Abstract
We characterized a unique group of patients with neuromyelitis optica spectrum disorder (NMOSD) who carried autoantibodies of aquaporin-4 (AQP4) and myelin-oligodendrocyte glycoprotein (MOG). Among the 125 NMOSD patients, 10 (8.0%) were AQP4- and MOG-ab double positive, and 14 (11.2%) were MOG-ab single positive. The double-positive patients had a multiphase disease course with a high annual relapse rate (P=0.0431), and severe residual disability (P>0.0001). Of the double- positive patients, 70% had MS-like brain lesions, more severe edematous, multifocal regions on spinal magnetic resonance imaging (MRI), pronounced decreases of retinal nerve fiber layer thickness and atrophy of optic nerves. In contrast, patients with only MOG-ab had a higher ratio of monophasic disease course and mild residual disability. Spinal cord MRI illustrated multifocal cord lesions with mild edema, and brain MRIs showed more lesions around lateral ventricles. NMOSD patients carrying both autoantibodies to AQP4 and MOG existed and exhibited combined features of prototypic NMO and relapsing- remitting form of MS, whereas NMOSD with antibodies to MOG only exhibited an “intermediate” phenotype between NMOSD and MS. Our study suggests that antibodies against MOG might be pathogenic in NMOSD patients and that determination of anti-MOG antibodies maybe instructive for management of NMOSD patients.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
References
Berger, T., Rubner, P., Schautzer, F., Egg, R., Ulmer, H., Mayringer, I., Dilitz, E., Deisenhammer, F., and Reindl, M. (2003). Antimyelin antibodies as a predictor of clinically definite multiple sclerosis after a first demyelinating event. N Engl J Med 349, 139–145.
Bettelli, E., Baeten, D., Jager, A., Sobel, R.A., and Kuchroo, V.K. (2006). Myelin oligodendrocyte glycoprotein-specific T and B cells cooperate to induce a Devic-like disease in mice. J Clin Invest 116, 2393–2402.
Dale, R.C., de Sousa, C., Chong, W.K., Cox, T.C., Harding, B., and Neville, B.G. (2000). Acute disseminated encephalomyelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis in children. Brain 123 Pt 12, 2407–2422.
Eichel, R., Meiner, Z., Abramsky, O., and Gotkine, M. (2008). Acute disseminating encephalomyelitis in neuromyelitis optica: closing the floodgates. Arch Neurol 65, 267–271.
Granieri, L., Marnetto, F., Valentino, P., Frau, J., Patanella, A.K., Nytrova, P., Sola, P., Capobianco, M., Jarius, S., and Bertolotto, A. (2012). Evaluation of a multiparametric immunofluorescence assay for standardization of neuromyelitis optica serology. PLoS One 7, e38896.
Jarius, S., Ruprecht, K., Wildemann, B., Kuempfel, T., Ringelstein, M., Geis, C., Kleiter, I., Kleinschnitz, C., Berthele, A., Brettschneider, J., Hellwig, K., Hemmer, B., Linker, R.A., Lauda, F., Mayer, C.A., Tumani, H., Melms, A., Trebst, C., Stangel, M., Marziniak, M., Hoffmann, F., Schippling, S., Faiss, J.H., Neuhaus, O., Ettrich, B., Zentner, C., Guthke, K., Hofstadt-van Oy, U., Reuss, R., Pellkofer, H., Ziemann, U., Kern, P., Wandinger, K.P., Bergh, F.T., Boettcher, T., Langel, S., Liebetrau, M., Rommer, P.S., Niehaus, S., Munch, C., Winkelmann, A., Zettl, U.U., Metz, I., Veauthier, C., Sieb, J.P., Wilke, C., Hartung, H.P., Aktas, O., and Paul, F. (2012). Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: a multicentre study of 175 patients. J Neuroinflammation 9, 14.
Jiao, Y., Fryer, J.P., Lennon, V.A., McKeon, A., Jenkins, S.M., Smith, C.Y., Quek, A.M., Weinshenker, B.G., Wingerchuk, D.M., Shuster, E.A., Lucchinetti, C.F., and Pittock, S.J. (2014). Aquaporin 4 IgG serostatus and outcome in recurrent longitudinally extensive transverse myelitis. JAMA Neurol 71, 48–54.
