Myelin Oligodendrocyte Glycoprotein-IgG Contributes to Oligodendrocytopathy in the Presence of Complement, Distinct from Astrocytopathy Induced by AQP4-IgG

  • Ling Fang
  • Xinmei Kang
  • Zhen Wang
  • Shisi Wang
  • Jingqi Wang
  • Yifan Zhou
  • Chen Chen
  • Xiaobo Sun
  • Yaping Yan
  • Allan G. Kermode
  • Lisheng PengEmail author
  • Wei QiuEmail author
Original Article


Immunoglobulin G against myelin oligodendrocyte glycoprotein (MOG-IgG) is detectable in neuromyelitis optica spectrum disorder (NMOSD) without aquaporin-4 IgG (AQP4-IgG), but its pathogenicity remains unclear. In this study, we explored the pathogenic mechanisms of MOG-IgG in vitro and in vivo and compared them with those of AQP4-IgG. MOG-IgG-positive serum induced complement activation and cell death in human embryonic kidney (HEK)-293T cells transfected with human MOG. In C57BL/6 mice and Sprague-Dawley rats, MOG-IgG only caused lesions in the presence of complement. Interestingly, AQP4-IgG induced astroglial damage, while MOG-IgG mainly caused myelin loss. MOG-IgG also induced astrocyte damage in mouse brains in the presence of complement. Importantly, we also observed ultrastructural changes induced by MOG-IgG and AQP4-IgG. These findings suggest that MOG-IgG directly mediates cell death by activating complement in vitro and producing NMOSD-like lesions in vivo. AQP4-IgG directly targets astrocytes, while MOG-IgG mainly damages oligodendrocytes.


Neuromyelitis optica spectrum disorder Aquaporin-4 immunoglobulin G Myelin oligodendrocyte glycoprotein immunoglobulin G Complement-dependent cytotoxicity Transmission electron microscopy 



This work was supported by grants from the National Natural Science Foundation of China (81471218 and 81771300) and the Natural Science Foundation of Guangdong Province, China (2017A030313853). We thank Professors Yiwen Ruan and Yunfeng Shi at Jinan University who supported the electron microscopy experiments.

Conflict of Interest

The authors declare that they have no conflict of interest.


