Intrathecal pathogenic anti–aquaporin‐4 antibodies in early neuromyelitis optica
Jeffrey Bennett,Chiwah Lam,Sudhakar Reddy Kalluri,Philippe Saikali,Katherine Bautista,Cecily Dupree,Magdalena J. Glogowska,David Case,Jack P. Antel,Gregory P. Owens,Donald H. Gilden,Stefan Nessler,Christine Stadelmann,Bernhard Hemmer +13 more
TLDR
The serum of most neuromyelitis optica patients contains autoantibodies directed against the aquaporin‐4 water channel located on astrocyte foot processes in the perivessel and subpial areas of the brain, and their role in disease pathogenesis was determined.Abstract:
Objective
The serum of most neuromyelitis optica (NMO) patients contains autoantibodies (NMO-IgGs) directed against the aquaporin-4 (AQP4) water channel located on astrocyte foot processes in the perivessel and subpial areas of the brain. Our objectives were to determine the source of central nervous system (CNS) NMO-IgGs and their role in disease pathogenesis.
Methods
Fluorescence-activated cell sorting and single-cell reverse transcriptase polymerase chain reaction were used to identify overrepresented plasma cell immunoglobulin (Ig) sequences in the cerebrospinal fluid (CSF) of an NMO patient after a first clinical attack. Monoclonal recombinant antibodies (rAbs) were generated from the paired heavy and light chain sequences and tested for target specificity and Fc effector function. The effect of CSF rAbs on CNS immunopathology was investigated by delivering single rAbs to rats with experimental autoimmune encephalomyelitis (EAE).
Results
Repertoire analysis revealed a dynamic, clonally expanded plasma cell population with features of an antigen-targeted response. Using multiple independent assays, 6 of 11 rAbs generated from CSF plasma cell clones specifically bound to AQP4. AQP4-specific rAbs recognized conformational epitopes and mediated both AQP4-directed antibody-dependent cellular cytotoxicity and complement-mediated lysis. When administered to rats with EAE, an AQP4-specific NMO CSF rAb induced NMO immunopathology: perivascular astrocyte depletion, myelinolysis, and complement and Ig deposition.
Interpretation
Molecular characterization of the CSF plasma cell repertoire in an early NMO patient demonstrates that AQP4-specfic Ig is synthesized intrathecally at disease onset and directly contributes to CNS pathology. AQP4 is now the first confirmed antigenic target in human demyelinating disease. Ann Neurol 2009;66:617–629read more
Citations
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Journal ArticleDOI
Aquaporin water channels in the nervous system
TL;DR: The aquaporins (AQPs) are plasma membrane water-transporting proteins that are expressed in astrocytes and is involved in water movement, cell migration and neuroexcitation, and are potential drug targets for several neurological conditions.
Journal ArticleDOI
Contrasting disease patterns in seropositive and seronegative neuromyelitis optica: A multicentre study of 175 patients
Sven Jarius,Klemens Ruprecht,Brigitte Wildemann,Tania Kuempfel,Marius Ringelstein,Christian Geis,Ingo Kleiter,Ingo Kleiter,Christoph Kleinschnitz,Achim Berthele,Johannes Brettschneider,Kerstin Hellwig,Bernhard Hemmer,Ralf A. Linker,Ralf A. Linker,Florian Lauda,Christoph Mayer,Hayrettin Tumani,Arthur Melms,Corinna Trebst,Martin Stangel,Martin Marziniak,Frank Hoffmann,Sven Schippling,Jürgen H. Faiss,Oliver Neuhaus,Barbara Ettrich,Christian Zentner,Kersten Guthke,Ulrich Hofstadt-van Oy,Reinhard Reuss,Hannah L. Pellkofer,Ulf Ziemann,Peter Kern,Klaus Peter Wandinger,Florian Then Bergh,Tobias Boettcher,Stefan Langel,Martin Liebetrau,Paulus S. Rommer,Sabine Niehaus,Christoph Münch,Alexander Winkelmann,Uwe K Zettl U,Imke Metz,Christian Veauthier,Jörn P Sieb,C. Wilke,Hans Hartung,Orhan Aktas,Friedemann Paul +50 more
TL;DR: This study provides an overview of the clinical and paraclinical features of NMOSD in Caucasians and demonstrates a number of distinct disease characteristics in seropositive and seronegative patients.
