, et al. A pathogenic and clonally expanded B cell transcriptome in active multiple sclerosis. Proc Natl Acad Sci U S A. 2020;117(37):22932–22943. doi: 10.1073/pnas.2008523117.
   PubMed Web of Science ®Google Scholar
• Lazibat I, Rubinić-Majdak M, Županić S. Multiple sclerosis: new aspects of immunopathogenesis. Acta Clin Croat. 2018;57(2):352–361. doi: 10.20471/acc.2018.57.02.17.
   PubMed Web of Science ®Google Scholar
• Apostolidis SA, Kakara M, Painter MM, et al. Cellular and humoral immune responses following SARS-CoV-2 mRNA vaccination in patients with multiple sclerosis on anti-CD20 therapy. Nat Med. 2021;27(11):1990–2001. doi: 10.1038/s41591-021-01507-2.
   PubMed Web of Science ®Google Scholar
• Jelcic I, Al Nimer F, Wang J, et al. Memory B cells activate brain-homing, autoreactive CD4+ T cells in multiple sclerosis. Cell. 2018;175(1):85.e23–100.e23. doi: 10.1016/j.cell.2018.08.011.
   Web of Science ®Google Scholar
• Cencioni MT, Mattoscio M, Magliozzi R, et al. B cells in multiple sclerosis—from targeted depletion to immune reconstitution therapies. Nat Rev Neurol. 2021;17(7):399–414. doi: 10.1038/s41582-021-00498-5.
   PubMed Web of Science ®Google Scholar
• Reali C, Magliozzi R, Roncaroli F, et al. B cell rich meningeal inflammation associates with increased spinal cord pathology in multiple sclerosis. Brain Pathol. 2020;30(4):779–793. doi: 10.1111/bpa.12841.
   PubMed Web of Science ®Google Scholar
• Owens GP, Bennett JL, Gilden DH, et al. The B cell response in multiple sclerosis. Neurol Res. 2006;28(3):236–244. doi: 10.1179/016164106X98099.
   PubMed Web of Science ®Google Scholar
• Cross AH. MS: the return of the B cell. Neurology. 2000;54(6):1214–1215. doi: 10.1212/wnl.54.6.1214.
   PubMed Web of Science ®Google Scholar
• Link H, Huang Y-M. Oligoclonal bands in multiple sclerosis cerebrospinal fluid: an update on methodology and clinical usefulness. J Neuroimmunol. 2006;180(1-2):17–28. doi: 10.1016/j.jneuroim.2006.07.006.
   PubMed Web of Science ®Google Scholar
• Lopez JA, Denkova M, Ramanathan S, et al. Pathogenesis of autoimmune demyelination: from multiple sclerosis to neuromyelitis optica spectrum disorders and myelin oligodendrocyte glycoprotein antibody-associated disease. Clin Transl Immunol. 2021;10(7):e1316.
   PubMed Web of Science ®Google Scholar
• Greer JM, Trifilieff E, Pender MP. Correlation between anti-myelin proteolipid protein (PLP) antibodies and disease severity in multiple sclerosis patients with PLP response-permissive HLA types. Front Immunol. 2020;11:1891. doi: 10.3389/fimmu.2020.01891.
   PubMed Web of Science ®Google Scholar
• Bando Y. Mechanism of demyelination and remyelination in multiple sclerosis. Clinical & Exp Neuroim. 2020;11(S1):14–21. doi: 10.1111/cen3.12576.
   Google Scholar
• Challa DK, Bussmeyer U, Khan T, et al. Autoantibody depletion ameliorates disease in murine experimental autoimmune encephalomyelitis. MAbs. 2013;5(5):655–659. doi: 10.4161/mabs.25439.
   PubMed Web of Science ®Google Scholar
• Martinsen V, Kursula P. Multiple sclerosis and myelin basic protein: insights into protein disorder and disease. Amino Acids. 2022;54(1):99–109. doi: 10.1007/s00726-021-03111-7.
   PubMed Web of Science ®Google Scholar
• Garcia PS, Brum DG, Oliveira ON, et al. Nanoimmunosensor based on atomic force spectroscopy to detect anti-myelin basic protein related to early-stage multiple sclerosis. Ultramicroscopy. 2020;211:112946. doi: 10.1016/j.ultramic.2020.112946.
   PubMed Web of Science ®Google Scholar
• Engel S, Steffen F, Uphaus T, et al. Association of intrathecal pleocytosis and IgG synthesis with axonal damage in early MS. Neurol Neuroimmunol Neuroinflamm. 2020;7(3):e679. doi: 10.1212/NXI.0000000000000679.
   PubMed Web of Science ®Google Scholar
• Muñoz Ú, Sebal C, Escudero E, et al. High prevalence of intrathecal IgA synthesis in multiple sclerosis patients. Sci Rep. 2022;12(1):4247. doi: 10.1038/s41598-022-08099-y.
   PubMed Web of Science ®Google Scholar
• Pröbstel A-K, Zhou X, Baumann R, et al. Gut microbiota-specific IgA+ B cells traffic to the CNS in active multiple sclerosis. Sci Immunol. 2020;5(53):eabc7191. doi: 10.1126/sciimmunol.abc7191.
   PubMed Web of Science ®Google Scholar
• Lanz TV, Brewer RC, Ho PP, et al. Clonally expanded B cells in multiple sclerosis bind EBV EBNA1 and GlialCAM. Nature. 2022;603(7900):321–327. doi: 10.1038/s41586-022-04432-7.
   PubMed Web of Science ®Google Scholar
• Hassani A, Corboy JR, Al-Salam S, et al. Epstein-Barr virus is present in the brain of most cases of multiple sclerosis and may engage more than just B cells. PLOS One. 2018;13(2):e0192109. doi: 10.1371/journal.pone.0192109.
   PubMed Web of Science ®Google Scholar
• Mrad MF, Saba ES, Nakib L, et al. Exosomes from subjects with multiple sclerosis express EBV-Derived proteins and activate monocyte-derived macrophages. Neurol Neuroimmunol Neuroinflamm. 2021;8(4):e1004. doi: 10.1212/NXI.0000000000001004.
   PubMed Web of Science ®Google Scholar
• Tahmasebi S, Qasim MT, Krivenkova MV, et al. The effects of oxygen–ozone therapy on regulatory T-cell responses in multiple sclerosis patients. Cell Biol Int. 2021;45(7):1498–1509. doi: 10.1002/cbin.11589.
   PubMed Web of Science ®Google Scholar
• Tapia-Maltos M, Treviño-Frenk I, García-González H, et al. Identification of regulatory T cell molecules associated with severity of multiple sclerosis. Mult Scler. 2021;27(11):1695–1705. doi: 10.1177/1352458520977045.
   PubMed Web of Science ®Google Scholar
• Howlett-Prieto Q, Feng X, Kramer JF, et al. Anti-CD20 therapy corrects a CD8 regulatory T cell deficit in multiple sclerosis. Mult Scler. 2021;27(14):2170–2179. doi: 10.1177/13524585211003301.
   PubMed Web of Science ®Google Scholar
• Quan C, ZhangBao J, Lu J, et al. The immune balance between memory and regulatory B cells in NMO and the changes of the balance after methylprednisolone or rituximab therapy. J Neuroimmunol. 2015;282:45–53. doi: 10.1016/j.jneuroim.2015.03.016.
   PubMed Web of Science ®Google Scholar
• Sabatino JJ, Wilson MR, Calabresi PA, et al. Anti-CD20 therapy depletes activated myelin-specific CD8+ T cells in multiple sclerosis. Proc Natl Acad Sci U S A. 2019;116(51):25800–25807. doi: 10.1073/pnas.1915309116.
   PubMed Web of Science ®Google Scholar
• Li R, Tang H, Burns JC, et al. BTK inhibition limits B-cell–T-cell interaction through modulation of B-cell metabolism: implications for multiple sclerosis therapy. Acta Neuropathol. 2022;143(4):505–521. doi: 10.1007/s00401-022-02411-w.
