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Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions

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Abstract

Neuromyelitis optica (NMO) is a chronic, mostly relapsing inflammatory demyelinating disease of the CNS characterized by serum anti-aquaporin 4 (AQP4) antibodies in the majority of patients. Anti-AQP4 antibodies derived from NMO patients target and deplete astrocytes in experimental models when co-injected with complement. However, the time course and mechanisms of oligodendrocyte loss and demyelination and the fate of oligodendrocyte precursor cells (OPC) have not been examined in detail. Also, no studies regarding astrocyte repopulation of experimental NMO lesions have been reported. We utilized two rat models using either systemic transfer or focal intracerebral injection of recombinant human anti-AQP4 antibodies to generate NMO-like lesions. Time-course experiments were performed to examine oligodendroglial and astroglial damage and repair. In addition, oligodendrocyte pathology was studied in early human NMO lesions. Apart from early complement-mediated astrocyte destruction, we observed a prominent, very early loss of oligodendrocytes and oligodendrocyte precursor cells (OPCs) as well as a delayed loss of myelin. Astrocyte repopulation of focal NMO lesions was already substantial after 1 week. Olig2-positive OPCs reappeared before NogoA-positive, mature oligodendrocytes. Thus, using two experimental models that closely mimic the human disease, our study demonstrates that oligodendrocyte and OPC loss is an extremely early feature in the formation of human and experimental NMO lesions and leads to subsequent, delayed demyelination, highlighting an important difference in the pathogenesis of MS and NMO.

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References

  1. Bennett JL, Lam C, Kalluri SR, Saikali P, Bautista K, Dupree C, Glogowska M, Case D, Antel JP, Owens GP, Gilden D, Nessler S, Stadelmann C, Hemmer B (2009) Intrathecal pathogenic anti-aquaporin-4 antibodies in early neuromyelitis optica. Ann Neurol 66(5):617–629. doi:10.1002/ana.21802

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Blakemore WF, Gilson JM, Crang AJ (2003) The presence of astrocytes in areas of demyelination influences remyelination following transplantation of oligodendrocyte progenitors. Exp Neurol 184(2):955–963. doi:10.1016/S0014-4886(03)00347-9

    Article  PubMed  Google Scholar 

  3. Bradl M, Misu T, Takahashi T, Watanabe M, Mader S, Reindl M, Adzemovic M, Bauer J, Berger T, Fujihara K, Itoyama Y, Lassmann H (2009) Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo. Ann Neurol 66(5):630–643. doi:10.1002/ana.21837

    Article  CAS  PubMed  Google Scholar 

  4. Bruck W, Popescu B, Lucchinetti CF, Markovic-Plese S, Gold R, Thal DR, Metz I (2012) Neuromyelitis optica lesions may inform multiple sclerosis heterogeneity debate. Ann Neurol 72(3):385–394. doi:10.1002/ana.23621

    Article  PubMed  Google Scholar 

  5. Furman CS, Gorelick-Feldman DA, Davidson KG, Yasumura T, Neely JD, Agre P, Rash JE (2003) Aquaporin-4 square array assembly: opposing actions of M1 and M23 isoforms. Proc Natl Acad Sci USA 100(23):13609–13614. doi:10.1073/pnas.2235843100

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  6. 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(24):2221–2231. doi:10.1212/01.WNL.0000289761.64862.ce

    Article  CAS  PubMed  Google Scholar 

  7. Hinson SR, Roemer SF, Lucchinetti CF, Fryer JP, Kryzer TJ, Chamberlain JL, Howe CL, Pittock SJ, Lennon VA (2008) Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2. J Exp Med 205(11):2473–2481. doi:10.1084/jem.20081241

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  8. Hinson SR, Romero MF, Popescu BF, Lucchinetti CF, Fryer JP, Wolburg H, Fallier-Becker P, Noell S, Lennon VA (2012) Molecular outcomes of neuromyelitis optica (NMO)-IgG binding to aquaporin-4 in astrocytes. Proc Natl Acad Sci USA 109(4):1245–1250. doi:10.1073/pnas.1109980108

