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Brain Advance Access originally published online on February 4, 2007
Brain 2007 130(5):1194-1205; doi:10.1093/brain/awl371
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© The Author (2007). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Pattern-specific loss of aquaporin-4 immunoreactivity distinguishes neuromyelitis optica from multiple sclerosis

Shanu F. Roemer1, Joseph E. Parisi2, Vanda A. Lennon1–3, Eduardo E. Benarroch1, Hans Lassmann4, Wolfgang Bruck5, Raul N. Mandler6, Brian G. Weinshenker1, Sean J. Pittock1,2, Dean M. Wingerchuk7 and Claudia F. Lucchinetti1

Departments of 1Neurology, 2Laboratory Medicine and Pathology and 3Immunology, Mayo Clinic College of Medicine, Rochester, MN, USA, 4Center for the Clinical Trials Network, National Institutes of Health, Bethesda, MD, 5Department of Neurology, Mayo Clinic College of Medicine, Scottsdale, AZ, USA, 6Center for Brain Research, Medical University of Vienna, Vienna, Austria and 7Department of Neuropathology, Institute for Multiple Sclerosis Research, Georg-August University, Gottingen, Germany

Correspondence to: Claudia F. Lucchinetti, MD, Neurology, Mayo Clinic, College of Medicine, 200 First St. SW, Rochester MN 55905, USA E-mail: lucchinetti.claudia{at}mayo.edu

Neuromyelitis optica (NMO) is an inflammatory demyelinating disease that typically affects optic nerves and spinal cord. Its pathogenic relationship to multiple sclerosis (MS) is uncertain. Unlike MS, NMO lesions are characterized by deposits of IgG and IgM co-localizing with products of complement activation in a vasculocentric pattern around thickened hyalinized blood vessels, suggesting a pathogenic role for humoral immunity targeting an antigen in the perivascular space. A recently identified specific serum autoantibody biomarker, NMO-IgG, targets aquaporin-4 (AQP4), the most abundant water channel protein in the CNS, which is highly concentrated in astrocytic foot processes. We analysed and compared patterns of AQP4 immunoreactivity in CNS tissues of nine patients with NMO, 13 with MS, nine with infarcts and five normal controls. In normal brain, optic nerve and spinal cord, the distribution of AQP4 expression resembles the vasculocentric pattern of immune complex deposition observed in NMO lesions. In contrast to MS lesions, which exhibit stage-dependent loss of AQP4, all NMO lesions demonstrate a striking loss of AQP4 regardless of the stage of demyelinating activity, extent of tissue necrosis, or site of CNS involvement. We identified a novel NMO lesion in the spinal cord and medullary tegmentum extending into the area postrema, characterized by AQP4 loss in foci that were inflammatory and oedematous, but neither demyelinated nor necrotic. Foci of AQP4 loss coincided with sites of intense vasculocentric immune complex deposition. These findings strongly support a role for a complement activating AQP4-specific autoantibody as the initiator of the NMO lesion, and further distinguish NMO from MS.

Key Words: neuromyelitis optica; aquaporin-4; multiple sclerosis; demyelination; astrocyte; blood–brain barrier

Abbreviations: AQP4, aquaporin-4; HIVE, human immunodeficiency virus encephalitis; GFAP, glial fibrillary acidic protein; NMO, Neuromyelitis optica; PML, progressive multifocal leucoencephalopathy

Received August 25, 2006. Revised November 3, 2006. Accepted December 12, 2006.


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