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Myelin injury without astrocytopathy in neuroinflammatory disorders with MOG antibodies
  1. Kimihiko Kaneko1,
  2. Douglas Kazutoshi Sato1,2,
  3. Ichiro Nakashima1,
  4. Shuhei Nishiyama1,
  5. Satoru Tanaka3,
  6. Romain Marignier4,
  7. Jae-Won Hyun5,
  8. Luana Michelli de Oliveira2,
  9. Markus Reindl6,
  10. Thomas Seifert-Held7,
  11. Maria Sepulveda8,
  12. Sasitorn Siritho9,
  13. Patrick Joseph Waters10,
  14. Kazuhiro Kurosawa1,
  15. Tetsuya Akaishi1,
  16. Hiroshi Kuroda1,
  17. Tatsuro Misu2,
  18. Naraporn Prayoonwiwat9,
  19. Thomas Berger6,
  20. Albert Saiz8,
  21. Ho Jin Kim5,
  22. Kyoichi Nomura3,
  23. Dagoberto Callegaro2,
  24. Kazuo Fujihara1,
  25. Masashi Aoki1
  1. 1Departments of Neurology and Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, Sendai, Japan
  2. 2Faculty of Medicine, Department of Neurology, University of São Paulo, São Paulo, Brazil
  3. 3Department of Neurology, Saitama Medical Center, Kawagoe, Japan
  4. 4Lyon Neuroscience Research Center INSERM U 1028/CNRS 5292, Lyon, France
  5. 5Research Institute and Hospital of National Cancer Center, Seoul, Republic of Korea
  6. 6Clinical Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria
  7. 7Department of Neurology, Medical University of Graz, Graz, Austria
  8. 8Service of Neurology, Hospital Clinic and Institute d'Investigación Biomèdica August Pi Sunyer, University of Barcelona, Barcelona, Spain
  9. 9Department of Neurology, Siriraj Hospital, Mahidol University, Bangkok, Thailand
  10. 10Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK
  1. Correspondence to Dr Douglas Kazutoshi Sato, Department of Multiple Sclerosis Therapeutics, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Miyagi, Japan; douglas.sato{at}med.tohoku.ac.jp

https://doi.org/10.1136/jnnp-2015-312676

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    Background

    Acquired inflammatory central nervous system (CNS) disorders include multiple sclerosis (MS), neuromyelitis optica spectrum disorders (NMOSD), acute disseminated encephalomyelitis (ADEM), optic neuritis (ON), transverse myelitis and other less prevalent disorders.1 Differential diagnosis between these entities may be challenging in some cases due to overlapping clinical characteristics.

    Antibodies against aquaporin-4 (AQP4-Ab) suggest the diagnosis of NMOSD and promote severe immune-mediated astrocyte damage. However, some patients who are clinically diagnosed with NMOSD are AQP4-Ab-seronegative despite the use of highly sensitive cell-based assays (CBAs); therefore, other CNS molecules may be implicated as autoimmune targets in such cases.

    Recently, we reported the presence of conformational-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG-Ab) in a portion of AQP4-Ab-seronegative NMOSD,2 ADEM and ON cases, but these antibodies are not usually found in typical MS, using highly specific CBAs.

    Thus, it is interesting to study how MOG-Ab+ cases pathologically and immunologically differ from AQP4-Ab+ cases and MS cases. In this multicentre international collaborative study, we evaluated MOG-Ab and AQP4-Ab antibodies in the CSF, and compared markers of myelin and astrocyte damage in the CSF as well as other routine CSF parameters between the three groups.

    Patients and methods

    We enrolled a total of 90 patients diagnosed with acquired inflammatory CNS disorders and serum positivity for MOG-Ab or AQP4-Ab antibodies, using CBAs from Japan, Brazil, Republic of Korea, Spain, France, Austria and Thailand. For the European countries, serum antibody testing was performed in each respective country. We also included CSF samples from 40 relapsing-remitting patients with MS who fulfilled the 2010 McDonald criteria3 and 16 samples from patients with non-inflammatory neurological disorders (spinal cord infarction, cerebral infarction, spinocerebellar degeneration=2, Parkinson's disease=2, progressive supranuclear palsy=2, amyotrophic lateral sclerosis=2, Alzheimer dementia=1, NPH=1, migraine=2, somatoform disorder=2) as controls. All samples were shipped in dry ice to Sendai, Japan, and stored at −80°C …

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    Footnotes

    • Contributors KK, DKS, RM, MR, PJW and KF were involved in the study conception, data analysis and drafting of the manuscript: IN, HJK and DC were involved in the study conception, data analysis and reviewing of the manuscript; SN, ST, J-WH, LMdO, TS-H, MS, SS, KK. TA, HK TM, NP, TB and AS were involved in the data acquisition and reviewing of the manuscript : KN and MA were involved in the study conception and reviewing of the manuscript.

