Abstract
Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system that can cause paralysis and blindness. The pathogenesis of NMO involves binding of immunoglobulin G autoantibodies to aquaporin-4 (AQP4) on astrocytes, which is thought to cause complement-dependent cytotoxicity (CDC) and a secondary inflammatory response leading to oligodendrocyte and neuronal damage. Here, we investigate in vivo the role of antibody-dependent cell-mediated cytotoxicity (ADCC) triggered by AQP4 autoantibodies (AQP4-IgG) in the development of NMO pathology. A high-affinity, human recombinant monoclonal AQP4-IgG was mutated in its Fc region to produce ‘NMO superantibodies’ with enhanced CDC and/or ADCC effector functions, without altered AQP4 binding. Pathological effects of these antibodies were studied in a mouse model of NMO produced by intracerebral injection of AQP4-IgG and human complement. The original (non-mutated) antibody produced large NMO lesions in this model, with loss of AQP4 and GFAP immunoreactivity, inflammation and demyelination, as did a mutated antibody with enhanced CDC and ADCC effector functions. As anticipated, a mutated AQP4-IgG lacking CDC, but having tenfold enhanced ADCC, produced little pathology. However, unexpectedly, a mutated antibody with ninefold enhanced CDC, but lacking ADCC, produced much less pathology than the original AQP4-IgG. Also, pathology was greatly reduced following administration of AQP4-IgG and complement to mice lacking the FcγIII receptor involved in effector cell activation during ADCC, and to normal mice injected with an Fcγ receptor blocking antibody. Our results provide evidence for the central involvement of ADCC in NMO pathology and suggest ADCC as a new therapeutic target in NMO.
Similar content being viewed by others
References
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
Bruhns P (2012) Properties of mouse and human IgG receptors and their contribution to disease models. Blood 119(24):5640–5649. doi:10.1182/blood-2012-01-380121
Crane JM, Bennett JL, Verkman AS (2009) Live cell analysis of aquaporin-4 m1/m23 interactions and regulated orthogonal array assembly in glial cells. J Biol Chem 284(51):35850–35860. doi:10.1074/jbc.M109.071670
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
Diaz de Stahl T, Andren M, Martinsson P, Verbeek JS, Kleinau S (2002) Expression of FcgammaRIII is required for development of collagen-induced arthritis. Eur J Immunol 32(10):2915–2922. doi:10.1002/1521-4141(2002010)32:10<2915:AID-IMMU2915>3.0.CO;2-4
Gessner JE, Heiken H, Tamm A, Schmidt RE (1998) The IgG Fc receptor family. Ann Hematol 76(6):231–248
Hazenbos WL, Gessner JE, Hofhuis FM, Kuipers H, Meyer D, Heijnen IA, Schmidt RE, Sandor M, Capel PJ, Daeron M, van de Winkel JG, Verbeek JS (1996) Impaired IgG-dependent anaphylaxis and Arthus reaction in Fc gamma RIII (CD16) deficient mice. Immunity 5(2):181–188 [pii]:S1074-7613(00)80494-X
Idusogie EE, Wong PY, Presta LG, Gazzano-Santoro H, Totpal K, Ultsch M, Mulkerrin MG (2001) Engineered antibodies with increased activity to recruit complement. J Immunol 166(4):2571–2575
Jacob A, Saadoun S, Kitley J, Leite M, Palace J, Schon F, Papadopoulos MC (2012) Detrimental role of granulocyte-colony stimulating factor in neuromyelitis optica: clinical case and histological evidence. Mult Scler 18(12):1801–1803. doi:10.1177/1352458512443994
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
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
Kuroda H, Fujihara K, Takano R, Takai Y, Takahashi T, Misu T, Nakashima I, Sato S, Itoyama Y, Aoki M (2013) Increase of complement fragment C5a in cerebrospinal fluid during exacerbation of neuromyelitis optica. J Neuroimmunol 254(1–2):178–182. doi:10.1016/j.jneuroim.2012.09.002
Lazar GA, Dang W, Karki S, Vafa O, Peng JS, Hyun L, Chan C, Chung HS, Eivazi A, Yoder SC, Vielmetter J, Carmichael DF, Hayes RJ, Dahiyat BI, 11 (2006) Engineered antibody Fc variants with enhanced effector function. Proc Natl Acad Sci USA 103:4005. doi:10.1073/pnas.0508123103 103
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
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
Liu XY, Pop LM, Vitetta ES (2008) Engineering therapeutic monoclonal antibodies. Immunol Rev 222:9–27. doi:10.1111/j.1600-065X.2008.00601.xIMR601