   PubMed Web of Science ®Google Scholar
• Luo L, Hu X, Dixon ML, et al. Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis. J Neuroinflamm. 2021;18(1):27.
   PubMed Web of Science ®Google Scholar
• Lanjakornsiripan D, Pior B-J, Kawaguchi D, et al. Layer-specific morphological and molecular differences in neocortical astrocytes and their dependence on neuronal layers. Nat Comm. 2018;9(1):1623.
   PubMedGoogle Scholar
• Ponath G, Park C, Pitt D. The role of astrocytes in multiple sclerosis. Front Immunol. 2018;9:217.
   PubMed Web of Science ®Google Scholar
• Nicolas CS, Amici M, Bortolotto ZA, et al. The role of JAK-STAT signaling within the CNS. JAKSTAT. 2013;2(1):e22925. doi: 10.4161/jkst.22925.
   PubMedGoogle Scholar
• Haroon F, Drögemüller K, Händel U, et al. Gp130-dependent astrocytic survival is critical for the control of autoimmune Central nervous system inflammation. J Immunol. 2011;186(11):6521–6531. doi: 10.4049/jimmunol.1001135.
   PubMed Web of Science ®Google Scholar
• Baert L, Benkhoucha M, Popa N, et al. A proliferation‐inducing ligand–mediated anti‐inflammatory response of astrocytes in multiple sclerosis. Ann Neurol. 2019;85(3):406–420. doi: 10.1002/ana.25415.
   PubMed Web of Science ®Google Scholar
• Wu GF, Shindler KS, Allenspach EJ, et al. Limited sufficiency of antigen presentation by dendritic cells in models of central nervous system autoimmunity. J Autoimmun. 2011;36(1):56–64. doi: 10.1016/j.jaut.2010.10.006.
   PubMed Web of Science ®Google Scholar
• Blanco P, Palucka AK, Pascual V, et al. Dendritic cells and cytokines in human inflammatory and autoimmune diseases. Cytokine Growth Factor Rev. 2008;19(1):41–52. doi: 10.1016/j.cytogfr.2007.10.004.
   PubMed Web of Science ®Google Scholar
• Ludewig B, Junt T, Hengartner H, et al. Dendritic cells in autoimmune diseases. Curr Opin Immunol. 2001;13(6):657–662. doi: 10.1016/s0952-7915(01)00275-8.
   PubMed Web of Science ®Google Scholar
• Misrielal C, Mauthe M, Reggiori F, et al. Autophagy in multiple sclerosis: two sides of the same coin. Front Cell Neurosci. 2020;14:603710. doi: 10.3389/fncel.2020.603710.
   PubMed Web of Science ®Google Scholar
• Yogev N, Frommer F, Lukas D, et al. Dendritic cells ameliorate autoimmunity in the CNS by controlling the homeostasis of PD-1 receptor + regulatory T cells. Immunity. 2012;37(2):264–275. doi: 10.1016/j.immuni.2012.05.025.
   PubMed Web of Science ®Google Scholar
• Feng C, Li L, Li Q, et al. Docosahexaenoic acid ameliorates autoimmune inflammation by activating GPR120 signaling pathway in dendritic cells. Int Immunopharmacol. 2021;97:107698. doi: 10.1016/j.intimp.2021.107698.
   PubMed Web of Science ®Google Scholar
• Fiedler SE, Spain RI, Kim E, et al. Lipoic acid modulates inflammatory responses of monocytes and monocyte-derived macrophages from healthy and relapsing-remitting multiple sclerosis patients. Immunol Cell Biol. 2021;99(1):107–115. doi: 10.1111/imcb.12392.
   PubMed Web of Science ®Google Scholar
• Prineas JW, Parratt JDE. Multiple sclerosis: microglia, monocytes, and macrophage-mediated demyelination. J Neuropathol Exp Neurol. 2021;80(10):975–996. doi: 10.1093/jnen/nlab083.
   PubMed Web of Science ®Google Scholar
• Amoruso A, Blonda M, Gironi M, et al. Immune and Central nervous system-related miRNAs expression profiling in monocytes of multiple sclerosis patients. Sci Rep. 2020;10(1):6125. doi: 10.1038/s41598-020-63282-3.
   PubMed Web of Science ®Google Scholar
• Couloume L, Ferrant J, Le Gallou S, et al. Mass cytometry identifies expansion of T-bet + B cells and CD206+ monocytes in early multiple sclerosis. Front Immunol. 2021;12:653577. doi: 10.3389/fimmu.2021.653577.
   PubMed Web of Science ®Google Scholar
• Adriani M, Nytrova P, Mbogning C, et al. Monocyte NOTCH2 expression predicts IFN-β immunogenicity in multiple sclerosis patients. JCI Insight. 2018;3(11):e99274. doi: 10.1172/jci.insight.99274.
   PubMed Web of Science ®Google Scholar
• Fischer HJ, Finck TLK, Pellkofer HL, et al. Glucocorticoid therapy of multiple sclerosis patients induces anti-inflammatory polarization and increased chemotaxis of monocytes. Front Immunol. 2019;10:1200. doi: 10.3389/fimmu.2019.01200.
   PubMed Web of Science ®Google Scholar
• Sadeghi Hassanabadi N, Broux B, Marinović S, et al. Innate lymphoid Cells - Neglected players in multiple sclerosis. Front Immunol. 2022;13:909275. doi: 10.3389/fimmu.2022.909275.
   PubMed Web of Science ®Google Scholar
• Yeung SS-H, Ho Y-S, Chang RC-C. The role of meningeal populations of type II innate lymphoid cells in modulating neuroinflammation in neurodegenerative diseases. Exp Mol Med. 2021;53(9):1251–1267. doi: 10.1038/s12276-021-00660-5.
   PubMed Web of Science ®Google Scholar
• Grigg JB, Shanmugavadivu A, Regen T, et al. Antigen-presenting innate lymphoid cells orchestrate neuroinflammation. Nature. 2021;600(7890):707–712. doi: 10.1038/s41586-021-04136-4.
   PubMed Web of Science ®Google Scholar
• Hirose S, Jahani PS, Wang S, et al. Type 2 innate lymphoid cells induce CNS demyelination in an HSV-IL-2 mouse model of multiple sclerosis. iScience. 2020;23(10):101549. doi: 10.1016/j.isci.2020.101549.
   PubMed Web of Science ®Google Scholar
• Miljković Đ, Jevtić B, Stojanović I, et al. ILC3, a Central innate immune component of the gut-brain axis in multiple sclerosis. Front Immunol. 2021;12:657622. doi: 10.3389/fimmu.2021.657622.
   PubMedGoogle Scholar
• Rodríguez-Lorenzo S, van Olst L, Rodriguez-Mogeda C, et al. Single-cell profiling reveals periventricular CD56bright NK cell accumulation in multiple sclerosis. Elife. 2022;11:e73849. doi: 10.7554/eLife.73849.
   PubMed Web of Science ®Google Scholar
• Nielsen N, Ødum N, Ursø B, et al. Cytotoxicity of CD56bright NK cells towards autologous activated CD4+ T cells is mediated through NKG2D, LFA-1 and TRAIL and dampened via CD94/NKG2A. PLOS One. 2012;7(2):e31959. doi: 10.1371/journal.pone.0031959.
   PubMed Web of Science ®Google Scholar
• Darlington PJ, Stopnicki B, Touil T, et al. Natural killer cells regulate Th17 cells after autologous hematopoietic stem cell transplantation for relapsing remitting multiple sclerosis. Front Immunol. 2018;9:834. doi: 10.3389/fimmu.2018.00834.
   PubMed Web of Science ®Google Scholar
• Sarma JV, Ward PA. The complement system. Cell Tissue Res. 2011;343(1):227–235. doi: 10.1007/s00441-010-1034-0.
   PubMed Web of Science ®Google Scholar
• Ziabska K, Ziemka-Nalecz M, Pawelec P, et al. Aberrant complement system activation in neurological disorders. Int J Mol Sci. 2021;22(9):4675. doi: 10.3390/ijms22094675.
