Abstract
Neuromyelitis optica (NMO) and myelin oligodendrocyte glycoprotein (MOG) antibody-related disease (MOG disease) are inflammatory demyelinating diseases of the central nervous system (CNS). The disruption of the blood–brain barrier (BBB) is considered a key step in the pathogenesis of NMO and MOG disease. Although a previous report indicated that circulating immunoglobulin G (IgG) from NMO patients disrupts the BBB, the effect of IgG from patients with MOG disease has not been elucidated. In addition, it has been reported that some disease-modifying drugs for multiple sclerosis are harmful to NMO by an unknown mechanism. This study aimed to examine the effects of IgG from patients with NMO or MOG disease on BBB integrity. We also examined the effects of disease-modifying drugs (fingolimod [FTY720] and dimethyl fumarate [DMF]) on IgG-treated brain capillary endothelial cells. We used in vitro BBB models constructed with rat brain capillary endothelial cells (RBECs) to examine the effects on BBB function. The integrity of the RBECs was assessed by measuring transendothelial resistance (TEER) and cell viability. NMO or MOG-IgG treatment decreased TEER and cell viability in the endothelial monolayer model. Although FTY720 and DMF did not affect barrier function or cell viability under normal conditions, disease IgG-induced barrier dysfunctions were worsened by the presence of FTY720. These data indicate that circulating IgG in patients with NMO or MOG disease worsens BBB function. Furthermore, in patients with NMO or MOG disease treated with FTY720, changes in the integrity of the BBB were found to exacerbate the disease.
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References
Abbott NJ, Ronnback L, Hansson E (2006) Astrocyte-endothelial interactions at the blood-brain barrier. Nat Rev Neurosci 7:41–53. https://doi.org/10.1038/nrn1824
Ahmad A, Patel V, Xiao J, Khan MM (2020) The role of neurovascular system in neurodegenerative diseases. Mol Neurobiol. https://doi.org/10.1007/s12035-020-02023-z
Brimberg L, Mader S, Fujieda Y, Arinuma Y, Kowal C, Volpe BT, Diamond B (2015) Antibodies as Mediators of Brain Pathology. Trends Immunol 36:709–724. https://doi.org/10.1016/j.it.2015.09.008
Camm J, Hla T, Bakshi R, Brinkmann V (2014) Cardiac and vascular effects of fingolimod: mechanistic basis and clinical implications. Am Heart J 168:632–644. https://doi.org/10.1016/j.ahj.2014.06.028
Camp SM et al (2015) Pulmonary endothelial cell barrier enhancement by novel FTY720 analogs: methoxy-FTY720, fluoro-FTY720, and beta-glucuronide-FTY720. Chem Phys Lipids 191:16–24. https://doi.org/10.1016/j.chemphyslip.2015.08.004
Chun J, Brinkmann V (2011) A mechanistically novel, first oral therapy for multiple sclerosis: the development of fingolimod (FTY720, Gilenya). Discov Med 12:213–228
Daniels BP et al (2017) Regional astrocyte IFN signaling restricts pathogenesis during neurotropic viral infection. J Clin Invest 127:843–856. https://doi.org/10.1172/JCI88720
Dargahi N, Katsara M, Tselios T, Androutsou ME, Courten de M, Matsoukas J, Apostolopoulos V (2017) Multiple sclerosis: immunopathology and treatment update Brain Sci 7. https://doi.org/10.3390/brainsci7070078
Hinson SR, Pittock SJ, Lucchinetti CF, Roemer SF, Fryer JP, Kryzer TJ, Lennon VA (2007) Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica. Neurology 69:2221–2231. https://doi.org/10.1212/01.WNL.0000289761.64862.ce
Huwiler A, Zangemeister-Wittke U (2018) The sphingosine 1-phosphate receptor modulator fingolimod as a therapeutic agent: recent findings and new perspectives. Pharmacol Ther 185:34–49. https://doi.org/10.1016/j.pharmthera.2017.11.001
Jasiak-Zatonska M, Kalinowska-Lyszczarz A, Michalak S, Kozubski W (2016) The immunology of neuromyelitis optica-current knowledge, clinical implications, controversies and future perspectives. Int J Mol Sci 17:273. https://doi.org/10.3390/ijms17030273
Kraus J, Oschmann P (2006) The impact of interferon-beta treatment on the blood-brain barrier. Drug Discov Today 11:755–762. https://doi.org/10.1016/j.drudis.2006.06.008
Kraus J et al (2008) Interferon-beta stabilizes barrier characteristics of the blood-brain barrier in four different species in vitro. Mult Scler 14:843–852. https://doi.org/10.1177/1352458508088940
Lana-Peixoto MA, Talim N (2019) Neuromyelitis optica spectrum disorder and anti-MOG syndromes Biomed 7. https://doi.org/10.3390/biomedicines7020042
Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR (2005) IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202:473–477. https://doi.org/10.1084/jem.20050304
Magana SM et al (2009) Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders. Neurology 72:712–717. https://doi.org/10.1212/01.wnl.0000343001.36493.ae
Mayer MC et al (2013) Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J Immunol 191:3594–3604. https://doi.org/10.4049/jimmunol.1301296
Min JH, Kim BJ, Lee KH (2012) Development of extensive brain lesions following fingolimod (FTY720) treatment in a patient with neuromyelitis optica spectrum disorder. Mult Scler 18:113–115. https://doi.org/10.1177/1352458511431973
