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Unique neuromyelitis optica pathology produced in naïve rats by intracerebral administration of NMO-IgG

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Abstract

Animal models of neuromyelitis optica (NMO) are needed for elucidation of disease mechanisms and for testing new therapeutics. Prior animal models of NMO involved administration of human anti-aquaporin-4 immunoglobulin G antibody (NMO-IgG) to rats with pre-existing neuroinflammation, or to naïve mice supplemented with human complement. We report here the development of NMO pathology following passive transfer of NMO-IgG to naïve rats. A single intracerebral infusion of NMO-IgG to adult Lewis rats produced robust lesions around the needle track in 100 % of rats; at 5 days there was marked loss of aquaporin-4 (AQP4), glial fibrillary acidic protein (GFAP) and myelin, granulocyte and macrophage infiltration, vasculocentric complement deposition, blood–brain barrier disruption, microglial activation and neuron death. Remarkably, a distinct ‘penumbra’ was seen around lesions, with loss of AQP4 but not of GFAP or myelin. No lesions or penumbra were seen in rats receiving control IgG. The size of the main lesion with loss of myelin was greatly reduced in rats made complement-deficient by cobra venom factor or administered NMO-IgG lacking complement-dependent cytotoxicity (CDC) effector function. However, the penumbra was seen under these conditions, suggesting a complement-independent pathogenesis mechanism. The penumbra was absent with NMO-IgG lacking both CDC and antibody-dependent cellular cytotoxicity (ADCC) effector functions. Finally, lesion size was significantly reduced after macrophage depletion with clodronate liposomes. These results: (i) establish a robust, passive-transfer model of NMO in rats that does not require pre-existing neuroinflammation or complement administration; (ii) implicate ADCC as responsible for a unique type of pathology also seen in human NMO; and (iii) support a pathogenic role of macrophages in NMO.

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Abbreviations

ADCC:

Antibody-dependent cellular cytotoxicity

AQP4:

Aquaporin-4

CDC:

Complement-dependent cytotoxicity

CDCC:

Complement-dependent cell-mediated cytotoxicity

EAE:

Experimental autoimmune encephalomyelitis

GFAP:

Glial fibrillary acidic protein

MBP:

Myelin basic protein

NMO:

Neuromyelitis optica

NMO-IgG:

Neuromyelitis optica immunoglobulin G antibody

WGA:

Wheat germ agglutinin

References

  1. Aoyama M, Kakita H, Kato S, Tomita M, Asai K (2012) Region-specific expression of a water channel protein, aquaporin 4, on brain astrocytes. J Neurosci Res 90(12):2272–2280. doi:10.1002/jnr.23117

    Article  CAS  PubMed  Google Scholar 

  2. 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 

  3. Bergman I, Basse PH, Barmada MA, Griffin JA, Cheung NK (2000) Comparison of in vitro antibody-targeted cytotoxicity using mouse, rat and human effectors. Cancer Immunol Immunother 49(4–5):259–266

    Article  CAS  PubMed  Google Scholar 

  4. Bodega G, Suarez I, Lopez-Fernandez LA, Almonacid L, Zaballos A, Fernandez B (2006) Possible implication of ciliary neurotrophic factor (CNTF) and beta-synuclein in the ammonia effect on cultured rat astroglial cells: a study using DNA and protein microarrays. Neurochem Int 48(8):729–738. doi:S0197-0186(06)00004-0

    Article  CAS  PubMed  Google Scholar 

  5. Bush TG, Puvanachandra N, Horner CH, Polito A, Ostenfeld T, Svendsen CN, Mucke L, Johnson MH, Sofroniew MV (1999) Leukocyte infiltration, neuronal degeneration, and neurite outgrowth after ablation of scar-forming, reactive astrocytes in adult transgenic mice. Neuron 23(2):297–308

    Article  CAS  PubMed  Google Scholar 

  6. Crane JM, Lam C, Rossi A, Gupta T, Bennett JL, Verkman AS (2011) Binding affinity and specificity of neuromyelitis optica autoantibodies to aquaporin-4 M1/M23 isoforms and orthogonal arrays. J Biol Chem 286(18):16516–16524. doi:10.1074/jbc.M111.227298

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Faulkner JR, Herrmann JE, Woo MJ, Tansey KE, Doan NB, Sofroniew MV (2004) Reactive astrocytes protect tissue and preserve function after spinal cord injury. J Neurosci 24(9):2143–2155. doi:10.1523/JNEUROSCI.3547-03.2004

    Article  CAS  PubMed  Google Scholar 

  8. Frigeri A, Gropper MA, Turck CW, Verkman AS (1995) Immunolocalization of the mercurial-insensitive water channel and glycerol intrinsic protein in epithelial cell plasma membranes. Proc Natl Acad Sci USA 92(10):4328–4331