   PubMed Web of Science ®Google Scholar
• Zelek WM, Fathalla D, Morgan A, et al. Cerebrospinal fluid complement system biomarkers in demyelinating disease. Mult Scler. 2020;26(14):1929–1937. doi: 10.1177/1352458519887905.
   PubMed Web of Science ®Google Scholar
• Morgan BP, Gommerman JL, Ramaglia V. An “outside-in” and “inside-out” consideration of complement in the multiple sclerosis brain: lessons from development and neurodegenerative diseases. Front Cell Neurosci. 2020;14:600656. doi: 10.3389/fncel.2020.600656.
   PubMed Web of Science ®Google Scholar
• Magliozzi R, Hametner S, Facchiano F, et al. Iron homeostasis, complement, and coagulation Cascade as CSF signature of cortical lesions in early multiple sclerosis. Ann Clin Transl Neurol. 2019;6(11):2150–2163. doi: 10.1002/acn3.50893.
   PubMed Web of Science ®Google Scholar
• Ingram G, Hakobyan S, Robertson NP, et al. Complement in multiple sclerosis: its role in disease and potential as a biomarker. Clin Exp Immunol. 2009;155(2):128–139. doi: 10.1111/j.1365-2249.2008.03830.x.
   PubMed Web of Science ®Google Scholar
• Cheng J, Lucas PC, McAllister-Lucas LM. Canonical and non-Canonical roles of GRK2 in lymphocytes. Cells. 2021;10(2):307. doi: 10.3390/cells10020307.
   PubMed Web of Science ®Google Scholar
• Khan S. IGFBP-2 signaling in the brain: from brain development to higher order brain functions. Front Endocrinol. 2019;10:822. doi: 10.3389/fendo.2019.00822.
   PubMed Web of Science ®Google Scholar
• Rajendran R, Böttiger G, Stadelmann C, et al. FGF/FGFR pathways in multiple sclerosis and in its disease models. Cells. 2021;10(4):884. doi: 10.3390/cells10040884.
   PubMed Web of Science ®Google Scholar
• Jari M, Sadeghi Allah Abadi J, Fathi D, et al. Fibroblast growth factor-2 levels are elevated in the serum of patients with multiple sclerosis. Iranian J Immunol. 2022;19(2):201–206.
   PubMed Web of Science ®Google Scholar
• Ridolfi E, Fenoglio C, Cantoni C, et al. Expression and genetic analysis of microRNAs involved in multiple sclerosis. Int J Mol Sci. 2013;14(3):4375–4384. doi: 10.3390/ijms14034375.
   PubMed Web of Science ®Google Scholar
• Kamali S, Rajendran R, Stadelmann C, et al. Oligodendrocyte‐specific deletion of FGFR2 ameliorates MOG35‐55‐induced EAE through ERK and akt signalling. Brain Pathol. 2021;31(2):297–311. doi: 10.1111/bpa.12916.
   PubMed Web of Science ®Google Scholar
• Lindner M, Thümmler K, Arthur A, et al. Fibroblast growth factor signalling in multiple sclerosis: inhibition of myelination and induction of pro-inflammatory environment by FGF9. Brain. 2015;138(Pt 7):1875–1893. doi: 10.1093/brain/awv102.
   PubMedGoogle Scholar
• Upadhayay S, Mehan S. Targeting Nrf2/HO-1 anti-oxidant signaling pathway in the progression of multiple sclerosis and influences on neurological dysfunctions. Brain Disord. 2021;3:100019. doi: 10.1016/j.dscb.2021.100019.
   Google Scholar
• Nellessen A, Nyamoya S, Zendedel A, et al. Nrf2 deficiency increases oligodendrocyte loss, demyelination, neuroinflammation and axonal damage in an MS animal model. Metab Brain Dis. 2020;35(2):353–362. doi: 10.1007/s11011-019-00488-z.
   PubMed Web of Science ®Google Scholar
• Rayatpour A, Foolad F, Heibatollahi M, et al. Ferroptosis inhibition by deferiprone, attenuates myelin damage and promotes neuroprotection in demyelinated optic nerve. Sci Rep. 2022;12(1):19630. doi: 10.1038/s41598-022-24152-2.
   PubMed Web of Science ®Google Scholar
• Chang L-C, Chiang S-K, Chen S-E, et al. Heme oxygenase-1 mediates Bay 11–7085 induced ferroptosis. Cancer Lett. 2018;416:124–137. doi: 10.1016/j.canlet.2017.12.025.
   PubMed Web of Science ®Google Scholar
• Zheng K-M, Zhang J, Zhang C-L, et al. Curcumin inhibits appoptosin-induced apoptosis via upregulating heme oxygenase-1 expression in SH-SY5Y cells. Acta Pharmacol Sin. 2015;36(5):544–552. doi: 10.1038/aps.2014.166.
   PubMed Web of Science ®Google Scholar
• Zhou Z, Liu C, Chen S, et al. Activation of the Nrf2/ARE signaling pathway by probucol contributes to inhibiting inflammation and neuronal apoptosis after spinal cord injury. Oncotarget. 2017;8(32):52078–52093. doi: 10.18632/oncotarget.19107.
   PubMedGoogle Scholar
• Upadhayay S, Mehan S, Prajapati A, et al. Nrf2/HO-1 signaling stimulation through acetyl-11-Keto-Beta-Boswellic acid (AKBA) provides neuroprotection in ethidium Bromide-Induced experimental model of multiple sclerosis. Genes. 2022;13(8):1324. doi: 10.3390/genes13081324.
   PubMed Web of Science ®Google Scholar
• Fetoni AR, Zorzi V, Paciello F, et al. Cx26 partial loss causes accelerated presbycusis by redox imbalance and dysregulation of Nfr2 pathway. Redox Biol. 2018;19:301–317. doi: 10.1016/j.redox.2018.08.002.
   PubMed Web of Science ®Google Scholar
• Maldonado PP, Guevara C, Olesen MA, et al. Neurodegeneration in multiple sclerosis: the role of Nrf2-dependent pathways. Antioxidants. 2022;11(6):1146. doi: 10.3390/antiox11061146.
   Web of Science ®Google Scholar
• Cui Y, Yu H, Bu Z, et al. Focus on the role of the NLRP3 inflammasome in multiple sclerosis: pathogenesis, diagnosis, and therapeutics. Front Mol Neurosci. 2022;15:894298. doi: 10.3389/fnmol.2022.894298.
   PubMed Web of Science ®Google Scholar
• Voet S, Mc Guire C, Hagemeyer N, et al. A20 critically controls microglia activation and inhibits inflammasome-dependent neuroinflammation. Nat Commun. 2018;9(1):2036. doi: 10.1038/s41467-018-04376-5.
   PubMedGoogle Scholar
• Inoue M, Williams KL, Gunn MD, et al. NLRP3 inflammasome induces chemotactic immune cell migration to the CNS in experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A. 2012;109(26):10480–10485. doi: 10.1073/pnas.1201836109.
   PubMed Web of Science ®Google Scholar
• Bai X-Y, Wang X-F, Zhang L-S, et al. Tetramethylpyrazine ameliorates experimental autoimmune encephalomyelitis by modulating the inflammatory response. Biochem Biophys Res Commun. 2018;503(3):1968–1972. doi: 10.1016/j.bbrc.2018.07.143.
   PubMed Web of Science ®Google Scholar
• Olcum M, Tastan B, Kiser C, et al. Chapter Seven - Microglial NLRP3 inflammasome activation in multiple sclerosis. In: Donev R, editor. Advances in protein chemistry and structural biology. Vol. 119. Cambridge (MA): Academic Press; 2020. p. 247–308.
   Google Scholar
• Yuan X, Wang L, Bhat OM, et al. Differential effects of short chain fatty acids on endothelial Nlrp3 inflammasome activation and neointima formation: antioxidant action of butyrate. Redox Biol. 2018;16:21–31. doi: 10.1016/j.redox.2018.02.007.