Kezuka, T., Usui, Y., Yamakawa, N., Matsunaga, Y., Matsuda, R., Masuda, M., Utsumi, H., Tanaka, K., and Goto, H. (2012). Relationship between NMO-antibody and anti-MOG antibody in optic neuritis. J Neuroophthalmol 32, 107–110.
Kitley, J., Leite, M.I., Kuker, W., Quaghebeur, G., George, J., Waters, P., Woodhall, M., Vincent, A., and Palace, J. (2013). Longitudinally extensive transverse myelitis with and without aquaporin 4 antibodies. JAMA Neurol 70, 1375–1381.
Kitley, J., Waters, P., Woodhall, M., Leite, M.I., Murchison, A., George, J., Kuker, W., Chandratre, S., Vincent, A., and Palace, J. (2014). Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 71, 276–283.
Kitley, J., Woodhall, M., Waters, P., Leite, M.I., Devenney, E., Craig, J., Palace, J., and Vincent, A. (2012). Myelin-oligodendrocyte glycoprotein antibodies in adults with a neuromyelitis optica phenotype. Neurology 79, 1273–1277.
Kuhle, J., Pohl, C., Mehling, M., Edan, G., Freedman, M.S., Hartung, H.P., Polman, C.H., Miller, D.H., Montalban, X., Barkhof, F., Bauer, L., Dahms, S., Lindberg, R., Kappos, L., and Sandbrink, R. (2007). Lack of association between antimyelin antibodies and progression to multiple sclerosis. N Engl J Med 356, 371–378.
Lennon, V.A., Kryzer, T.J., Pittock, S.J., Verkman, A.S., and Hinson, S.R. (2005). IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med 202, 473–477.
Liu, J., Yeung, P.K., Cheng, L., Lo, A.C., Chung, S.S., and Chung, S.K. (2015). Epac2-deficiency leads to more severe retinal swelling, glial reactivity and oxidative stress in transient middle cerebral artery occlusion induced ischemic retinopathy. Sci China Life Sci 58, 521–530.
Mader, S., Gredler, V., Schanda, K., Rostasy, K., Dujmovic, I., Pfaller, K., Lutterotti, A., Jarius, S., Di Pauli, F., Kuenz, B., Ehling, R., Hegen, H., Deisenhammer, F., Aboul-Enein, F., Storch, M.K., Koson, P., Drulovic, J., Kristoferitsch, W., Berger, T., and Reindl, M. (2011). Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J Neuroinflammation 8, 184.
Marta, C.B., Oliver, A.R., Sweet, R.A., Pfeiffer, S.E., and Ruddle, N.H. (2005). Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology. Proc Natl Acad Sci USA 102, 13992–13997.
Matthews, L., Marasco, R., Jenkinson, M., Kuker, W., Luppe, S., Leite, M.I., Giorgio, A., De Stefano, N., Robertson, N., Johansen-Berg, H., Evangelou, N., and Palace, J. (2013). Distinction of seropositive NMO spectrum disorder and MSbrain lesion distribution. Neurology 80, 1330–1337.
Papadopoulos, M.C., and Verkman, A.S. (2012). Aquaporin 4 and neuromyelitis optica. Lancet Neurol 11, 535–544.
Pittock, S.J., Lennon, V.A., Krecke, K., Wingerchuk, D.M., Lucchinetti, C.F., and Weinshenker, B.G. (2006). Brain abnormalities in neuromyelitis optica. Arch Neurol 63, 390–396.
Polman, C.H., Reingold, S.C., Banwell, B., Clanet, M., Cohen, J.A., Filippi, M., Fujihara, K., Havrdova, E., Hutchinson, M., Kappos, L., Lublin, F.D., Montalban, X., O’ Connor, P., Sandberg-Wollheim, M., Thompson, A.J., Waubant, E., Weinshenker, B., and Wolinsky, J.S. (2011). Diagnostic criteria for multiple sclerosis: 2010 revisions to the McDonald criteria. Ann Neurol 69, 292–302.