Misu T et al (2007) Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 130:1224–1234. https://doi.org/10.1093/brain/awm047
Mohseni SH, Skejoe HPB, Wuerfel J, Paul F, Reindl M, Jarius S, Asgari N (2018) Leptomeningeal and intraparenchymal blood barrier disruption in a MOG-IgG-positive patient. Case Rep Neurol Med 2018:1365175. https://doi.org/10.1155/2018/1365175
Morofuji Y, Nakagawa S (2020) Drug development for central nervous system diseases using in vitro blood-brain barrier models and drug repositioning. Curr Pharm Des. https://doi.org/10.2174/1381612826666200224112534
Muller HC et al (2011) The Sphingosine-1 Phosphate receptor agonist FTY720 dose dependently affected endothelial integrity in vitro and aggravated ventilator-induced lung injury in mice. Pulm Pharmacol Ther 24:377–385. https://doi.org/10.1016/j.pupt.2011.01.017
Nakagawa S, Aruga J (2020) Sphingosine 1-phosphate signaling is involved in impaired blood-brain barrier function in ischemia-reperfusion injury. Mol Neurobiol 57:1594–1606. https://doi.org/10.1007/s12035-019-01844-x
Nakagawa S et al (2009) A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int 54:253–263. https://doi.org/10.1016/j.neuint.2008.12.002
Nakajima H, Hosokawa T, Doi Y, Ikemoto T, Ishida S, Kimura F, Hanafusa T (2012) Interferon-beta1b increases Th2 response in neuromyelitis optica. Int J Mol Sci 13:12213–12223. https://doi.org/10.3390/ijms131012213
Papadopoulos MC, Bennett JL, Verkman AS (2014) Treatment of neuromyelitis optica: state-of-the-art and emerging therapies. Nat Rev Neurol 10:493–506. https://doi.org/10.1038/nrneurol.2014.141
Popiel M, Psujek M, Bartosik-Psujek H (2018) Severe disease exacerbation in a patient with neuromyelitis optica spectrum disorder during treatment with dimethyl fumarate. Mult Scler Relat Disord 26:204–206. https://doi.org/10.1016/j.msard.2018.09.011
Prager B, Spampinato SF, Ransohoff RM (2015) Sphingosine 1-phosphate signaling at the blood-brain barrier. Trends Mol Med 21:354–363. https://doi.org/10.1016/j.molmed.2015.03.006
Ruggieri S, Tortorella C, Gasperini C (2014) Pharmacology and clinical efficacy of dimethyl fumarate (BG-12) for treatment of relapsing-remitting multiple sclerosis. Ther Clin Risk Manag 10:229–239. https://doi.org/10.2147/TCRM.S53285
Sabater L et al (2009) Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: an in vitro study. J Neuroimmunol 215:31–35. https://doi.org/10.1016/j.jneuroim.2009.07.014
Shimizu F, Nishihara H, Kanda T (2018) Blood-brain barrier dysfunction in immuno-mediated neurological diseases. Immunol Med 41:120–128. https://doi.org/10.1080/25785826.2018.1531190
Shimizu F et al (2017) Glucose-regulated protein 78 autoantibody associates with blood-brain barrier disruption in neuromyelitis optica Sci Transl Med 9. https://doi.org/10.1126/scitranslmed.aai9111
Shimizu F et al (2014) Sera from remitting and secondary progressive multiple sclerosis patients disrupt the blood-brain barrier. PLoS ONE 9:e92872. https://doi.org/10.1371/journal.pone.0092872
Shimizu J et al (2010) IFNbeta-1b may severely exacerbate Japanese optic-spinal MS in neuromyelitis optica spectrum. Neurology 75:1423–1427. https://doi.org/10.1212/WNL.0b013e3181f8832e
Takeshita Y et al (2017) Effects of neuromyelitis optica-IgG at the blood-brain barrier in vitro. Neurol Neuroimmunol Neuroinflamm 4:e311. https://doi.org/10.1212/NXI.0000000000000311
Tasaki A et al (2014) Autocrine MMP-2/9 secretion increases the BBB permeability in neuromyelitis optica. J Neurol Neurosurg Psychiatry 85:419–430. https://doi.org/10.1136/jnnp-2013-305907
Vincent T, Saikali P, Cayrol R, Roth AD, Bar-Or A, Prat A, Antel JP (2008) Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment. J Immunol 181:5730–5737. https://doi.org/10.4049/jimmunol.181.8.5730
Warabi Y, Takahashi T, Isozaki E (2019) Dimethyl Fumarate Was Ineffective but Not Harmful for a Patient with Myelin Oligodendrocyte Glycoprotein Antibody Disease. Cureus 11:e6040. https://doi.org/10.7759/cureus.6040
Wu Y, Zhong L, Geng J (2019) Neuromyelitis optica spectrum disorder: Pathogenesis, treatment, and experimental models. Mult Scler Relat Disord 27:412–418. https://doi.org/10.1016/j.msard.2018.12.002
Wynford-Thomas R, Jacob A, Tomassini V (2019) Neurological update: MOG antibody disease. J Neurol 266:1280–1286. https://doi.org/10.1007/s00415-018-9122-2
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This work was supported by JSPS KAKENHI Grant Number 26462167 and 17K10838 from the Japan Society for the Promotion of Science (JSPS).
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Yoshimura, S., Nakagawa, S., Takahashi, T. et al. FTY720 Exacerbates Blood–Brain Barrier Dysfunction Induced by IgG Derived from Patients with NMO and MOG Disease. Neurotox Res 39, 1300–1309 (2021). https://doi.org/10.1007/s12640-021-00373-7
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DOI: https://doi.org/10.1007/s12640-021-00373-7