    • Funding This study was partially supported by a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), the Health and Labour Sciences Research Grant on Intractable Diseases (Neuroimmunological Diseases) from the Ministry of Health, Labour and Welfare of Japan, CAPES/Brasil (CSF-PAJT—88887.091277/2014-00), the Bio and Medical Technology Development Program (M3A9B6069339) through the Ministry of Science, ICT and Future Planning, Republic of Korea, and Marató de TV3 (AS; 20141830).

    • Competing interests DKS has received a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, a grant-in-aid for scientific research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), research support from CAPES/Brasil (CSF-PAJT—88887.091277/2014-00) and speaker honoraria from Novartis; IN reports grants from Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, and from Ministry of Health, Labour and Welfare of Japan, personal fees from Mitsubishi Tanabe Pharma Corporation, Biogen Idec Japan, Novartis Pharmaceuticals Japan, Bayer Yakuhin, Ltd, and grants from LSI Medience Corporation; SN JSPS KAKENHI Grant (Grant-in-Aid for Young Scientists(B)) Number 26860656; RM serves on the scientific advisory board for MedImmune and has received funding for travel and honoraria from Biogen Idec, Merck Serono, Novartis, Sanofi-Genzyme and Teva; PJW reports personal fees from Biogen Idec, personal fees from Euroimmun AG, and others from Guthy-Jackson Charitable Foundation, outside the submitted work; In addition, PJW and the University of Oxford hold a patent for antibody testing against CASPR2/LGI1 with royalties paid by Euroimmun AG, and a patent on testing for antibodies to the GABAAR; HK reports grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan; TM has received speaker honoraria from Bayer Schering Pharma, Biogen Idec Japan, Mitsubishi Tanabe Pharma Corporation, Asahi Kasei Medical Co, and Astellas Pharma Inc, and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical Co, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical KK, Mitsubishi Tanabe Pharma Corporation, Teijin Pharma and Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology, and the Ministry of Health, Labor and Welfare of Japan; NP reports grants from Siriraj Research and Development Fund, and personal fees from Novartis and UCB; AS has received compensation for consulting services and for speaking from Bayer-Schering, Merck-Serono, Biogen-Idec, Sanofi-Aventis, Teva Pharmaceutical Industries Ltd and Novartis; HJK has received research grants from the Ministry of Science, ICT and Future Planning, Republic of Korea, Genzyme, Kael-GemVax and Merck Serono; and has given talks, consulted with and received honoraria from Bayer Schering Pharma, Biogen Idec, Genzyme Corp, Merck Serono, Novartis, Teva-Handok and UCB. He serves on a steering committee for MedImmune and as an editor for Multiple Sclerosis Journal-Experimental, Translational and Clinical; KN reports personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Astellas Pharma Inc, personal fees from Chemo-Sero-Therapeutic Research Institute and personal fees from Teijin Pharma; KF serves on scientific advisory boards for Bayer Schering Pharma, Biogen Idec, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical, Merck Serono, Alexion Pharmaceuticals, Medimmune and Medical Review; has received funding for travel and speaker honoraria from Bayer Schering Pharma, Biogen Idec, Eisai Inc, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma Inc, Takeda Pharmaceutical Company Limited, Asahi Kasei Medical Co, Daiichi Sankyo and Nihon Pharmaceutical; serves as an editorial board member of Clinical and Experimental Neuroimmunology (2009-present) and is an advisory board member of Sri Lanka Journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, The Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical and Genzyme Japan; and is funded as the secondary investigator (#22229008, 2010–2015) by the Grants-in-Aid for Scientific Research from the Ministry of Education, Science and Technology of Japan and as the secondary investigator by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labor of Japan (2010-present).

    • Ethics approval Ethics committee Tohoku University.

    • Provenance and peer review Not commissioned; externally peer reviewed.