  1. 1.
    Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 2004, 364: 2106–2112.CrossRefGoogle Scholar
  2. 2.
    Parratt JD, Prineas JW. Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes. Mult Scler 2010, 16: 1156–1172.CrossRefGoogle Scholar
  3. 3.
    Wingerchuk DM, Banwell B, Bennett JL, Cabre P, Carroll W, Chitnis T, et al. International consensus diagnostic criteria for neuromyelitis optica spectrum disorders. Neurology 2015, 85: 177–189.CrossRefGoogle Scholar
  4. 4.
    Sato DK, Callegaro D, Lana-Peixoto MA, Waters PJ, de Haidar JF, Takahashi T, et al. Distinction between MOG antibody-positive and AQP4 antibody-positive NMO spectrum disorders. Neurology 2014, 82: 474–481.CrossRefGoogle Scholar
  5. 5.
    Hamid S, Whittam D, Mutch K, Linaker S, Solomon T, Das K, et al. What proportion of AQP4-IgG-negative NMO spectrum disorder patients are MOG-IgG positive? A cross sectional study of 132 patients. J Neurol 2017, 264: 2088–2094.CrossRefGoogle Scholar
  6. 6.
    O’Connor KC, McLaughlin KA, De Jager PL, Chitnis T, Bettelli E, Xu C, et al. Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein. Nat Med 2007, 13: 211–217.CrossRefGoogle Scholar
  7. 7.
    Waters P, Reindl M, Saiz A, Schanda K, Tuller F, Kral V, et al. Multicentre comparison of a diagnostic assay: aquaporin-4 antibodies in neuromyelitis optica. J Neurol Neurosurg Psychiatry 2016, 87: 1005–1015.CrossRefGoogle Scholar
  8. 8.
    Sepulveda M, Armangue T, Martinez-Hernandez E, Arrambide G, Sola-Valls N, Sabater L, et al. Clinical spectrum associated with MOG autoimmunity in adults: significance of sharing rodent MOG epitopes. J Neurol 2016, 263: 1349–1360.CrossRefGoogle Scholar
  9. 9.
    Jarius S, Ruprecht K, Kleiter I, Borisow N, Asgari N, Pitarokoili K, et al. MOG-IgG in NMO and related disorders: a multicenter study of 50 patients. Part 2: Epidemiology, clinical presentation, radiological and laboratory features, treatment responses, and long-term outcome. J Neuroinflammation 2016, 13: 280.CrossRefGoogle Scholar
  10. 10.
    Yan Y, Li Y, Fu Y, Yang L, Su L, Shi K, et al. Autoantibody to MOG suggests two distinct clinical subtypes of NMOSD. Sci China Life Sci 2016, 59: 1270–1281.CrossRefGoogle Scholar
  11. 11.
    Haase CG, Guggenmos J, Brehm U, Andersson M, Olsson T, Reindl M, et al. The fine specificity of the myelin oligodendrocyte glycoprotein autoantibody response in patients with multiple sclerosis and normal healthy controls. J Neuroimmunol 2001, 114: 220–225.CrossRefGoogle Scholar
  12. 12.
    von Budingen HC, Hauser SL, Fuhrmann A, Nabavi CB, Lee JI, Genain CP. Molecular characterization of antibody specificities against myelin/oligodendrocyte glycoprotein in autoimmune demyelination. Proc Natl Acad Sci U S A 2002, 99: 8207–8212.CrossRefGoogle Scholar
  13. 13.
    Breithaupt C, Schubart A, Zander H, Skerra A, Huber R, Linington C, et al. Structural insights into the antigenicity of myelin oligodendrocyte glycoprotein. Proc Natl Acad Sci U S A 2003, 100: 9446–9451.CrossRefGoogle Scholar
  14. 14.
    von Budingen HC, Hauser SL, Ouallet JC, Tanuma N, Menge T, Genain CP. Frontline: Epitope recognition on the myelin/oligodendrocyte glycoprotein differentially influences disease phenotype and antibody effector functions in autoimmune demyelination. Eur J Immunol 2004, 34: 2072–2083.CrossRefGoogle Scholar
  15. 15.
    Brehm U, Piddlesden SJ, Gardinier MV, Linington C. Epitope specificity of demyelinating monoclonal autoantibodies directed against the human myelin oligodendrocyte glycoprotein (MOG). J Neuroimmunol 1999, 97: 9–15.CrossRefGoogle Scholar
  16. 16.
    Kitley J, Waters P, Woodhall M, Leite MI, Murchison A, George J, et al. Neuromyelitis optica spectrum disorders with aquaporin-4 and myelin-oligodendrocyte glycoprotein antibodies: a comparative study. JAMA Neurol 2014, 71: 276–283.CrossRefGoogle Scholar
  17. 17.
    Hyun JW, Woodhall MR, Kim SH, Jeong IH, Kong B, Kim G, et al. Longitudinal analysis of myelin oligodendrocyte glycoprotein antibodies in CNS inflammatory diseases. J Neurol Neurosurg Psychiatry 2017, 88: 811–817.CrossRefGoogle Scholar
  18. 18.
    Stiebel-Kalish H, Lotan I, Brody J, Chodick G, Bialer O, Marignier R, et al. Retinal nerve fiber layer may be better preserved in MOG-IgG versus AQP4-IgG optic neuritis: a cohort study. PLoS One 2017, 12: e170847.CrossRefGoogle Scholar
  19. 19.
    Pandit L, Nakashima I, Mustafa S, Takahashi T, Kaneko K. Anti Myelin Oligodendrocyte Glycoprotein associated Immunoglobulin G (AntiMOG-IgG)-associated neuromyelitis optica spectrum disorder with persistent disease activity and residual cognitive impairment. Ann Indian Acad Neurol 2017, 20: 411–413.CrossRefGoogle Scholar
  20. 20.
    Hamid S, Whittam D, Saviour M, Alorainy A, Mutch K, Linaker S, et al. Seizures and encephalitis in myelin oligodendrocyte glycoprotein IgG disease vs aquaporin 4 IgG disease. JAMA Neurol 2018, 75: 65–71.CrossRefGoogle Scholar
  21. 21.
