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  • CSF cytokine profile in MOG-IgG+ neurological disease is similar to AQP4-IgG+ NMOSD but distinct from MS: a cross-sectional study and potential therapeutic implications

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Neuro-inflammation
Research paper
CSF cytokine profile in MOG-IgG+ neurological disease is similar to AQP4-IgG+ NMOSD but distinct from MS: a cross-sectional study and potential therapeutic implications
  1. Kimihiko Kaneko1,
  2. Douglas Kazutoshi Sato1,2,3,
  3. Ichiro Nakashima1,4,
  4. Ryo Ogawa1,
  5. Tetsuya Akaishi1,5,
  6. Yoshiki Takai1,
  7. Shuhei Nishiyama1,
  8. Toshiyuki Takahashi1,5,
  9. Tatsuro Misu1,
  10. Hiroshi Kuroda1,
  11. Satoru Tanaka6,
  12. Kyoichi Nomura6,
  13. Yuji Hashimoto7,
  14. Dagoberto Callegaro3,
  15. Lawrence Steinman8,
  16. Kazuo Fujihara1,9,10,
  17. Masashi Aoki1
  1. 1 Department of Neurology, Tohoku University Graduate School of Medicine, Sendai, Japan
  2. 2 Department of Neurology, Brain Institute and Hospital Sao Lucas Pontifical Catholic University of Rio Grande do Sul, Porto Alegre, Brazil
  3. 3 Department of Neurology, São Paulo University, São Paulo, Brazil
  4. 4 Department of Neurology, Tohoku Medical and Pharmaceutical University, Sendai, Japan
  5. 5 Department of Neurology, Yonezawa National Hospital, Yonezawa, Japan
  6. 6 Department of Neurology, Saitama Medical University, Kawagoe, Japan
  7. 7 Department of Pediatrics, Chiba Kaihin Municipal Hospital, Chiba, Japan
  8. 8 Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, California, USA
  9. 9 Department of Multiple Sclerosis Therapeutics, Fukushima Medical University, Fukushima, Japan
  10. 10 Multiple Sclerosis and Neuromyelitis Optica Center, Tohoku Research Institute for Neuroscience, Koriyama, Japan
  1. Correspondence to Dr. Douglas Kazutoshi Sato; douglas.sato{at}pucrs.br and Dr Kazuo Fujihara, Department of Neurology, Tohoku University School of Medicine, Sendai 980-8577, Japan; fujikazu{at}med.tohoku.ac.jp

Abstract

Objective To evaluate cerebrospinal fluid (CSF) cytokine profiles in myelin oligodendrocyte glycoprotein IgG-positive (MOG-IgG+) disease in adult and paediatric patients.

Methods In this cross-sectional study, we measured 27 cytokines in the CSF of MOG-IgG+ disease in acute phase before treatment (n=29). The data were directly compared with those in aquaporin-4 antibody-positive (AQP4-IgG+) neuromyelitis optica spectrum disorder (NMOSD) (n=20), multiple sclerosis (MS) (n=20) and non-inflammatory controls (n=14).

Results In MOG-IgG+ disease, there was no female preponderance and the ages were younger (mean 18 years, range 3–68; 15 were below 18 years) relative to AQP4-IgG+ NMOSD (41, 15–77) and MS (34, 17–48). CSF cell counts were higher and oligoclonal IgG bands were mostly negative in MOG-IgG+ disease and AQP4-IgG+ NMOSD compared with MS. MOG-IgG+ disease had significantly elevated levels of interleukin (IL)-6, IL-8, granulocyte-colony stimulating factor and granulocyte macrophage-colony stimulating factor, interferon-γ, IL-10, IL-1 receptor antagonist, monocyte chemotactic protein-1 and macrophage inflammatory protein-1α as compared with MS. No cytokine in MOG-IgG+ disease was significantly different from AQP4-IgG+ NMOSD. Moreover many elevated cytokines were correlated with each other in MOG-IgG+ disease and AQP4-IgG+ NMOSD but not in MS. No difference in the data was seen between adult and paediatric MOG-IgG+ cases.

Conclusions The CSF cytokine profile in the acute phase of MOG-IgG+ disease is characterised by coordinated upregulation of T helper 17 (Th17) and other cytokines including some Th1-related and regulatory T cells-related ones in adults and children, which is similar to AQP4-IgG+ NMOSD but clearly different from MS. The results suggest that as with AQP4-IgG+ NMOSD, some disease-modifying drugs for MS may be ineffective in MOG-IgG+ disease while they may provide potential therapeutic targets.