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, Lang W, Reindl M, Vincent A, Kristoferitsch W (2008) Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain 131(Pt 11):3072–3080. doi:10.1093/brain/awn240

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  10. Kalluri SR, Rothhammer V, Staszewski O, Srivastava R, Petermann F, Prinz M, Hemmer B, Korn T (2011) Functional characterization of aquaporin-4 specific T cells: towards a model for neuromyelitis optica. PLoS ONE 6(1):e16083. doi:10.1371/journal.pone.0016083

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Kinoshita M, Nakatsuji Y, Kimura T, Moriya M, Takata K, Okuno T, Kumanogoh A, Kajiyama K, Yoshikawa H, Sakoda S (2009) Neuromyelitis optica: passive transfer to rats by human immunoglobulin. Biochem Biophys Res Commun 386(4):623–627. doi:10.1016/j.bbrc.2009.06.085

    Article  CAS  PubMed  Google Scholar 

  12. 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(4):473–477. doi:10.1084/jem.20050304

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Lennon VA, Wingerchuk DM, Kryzer TJ, Pittock SJ, Lucchinetti CF, Fujihara K, Nakashima I, Weinshenker BG (2004) A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet 364(9451):2106–2112. doi:10.1016/S0140-6736(04)17551-X

    Article  CAS  PubMed  Google Scholar 

  14. Linington C, Berger T, Perry L, Weerth S, Hinze-Selch D, Zhang Y, Lu HC, Lassmann H, Wekerle H (1993) T cells specific for the myelin oligodendrocyte glycoprotein mediate an unusual autoimmune inflammatory response in the central nervous system. Eur J Immunol 23(6):1364–1372. doi:10.1002/eji.1830230627

    Article  CAS  PubMed  Google Scholar 

  15. Linington C, Bradl M, Lassmann H, Brunner C, Vass K (1988) Augmentation of demyelination in rat acute allergic encephalomyelitis by circulating mouse monoclonal antibodies directed against a myelin/oligodendrocyte glycoprotein. Am J Pathol 130(3):443–454

    CAS  PubMed Central  PubMed  Google Scholar 

  16. Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H (2002) A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain 125(Pt 7):1450–1461

    Article  PubMed  Google Scholar 

  17. Mandler RN, Davis LE, Jeffery DR, Kornfeld M (1993) Devic’s neuromyelitis optica: a clinicopathological study of 8 patients. Ann Neurol 34(2):162–168. doi:10.1002/ana.410340211

    Article  CAS  PubMed  Google Scholar 

  18. Marignier R, Nicolle A, Watrin C, Touret M, Cavagna S, Varrin-Doyer M, Cavillon G, Rogemond V, Confavreux C, Honnorat J, Giraudon P (2010) Oligodendrocytes are damaged by neuromyelitis optica immunoglobulin G via astrocyte injury. Brain 133(9):2578–2591. doi:10.1093/brain/awq177

    Article  PubMed  Google Scholar 

  19. Matthieu JM, Waehneldt TV, Eschmann N (1986) Myelin-associated glycoprotein and myelin basic protein are present in central and peripheral nerve myelin throughout phylogeny. Neurochem Int 8(4):521–526 pii:0197-0186(86)90186-5

    Article  CAS  PubMed  Google Scholar 

  20. Merkler D, Boretius S, Stadelmann C, Ernsting T, Michaelis T, Frahm J, Bruck W (2005) Multicontrast MRI of remyelination in the central nervous system. NMR Biomed 18(6):395–403. doi:10.1002/nbm.972

    Article  PubMed  Google Scholar 

  21. Merkler D, Ernsting T, Kerschensteiner M, Bruck W, Stadelmann C (2006) A new focal EAE model of cortical demyelination: multiple sclerosis-like lesions with rapid resolution of inflammation and extensive remyelination. Brain 129(Pt 8):1972–1983. doi:10.1093/brain/awl135