   PubMed Web of Science ®Google Scholar
• Malhotra S, Fissolo N, Tintoré M, et al. Role of high mobility group box protein 1 (HMGB1) in peripheral blood from patients with multiple sclerosis. J Neuroinflamm. 2015;12(1):1–5.
   Google Scholar
• Shi Y, Zhang L, Teng J, et al. HMGB1 mediates microglia activation via the TLR4/NF-κB pathway in coriaria lactone induced epilepsy. Mol Med Rep. 2018;17(4):5125–5131.
   PubMed Web of Science ®Google Scholar
• Naeem AG, El-Naga RN, Michel HE. Nebivolol elicits a neuroprotective effect in the cuprizone model of multiple sclerosis in mice: emphasis on M1/M2 polarization and inhibition of NLRP3 inflammasome activation. Inflammopharmacology. 2022;30(6):2197–2209. doi: 10.1007/s10787-022-01045-4.
   PubMed Web of Science ®Google Scholar
• Ammar RA, Mohamed AF, Kamal MM, et al. Neuroprotective effect of liraglutide in an experimental mouse model of multiple sclerosis: role of AMPK/SIRT1 signaling and NLRP3 inflammasome. Inflammopharmacology. 2022;30(3):919–934. doi: 10.1007/s10787-022-00956-6.
   PubMed Web of Science ®Google Scholar
• Shao Y, Chen C, Zhu T, et al. TRPM2 contributes to neuroinflammation and cognitive deficits in a cuprizone-induced multiple sclerosis model via NLRP3 inflammasome. Neurobiol Dis. 2021;160:105534. doi: 10.1016/j.nbd.2021.105534.
   PubMed Web of Science ®Google Scholar
• Zhang Y, Hou B, Liang P, et al. TRPV1 channel mediates NLRP3 inflammasome-dependent neuroinflammation in microglia. Cell Death Dis. 2021;12(12):1159. doi: 10.1038/s41419-021-04450-9.
   PubMed Web of Science ®Google Scholar
• Sawcer S, Hellenthal G, Pirinen M, et al. Genetic risk and a primary role for cell-mediated immune mechanisms in multiple sclerosis. Nature. 2011;476(7359):214–219.
   PubMed Web of Science ®Google Scholar
• Hollenbach JA, Oksenberg JR. The immunogenetics of multiple sclerosis: a comprehensive review. J Autoimmun. 2015;64:13–25. doi: 10.1016/j.jaut.2015.06.010.
   PubMed Web of Science ®Google Scholar
• Hensiek A, Sawcer S, Feakes R, et al. HLA-DR 15 is associated with female sex and younger age at diagnosis in multiple sclerosis. J Neurol Neurosurg Psychiatry. 2002;72(2):184–187. doi: 10.1136/jnnp.72.2.184.
   PubMed Web of Science ®Google Scholar
• Galym A, Akhmetova N, Zhaksybek M, et al. Clinical and genetic analysis in pediatric patients with multiple sclerosis and related conditions: focus on DR genes of the major histocompatibility complex. Open Neurol J. 2022;16(1):219–225.
   Google Scholar
• Spinner CA, Guan Y, Fan Y, et al. Pathogenic ILC1 and NKp46+ ILC3 are defined by core and tissue-specific transcriptional signatures in autoimmune neuroinflammation. J Immunol. 2021;206(1_Suppl):60.06–60.06. doi: 10.4049/jimmunol.206.Supp.60.06.
   Google Scholar
• Taşan M, Musso G, Hao T, et al. Selecting causal genes from genome-wide association studies via functionally coherent subnetworks. Nat Methods. 2015;12(2):154–159. doi: 10.1038/nmeth.3215.
   PubMed Web of Science ®Google Scholar
• Hoppmann N, Graetz C, Paterka M, et al. New candidates for CD4 T cell pathogenicity in experimental neuroinflammation and multiple sclerosis. Brain. 2015;138(Pt 4):902–917. doi: 10.1093/brain/awu408.
   PubMedGoogle Scholar
• Nasl-Khameneh AM, Mirshafiey A, Moghadasi AN, et al. The immunomodulatory effects of all-trans retinoic acid and docosahexaenoic acid combination treatment on the expression of IL-2, IL-4, T-bet, and GATA3 genes in PBMCs of multiple sclerosis patients. Neurol Res. 2023;45(6):510–519.
   PubMed Web of Science ®Google Scholar
• Mousavi Nasl-Khameneh A, Mirshafiey A, Naser Moghadasi A, et al. Combination treatment of docosahexaenoic acid (DHA) and all-trans-retinoic acid (ATRA) inhibit IL-17 and RORγt gene expression in PBMCs of patients with relapsing-remitting multiple sclerosis. Neurol Res. 2018;40(1):11–17. doi: 10.1080/01616412.2017.1382800.
   PubMed Web of Science ®Google Scholar
• Martin CR, Osadchiy V, Kalani A, et al. The brain-gut-microbiome axis. Cell Mol Gastroenterol Hepatol. 2018;6(2):133–148. doi: 10.1016/j.jcmgh.2018.04.003.
   PubMed Web of Science ®Google Scholar
• Galland L. The gut microbiome and the brain. J Med Food. 2014;17(12):1261–1272. doi: 10.1089/jmf.2014.7000.
   PubMed Web of Science ®Google Scholar
• Ochoa-Repáraz J, Kirby TO, Kasper LH. The gut microbiome and multiple sclerosis. Cold Spring Harb Perspect Med. 2018;8(6):a029017. doi: 10.1101/cshperspect.a029017.
   PubMed Web of Science ®Google Scholar
• Chen J, Chia N, Kalari KR, et al. Multiple sclerosis patients have a distinct gut microbiota compared to healthy controls. Sci Rep. 2016;6(1):28484. doi: 10.1038/srep28484.
   PubMed Web of Science ®Google Scholar
• Jangi S, Gandhi R, Cox LM, et al. Alterations of the human gut microbiome in multiple sclerosis. Nature Commun. 2016;7(1):12015.
   PubMedGoogle Scholar
• Tremlett H, Fadrosh DW, Faruqi AA, et al. Gut microbiota in early pediatric multiple sclerosis: a case-control study. Eur J Neurol. 2016;23(8):1308–1321. doi: 10.1111/ene.13026.
   PubMed Web of Science ®Google Scholar
• Cosorich I, Dalla-Costa G, Sorini C, et al. High frequency of intestinal T(H)17 cells correlates with microbiota alterations and disease activity in multiple sclerosis. Sci Adv. 2017;3(7):e1700492. doi: 10.1126/sciadv.1700492.
   PubMed Web of Science ®Google Scholar
• Honda K, Littman DR. The microbiota in adaptive immune homeostasis and disease. Nature. 2016;535(7610):75–84. doi: 10.1038/nature18848.
   PubMed Web of Science ®Google Scholar
• Cekanaviciute E, Yoo BB, Runia TF, et al. Gut bacteria from multiple sclerosis patients modulate human T cells and exacerbate symptoms in mouse models. Proc Natl Acad Sci U S A. 2017;114(40):10713–10718. doi: 10.1073/pnas.1711235114.
   PubMed Web of Science ®Google Scholar
• Baecher-Allan C, Kaskow BJ, Weiner HL. Multiple sclerosis: mechanisms and immunotherapy. Neuron. 2018;97(4):742–768. doi: 10.1016/j.neuron.2018.01.021.
   PubMed Web of Science ®Google Scholar
• Walczak A, Siger M, Ciach A, et al. Transdermal application of myelin peptides in multiple sclerosis treatment. JAMA Neurol. 2013;70(9):1105–1109. doi: 10.1001/jamaneurol.2013.3022.
   PubMed Web of Science ®Google Scholar
• Juryńczyk M, Walczak A, Jurewicz A, et al. Immune regulation of multiple sclerosis by transdermally applied myelin peptides. Ann Neurol. 2010;68(5):593–601. doi: 10.1002/ana.22219.
