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Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss

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Abstract

The pathogenesis of neuromyelitis optica (NMO) involves targeting of NMO-immunoglobulin G (NMO-IgG) to aquaporin-4 (AQP4) on astrocytes in the central nervous system. Prior work provided evidence for complement-dependent cytotoxicity (CDC) in NMO lesion development. Here, we show that antibody-dependent cellular cytotoxicity (ADCC), in the absence of complement, can also produce NMO-like lesions. Antibody-dependent cellular cytotoxicity was produced in vitro by incubation of mouse astrocyte cultures with human recombinant monoclonal NMO-IgG and human natural killer cells (NK-cells). Injection of NMO-IgG and NK-cells in mouse brain caused loss of AQP4 and GFAP, two characteristic features of NMO lesions, but little myelin loss. Lesions were minimal or absent following injection of: (1) control (non-NMO) IgG with NK-cells; (2) NMO-IgG and NK-cells in AQP4-deficient mice; or (3) NMO-IgG and NK-cells in wild-type mice together with an excess of mutated NMO-IgG lacking ADCC effector function. NK-cells greatly exacerbated NMO lesions produced by NMO-IgG and complement in an ex vivo spinal cord slice model of NMO, causing marked myelin loss. NMO-IgG can thus produce astrocyte injury by ADCC in a complement-independent and dependent manner, suggesting the potential involvement of ADCC in NMO pathogenesis.

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References

  1. Alderson KL, Sondel PM (2011) Clinical cancer therapy by NK cells via antibody-dependent cell-mediated cytotoxicity. J Biomed Biotechnol 2011:379123

    Article  PubMed  Google Scholar 

  2. Becknell B, Caligiuri MA (2008) Natural killer cells in innate immunity and cancer. J Immunother 31(8):685–692

    Article  PubMed  Google Scholar 

  3. 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

    Article  PubMed  CAS  Google Scholar 

  4. Burgoon MP, Williamson RA, Owens GP, Ghausi O, Bastidas RB, Burton DR, Gilden DH (1999) Cloning the antibody response in humans with inflammatory CNS disease: isolation of measles virus-specific antibodies from phage display libraries of a subacute sclerosing panencephalitis brain. J Neuroimmunol 94(1–2):204–211

    Article  PubMed  CAS  Google Scholar 

  5. Capel PJ, van de Winkel JG, van den Herik-Oudijk IE, Verbeek JS (1994) Heterogeneity of human IgG Fc receptors. Immunomethods 4(1):25–34

    Article  PubMed  CAS  Google Scholar 

  6. Chiorean EG, Miller JS (2001) The biology of natural killer cells and implications for therapy of human disease. J Hematother Stem Cell Res 10(4):451–463

    Article  PubMed  CAS  Google Scholar 

  7. Crane JM, Verkman AS (2009) Determinants of aquaporin-4 assembly in orthogonal arrays revealed by live-cell single-molecule fluorescence imaging. J Cell Sci 122(Pt 6):813–821

    Article  PubMed  CAS  Google Scholar 

  8. Diamond B, Huerta PT, Mina-Osorio P, Kowal C, Volpe BT (2009) Losing your nerves? Maybe it’s the antibodies. Nat Rev Immunol 9(6):449–456

    Article  PubMed  CAS  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

    PubMed  CAS  Google Scholar 

  10. Hinson SR, McKeon A, Fryer JP, Apiwattanakul M, Lennon VA, Pittock SJ (2009) Prediction of neuromyelitis optica attack severity by quantitation of complement-mediated injury to aquaporin-4-expressing cells. Arch Neurol 66(9):1164–1167

    Article  PubMed  Google Scholar 

  11. Hinson SR, McKeon A, Lennon VA (2010) Neurological autoimmunity targeting aquaporin-4. Neuroscience 168(4):1009–1018

    Article  PubMed  CAS  Google Scholar 

  12. 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

    Article  PubMed  CAS  Google Scholar 

  13. Hubert P, Heitzmann A, Viel S, Nicolas A, Sastre-Garau X, Oppezzo P, Pritsch O, Osinaga E, Amigorena S (2011) Antibody-dependent cell cytotoxicity synapses form in mice during tumor-specific antibody immunotherapy. Cancer Res 71(15):5134–5143