Journal ArticleDOI
Update on the diagnosis and treatment of neuromyelitis optica: recommendations of the Neuromyelitis Optica Study Group (NEMOS)
Corinna Trebst,Sven Jarius,Achim Berthele,Friedemann Paul,Friedemann Paul,Sven Schippling,Brigitte Wildemann,Nadja Borisow,Ingo Kleiter,Orhan Aktas,Tania Kümpfel +10 more
TL;DR: The Neuromyelitis Optica Study Group (NEMOS) summarizes recently obtained knowledge on NMO and highlights new developments in its diagnosis and treatment, based on current guidelines, the published literature and expert discussion at regular NEMOS meetings.
Journal ArticleDOI
Neuromyelitis optica: pathogenicity of patient immunoglobulin in vivo.
Monika Bradl,Tatsuro Misu,Toshiyuki Takahashi,Mitsutoshi Watanabe,Simone Mader,Markus Reindl,Milena Z. Adzemovic,Jan Bauer,Thomas Berger,Kazuo Fujihara,Yasuto Itoyama,Hans Lassmann +11 more
TL;DR: A diagnostic hallmark of this disease is the presence of serum autoantibodies against the water channel aquaporin‐4 (AQP‐4) on astrocytes.
Journal ArticleDOI
Intra-cerebral injection of neuromyelitis optica immunoglobulin G and human complement produces neuromyelitis optica lesions in mice
Samira Saadoun,Patrick Waters,B. Anthony Bell,Angela Vincent,Alan S. Verkman,Marios C. Papadopoulos +5 more
TL;DR: In the mouse model, immunoglobulin G from neuromyelitis optica patients does not require pre-existing central nervous system inflammation to produce lesions and co-injection of immunoglOBulin G with human complement reproduces the key histological features of neuromyELitis optic and aquaporin-4 is necessary and sufficient to exert its effect.
References
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Journal ArticleDOI
A serum autoantibody marker of neuromyelitis optica : distinction from multiple sclerosis
Vanda A. Lennon,Dean M. Wingerchuk,Thomas J. Kryzer,Sean J. Pittock,C. F. Lucchinetti,Kazuo Fujihara,Ichiro Nakashima,Brian G. Weinshenker +7 more
TL;DR: NMO-IgG is a specific marker autoantibody of neuromyelitis optica and binds at or near the blood-brain barrier that distinguishes neuromyleitis opticas from multiple sclerosis.
Journal ArticleDOI
Revised diagnostic criteria for neuromyelitis optica
TL;DR: Revised diagnostic criteria for definite neuromyelitis optica (NMO) that require optic neuritis, myelitis, and at least two of three supportive criteria: MRI evidence of a contiguous spinal cord lesion 3 or more segments in length, onset brain MRI nondiagnostic for multiple sclerosis, or NMO-IgG seropositivity.
Journal ArticleDOI
IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel.
TL;DR: It is shown that NMO-IgG binds selectively to the aquaporin-4 water channel, a component of the dystroglycan protein complex located in astrocytic foot processes at the blood-brain barrier, which may represent the first example of a novel class of autoimmune channelopathy.
Journal ArticleDOI
The spectrum of neuromyelitis optica
Dean M. Wingerchuk,Vanda A. Lennon,Claudia F. Lucchinetti,Sean J. Pittock,Brian G. Weinshenker +4 more
TL;DR: Data suggest that autoantibodies to aquaporin 4 derived from peripheral B cells cause the activation of complement, inflammatory demyelination, and necrosis that is seen in neuromyelitis optica.
Journal ArticleDOI
A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica
C. F. Lucchinetti,Raul N. Mandler,Dorian B. McGavern,Wolfgang Brück,Gerald J. Gleich,Richard M. Ransohoff,Corinna Trebst,Brian G. Weinshenker,Dean M. Wingerchuk,Joseph E. Parisi,Hans Lassmann +10 more
TL;DR: The extent of complement activation, eosinophilic infiltration and vascular fibrosis observed in the Devic NMO cases is more prominent compared with that in prototypic multiple sclerosis, and supports a role for humoral immunity in the pathogenesis of NMO.