Probstel, A.K., Rudolf, G., Dornmair, K., Collongues, N., Chanson, J.B., Sanderson, N.S., Lindberg, R.L., Kappos, L., de Seze, J., and Derfuss, T. (2015). Anti-MOG antibodies are present in a subgroup of patients with a neuromyelitis optica phenotype. J Neuroinflammation 12, 46.
Ratelade, J., Zhang, H., Saadoun, S., Bennett, J.L., Papadopoulos, M.C., and Verkman, A.S. (2012). Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss. Acta Neuropathol 123, 861–872.
Reindl, M., Di Pauli, F., Rostasy, K., and Berger, T. (2013). The spectrum of MOG autoantibody-associated demyelinating diseases. Nat Rev Neurol 9, 455–461.
Rostasy, K., Mader, S., Hennes, E.M., Schanda, K., Gredler, V., Guenther, A., Blaschek, A., Korenke, C., Pritsch, M., Pohl, D., Maier, O., Kuchukhidze, G., Brunner-Krainz, M., Berger, T., and Reindl, M. (2013). Persisting myelin oligodendrocyte glycoprotein antibodies in aquaporin-4 antibody negative pediatric neuromyelitis optica. Mult Scler 19, 1052–1059.
Saadoun, S., Waters, P., Bell, B.A., Vincent, A., Verkman, A.S., and Papadopoulos, M.C. (2010). Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain 133, 349–361.
Saadoun, S., Waters, P., Owens, G.P., Bennett, J.L., Vincent, A., and Papadopoulos, M.C. (2014). Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol Commun 2, 35.
Sato, D.K., Callegaro, D., Lana-Peixoto, M.A., Waters, P.J., de Haidar Jorge, F.M., Takahashi, T., Nakashima, I., Apostolos-Pereira, S.L., Talim, N., Simm, R.F., Lino, A.M., Misu, T., Leite, M.I., Aoki, M., and Fujihara, K. (2014). Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 82, 474–481.
Tackley, G., Kuker, W., and Palace, J. (2014). Magnetic resonance imaging in neuromyelitis optica. Mult Scler, 20, 1153–1164.
Tanaka, M., and Tanaka, K. (2014). Anti-MOG antibodies in adult patients with demyelinating disorders of the central nervous system. J Neuroimmunol 270, 98–99.
Waters, P.J., McKeon, A., Leite, M.I., Rajasekharan, S., Lennon, V.A., Villalobos, A., Palace, J., Mandrekar, J.N., Vincent, A., Bar-Or, A., and Pittock, S.J. (2012). Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 78, 665–671; 669.
Weinshenker, B.G., and Wingerchuk, D.M. (2014). The two faces of neuromyelitis optica. Neurology 82, 466–467.
Wingerchuk, D.M., Lennon, V.A., Lucchinetti, C.F., Pittock, S.J., and Weinshenker, B.G. (2007). The spectrum of neuromyelitis optica. Lancet Neurol 6, 805–815.
Woodhall, M., Coban, A., Waters, P., Ekizoglu, E., Kurtuncu, M., Shugaiv, E., Turkoglu, R., Akman-Demir, G., Eraksoy, M., Vincent, A., and Tuzun, E. (2013). Glycine receptor and myelin oligodendrocyte glycoprotein antibodies in Turkish patients with neuromyelitis optica. J Neurol Sci 335, 221–223.
Zhou, D., Srivastava, R., Nessler, S., Grummel, V., Sommer, N., Bruck, W., Hartung, H.P., Stadelmann, C., and Hemmer, B. (2006). Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci USA 103, 19057–19062.
Acknowledgements
We thank Neuroimmunology teams in Tianjin and Barrow for support. This study was supported by National Basic Research Program of China Grant (2013CB96690), the Natural Science Foundation of China Grants (81100888, 81230028, 81371372), the National Key Clinical Specialty Construction Program of China, US National Institute of Health (R01AI083294), and the American Heart Association (14GRNT-18970031).
Author information
Authors and Affiliations
Corresponding authors
Additional information
This article is published with open access at link.springer.com
Rights and permissions
Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.
About this article
Cite this article
Yan, Y., Li, Y., Fu, Y. et al. Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD. Sci. China Life Sci. 59, 1270–1281 (2016). https://doi.org/10.1007/s11427-015-4997-y
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11427-015-4997-y