    Article  PubMed  CAS  Google Scholar 

  14. Jarius S, Wildemann B (2010) AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol 6(7):383–392

    Article  PubMed  CAS  Google Scholar 

  15. 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

    Article  PubMed  CAS  Google Scholar 

  16. 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

    Article  PubMed  CAS  Google Scholar 

  17. Li L, Zhang H, Varrin-Doyer M, Zamvil SS, Verkman AS (2011) Proinflammatory role of aquaporin-4 in autoimmune neuroinflammation. FASEB J 25(5):1556–1566

    Article  PubMed  CAS  Google Scholar 

  18. 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 

  19. Ma T, Yang B, Gillespie A, Carlson EJ, Epstein CJ, Verkman AS (1997) Generation and phenotype of a transgenic knockout mouse lacking the mercurial-insensitive water channel aquaporin-4. J Clin Invest 100(5):957–962

    Article  PubMed  CAS  Google Scholar 

  20. Makrides SC (1998) Therapeutic inhibition of the complement system. Pharmacol Rev 50(1):59–87

    PubMed  CAS  Google Scholar 

  21. Manley GT, Fujimura M, Ma T, Noshita N, Filiz F, Bollen AW, Chan P, Verkman AS (2000) Aquaporin-4 deletion in mice reduces brain edema after acute water intoxication and ischemic stroke. Nat Med 6(2):159–163

    Article  PubMed  CAS  Google Scholar 

  22. 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

    Article  PubMed  CAS  Google Scholar 

  23. Nicchia GP, Mastrototaro M, Rossi A, Pisani F, Tortorella C, Ruggieri M, Lia A, Trojano M, Frigeri A, Svelto M (2009) Aquaporin-4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies. Glia 57(13):1363–1373

    Article  PubMed  Google Scholar 

  24. 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

    PubMed  CAS  Google Scholar 

  25. Phuan PW, Ratelade J, Rossi A, Tradtrantip L, Verkman AS (2012) Complement-dependent cytotoxicity in neuromyelitis optica requires aquaporin-4 assembly in orthogonal arrays. J Biol Chem 287:13829–13839

    Google Scholar 

  26. Ramos OF, Nilsson B, Nilsson K, Eggertsen G, Yefenof E, Klein E (1989) Elevated NK-mediated lysis of Raji and Daudi cells carrying fixed iC3b fragments. Cell Immunol 119(2):459–469

    Article  PubMed  CAS  Google Scholar 

  27. 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

    Article  PubMed  CAS  Google Scholar 

  28. 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

    Article  PubMed  CAS  Google Scholar 

  29. Robel S, Bardehle S, Lepier A, Brakebusch C, Gotz M (2011) Genetic deletion of cdc42 reveals a crucial role for astrocyte recruitment to the injury site in vitro and in vivo. J Neurosci 31(35):12471–12482

    Article  PubMed  CAS  Google Scholar 

  30. 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

    Article  PubMed  Google Scholar 

  31. 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

    Article  PubMed  Google Scholar 

  32. 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

    Article  PubMed  CAS  Google Scholar 

  33. Sabater L, Giralt A, Boronat A, Hankiewicz K, Blanco Y, Llufriu S, Alberch J, Graus F, Saiz A (2009) Cytotoxic effect of neuromyelitis optica antibody (NMO-IgG) to astrocytes: an in vitro study. J Neuroimmunol 215(1–2):31–35

    Article  PubMed  CAS  Google Scholar 

  34. Siders WM, Shields J, Garron C, Hu Y, Boutin P, Shankara S, Weber W, Roberts B, Kaplan JM (2010) Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models. Leuk Lymphoma 51(7):1293–1304