   PubMed Web of Science ®Google Scholar
• Casella G, Rasouli J, Boehm A, et al. Oligodendrocyte-derived extracellular vesicles as antigen-specific therapy for autoimmune neuroinflammation in mice. Sci Transl Med. 2020;12(568):eaba0599. doi: 10.1126/scitranslmed.aba0599.
   PubMed Web of Science ®Google Scholar
• Casella G, Colombo F, Finardi A, et al. Extracellular vesicles containing IL-4 modulate neuroinflammation in a mouse model of multiple sclerosis. Mol Ther. 2018;26(9):2107–2118. doi: 10.1016/j.ymthe.2018.06.024.
   PubMed Web of Science ®Google Scholar
• Napier J, Rose L, Adeoye O, et al. Modulating acute neuroinflammation in intracerebral hemorrhage: the potential promise of currently approved medications for multiple sclerosis. Immuno­pharmacol Immunotoxicol. 2019;41(1):7–15. doi: 10.1080/08923973.2019.1566361.
   PubMed Web of Science ®Google Scholar
• Selewski DT, Shah GV, Segal BM, et al. Natalizumab (tysabri). AJNR Am J Neuroradiol. 2010;31(9):1588–1590. doi: 10.3174/ajnr.A2226.
   PubMed Web of Science ®Google Scholar
• Chisari CG, Comi G, Filippi M, et al. PML risk is the main factor driving the choice of discontinuing natalizumab in a large multiple sclerosis population: results from an italian multicenter retrospective study. J Neurol. 2022;269(2):933–944. doi: 10.1007/s00415-021-10676-6.
   PubMed Web of Science ®Google Scholar
• Goodin DS, Cohen BA, O’Connor P, et al. Assessment: the use of natalizumab (tysabri) for the treatment of multiple sclerosis (an evidence-based review). J Drug Assess. 2008;71(10):766–773.)doi: 10.1212/01.wnl.0000320512.21919.d2.
   Google Scholar
• Mathew T, Kamath V, John SK, et al. A real world multi center study on efficacy and safety of natalizumab in indian patients with multiple sclerosis. Mult Scler Relat Disord. 2022;66:104059. doi: 10.1016/j.msard.2022.104059.
   PubMed Web of Science ®Google Scholar
• Butzkueven H, Kappos L, Pellegrini F, et al. Efficacy and safety of natalizumab in multiple sclerosis: interim observational programme results. J Neurol Neurosurg Psychiatry. 2014;85(11):1190–1197. doi: 10.1136/jnnp-2013-306936.
   PubMed Web of Science ®Google Scholar
• Beume L-A, Dersch R, Fuhrer H, et al. Massive exacerbation of multiple sclerosis after withdrawal and early restart of treatment with natalizumab. J Clin Neurosci. 2015;22(2):400–401. doi: 10.1016/j.jocn.2014.05.028.
   PubMed Web of Science ®Google Scholar
• Foley JF, Defer G, Ryerson LZ, et al. Comparison of switching to 6-week dosing of natalizumab versus continuing with 4-week dosing in patients with relapsing-remitting multiple sclerosis (NOVA): a randomised, controlled, open-label, phase 3b trial. Lancet Neurol. 2022;21(7):608–619.
   PubMed Web of Science ®Google Scholar
• De Mercanti SF, Signori A, Cordioli C, et al. MRI activity and extended interval of natalizumab dosing regimen: a multicentre italian study. J Neurol Sci. 2021;424:117385. doi: 10.1016/j.jns.2021.117385.
   PubMed Web of Science ®Google Scholar
• Correia I, Batista S, Galego O, et al. Long-term effectiveness and safety of natalizumab in a portuguese population. Int Immunopharmacol. 2017;46:105–111. doi: 10.1016/j.intimp.2017.03.006.
   PubMed Web of Science ®Google Scholar
• Karanasios P, Karachalios G, Gourgioti R, et al. Patient and treatment characteristics and safety outcomes of patients with relapsing-remitting multiple sclerosis treated with natalizumab in Greece: results from the multicenter, 5-year prospective observational study ‘TOPICS Greece. Mult Scler J Exp Transl Clin. 2021;7(3):20552173211035803. doi: 10.1177/20552173211035803.
   Google Scholar
• Havrdova E, Horakova D, Kovarova I. Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use. Ther Adv Neurol Disord. 2015;8(1):31–45. doi: 10.1177/1756285614563522.
   PubMed Web of Science ®Google Scholar
• Ruck T, Bittner S, Wiendl H, et al. Alemtuzumab in multiple sclerosis: mechanism of action and beyond. Int J Mol Sci. 2015;16(7):16414–16439. doi: 10.3390/ijms160716414.
   PubMed Web of Science ®Google Scholar
• Scappaticcio L, Castellana M, Virili C, et al. Alemtuzumab-induced thyroid events in multiple sclerosis: a systematic review and meta-analysis. J Endocrinol Invest. 2020;43(2):219–229. doi: 10.1007/s40618-019-01105-7.
   PubMed Web of Science ®Google Scholar
• Ziemssen T, Bass AD, Berkovich R, et al. Efficacy and safety of alemtuzumab through 9 years of follow-up in patients with highly active disease: post hoc analysis of CARE-MS I and II patients in the TOPAZ extension study. CNS Drugs. 2020;34(9):973–988. doi: 10.1007/s40263-020-00749-x.
   PubMed Web of Science ®Google Scholar
• Tuohy O, Costelloe L, Hill-Cawthorne G, et al. Alemtuzumab treatment of multiple sclerosis: long-term safety and efficacy. J Neurol Neurosurg Psychiatry. 2015;86(2):208–215. doi: 10.1136/jnnp-2014-307721.
   PubMed Web of Science ®Google Scholar
• Syed YY. Ocrelizumab: a review in multiple sclerosis. CNS Drugs. 2018;32(9):883–890. doi: 10.1007/s40263-018-0568-7.
   PubMed Web of Science ®Google Scholar
• Mulero P, Midaglia L, Montalban X. Ocrelizumab: a new milestone in multiple sclerosis therapy. Ther Adv Neurol Disord. 2018;11:1756286418773025. doi: 10.1177/1756286418773025.
   Web of Science ®Google Scholar
• Kappos L, Li D, Calabresi PA, et al. Ocrelizumab in relapsing-remitting multiple sclerosis: a phase 2, randomised, placebo-controlled, multicentre trial. Lancet. 2011;378(9805):1779–1787. doi: 10.1016/S0140-6736(11)61649-8.
   PubMed Web of Science ®Google Scholar
• Cree BA, Pradhan A, Pei J, et al. Efficacy and safety of ocrelizumab vs interferon beta-1a in participants of african descent with relapsing multiple sclerosis in the phase III OPERA I and OPERA II studies. Mult Scler Relat Disord. 2021;52:103010. doi: 10.1016/j.msard.2021.103010.
   PubMed Web of Science ®Google Scholar
• Morales-Ruiz V, Juárez-Vaquera VH, Rosetti-Sciutto M, et al. Efficacy of intravenous immunoglobulin in autoimmune neurological diseases. Literature systematic review and meta-analysis. Autoimmun Rev. 2022;21(3):103019. doi: 10.1016/j.autrev.2021.103019.
   PubMed Web of Science ®Google Scholar
• Wolinsky JS, Arnold DL, Brochet B, et al. Long-term follow-up from the ORATORIO trial of ocrelizumab for primary progressive multiple sclerosis: a post-hoc analysis from the ongoing open-label extension of the randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2020;19(12):998–1009. doi: 10.1016/S1474-4422(20)30342-2.
   PubMed Web of Science ®Google Scholar
• Preiningerova JL, Vachova M. Daclizumab high-yield process in the treatment of relapsing–remitting multiple sclerosis. Ther Adv Neurol Disord. 2017;10(1):67–75. doi: 10.1177/1756285616671887.
   PubMed Web of Science ®Google Scholar
• Rommer PS, Berger K, Ellenberger D, et al. Management of MS patients treated with daclizumab–a case series of 267 patients. Front Neurol. 2020;11:996. doi: 10.3389/fneur.2020.00996.