    Article  PubMed  Google Scholar 

  22. Misu T, Fujihara K, Itoyama Y (2008) Neuromyelitis optica and anti-aquaporin 4 antibody—an overview. Brain Nerve 60(5):527–537

    CAS  PubMed  Google Scholar 

  23. Misu T, Fujihara K, Kakita A, Konno H, Nakamura M, Watanabe S, Takahashi T, Nakashima I, Takahashi H, Itoyama Y (2007) Loss of aquaporin 4 in lesions of neuromyelitis optica: distinction from multiple sclerosis. Brain 130(Pt 5):1224–1234. doi:10.1093/brain/awm047

    Article  CAS  PubMed  Google Scholar 

  24. Nelson PA, Khodadoust M, Prodhomme T, Spencer C, Patarroyo JC, Varrin-Doyer M, Ho JD, Stroud RM, Zamvil SS (2010) Immunodominant T cell determinants of aquaporin-4, the autoantigen associated with neuromyelitis optica. PLoS ONE 5(11):e15050. doi:10.1371/journal.pone.0015050

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Oertle T, van der Haar ME, Bandtlow CE, Robeva A, Burfeind P, Buss A, Huber AB, Simonen M, Schnell L, Brosamle C, Kaupmann K, Vallon R, Schwab ME (2003) Nogo-A inhibits neurite outgrowth and cell spreading with three discrete regions. J Neurosci 23(13):5393–5406. pii:23/13/5393

    CAS  PubMed  Google Scholar 

  26. Parratt JD, Prineas JW (2010) Neuromyelitis optica: a demyelinating disease characterized by acute destruction and regeneration of perivascular astrocytes. Mult Scler 16(10):1156–1172. doi:10.1177/1352458510382324

    Article  PubMed  Google Scholar 

  27. Pohl M, Fischer MT, Mader S, Schanda K, Kitic M, Sharma R, Wimmer I, Misu T, Fujihara K, Reindl M, Lassmann H, Bradl M (2011) Pathogenic T cell responses against aquaporin 4. Acta Neuropathol 122(1):21–34. doi:10.1007/s00401-011-0824-0

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Rash JE, Davidson KG, Yasumura T, Furman CS (2004) Freeze-fracture and immunogold analysis of aquaporin-4 (AQP4) square arrays, with models of AQP4 lattice assembly. Neuroscience 129(4):915–934. doi:10.1016/j.neuroscience.2004.06.076

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  29. Ratelade J, Asavapanumas N, Ritchie AM, Wemlinger S, Bennett JL, Verkman AS (2013) Involvement of antibody-dependent cell-mediated cytotoxicity in inflammatory demyelination in a mouse model of neuromyelitis optica. Acta Neuropathol 126(5):699–709. doi:10.1007/s00401-013-1172-z

    Google Scholar 

  30. Ratelade J, Bennett JL, Verkman AS (2011) Evidence against cellular internalization in vivo of NMO-IgG, aquaporin-4, and excitatory amino acid transporter 2 in neuromyelitis optica. J Biol Chem 286(52):45156–45164. doi:10.1074/jbc.M111.297275

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Ratelade J, Zhang H, Saadoun S, Bennett JL, Papadopoulos MC, Verkman AS (2012) Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss. Acta Neuropathol 123(6):861–872. doi:10.1007/s00401-012-0986-4

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Roemer SF, Parisi JE, Lennon VA, Benarroch EE, Lassmann H, Bruck W, Mandler RN, Weinshenker BG, Pittock SJ, Wingerchuk DM, Lucchinetti CF (2007) Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis. Brain 130(Pt 5):1194–1205. doi:10.1093/brain/awl371