    Zhou Y, Jia X, Yang H, Chen C, Sun X, Peng L, et al. Myelin oligodendrocyte glycoprotein (MOG) antibody-associated demyelination: comparison between onset phenotypes. Eur J Neurol 2018,26:175–183.CrossRefGoogle Scholar
  22. 22.
    Chen L, Chen C, Zhong X, Sun X, Zhu H, Li X, et al. Different features between pediatric-onset and adult-onset patients who are seropositive for MOG-IgG: A multicenter study in South China. J Neuroimmunol 2018, 321: 83–91.CrossRefGoogle Scholar
  23. 23.
    Kinoshita M, Nakatsuji Y, Kimura T, Moriya M, Takata K, Okuno T, et al. Neuromyelitis optica: passive transfer to rats by human immunoglobulin. Biochem Biophys Res Commun 2009, 386: 623–627.CrossRefGoogle Scholar
  24. 24.
    Linington C, Bradl M, Lassmann H, Brunner C, Vass K. Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 1988, 130: 443–454.Google Scholar
  25. 25.
    Piddlesden SJ, Lassmann H, Zimprich F, Morgan BP, Linington C. The demyelinating potential of antibodies to myelin oligodendrocyte glycoprotein is related to their ability to fix complement. Am J Pathol 1993, 143: 555–564.Google Scholar
  26. 26.
    Mayer MC, Breithaupt C, Reindl M, Schanda K, Rostasy K, Berger T, et al. Distinction and temporal stability of conformational epitopes on myelin oligodendrocyte glycoprotein recognized by patients with different inflammatory central nervous system diseases. J Immunol 2013, 191: 3594–3604.CrossRefGoogle Scholar
  27. 27.
    Marta CB, Oliver AR, Sweet RA, Pfeiffer SE, Ruddle NH. Pathogenic myelin oligodendrocyte glycoprotein antibodies recognize glycosylated epitopes and perturb oligodendrocyte physiology. Proc Natl Acad Sci U S A 2005, 102: 13992–13997.CrossRefGoogle Scholar
  28. 28.
    Saadoun S, Waters P, Owens GP, Bennett JL, Vincent A, Papadopoulos MC. Neuromyelitis optica MOG-IgG causes reversible lesions in mouse brain. Acta Neuropathol Commun 2014, 2: 35.CrossRefGoogle Scholar
  29. 29.
    Peschl P, Schanda K, Zeka B, Given K, Bohm D, Ruprecht K, et al. Human antibodies against the myelin oligodendrocyte glycoprotein can cause complement-dependent demyelination. J Neuroinflammation 2017, 14: 208.CrossRefGoogle Scholar
  30. 30.
    Weinshenker BG, Wingerchuk DM. Neuromyelitis spectrum disorders. Mayo Clin Proc 2017, 92: 663–679.CrossRefGoogle Scholar
  31. 31.
    Mader S, Gredler V, Schanda K, Rostasy K, Dujmovic I, Pfaller K, et al. Complement activating antibodies to myelin oligodendrocyte glycoprotein in neuromyelitis optica and related disorders. J Neuroinflammation 2011, 8: 184.CrossRefGoogle Scholar
  32. 32.
    Zhou D, Srivastava R, Nessler S, Grummel V, Sommer N, Bruck W, et al. Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci U S A 2006, 103: 19057–19062.CrossRefGoogle Scholar
  33. 33.
    Spadaro M, Winklmeier S, Beltran E, Macrini C, Hoftberger R, Schuh E, et al. Pathogenicity of human antibodies against myelin oligodendrocyte glycoprotein. Ann Neurol 2018, 84: 315–328.CrossRefGoogle Scholar
  34. 34.
    Ratelade J, Verkman AS. Inhibitor(s) of the classical complement pathway in mouse serum limit the utility of mice as experimental models of neuromyelitis optica. Mol Immunol 2014, 62: 104–113.CrossRefGoogle Scholar
  35. 35.
    Asavapanumas N, Ratelade J, Verkman AS. Unique neuromyelitis optica pathology produced in naive rats by intracerebral administration of NMO-IgG. Acta Neuropathol 2014, 127: 539–551.CrossRefGoogle Scholar
  36. 36.
    Asavapanumas N, Verkman AS. Neuromyelitis optica pathology in rats following intraperitoneal injection of NMO-IgG and intracerebral needle injury. Acta Neuropathol Commun 2014, 2: 48.CrossRefGoogle Scholar
  37. 37.
    Dale RC, Tantsis EM, Merheb V, Kumaran RY, Sinmaz N, Pathmanandavel K, et al. Antibodies to MOG have a demyelination phenotype and affect oligodendrocyte cytoskeleton. Neurol Neuroimmunol Neuroinflamm 2014, 1: e12.CrossRefGoogle Scholar
  38. 38.
    Mariotto S, Ferrari S, Monaco S, Benedetti MD, Schanda K, Alberti D, et al. Clinical spectrum and IgG subclass analysis of anti-myelin oligodendrocyte glycoprotein antibody-associated syndromes: a multicenter study. J Neurol 2017, 264: 2420–2430.CrossRefGoogle Scholar
  39. 39.
    Fang X, Sun D, Wang Z, Yu Z, Liu W, Pu Y, et al. MiR-30a positively regulates the inflammatory response of microglia in experimental autoimmune encephalomyelitis. Neurosci Bull 2017, 33: 603–615.CrossRefGoogle Scholar
  40. 40.
    Li AL, Zhang JD, Xie W, Strong JA, Zhang JM. Inflammatory changes in paravertebral sympathetic ganglia in two rat pain models. Neurosci Bull 2018, 34: 85–97.CrossRefGoogle Scholar
  41. 41.
    Tradtrantip L, Yao X, Su T, Smith AJ, Verkman AS. Bystander mechanism for complement-initiated early oligodendrocyte injury in neuromyelitis optica. Acta Neuropathol 2017, 134: 35–44.CrossRefGoogle Scholar
  42. 42.
    Weil M, Mobius W, Winkler A, Ruhwedel T, Wrzos C, Romanelli E, et al. Loss of myelin basic protein function triggers myelin breakdown in models of demyelinating diseases. Cell Reports 2016, 16: 314–322.Google Scholar