   PubMed Web of Science ®Google Scholar
• White RJ, Durr FE. Development of mitoxantrone. Invest New Drugs. 1985;3(2):85–93. doi: 10.1007/BF00174154.
   PubMed Web of Science ®Google Scholar
• Jain KK. Evaluation of mitoxantrone for the treatment of multiple sclerosis. Expert Opin Investig Drugs. 2000;9(5):1139–1149. doi: 10.1517/13543784.9.5.1139.
   PubMed Web of Science ®Google Scholar
• Etemadifar M, Afzali P, Abtahi S-H, et al. Safety and efficacy of mitoxantrone in pediatric patients with aggressive multiple sclerosis. Eur J Paediatr Neurol. 2014;18(2):119–125. doi: 10.1016/j.ejpn.2013.09.001.
   PubMed Web of Science ®Google Scholar
• Rammohan K, Coyle PK, Sylvester E, et al. The development of cladribine tablets for the treatment of multiple sclerosis: a comprehensive review. Drugs. 2020;80(18):1901–1928. doi: 10.1007/s40265-020-01422-9.
   PubMed Web of Science ®Google Scholar
• Rejdak K, Zasybska A, Pietruczuk A, et al. Long-term safety and efficacy of subcutaneous cladribine used in increased dosage in patients with relapsing multiple sclerosis: 20-year observational study. J Clin Med. 2021;10(21):5207. doi: 10.3390/jcm10215207.
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Soelberg Sorensen P, Cook S, et al. Safety and efficacy of cladribine tablets in patients with relapsing–remitting multiple sclerosis: results from the randomized extension trial of the CLARITY study. Mult Scler. 2018;24(12):1594–1604. doi: 10.1177/1352458517727603.
   PubMed Web of Science ®Google Scholar
• Chitnis T, Banwell B, Kappos L, et al. Safety and efficacy of teriflunomide in paediatric multiple sclerosis (TERIKIDS): a multicentre, double-blind, phase 3, randomised, placebo-controlled trial. Lancet Neurol. 2021;20(12):1001–1011. doi: 10.1016/S1474-4422(21)00364-1.
   PubMed Web of Science ®Google Scholar
• Wiese MD, Rowland A, Polasek TM, et al. Pharmacokinetic evaluation of teriflunomide for the treatment of multiple sclerosis. Expert Opin Drug Metab Toxicol. 2013;9(8):1025–1035. doi: 10.1517/17425255.2013.800483.
   PubMed Web of Science ®Google Scholar
• Tilly G, Cadoux M, Garcia A, et al. Teriflunomide treatment of multiple sclerosis selectively modulates CD8 memory T cells. Front Immunol. 2021;12:730342.
   PubMed Web of Science ®Google Scholar
• Comi G, Freedman MS, Meca-Lallana JE, et al. Prior treatment status: impact on the efficacy and safety of teriflunomide in multiple sclerosis. BMC Neurol. 2020;20(1):364. doi: 10.1186/s12883-020-01937-4.
   PubMed Web of Science ®Google Scholar
• Miller AE, Olsson TP, Wolinsky JS, et al. Long-term safety and efficacy of teriflunomide in patients with relapsing multiple sclerosis: results from the TOWER extension study. Mult Scler Relat Disord. 2020;46:102438. doi: 10.1016/j.msard.2020.102438.
   PubMed Web of Science ®Google Scholar
• Miller AE, Vermersch P, Kappos L, et al. Long-term outcomes with teriflunomide in patients with clinically isolated syndrome: results of the TOPIC extension study∗∗. Mult Scler Relat Disord. 2019;33:131–138. doi: 10.1016/j.msard.2019.05.014.
   PubMed Web of Science ®Google Scholar
• Miller AE, Xu X, Macdonell R, et al. Efficacy and safety of teriflunomide in asian patients with relapsing forms of multiple sclerosis: a subgroup analysis of the phase 3 tower study. J Clin Neurosci. 2019;59:229–231. doi: 10.1016/j.jocn.2018.09.012.
   PubMed Web of Science ®Google Scholar
• Boster A, Bartoszek MP, O’Connell C, et al. Efficacy, safety, and cost-effectiveness of glatiramer acetate in the treatment of relapsing–remitting multiple sclerosis. Ther Adv Neurol Disord. 2011;4(5):319–332. doi: 10.1177/1756285611422108.
   PubMedGoogle Scholar
• Khan O, Rieckmann P, Boyko A, et al. Efficacy and safety of a three-times-weekly dosing regimen of glatiramer acetate in relapsing–remitting multiple sclerosis patients: 3-year results of the glatiramer acetate low-Frequency administration open-label extension study. Mult Scler. 2017;23(6):818–829. doi: 10.1177/1352458516664033.
   PubMed Web of Science ®Google Scholar
• Rieckmann P, Zivadinov R, Boyko A, et al. Long-term efficacy and safety of three times weekly dosing regimen of glatiramer acetate in relapsing multiple sclerosis patients: seven-year results of the glatiramer acetate low-frequency administration (GALA) open-label extension study. Mult Scler J Exp Transl Clin. 2021;7(4):20552173211061550. doi: 10.1177/20552173211061550.
   Google Scholar
• Boster AL, Ford CC, Neudorfer O, et al. Glatiramer acetate: long-term safety and efficacy in relapsing-remitting multiple sclerosis. Expert Rev Neurother. 2015;15(6):575–586. doi: 10.1586/14737175.2015.1040768.
   PubMed Web of Science ®Google Scholar
• Filipi M, Jack S. Interferons in the treatment of multiple sclerosis: a clinical efficacy, safety, and tolerability update. Int J MS Care. 2020;22(4):165–172. doi: 10.7224/1537-2073.2018-063.
   PubMedGoogle Scholar
• Calabresi PA, Radue E-W, Goodin D, et al. Safety and efficacy of fingolimod in patients with relapsing-remitting multiple sclerosis (FREEDOMS II): a double-blind, randomised, placebo-controlled, phase 3 trial. Lancet Neurol. 2014;13(6):545–556. doi: 10.1016/S1474-4422(14)70049-3.
   PubMed Web of Science ®Google Scholar
• Lublin F, Miller DH, Freedman MS, et al. Oral fingolimod in primary progressive multiple sclerosis (INFORMS): a phase 3, randomised, double-blind, placebo-controlled trial. Lancet. 2016;387(10023):1075–1084. doi: 10.1016/S0140-6736(15)01314-8.
   PubMed Web of Science ®Google Scholar
• Montalban X, Comi G, Antel J, et al. Long-term results from a phase 2 extension study of fingolimod at high and approved dose in relapsing multiple sclerosis. J Neurol. 2015;262(12):2627–2634. doi: 10.1007/s00415-015-7834-0.
   PubMed Web of Science ®Google Scholar
• Saida T, Itoyama Y, Kikuchi S, et al. Long-term efficacy and safety of fingolimod in japanese patients with relapsing multiple sclerosis: 3-year results of the phase 2 extension study. BMC Neurol. 2017;17(1):17. doi: 10.1186/s12883-017-0794-5.
   PubMedGoogle Scholar
• Gold R, Arnold DL, Bar-Or A, et al. Long-term safety and efficacy of dimethyl fumarate for up to 13 years in patients with relapsing-remitting multiple sclerosis: final ENDORSE study results. Mult Scler. 2022;28(5):801–816. doi: 10.1177/13524585211037909.
   PubMed Web of Science ®Google Scholar
• Saida T, Yamamura T, Kondo T, et al. A randomized placebo-controlled trial of delayed-release dimethyl fumarate in patients with relapsing-remitting multiple sclerosis from east asia and other countries. BMC Neurol. 2019;19(1):5. doi: 10.1186/s12883-018-1220-3.