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Frigeri A, Gropper MA, Umenishi F, Kawashima M, Brown D, Verkman AS (1995) Localization of MIWC and GLIP water channel homologs in neuromuscular, epithelial and glandular tissues. J Cell Sci 108(Pt 9):2993–3002

    CAS  PubMed  Google Scholar 

  10. 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:01.WNL.0000289761.64862.ce

    Article  CAS  PubMed  Google Scholar 

  11. Jacob A, McKeon A, Nakashima I, Sato DK, Elsone L, Fujihara K, de Seze J (2013) Current concept of neuromyelitis optica (NMO) and NMO spectrum disorders. J Neurol Neurosurg Psychiatry 84(8):922–930. doi:10.1136/jnnp-2012-302310

    Article  PubMed  Google Scholar 

  12. Jarius S, Paul F, Franciotta D, Waters P, Zipp F, Hohlfeld R, Vincent A, Wildemann B (2008) Mechanisms of disease: aquaporin-4 antibodies in neuromyelitis optica. Nat Clin Pract Neurol 4(4):202–214. doi:10.1038/ncpneuro0764

    CAS  PubMed  Google Scholar 

  13. Jarius S, Wildemann B (2010) AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 6(7):383–392. doi:10.1038/nrneurol.2010.72

    Article  CAS  PubMed  Google Scholar 

  14. Kigerl KA, Gensel JC, Ankeny DP, Alexander JK, Donnelly DJ, Popovich PG (2009) Identification of two distinct macrophage subsets with divergent effects causing either neurotoxicity or regeneration in the injured mouse spinal cord. J Neurosci 29(43):13435–13444. doi:10.1523/JNEUROSCI.3257-09.2009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. 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 

  16. Kinoshita M, Nakatsuji Y, Kimura T, Moriya M, Takata K, Okuno T, Kumanogoh A, Kajiyama K, Yoshikawa H, Sakoda S (2010) Anti-aquaporin-4 antibody induces astrocytic cytotoxicity in the absence of CNS antigen-specific T cells. Biochem Biophys Res Commun 394(1):205–210. doi:10.1016/j.bbrc.2010.02.157

    Article  CAS  PubMed  Google Scholar 

  17. Kira J (2011) Autoimmunity in neuromyelitis optica and opticospinal multiple sclerosis: astrocytopathy as a common denominator in demyelinating disorders. J Neurol Sci 311(1–2):69–77. doi:10.1016/j.jns.2011.08.043

    Article  CAS  PubMed  Google Scholar 

  18. Klos A, Tenner AJ, Johswich KO, Ager RR, Reis ES, Kohl J (2009) The role of the anaphylatoxins in health and disease. Mol Immunol 46(14):2753–2766. doi:10.1016/j.molimm.2009.04.027

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. 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:jem.20050304

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Levin ME, Jin JG, Ji RR, Tong J, Pomonis JD, Lavery DJ, Miller SW, Chiang LW (2008) Complement activation in the peripheral nervous system following the spinal nerve ligation model of neuropathic pain. Pain 137(1):182–201. doi:S0304-3959(07)00672-0

    Article  CAS  PubMed  Google Scholar 

  21. 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 

  22. Machnik A, Neuhofer W, Jantsch J, Dahlmann A, Tammela T, Machura K, Park JK, Beck FX, Muller DN, Derer W, Goss J, Ziomber A, Dietsch P, Wagner H, van Rooijen N, Kurtz A, Hilgers KF, Alitalo K, Eckardt KU, Luft FC, Kerjaschki D, Titze J (2009) Macrophages regulate salt-dependent volume and blood pressure by a vascular endothelial growth factor-C-dependent buffering mechanism. Nat Med 15(5):545–552. doi:10.1038/nm.1960

    Article  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:awm047

    Article  CAS  PubMed  Google Scholar 

  24. Misu T, Hoftberger R, Fujihara K, Wimmer I, Takai Y, Nishiyama S, Nakashima I, Konno H, Bradl M, Garzuly F, Itoyama Y, Aoki M, Lassmann H (2013) Presence of six different lesion types suggests diverse mechanisms of tissue injury in neuromyelitis optica. Acta Neuropathol 125(6):815–827. doi:10.1007/s00401-013-1116-7

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Nielsen S, Nagelhus EA, Amiry-Moghaddam M, Bourque C, Agre P, Ottersen OP (1997) Specialized membrane domains for water transport in glial cells: high-resolution immunogold cytochemistry of aquaporin-4 in rat brain. J Neurosci 17(1):171–180

    CAS  PubMed  Google Scholar 

  26. Papadopoulos MC, Verkman AS (2012) Aquaporin 4 and neuromyelitis optica. Lancet Neurol 11(6):535–544. doi:10.1016/S1474-4422(12)70133-3

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14(4):265–277. doi:10.1038/nrn3468

    Article  CAS  PubMed  Google Scholar 

  28. Phuan PW, Ratelade J, Rossi A, Tradtrantip L, Verkman AS (2012) Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 protein assembly in orthogonal arrays. J Biol Chem 287(17):13829–13839. doi:10.1074/jbc.M112.344325

