| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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.
This article has been cited by other articles:
|
|
 |
|
  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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
 |
|
 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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
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]
|
|
|
|
|
|
G. Giovannoni To test or not to test: NMO-IgG and optic neuritis Neurology, June 3, 2008; 70(23): 2192 - 2193. [Full Text] [PDF]
|
|
|
|
|
|
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 |