   PubMed Web of Science ®Google Scholar
• Vucic S, Ryder J, Mekhael L, et al. Phase 2 randomized placebo controlled double blind study to assess the efficacy and safety of tecfidera in patients with amyotrophic lateral sclerosis (TEALS study): study protocol clinical trial (SPIRIT compliant). Medicine. 2020;99(6):e18904. doi: 10.1097/MD.0000000000018904.
   PubMed Web of Science ®Google Scholar
• Freedman MS, Pozzilli C, Havrdova EK, et al. Long-term treatment with ponesimod in relapsing-remitting multiple sclerosis: results from randomized phase 2b core and extension studies. Neurology. 2022;99(8):e762–e774. doi: 10.1212/WNL.0000000000200606.
   PubMed Web of Science ®Google Scholar
• Olsson T, Boster A, Fernández Ó, et al. Oral ponesimod in relapsing–remitting multiple sclerosis: a randomised phase II trial. J Neurol Neurosurg Psychiatry. 2014;85(11):1198–1208. doi: 10.1136/jnnp-2013-307282.
   PubMed Web of Science ®Google Scholar
• Mandalfino P, Rice G, Smith A, et al. Bone marrow transplantation in multiple sclerosis. J Neurol. 2000;247(9):691–695. doi: 10.1007/s004150070112.
   PubMed Web of Science ®Google Scholar
• Patti F, Cataldi M, Nicoletti F, et al. Combination of cyclophosphamide and interferon-β halts progression in patients with rapidly transitional multiple sclerosis. J Neurol Neurosurg Psychiatry. 2001;71(3):404–407. doi: 10.1136/jnnp.71.3.404.
   PubMed Web of Science ®Google Scholar
• Perini P, Calabrese M, Rinaldi L, et al. The safety profile of cyclophosphamide in multiple sclerosis therapy. Expert Opin Drug Saf. 2007;6(2):183–190. doi: 10.1517/14740338.6.2.183.
   PubMed Web of Science ®Google Scholar
• Perini P, Gallo P. Cyclophosphamide is effective in stabilizing rapidly deteriorating secondary progressive multiple sclerosis. J Neurol. 2003;250(7):834–838. doi: 10.1007/s00415-003-1089-x.
   PubMed Web of Science ®Google Scholar
• Fernández O, Guerrero M, Mayorga C, et al. Combination therapy with interferon beta-1b and azathioprine in secondary progressive multiple sclerosis. J Neurol. 2002;249(8):1058–1062. doi: 10.1007/s00415-002-0787-0.
   PubMed Web of Science ®Google Scholar
• Havrdova E, Zivadinov R, Krasensky J, et al. Randomized study of interferon beta-1a, low-dose azathioprine, and low-dose corticosteroids in multiple sclerosis. Mult Scler. 2009;15(8):965–976. doi: 10.1177/1352458509105229.
   PubMedGoogle Scholar
• Lus G, Romano F, Scuotto A, et al. Azathioprine and interferon β1a in relapsing-remitting multiple sclerosis patients: increasing efficacy of combined treatment. Eur Neurol. 2004;51(1):15–20. doi: 10.1159/000074912.
   PubMed Web of Science ®Google Scholar
• Goodkin DE, Rudick RA, Medendorp SV, et al. Low‐dose (7.5 mg) oral methotrexate reduces the rate of progression in chronic progressive multiple sclerosis. Ann Neurol. 1995;37(1):30–40. doi: 10.1002/ana.410370108.
   PubMed Web of Science ®Google Scholar
• Le Page E, Leray E, Taurin G, et al. Mitoxantrone as induction treatment in aggressive relapsing remitting multiple sclerosis: treatment response factors in a 5 year follow-up observational study of 100 consecutive patients. J Neurol Neurosurg Psychiatry. 2008;79(1):52–56. doi: 10.1136/jnnp.2007.124958.
   PubMed Web of Science ®Google Scholar
• Lugaresi A, Caporale C, Farina D, et al. Low-dose oral methotrexate treatment in chronic progressive multiple sclerosis. Neurol Sci. 2001;22(2):209–210. doi: 10.1007/s100720170026.
   PubMed Web of Science ®Google Scholar
• Frohman EM, Cutter G, Remington G, et al. A randomized, blinded, parallel-group, pilot trial of mycophenolate mofetil (CellCept) compared with interferon beta-1a (avonex) in patients with relapsing-remitting multiple sclerosis. Ther Adv Neurol Disord. 2010;3(1):15–28. doi: 10.1177/1756285609353354.
   PubMedGoogle Scholar
• Remington GM, Treadaway K, Frohman T, et al. A one-year prospective, randomized, placebo-controlled, quadruple-blinded, phase II safety pilot trial of combination therapy with interferon beta-1a and mycophenolate mofetil in early relapsing—remitting multiple sclerosis (TIME MS). Ther Adv Neurol Disord. 2010;3(1):3–13. doi: 10.1177/1756285609355851.
   PubMedGoogle Scholar
• Lattanzi S, Cagnetti C, Danni M, et al. Oral and intravenous steroids for multiple sclerosis relapse: a systematic review and meta-analysis. J Neurol. 2017;264(8):1697–1704. doi: 10.1007/s00415-017-8505-0.
   PubMed Web of Science ®Google Scholar
• Le Page E, Veillard D, Laplaud DA, et al. Oral versus intravenous high-dose methylprednisolone for treatment of relapses in patients with multiple sclerosis (COPOUSEP): a randomised, controlled, double-blind, non-inferiority trial. Lancet. 2015;386(9997):974–981. doi: 10.1016/S0140-6736(15)61137-0.
   PubMed Web of Science ®Google Scholar
• Fazekas F, Lublin F, Li D, et al. Intravenous immunoglobulin in relapsing-remitting multiple sclerosis: a dose-finding trial. Neurology. 2008;71(4):265–271. doi: 10.1212/01.wnl.0000318281.98220.6f.
   PubMed Web of Science ®Google Scholar
• Hommes OR, Sørensen PS, Fazekas F, et al. Intravenous immunoglobulin in secondary progressive multiple sclerosis: randomised placebo-controlled trial. Lancet. 2004;364(9440):1149–1156. doi: 10.1016/S0140-6736(04)17101-8.
   PubMed Web of Science ®Google Scholar
• Pöhlau D, Przuntek H, Sailer M, et al. Intravenous immunoglobulin in primary and secondary chronic progressive multiple sclerosis: a randomized placebo controlled multicentre study. Mult Scler. 2007;13(9):1107–1117. doi: 10.1177/1352458507078400.
   PubMed Web of Science ®Google Scholar
• Alcalá C, Gascón F, Pérez-Miralles F, et al. Efficacy and safety of rituximab in relapsing and progressive multiple sclerosis: a hospital-based study. J Neurol. 2018;265(7):1690–1697. doi: 10.1007/s00415-018-8899-3.
   PubMed Web of Science ®Google Scholar
• Torgauten HM, Myhr K-M, Wergeland S, et al. Safety and efficacy of rituximab as first-and second line treatment in multiple sclerosis–a cohort study. Mult Scler J Exp Transl Clin. 2021;7(1):2055217320973049. doi: 10.1177/2055217320973049.
   Google Scholar
• Lin Y, Oji S, Miyamoto K, et al. Real‐world application of plasmapheresis for neurological disease: results from the Japan‐plasmapheresis outcome and practice patterns study. Ther Apher Dial. 2022;27(1):123–135. doi: 10.1111/1744-9987.13906.
   PubMed Web of Science ®Google Scholar
• Bar-Or A, Grove RA, Austin DJ, et al. Subcutaneous ofatumumab in patients with relapsing-remitting multiple sclerosis: the MIRROR study. Neurology. 2018;90(20):e1805–e14. doi: 10.1212/WNL.0000000000005516.
   PubMed Web of Science ®Google Scholar
• Gärtner J, Hauser SL, Bar-Or A, et al. Efficacy and safety of ofatumumab in recently diagnosed, treatment-naive patients with multiple sclerosis: results from ASCLEPIOS I and II. Multiple Scler J. 2022;28(10): 1562–1575
   PubMed Web of Science ®Google Scholar
• Cree BA, Hartung H-P, Barnett M. New drugs for multiple sclerosis: new treatment algorithms. Curr Opin Neurol. 2022;35(3):262–270. doi: 10.1097/WCO.0000000000001063.
