Neurology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
 QUICK SEARCH:   [advanced]


     


Published online before print October 10, 2007, doi:10.1212/01.WNL.0000289761.64862.ce)
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow CME: Take the course for this article:
Volume 69, Number 24, December 11, 2007
Right arrow Video
Right arrow Data Supplement
Right arrow All Versions of this Article:
01.WNL.0000289761.64862.cev1
69/24/2221    most recent
Right arrow Correspondence:
Submit a response
Right arrow Alert me when this article is cited
Right arrow Alert me when Correspondence are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hinson, S. R.
Right arrow Articles by Lennon, V. A.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hinson, S. R.
Right arrow Articles by Lennon, V. A.
NEUROLOGY 2007;69:2221-2231
© 2007 American Academy of Neurology

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

S. R. Hinson, PhD, S. J. Pittock, MD, C. F. Lucchinetti, MD, S. F. Roemer, MD, J. P. Fryer, MS, T. J. Kryzer, AS and V. A. Lennon, MD, PhD

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.


Formula

Formula

Formula

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.




This article has been cited by other articles:


Home page
Arch NeurolHome page
N. Kale, S. J. Pittock, V. A. Lennon, K. Thomsen, S. Roemer, A. McKeon, and C. F. Lucchinetti
Humoral Pattern II Multiple Sclerosis Pathology Not Associated With Neuromyelitis Optica IgG
Arch Neurol, October 1, 2009; 66(10): 1298 - 1299.
[Full Text] [PDF]


Home page
Arch NeurolHome page
A. Jacob, M. Matiello, B. G. Weinshenker, D. M. Wingerchuk, C. Lucchinetti, E. Shuster, J. Carter, B. M. Keegan, O. H. Kantarci, and S. J. Pittock
Treatment of Neuromyelitis Optica With Mycophenolate Mofetil: Retrospective Analysis of 24 Patients
Arch Neurol, September 1, 2009; 66(9): 1128 - 1133.
[Abstract] [Full Text] [PDF]


Home page
Arch NeurolHome page
S. R. Hinson, A. McKeon, J. P. Fryer, M. Apiwattanakul, V. A. Lennon, and S. J. Pittock
Prediction of Neuromyelitis Optica Attack Severity by Quantitation of Complement-Mediated Injury to Aquaporin-4-Expressing Cells
Arch Neurol, September 1, 2009; 66(9): 1164 - 1167.
[Abstract] [Full Text] [PDF]


Home page
Mult SclerHome page
M Nakamura, T Misu, K Fujihara, I Miyazawa, I Nakashima, T Takahashi, S Watanabe, and Y Itoyama
Occurrence of acute large and edematous callosal lesions in neuromyelitis optica
Multiple Sclerosis, June 1, 2009; 15(6): 695 - 700.
[Abstract] [PDF]


Home page
J. Neurol. Neurosurg. PsychiatryHome page
T Misu, R Takano, K Fujihara, T Takahashi, S Sato, and Y Itoyama
Marked increase in cerebrospinal fluid glial fibrillar acidic protein in neuromyelitis optica: an astrocytic damage marker
J. Neurol. Neurosurg. Psychiatry, May 1, 2009; 80(5): 575 - 577.
[Abstract] [Full Text] [PDF]


Home page
Mult SclerHome page
M Bonnan, R Valentino, S Olindo, H Mehdaoui, D Smadja, and P Cabre
Plasma exchange in severe spinal attacks associated with neuromyelitis optica spectrum disorder
Multiple Sclerosis, April 1, 2009; 15(4): 487 - 492.
[Abstract] [PDF]


Home page
Mult SclerHome page
H Doi, T Matsushita, N Isobe, T Matsuoka, M Minohara, H Ochi, and J. Kira
Hypercomplementemia at relapse in patients with anti-aquaporin-4 antibody
Multiple Sclerosis, March 1, 2009; 15(3): 304 - 310.
[Abstract] [PDF]


