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This Article Figures Only Full Text Full Text (PDF) CME: Take the course for this article: Volume 69, Number 24, December 11, 2007 Video Data Supplement All Versions of this Article: 01.WNL.0000289761.64862.cev1 69/24/2221    most recent Correspondence: Submit a response Alert me when this article is cited Alert me when Correspondence are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hinson, S. R. Articles by Lennon, V. A. Search for Related Content PubMed PubMed Citation Articles by Hinson, S. R. Articles by Lennon, V. A.

Pathogenic potential of IgG binding to water channel extracellular domain in neuromyelitis optica

From the Departments of Laboratory Medicine and Pathology (S.R.H., S.J.P., J.P.F., T.J.K., V.A.L.), Neurology (S.J.P., C.F.L., S.F.R., V.A.L), and Immunology (V.A.L.), Mayo Clinic College of Medicine, Rochester, MN.

Address correspondence and reprint requests to Dr Lennon, 828 Guggenheim Building, Mayo Clinic College of Medicine, Rochester MN 55905 lennon.vanda{at}mayo.edu

Background: Autoantibody specific for the aquaporin-4 astrocytic water channel is restricted to serum and CSF of patients with neuromyelitis optica (NMO) and related CNS inflammatory demyelinating disorders (relapsing optic neuritis and longitudinally extensive transverse myelitis). NMO-typical lesions are distinct from MS-typical lesions. Aquaporin-4 is lost selectively at vasculocentric sites of edema/inflammation coinciding with focal deposits of immunoglobulins (Ig) G, M, and terminal complement products, with and without myelin loss. Evidence for antigen-specific autoantibody pathogenicity is lacking.

Methods: We used confocal microscopy and flow cytometry to evaluate the selectivity and immunopathological consequences of Ig binding to surface epitopes of living target cells expressing aquaporin-4 fused at its cytoplasmic N-terminus with GFP. We tested serum, IgG-enriched and IgG-depleted serum fractions, and CSF from patients with NMO, neurologic control patients, and healthy subjects. We also analyzed aquaporin-4 immunoreactivity in myelinated adult mouse optic nerves and spinal cord, and plasma cell Ig isotypes in archived brain tissue from an NMO patient.

Results: Serum IgG from patients with NMO binds to the extracellular domain of aquaporin-4; it is predominantly IgG₁, and it initiates two potentially competing outcomes, aquaporin-4 endocytosis/degradation and complement activation. Serum and CSF lack aquaporin-4-specific IgM, and plasma cells in CNS lesions of NMO contain only IgG. Paranodal astrocytic endfeet highly express aquaporin-4.

Conclusions: NMO patients’ serum IgG has a selective pathologic effect on cell membranes expressing aquaporin-4. IgG targeting astrocytic processes around nodes of Ranvier could initiate demyelination.

Abbreviations: AQP4 = aquaporin-4; GFP = green fluorescent protein; HEK293 = human embryonic kidney cell line; MS = multiple sclerosis; NMO = neuromyelitis optica.

Supplemental data at www.neurology.org

e-Pub ahead of print on October 10, 2007, at www.neurology.org.

This work was supported by the Mayo Foundation and a grant from the Ralph Wilson Medical Research Foundation.

Disclosure: In accordance with the Bayh–Dole Act of 1980 and Mayo Foundation policy, Drs. Lennon and Lucchinetti and Mr. Kryzer stand to receive royalties for intellectual property related to the AQP4 autoantigen. This intellectual property is licensed to a commercial entity for development of a simple antigen-specific assay to be made available worldwide for patient care. The test will not be exclusive to Mayo Clinic. To date, the authors have received a total of <$10,000 in royalties. Mayo Clinic offers the test as an indirect immunofluorescence assay to aid the diagnosis of neuromyelitis optica, but the authors do not benefit personally from the performance of the test. The other authors report no conflicts of interest.

Presented by Dr. Vanda Lennon as a "Frontiers in Neuroscience" Lecture at the 58th Annual Meeting of the American Association of Neurologists, San Diego, CA, April 6, 2006.

Received June 13, 2007. Accepted in final form September 4, 2007.

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