   PubMed Web of Science ®Google Scholar
• Wei W, Ma D, Li L, et al. Pharmacotherapy of multiple sclerosis and treatment strategies. Front Pharmacol. 2021;12:724718. p
   PubMedGoogle Scholar
• Park C-S, Kim S-H, Lee C-K. Immunotherapy of autoimmune diseases with nonantibiotic properties of tetracyclines. Immune Netw. 2020;20(6):e47. doi: 10.4110/in.2020.20.e47.
   PubMed Web of Science ®Google Scholar
• Goodman AD, Gyang T, Smith AD.III Ibudilast for the treatment of multiple sclerosis. Expert Opin Investig Drugs. 2016;25(10):1231–1237. doi: 10.1080/13543784.2016.1221924.
   PubMed Web of Science ®Google Scholar
• Braune S, Bergmann A, Bezlyak V, et al. How do patients with secondary progressive multiple sclerosis enrolled in the EXPAND randomized controlled trial compare with those seen in german clinical practice in the NeuroTransData multiple sclerosis registry? J Cent Nerv Syst Dis. 2022;14:11795735221115912. doi: 10.1177/11795735221115912.
   Web of Science ®Google Scholar
• Bar-Or A, Weinstock-Guttman B, Mao-Draayer Y, et al. Safety and tolerability of conversion to siponimod with and without titration in patients with advancing forms of relapsing multiple sclerosis: interim results of the phase 3b EXCHANGE study (P7-4.007). Minneapolis: AAN Enterprises; 2022.
   Google Scholar
• Riolo JV, Yang L, Rano T, et al. DXT40 effect of the S1P1/5 receptor modulator ozanimod on cognitive processing speed in subjects with relapsing multiple sclerosis: design of the ENLIGHTEN study. Int J MS Care. 2020;22:e839.
   Google Scholar
• Cohen JA, Comi G, Arnold DL, et al. Efficacy and safety of ozanimod in multiple sclerosis: dose-blinded extension of a randomized phase II study. Mult Scler. 2019;25(9):1255–1262. doi: 10.1177/1352458518789884.
   PubMed Web of Science ®Google Scholar
• Giovannoni G, Knappertz V, Steinerman JR, et al. A randomized, placebo-controlled, phase 2 trial of laquinimod in primary progressive multiple sclerosis. Neurology. 2020;95(8):e1027–e40. doi: 10.1212/WNL.0000000000010284.
   PubMed Web of Science ®Google Scholar
• Deronic A, Tahvili S, Leanderson T, et al. The anti-tumor effect of the quinoline-3-carboxamide tasquinimod: blockade of recruitment of CD11b + Ly6Chi cells to tumor tissue reduces tumor growth. BMC Cancer. 2016;16(1):440. doi: 10.1186/s12885-016-2481-0.
   PubMedGoogle Scholar
• Mathais S, Moisset X, Pereira B, et al. Relapses in patients treated with high-dose biotin for progressive multiple sclerosis. Neurotherapeutics. 2021;18(1):378–386. doi: 10.1007/s13311-020-00926-2.
   PubMed Web of Science ®Google Scholar
• Kremer D, Akkermann R, Küry P, et al. Current advancements in promoting remyelination in multiple sclerosis. Mult Scler. 2019;25(1):7–14. doi: 10.1177/1352458518800827.
   PubMed Web of Science ®Google Scholar
• Omidian Z, Ahmed R, Giwa A, et al. IL-17 and limits of success. Cell Immunol. 2019;339:33–40. doi: 10.1016/j.cellimm.2018.09.001.
   PubMed Web of Science ®Google Scholar
• Phillips BE, Garciafigueroa Y, Trucco M, et al. Clinical tolerogenic dendritic cells: exploring therapeutic impact on human autoimmune disease. Front Immunol. 2017;8:1279. doi: 10.3389/fimmu.2017.01279.
   PubMed Web of Science ®Google Scholar
• Barbara W, Silvia P-R, Mansilla MJ, et al. Tolerogenic dendritic cell-based treatment for multiple sclerosis (MS): a harmonised study protocol for two phase I clinical trials comparing intradermal and intranodal cell administration. BMJ Open. 2019;9(9):e030309. doi: 10.1136/bmjopen-2019-030309.
   PubMed Web of Science ®Google Scholar
• Jakimovski D, Awan S, Eckert SP, et al. Multiple sclerosis in children: differential diagnosis, prognosis, and disease-modifying treatment. CNS Drugs. 2022;36(1):45–59. doi: 10.1007/s40263-021-00887-w.
   PubMed Web of Science ®Google Scholar
• Arevalo-Villalobos JI, Govea-Alonso DO, Bañuelos-Hernández B, et al. Inducible expression of antigens in plants: a study focused on peptides related to multiple sclerosis immunotherapy. J Biotechnol. 2020;318:51–56. doi: 10.1016/j.jbiotec.2020.03.013.
   PubMed Web of Science ®Google Scholar
• Ontaneda D, Fox RJ, Chataway J. Clinical trials in progressive multiple sclerosis: lessons learned and future perspectives. Lancet Neurol. 2015;14(2):208–223. doi: 10.1016/S1474-4422(14)70264-9.
   PubMed Web of Science ®Google Scholar
• Manouchehri N, Salinas VH, Rabi Yeganeh N, et al. Efficacy of disease modifying therapies in progressive MS and how immune senescence may explain their failure. Front Neurol. 2022;13:854390. doi: 10.3389/fneur.2022.854390.
   PubMed Web of Science ®Google Scholar
• Sättler MB, Bähr M. Future neuroprotective strategies. Exp Neurol. 2010;225(1):40–47. doi: 10.1016/j.expneurol.2009.08.016.
   PubMed Web of Science ®Google Scholar
• Correale J, Gaitán MI, Ysrraelit MC, et al. Progressive multiple sclerosis: from pathogenic mechanisms to treatment. Brain. 2017;140(3):527–546.
   PubMed Web of Science ®Google Scholar
• Ooijevaar RE, Terveer EM, Verspaget HW, et al. Clinical application and potential of fecal microbiota transplantation. Annu Rev Med. 2019;70(1):335–351. doi: 10.1146/annurev-med-111717-122956.
   PubMedGoogle Scholar
• Borody TJ, Brandt LJ, Paramsothy S. Therapeutic faecal microbiota transplantation: current status and future developments. Curr Opin Gastroenterol. 2014;30(1):97–105. doi: 10.1097/MOG.0000000000000027.
   PubMed Web of Science ®Google Scholar
• Makkawi S, Camara-Lemarroy C, Metz L. Fecal microbiota transplantation associated with 10 years of stability in a patient with SPMS. Neurol Neuroimmunol Neuroinflamm. 2018;5(4):e459. doi: 10.1212/NXI.0000000000000459.
   PubMed Web of Science ®Google Scholar
• Kürtüncü M, Tüzün E. Multiple sclerosis: could it be an epigenetic disease? Med Hypotheses. 2008;71(6):945–947. doi: 10.1016/j.mehy.2008.06.034.
   PubMed Web of Science ®Google Scholar
• Peedicayil J. Epigenetic drugs for multiple sclerosis. Curr Neuropharmacol. 2016;14(1):3–9. doi: 10.2174/1570159x13666150211001600.
   PubMed Web of Science ®Google Scholar
• Oh J, Bar-Or A. Emerging therapies to target CNS pathophysiology in multiple sclerosis. Nat Rev Neurol. 2022;18(8):466–475. doi: 10.1038/s41582-022-00675-0.
   PubMed Web of Science ®Google Scholar
• Mirshafiey A. Venom therapy in multiple sclerosis. Neuropharmacology. 2007;53(3):353–361. doi: 10.1016/j.neuropharm.2007.05.002.
   PubMed Web of Science ®Google Scholar