  • myelin oligodendrocyte glycoprotein-IgG
  • cytokine profile
  • demyelinating disease
  • aquaporin-4-IgG
  • neuromyelitis optica spectrum disorders
  • multiple sclerosis

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/

https://doi.org/10.1136/jnnp-2018-317969

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    Footnotes

    • Contributors KK: contributed to study conception, sample collection, cytokine analysis, interpretation of data, and drafting the manuscript including the figures, tables and references; completion of the work to be submitted; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. DKS: contributed to study conception, cytokine analysis, interpretation of data and revised the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. IN: contributed to study conception, interpretation of data and revised the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. RO: contributed to study conception, interpretation of data and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. TA: contributed to interpretation of data especially in statistical analysis, and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. YT and TM: contributed to interpretation of data and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. SN: contributed to interpretation of data, helped in measuring glial fibrillar acidic protein and myelin basic protein, and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. TT: contributed to study conception, sample collection and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. HK: contributed to interpretation of data and reviewing the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. ST: contributed to sample collection and reviewing of the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. KN: contributed to sample collection and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. YH: contributed to sample collection and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. DC: contributed to study conception and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. LS: contributed to interpretation of data and revised the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. KF: contributed to study conception, supervision of the acquisition, interpretation of data, revised the manuscript including the figures, tables and references; provided final approval of the version to be published; agreed to be accountable for all aspects of the work. MA: contributed to study conception, supervision of the acquisition, analysis and interpretation of data, and reviewed the manuscript; provided final approval of the version to be published; agreed to be accountable for all aspects of the work.

    • Funding This study was partially supported by a Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI), and the Health and Labour Sciences Research Grant on Intractable Diseases (neuroimmunological diseases) from the Ministry of Health, Labour and Welfare of Japan. This study was not industry-sponsored.

    • Competing interests DKS has received a scholarship from the Ministry of Education, Culture, Sports, Science and Technology (MEXT) of Japan, Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (KAKENHI 15K19472), research support from CAPES/Brazil (CSF-PAJT—88887.091277/ 2014-00) and speaker honoraria from Novartis. IN has received funding for travel and received speaker honoraria from Mitsubishi Tanabe Pharma Corporation and has received research funding from LSI Medience Corporation and Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. YT has received research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. SN has received research support from Grants-in-Aid for Scientific Research 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 and Astellas Pharma, and has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Kuraray Medical, 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, Culture, Sports, Science and Technology, and the Ministry of Health, Labour and Welfare of Japan. HK has received research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan. KN reports personal fees from Mitsubishi Tanabe Pharma Corporation, personal fees from Astellas Pharma, personal fees from Chemo-Sero-Therapeutic Research Institute and personal fees from Teijin Pharma. LS served on the scientific advisory board for Novartis, Receptos, Atreca, Tolerion and Teva, received travel funding and/or speaker honoraria from Biogen, Bayhill, Bayer, Celgene and Receptos, is on the editorial board for Multiple Sclerosis Journal and Proceedings of the National Academy of Science, holds patents for antigen-specific tolerance, has a patent pending for cytokines and type 1 interferons, is on the speakers' bureau for EMD Serono, received research support from NIH, has stock options and board membership in Tolerion, and is on the board of directors for BioAtla. KF serves on the 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, Mitsubishi Tanabe Pharma Corporation, Novartis Pharma, Astellas Pharma, Takeda Pharmaceutical Company, Asahi Kasei Medical, Daiichi Sankyo and Nihon Pharmaceutical; serves as an editorial board member of Clinical and Experimental Neuroimmunology (2009–present) and an advisory board member of Sri Lanka Journal of Neurology; has received research support from Bayer Schering Pharma, Biogen Idec Japan, Asahi Kasei Medical, Chemo-Sero-Therapeutic Research Institute, Teva Pharmaceutical, Mitsubishi Tanabe Pharma, Teijin Pharma, Chugai Pharmaceutical, Ono Pharmaceutical, Nihon Pharmaceutical and Genzyme Japan; is funded by the Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (#22229008, 2010-2015; #26293205, 2014-2016) and by the Grants-in-Aid for Scientific Research from the Ministry of Health, Welfare and Labour of Japan (2010–present). MA has received research support from Grants-in-Aid for Scientific Research from the Ministry of Education, Culture, Sports, Science and Technology, and the Ministry of Health, Labour and Welfare of Japan.

    • Patient consent Obtained.

    • Ethics approval Ethics approval was granted by the Ethics Committee of Tohoku University Graduate School of Medicine, Sendai, Japan. All the patients gave informed consent for their participation.

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

    • Correction notice Since this article was published online first changes have been made to the headings in table two.

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