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
Mihai S, Nimmerjahn F (2012) The role of Fc receptors and complement in autoimmunity. Autoimmun Rev. doi:10.1016/j.autrev.2012.10.008
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
Miyajima I, Dombrowicz D, Martin TR, Ravetch JV, Kinet JP, Galli SJ (1997) Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and Fc gammaRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis. J Clin Invest 99(5):901–914. doi:10.1172/JCI119255
Moore GL, Chen H, Karki S, Lazar GA (2010) Engineered Fc variant antibodies with enhanced ability to recruit complement and mediate effector functions. MAbs 2(2):181–189. (pii:11158)
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
Nimmerjahn F, Lux A, Albert H, Woigk M, Lehmann C, Dudziak D, Smith P, Ravetch JV (2010) FcgammaRIV deletion reveals its central role for IgG2a and IgG2b activity in vivo. Proc Natl Acad Sci USA 107(45):19396–19401. doi:10.1073/pnas.1014515107
Nimmerjahn F, Ravetch JV (2008) Fcgamma receptors as regulators of immune responses. Nat Rev Immunol 8(1):34–47. doi:10.1038/nri2206
Overdijk MB, Verploegen S, Ortiz Buijsse A, Vink T, Leusen JH, Bleeker WK, Parren PW (2012) Crosstalk between human IgG isotypes and murine effector cells. J Immunol 189(7):3430–3438. doi:10.4049/jimmunol.1200356
Papadopoulos MC, Verkman AS (2013) Aquaporin water channels in the nervous system. Nat Rev Neurosci 14(4):265–277. doi:10.1038/nrn3468nrn3468
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
Pittock SJ, Lennon VA, McKeon A, Mandrekar J, Weinshenker BG, Lucchinetti CF, O’Toole O, Wingerchuk DM (2013) Eculizumab in AQP4-IgG-positive relapsing neuromyelitis optica spectrum disorders: an open-label pilot study. Lancet Neurol 12(6):554–562. doi:10.1016/S1474-4422(13)70076-0
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
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
Ricklin D, Hajishengallis G, Yang K, Lambris JD (2010) Complement: a key system for immune surveillance and homeostasis. Nat Immunol 11(9):785–797. doi:10.1038/ni.1923ni.1923
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
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
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
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
Skokowa J, Ali SR, Felda O, Kumar V, Konrad S, Shushakova N, Schmidt RE, Piekorz RP, Nurnberg B, Spicher K, Birnbaumer L, Zwirner J, Claassens JW, Verbeek JS, van Rooijen N, Kohl J, Gessner JE (2005) Macrophages induce the inflammatory response in the pulmonary Arthus reaction through G alpha i2 activation that controls C5aR and Fc receptor cooperation. J Immunol 174(5):3041–3050 [pii]: 174/5/3041
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
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
Unkeless JC (1979) Characterization of a monoclonal antibody directed against mouse macrophage and lymphocyte Fc receptors. J Exp Med 150(3):580–596
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 [pii]: 181/8/5730
Willcocks LC, Smith KG, Clatworthy MR (2009) Low-affinity Fcgamma receptors, autoimmunity and infection. Expert Rev Mol Med 11:e24. doi:10.1017/S1462399409001161
Wingerchuk DM, Lennon VA, Lucchinetti CF, Pittock SJ, Weinshenker BG (2007) The spectrum of neuromyelitis optica. Lancet Neurol 6(9):805–815. doi:10.1016/S1474-4422(07)70216-8
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
Zhang H, Verkman AS (2013) Eosinophil pathogenicity mechanisms and therapeutics in neuromyelitis optica. J Clin Invest 123(5):2306–2316. doi:10.1172/JCI6755467554
Acknowledgments
This work was supported by grants from the Guthy-Jackson Charitable Foundation (ASV, JLB) and grants EY13574, EB00415, DK35124, HL73856, DK86125 and DK72517 (ASV) and EY022936 (JLB) from the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Ratelade, J., Asavapanumas, N., Ritchie, A.M. et al. Involvement of antibody-dependent cell-mediated cytotoxicity in inflammatory demyelination in a mouse model of neuromyelitis optica. Acta Neuropathol 126, 699–709 (2013). https://doi.org/10.1007/s00401-013-1172-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-013-1172-z