    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, Bennett JL, Verkman AS (2011) Intravenous neuromyelitis optica autoantibody in mice targets aquaporin-4 in peripheral organs and area postrema. PLoS ONE 6(11):e27412. doi:10.1371/journal.pone.0027412

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. 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 

  33. 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:awl371

    Article  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. Saadoun S, Waters P, MacDonald C, Bell BA, Vincent A, Verkman AS, Papadopoulos MC (2012) Neutrophil protease inhibition reduces neuromyelitis optica-immunoglobulin G-induced damage in mouse brain. Ann Neurol 71(3):323–333. doi:10.1002/ana.22686

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  37. Saadoun S, Waters P, Macdonald C, Bridges LR, Bell BA, Vincent A, Verkman AS, Papadopoulos MC (2011) T cell deficiency does not reduce lesions in mice produced by intracerebral injection of NMO-IgG and complement. J Neuroimmunol 235(1–2):27–32. doi:10.1016/j.jneuroim.2011.03.007

    Article  CAS  PubMed  Google Scholar 

  38. Schlesinger LS, Horwitz MA (1991) Phagocytosis of Mycobacterium leprae by human monocyte-derived macrophages is mediated by complement receptors CR1 (CD35), CR3 (CD11b/CD18), and CR4 (CD11c/CD18) and IFN-gamma activation inhibits complement receptor function and phagocytosis of this bacterium. J Immunol 147(6):1983–1994

    CAS  PubMed  Google Scholar 

  39. Tradtrantip L, Asavapanumas N, Verkman AS (2013) Therapeutic cleavage of anti-aquaporin-4 autoantibody in neuromyelitis optica by an IgG-selective proteinase. Mol Pharmacol 83(6):1268–1275. doi:10.1124/mol.113.086470

    Article  CAS  PubMed  Google Scholar 

  40. Tradtrantip L, Ratelade J, Zhang H, Verkman AS (2013) Enzymatic deglycosylation converts pathogenic neuromyelitis optica anti-aquaporin-4 immunoglobulin G into therapeutic antibody. Ann Neurol 73(1):77–85. doi:10.1002/ana.23741

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  41. 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 

  42. Van Rooijen N, Sanders A (1994) Liposome mediated depletion of macrophages: mechanism of action, preparation of liposomes and applications. J Immunol Meth 174(1–2):83–93

    Article  Google Scholar 

  43. Vogel CW, Fritzinger DC (2010) Cobra venom factor: structure, function, and humanization for therapeutic complement depletion. Toxicon 56(7):1198–1222. doi:10.1016/j.toxicon.2010.04.007

    Article  CAS  PubMed  Google Scholar 

  44. Voskuhl RR, Peterson RS, Song B, Ao Y, Morales LB, Tiwari-Woodruff S, Sofroniew MV (2009) Reactive astrocytes form scar-like perivascular barriers to leukocytes during adaptive immune inflammation of the CNS. J Neurosci 29(37):11511–11522. doi:10.1523/JNEUROSCI.1514-09.2009

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  45. Wanner IB, Anderson MA, Song B, Levine J, Fernandez A, Gray-Thompson Z, Ao Y, Sofroniew MV (2013) Glial scar borders are formed by newly proliferated, elongated astrocytes that interact to corral inflammatory and fibrotic cells via STAT3-dependent mechanisms after spinal cord injury. J Neurosci 33(31):12870–12886. doi:10.1523/JNEUROSCI.2121-13.2013

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6(9):805–815. doi:S1474-4422(07)70216-8

    Article  CAS  PubMed  Google Scholar 

  47. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG (2006) Revised diagnostic criteria for neuromyelitis optica. Neurology 66(10):1485–1489

    Article  CAS  PubMed  Google Scholar 

  48. Zhang H, Bennett JL, Verkman AS (2011) Ex vivo spinal cord slice model of neuromyelitis optica reveals novel immunopathogenic mechanisms. Ann Neurol 70(6):943–954. doi:10.1002/ana.22551

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  49. 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 

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Acknowledgments

This work was supported by grants EY13574, EB00415, DK35124, HL73856, DK86125 and DK72517 from the National Institutes of Health, and a grant from the Guthy-Jackson Charitable Foundation. We thank Dr. Jeffrey Bennett (Univ. Colorado Denver, Aurora, CO) for providing recombinant monoclonal NMO antibody and for Accelerated Cure (Waltham, MA) for providing human NMO sera.

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Correspondence to A. S. Verkman.

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Asavapanumas, N., Ratelade, J. & Verkman, A.S. Unique neuromyelitis optica pathology produced in naïve rats by intracerebral administration of NMO-IgG. Acta Neuropathol 127, 539–551 (2014). https://doi.org/10.1007/s00401-013-1204-8

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