    Article  PubMed  CAS  Google Scholar 

  35. Singhrao SK, Neal JW, Rushmere NK, Morgan BP, Gasque P (1999) Differential expression of individual complement regulators in the brain and choroid plexus. Lab Invest 79(10):1247–1259

    PubMed  CAS  Google Scholar 

  36. Tradtrantip L, Zhang H, Anderson MO, Saadoun S, Phuan PW, Papadopoulos MC, Bennett JL, Verkman AS (2012) Small-molecule inhibitors of NMO-IgG binding to aquaporin-4 reduce astrocyte cytotoxicity in neuromyelitis optica. FASEB J. doi:10.1096/fj.11-201608

  37. 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

    Article  PubMed  CAS  Google Scholar 

  38. Ulvestad E, Williams K, Matre R, Nyland H, Olivier A, Antel J (1994) Fc receptors for IgG on cultured human microglia mediate cytotoxicity and phagocytosis of antibody-coated targets. J Neuropathol Exp Neurol 53(1):27–36

    Article  PubMed  CAS  Google Scholar 

  39. Valerius T, Repp R, Kalden JR, Platzer E (1990) Effects of IFN on human eosinophils in comparison with other cytokines. A novel class of eosinophil activators with delayed onset of action. J Immunol 145(9):2950–2958

    PubMed  CAS  Google Scholar 

  40. Vance BA, Huizinga TW, Wardwell K, Guyre PM (1993) Binding of monomeric human IgG defines an expression polymorphism of Fc gamma RIII on large granular lymphocyte/natural killer cells. J Immunol 151(11):6429–6439

    PubMed  CAS  Google Scholar 

  41. Verkman AS, Ratelade J, Rossi A, Zhang H, Tradtrantip L (2011) Aquaporin-4: orthogonal array assembly, CNS functions, and role in neuromyelitis optica. Acta Pharmacol Sin 32(6):702–710

    Article  PubMed  CAS  Google Scholar 

  42. Vincent T, Saikali P, Cayrol R, Roth AD, Bar-Or A, Prat A, Antel JP (2008) Functional consequences of neuromyelitis optica-IgG astrocyte interactions on blood-brain barrier permeability and granulocyte recruitment. J Immunol 181(8):5730–5737

    PubMed  CAS  Google Scholar 

  43. Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6(9):805–815

    Article  PubMed  CAS  Google Scholar 

  44. Wu J, Edberg JC, Redecha PB, Bansal V, Guyre PM, Coleman K, Salmon JE, Kimberly RP (1997) A novel polymorphism of FcgammaRIIIa (CD16) alters receptor function and predisposes to autoimmune disease. J Clin Invest 100(5):1059–1070

    Article  PubMed  CAS  Google Scholar 

  45. Yanamadala V, Friedlander RM (2010) Complement in neuroprotection and neurodegeneration. Trends Mol Med 16(2):69–76

    Article  PubMed  CAS  Google Scholar 

  46. Yang C, Jones JL, Barnum SR (1993) Expression of decay-accelerating factor (CD55), membrane cofactor protein (CD46) and CD59 in the human astroglioma cell line, D54-MG, and primary rat astrocytes. J Neuroimmunol 47(2):123–132

    Article  PubMed  CAS  Google Scholar 

  47. Yusa S, Catina TL, Campbell KS (2002) SHP-1- and phosphotyrosine-independent inhibitory signaling by a killer cell Ig-like receptor cytoplasmic domain in human NK cells. J Immunol 168(10):5047–5057

    PubMed  CAS  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

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by grants from the Guthy-Jackson Charitable Foundation (ASV, MCP, JLB), Grants EY13574, EB00415, DK35124, HL73856, DK86125 and DK72517 from the National Institutes of Health (ASV) and grant RG4320 from the National Multiple Sclerosis Society (JLB).

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Correspondence to A. S. Verkman.

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Ratelade, J., Zhang, H., Saadoun, S. et al. Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss. Acta Neuropathol 123, 861–872 (2012). https://doi.org/10.1007/s00401-012-0986-4

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  • DOI: https://doi.org/10.1007/s00401-012-0986-4

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