Copyright information

© Shanghai Institutes for Biological Sciences, CAS 2019

Authors and Affiliations

  • Ling Fang
    • 1
  • Xinmei Kang
    • 1
  • Zhen Wang
    • 2
    • 3
  • Shisi Wang
    • 1
  • Jingqi Wang
    • 1
  • Yifan Zhou
    • 1
  • Chen Chen
    • 1
  • Xiaobo Sun
    • 1
  • Yaping Yan
    • 3
  • Allan G. Kermode
    • 1
    • 4
  • Lisheng Peng
    • 1
    Email author
  • Wei Qiu
    • 1
    Email author
  1. 1.Department of NeurologyThe Third Affiliated Hospital of Sun Yat-sen UniversityGuangzhouChina
  2. 2.Department of Neurology, Xuanwu HospitalCapital Medical UniversityBeijingChina
  3. 3.Key Laboratory of the Ministry of Education for Medicinal Resources and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Development of Endangered Crude Drugs in Northwest China, College of Life SciencesShaanxi Normal UniversityXi’anChina
  4. 4.Department of Neurology, Centre for Neuromuscular and Neurological Disorders, Queen Elizabeth II Medical Centre, Sir Charles Gairdner HospitalUniversity of Western AustraliaPerthAustralia

Personalised recommendations