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BMC Neurology

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Open Access 01-12-2013 | Research article

Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis

Authors: Harleen Saini, Robert Rifkin, Michael Gorelik, Hwa Huang, Zachary Ferguson, Melina V Jones, Michael Levy

Published in: BMC Neurology | Issue 1/2013

Abstract

Background

Neuromyelitis optica (NMO) is a devastating inflammatory disorder of the optic nerves and spinal cord characterized by frequently recurring exacerbations of humoral inflammation. NMO is associated with the highly specific NMO-IgG biomarker, an antibody that binds the aquaporin-4 water channel. Aquaporin-4 is present on glial endfeet in the central nervous system (CNS). In humans, the NMO-IgG portends more frequent exacerbations and a worse long-term clinical outcome.

Methods

We tested the longer-term outcome of mice with EAE injected with NMO-IgG and followed them for 60 days. Clinical exams and pathology of the spinal cord and optic nerves were compared to mice that received control human IgG.

Results

Passively transferred human NMO-IgG leads to more severe neurology disability over two months after onset of disease. Clinical worsening is associated with an increased concentration of large demyelinating lesions primarily to subpial AQP4-rich regions of the spinal cord.

Conclusions

NMO-IgG is pathogenic in the context of EAE in mice.

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Graber DJ, Levy M, Kerr D, Wade WF: Neuromyelitis optica pathogenesis and aquaporin 4. J Neuroinflammation. 2008, 5: 22-10.1186/1742-2094-5-22.CrossRefPubMedPubMedCentral

McKeon A, Fryer JP, Apiwattanakul M, Lennon VA, Hinson SR, Kryzer TJ, Lucchinetti CF, Weinshenker BG, Wingerchuk DM, Shuster EA, Pittock SJ: Diagnosis of neuromyelitis spectrum disorders: comparative sensitivities and specificities of immunohistochemical and immunoprecipitation assays. Arch Neurol. 2009, 66: 1134-1138. 10.1001/archneurol.2009.178.PubMed

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

Lucchinetti CF, Mandler RN, McGavern D, Bruck W, Gleich G, Ransohoff RM, Trebst C, Weinshenker B, Wingerchuk D, Parisi JE, Lassmann H: A role for humoral mechanisms in the pathogenesis of Devic's neuromyelitis optica. Brain. 2002, 125: 1450-1461. 10.1093/brain/awf151.CrossRefPubMed

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

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

Swanborg RH: Experimental autoimmune encephalomyelitis in the rat: lessons in T-cell immunology and autoreactivity. Immunol Rev. 2001, 184: 129-135. 10.1034/j.1600-065x.2001.1840112.x.CrossRefPubMed

Jarius S, Wildemann B: AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance. Nat Rev Neurol. 2010, 6: 383-392. 10.1038/nrneurol.2010.72.CrossRefPubMed

Jones MV, Nguyen TT, Deboy CA, Griffin JW, Whartenby KA, Kerr DA, Calabresi PA: Behavioral and pathological outcomes in MOG 35–55 experimental autoimmune encephalomyelitis. J Neuroimmunol. 2008, 199: 83-93. 10.1016/j.jneuroim.2008.05.013.CrossRefPubMed

10.

Hinson SR, McKeon A, Fryer JP, Apiwattanakul M, Lennon VA, Pittock SJ: Prediction of neuromyelitis optica attack severity by quantitation of complement-mediated injury to aquaporin-4-expressing cells. Arch Neurol. 2009, 66: 1164-1167. 10.1001/archneurol.2009.188.CrossRefPubMed

11.

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

12.

Cayrol R, Saikali P, Vincent T: Effector functions of antiaquaporin-4 autoantibodies in neuromyelitis optica. Ann N Y Acad Sci. 2009, 1173: 478-486. 10.1111/j.1749-6632.2009.04871.x.CrossRefPubMed

13.

Frohman EM, Kerr D: Is neuromyelitis optica distinct from multiple sclerosis?: something for “lumpers” and “splitters”. Arch Neurol. 2007, 64: 903-905. 10.1001/archneur.64.6.903.CrossRefPubMed

14.

Weinstock-Guttman B, Miller C, Yeh E, Stosic M, Umhauer M, Batra N, Munschauer F, Zivadinov R, Ramanathan M: Neuromyelitis optica immunoglobulins as a marker of disease activity and response to therapy in patients with neuromyelitis optica. Mult Scler. 2008, 14 (8): 1061-1067. 10.1177/1352458508092811.CrossRefPubMed

15.

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

16.

Lapointe BM, Herx LM, Gill V, Metz LM, Kubes P: IVIg therapy in brain inflammation: etiology-dependent differential effects on leucocyte recruitment. Brain. 2004, 127: 2649-2656. 10.1093/brain/awh297.CrossRefPubMed

17.

Tani T, Sakimura K, Tsujita M, Nakada T, Tanaka M, Nishizawa M, Tanaka K: Identification of binding sites for anti-aquaporin 4 antibodies in patients with neuromyelitis optica. J Neuroimmunol. 2009, 211: 110-113. 10.1016/j.jneuroim.2009.04.001.CrossRefPubMed

The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/13/104/prepub

Title: Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis
Authors: Harleen Saini
Robert Rifkin
Michael Gorelik
Hwa Huang
Zachary Ferguson
Melina V Jones
Michael Levy
Publication date: 01-12-2013
Publisher: BioMed Central
Published in: BMC Neurology / Issue 1/2013
Electronic ISSN: 1471-2377
DOI: https://doi.org/10.1186/1471-2377-13-104

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Passively transferred human NMO-IgG exacerbates demyelination in mouse experimental autoimmune encephalomyelitis

Abstract

Background

Methods

Results

Conclusions

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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