Home page
NeurologyHome page
S. M. Magana, M. Matiello, S. J. Pittock, A. McKeon, V. A. Lennon, A. A. Rabinstein, E. Shuster, O. H. Kantarci, C. F. Lucchinetti, and B. G. Weinshenker
Posterior reversible encephalopathy syndrome in neuromyelitis optica spectrum disorders
Neurology, February 24, 2009; 72(8): 712 - 717.
[Abstract] [Full Text] [PDF]


Home page
BrainHome page
S. Jarius, F. Aboul-Enein, P. Waters, B. Kuenz, A. Hauser, T. Berger, W. Lang, M. Reindl, A. Vincent, and W. Kristoferitsch
Antibody to aquaporin-4 in the long-term course of neuromyelitis optica
Brain, November 1, 2008; 131(11): 3072 - 3080.
[Abstract] [Full Text] [PDF]


Home page
JEMHome page
S. R. Hinson, S. F. Roemer, C. F. Lucchinetti, J. P. Fryer, T. J. Kryzer, J. L. Chamberlain, C. L. Howe, S. J. Pittock, and V. A. Lennon
Aquaporin-4-binding autoantibodies in patients with neuromyelitis optica impair glutamate transport by down-regulating EAAT2
J. Exp. Med., October 27, 2008; 205(11): 2473 - 2481.
[Abstract] [Full Text] [PDF]


Home page
J. Immunol.Home page
T. Vincent, P. Saikali, R. Cayrol, A. D. Roth, A. Bar-Or, A. Prat, and J. P. Antel
Functional Consequences of Neuromyelitis Optica-IgG Astrocyte Interactions on Blood-Brain Barrier Permeability and Granulocyte Recruitment
J. Immunol., October 15, 2008; 181(8): 5730 - 5737.
[Abstract] [Full Text] [PDF]


Home page
J. Neurol. Neurosurg. PsychiatryHome page
T Takahashi, I Miyazawa, T Misu, R Takano, I Nakashima, K Fujihara, M Tobita, and Y Itoyama
Intractable hiccup and nausea in neuromyelitis optica with anti-aquaporin-4 antibody: a herald of acute exacerbations
J. Neurol. Neurosurg. Psychiatry, September 1, 2008; 79(9): 1075 - 1078.
[Abstract] [Full Text] [PDF]


Home page
Mult SclerHome page
B Weinstock-Guttman, C Miller, E. Yeh, M Stosic, M Umhauer, N Batra, F Munschauer, R Zivadinov, and M Ramanathan
Neuromyelitis optica immunoglobulins as a marker of disease activity and response to therapy in patients with neuromyelitis optica
Multiple Sclerosis, September 1, 2008; 14(8): 1061 - 1067.
[Abstract] [PDF]


Home page
NeurologyHome page
A. McKeon, V. A. Lennon, T. Lotze, S. Tenenbaum, J. M. Ness, M. Rensel, N. L. Kuntz, J. P. Fryer, H. Homburger, J. Hunter, et al.
CNS aquaporin-4 autoimmunity in children
Neurology, July 8, 2008; 71(2): 93 - 100.
[Abstract] [Full Text] [PDF]


Home page
Arch NeurolHome page
P. Waters, S. Jarius, E. Littleton, M. I. Leite, S. Jacob, B. Gray, R. Geraldes, T. Vale, A. Jacob, J. Palace, et al.
Aquaporin-4 Antibodies in Neuromyelitis Optica and Longitudinally Extensive Transverse Myelitis
Arch Neurol, July 1, 2008; 65(7): 913 - 919.
[Abstract] [Full Text] [PDF]


Home page
NeurologyHome page
G. Giovannoni
To test or not to test: NMO-IgG and optic neuritis
Neurology, June 3, 2008; 70(23): 2192 - 2193.
[Full Text] [PDF]


Home page
Arch NeurolHome page
S. J. Pittock and V. A. Lennon
Aquaporin-4 Autoantibodies in a Paraneoplastic Context
Arch Neurol, May 1, 2008; 65(5): 629 - 632.
[Abstract] [Full Text] [PDF]




HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Copyright © 2007 by AAN Enterprises, Inc.