Top

Published in:

01-06-2012 | Original Paper

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

Authors: Julien Ratelade, Hua Zhang, Samira Saadoun, Jeffrey L. Bennett, Marios C. Papadopoulos, A. S. Verkman

Published in: Acta Neuropathologica | Issue 6/2012

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.

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

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

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):617–629PubMedCrossRef

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):204–211PubMedCrossRef

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

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):451–463PubMedCrossRef

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):813–821PubMedCrossRef

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):449–456PubMedCrossRef

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):2993–3002PubMed

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):1164–1167PubMedCrossRef

11.

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

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):2221–2231PubMedCrossRef

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):5134–5143PubMedCrossRef

14.

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

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):473–477PubMedCrossRef

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):2106–2112PubMedCrossRef

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):1556–1566PubMedCrossRef

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):1450–1461PubMedCrossRef

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):957–962PubMedCrossRef

20.

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

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):159–163PubMedCrossRef

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):1224–1234PubMedCrossRef

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):1363–1373PubMedCrossRef

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):171–180PubMed

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

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):459–469PubMedCrossRef

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):45156–45164PubMedCrossRef

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):e27412PubMedCrossRef

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):12471–12482PubMedCrossRef

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):1194–1205PubMedCrossRef

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):349–361PubMedCrossRef

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):323–333PubMedCrossRef

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):31–35PubMedCrossRef

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):1293–1304PubMedCrossRef

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):1247–1259PubMed

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):314–322PubMedCrossRef

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):27–36PubMedCrossRef

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):2950–2958PubMed

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):6429–6439PubMed

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):702–710PubMedCrossRef

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):5730–5737PubMed

43.

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

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):1059–1070PubMedCrossRef

45.

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

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):123–132PubMedCrossRef

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):5047–5057PubMed

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):943–954PubMedCrossRef

Title: Neuromyelitis optica IgG and natural killer cells produce NMO lesions in mice without myelin loss
Authors: Julien Ratelade
Hua Zhang
Samira Saadoun
Jeffrey L. Bennett
Marios C. Papadopoulos
A. S. Verkman
Publication date: 01-06-2012
Publisher: Springer-Verlag
Published in: Acta Neuropathologica / Issue 6/2012
Print ISSN: 0001-6322
Electronic ISSN: 1432-0533
DOI: https://doi.org/10.1007/s00401-012-0986-4

Keynote webinar | Spotlight on medication adherence

Springer Medicine

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

Abstract

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Please log in to get access to this content

Other articles of this Issue 6/2012

Lewy body pathology and typical Parkinson disease in a patient with a heterozygous (R275W) mutation in the Parkin gene (PARK2)

Gap junction pathology in multiple sclerosis lesions and normal-appearing white matter

Cognitive defects are reversible in inducible mice expressing pro-aggregant full-length human Tau

Neuropathology and its meetings: a difficult relationship between evolving partners

Saccular intracranial aneurysm: pathology and mechanisms

Extensive loss of connexins in Baló’s disease: evidence for an auto-antibody-independent astrocytopathy via impaired astrocyte–oligodendrocyte/myelin interaction