    Article  PubMed  Google Scholar 

  33. Rossi A, Ratelade J, Papadopoulos MC, Bennett JL, Verkman AS (2012) Neuromyelitis optica IgG does not alter aquaporin-4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly. Glia 60(12):2027–2039. doi:10.1002/glia.22417

    Article  PubMed Central  PubMed  Google Scholar 

  34. Saadoun S, Bridges LR, Verkman AS, Papadopoulos MC (2012) Paucity of natural killer and cytotoxic T cells in human neuromyelitis optica lesions. NeuroReport 23(18):1044–1047. doi:10.1097/WNR.0b013e32835ab480

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  35. Saadoun S, Waters P, Bell BA, Vincent A, Verkman AS, Papadopoulos MC (2010) Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice. Brain 133(Pt 2):349–361. doi:10.1093/brain/awp309

    Article  PubMed Central  PubMed  Google Scholar 

  36. Sharma R, Fischer MT, Bauer J, Felts PA, Smith KJ, Misu T, Fujihara K, Bradl M, Lassmann H (2010) Inflammation induced by innate immunity in the central nervous system leads to primary astrocyte dysfunction followed by demyelination. Acta Neuropathol 120(2):223–236. doi:10.1007/s00401-010-0704-z

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Takahashi T, Fujihara K, Nakashima I, Misu T, Miyazawa I, Nakamura M, Watanabe S, Shiga Y, Kanaoka C, Fujimori J, Sato S, Itoyama Y (2007) Anti-aquaporin-4 antibody is involved in the pathogenesis of NMO: a study on antibody titre. Brain 130(Pt 5):1235–1243. doi:10.1093/brain/awm062

    Article  PubMed  Google Scholar 

  38. Tradtrantip L, Zhang H, Saadoun S, Phuan PW, Lam C, Papadopoulos MC, Bennett JL, Verkman AS (2012) Anti-aquaporin-4 monoclonal antibody blocker therapy for neuromyelitis optica. Ann Neurol 71(3):314–322. doi:10.1002/ana.22657

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  39. Varrin-Doyer M, Spencer CM, Schulze-Topphoff U, Nelson PA, Stroud RM, Cree BA, Zamvil SS (2012) Aquaporin 4-specific T cells in neuromyelitis optica exhibit a Th17 bias and recognize Clostridium ABC transporter. Ann Neurol 72(1):53–64. doi:10.1002/ana.23651

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Waters P, Jarius S, Littleton E, Leite MI, Jacob S, Gray B, Geraldes R, Vale T, Jacob A, Palace J, Maxwell S, Beeson D, Vincent A (2008) Aquaporin-4 antibodies in neuromyelitis optica and longitudinally extensive transverse myelitis. Arch Neurol 65(7):913–919. doi:10.1001/archneur.65.7.913

    Article  PubMed  Google Scholar 

  41. Waters PJ, McKeon A, Leite MI, Rajasekharan S, Lennon VA, Villalobos A, Palace J, Mandrekar JN, Vincent A, Bar-Or A, Pittock SJ (2012) Serologic diagnosis of NMO: a multicenter comparison of aquaporin-4-IgG assays. Neurology 78(9):665–671. doi:10.1212/WNL.0b013e318248dec1 (discussion 669)

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Weissert R, Svenningsson A, Lobell A, de Graaf KL, Andersson R, Olsson T (1998) Molecular and genetic requirements for preferential recruitment of TCRBV8S2+ T cells in Lewis rat experimental autoimmune encephalomyelitis. J Immunol 160(2):681–690

    CAS  PubMed  Google Scholar 

  43. Wolburg H, Wolburg-Buchholz K, Fallier-Becker P, Noell S, Mack AF (2011) Structure and functions of aquaporin-4-based orthogonal arrays of particles. Int Rev Cell Mol Biol 287:1–41. doi:10.1016/B978-0-12-386043-9.00001-3

    Article  CAS  PubMed  Google Scholar 

  44. Zhang H, Verkman AS (2013) Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica. J Clin Invest 123(5):2306–2316. doi:10.1172/JCI67554

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Zhou D, Srivastava R, Nessler S, Grummel V, Sommer N, Bruck W, Hartung HP, Stadelmann C, Hemmer B (2006) Identification of a pathogenic antibody response to native myelin oligodendrocyte glycoprotein in multiple sclerosis. Proc Natl Acad Sci USA 103(50):19057–19062. doi:10.1073/pnas.0607242103

    Article  CAS  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We acknowledge the excellent technical support by Brigitte Maruschak, Jasmin Reichl, Katja Schulz, Angela Dettmar, Heidi Brodmerkel, Olga Kowatsch and Uta Scheidt and thank Christine Crozier and Cynthia Bunker for their help with language editing. C.S. and W.B. were supported by the DFG (TR-SFB43 “The brain as a target of inflammatory processes”). J.L.B. was supported by grants from the Guthy-Jackson Foundation and the National Institutes of Health (EY022936). We are indebted to our patients and their relatives.

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The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Institute of Neuropathology, University Medical Centre Göttingen, Robert-Koch-Str. 40, 37099, Göttingen, Germany

    Claudia Wrzos, Anne Winkler, Imke Metz, Christiane Wegner, Wolfgang Brück, Stefan Nessler & Christine Stadelmann

  2. Institute of Pathology, Städtisches Klinikum Görlitz, Görlitz, Germany

    Dieter M. Kayser

  3. Institute of Pathology/Laboratory for Neuropathology, University of Ulm, Ulm, Germany

    Dietmar R. Thal

  4. Departments of Neurology and Ophthalmology, University of Denver, Colorado, USA

    Jeffrey L. Bennett

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  1. Claudia Wrzos
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  2. Anne Winkler
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Correspondence to Christine Stadelmann.

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401_2013_1220_MOESM1_ESM.tif

Supplementary Figure 1: Perivenous parenchymal and inflammatory pathology in NMO and ctrl rAb-injected rats after EAE induction. 30 h after i.v. transfer of ctrl rAb into rats with gpMBP72-85-EAE no loss of astrocytic proteins is observed (a: AQP4, b: GFAP, c: S100β, d: EAAT2). In contrast, rats injected with NMO rAb show a well delineated perivenous loss of astrocytes (i: AQP4, j: GFAP, k: S100b, l: EAAT2). Additionally, ctrl rAb-transferred rats do not show the altered myelin staining (e: LFB/PAS) which is observed in NMO rAb-transferred animals (m). Obvious axonal loss is not a feature in either experimental group (h, p: Bielschowsky silver impregnation). However, T cell (f, n: CD3) and macrophage infiltration (g, o: ED1) is prominent also in ctrl rAb-injected rats due to immunization with gp MBP72-85. Foamy phagocytes are, however, predominantly observed in NMO rAb-injected rats. Note that EAAT2 is barely expressed in WM. Scale bars: 200 μm (TIFF 30863 kb)

401_2013_1220_MOESM2_ESM.tif

Supplementary Figure 2: Time course of early myelin damage in focal NMO. 24 h after focal injection of NMO rAb MBP IHC (a) appears pale whereas MAG (d), MOG (g), CNP (j) and PLP (m) are focally reduced, but largely preserved. 3 days after lesion induction MBP (b) and MAG (e) immunoreactivity has almost disappeared, whereas MOG (h), CNP (k) and PLP (n) are still reasonably preserved. After one week, myelin cannot be seen using MBP (c), MAG (f) and CNP (l) IHC, whereas MOG (i) and PLP (o) IHC still detect myelin sheaths in the lesion. Monastral blue marks the injection site. Scale bar: 100 μm (a-o) (TIFF 27921 kb)

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Wrzos, C., Winkler, A., Metz, I. et al. Early loss of oligodendrocytes in human and experimental neuromyelitis optica lesions. Acta Neuropathol 127, 523–538 (2014). https://doi.org/10.1007/s00401-013-1220-8

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