Evidence against Cellular Internalization in Vivo of NMO-IgG, Aquaporin-4, and Excitatory Amino Acid Transporter 2 in Neuromyelitis Optica

Ratelade, Julien; Bennett, Jeffrey L.; Verkman, A. S.

doi:10.1074/jbc.m111.297275

Cited by 63 publications

(80 citation statements)

References 29 publications

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“…Existe un reporte de eosinofilia en el líquido cefalorraquídeo en un niño con mielitis transversa recurrente y otro de vasculitis eosinofílica y pericarditis en un paciente que presentaba una enfermedad tipo NMO. (2,10,11,18) Por otra parte, la activación del complemento genera diferentes péptidos activos biológicamente que tienen potencialidades quimioatrayentes. El más relevante clínicamente es el factor quimiotáctico C5a, un producto de ruptura del quinto componente de este complejo.…”

Section: Papel De Los Eosinófilosunclassified

“…En EAE por transferencia pasiva, los eosinófilos invaden el nervio óptico y la médula espinal de 7 a 8 días después de transferidas las células T. (Figura No. 1) (2,3,20,21) Papel de los anticuerpos anti-MOG, anti-MBP y anti-proteína unidora de calcio de la astroglia (s100γ)…”

Section: Papel De Los Eosinófilosunclassified

“…En resumen, como se ha señalado, existen diferentes mecanismos involucrados en la patogénesis de la NMO. Estrategias terapéuticas futuras diseñadas para limitar el efecto perjudicial de la activación del complemento, la degranulación de eosinófilos y neutrófilos, activación de macrófagos y de la microglia deben ser investigadas (2,7,26).…”

Section: Papel De Los Eosinófilosunclassified

“…1) Las características tales como el dolor, el déficit visual, los fenómenos positivos y autonómicos no difieren de otras entidades. (2,35,36,37) La afectación medular suele presentarse como una mielitis transversa completa con debilidad bilateral de miembros superiores e inferiores dependiendo siempre del sitio de afectación medular, compromiso sensitivo y disfunción esfinteriana. Habitualmente se presentan dolores de tipo radicular.…”

Section: Papel De Las Células T Reguladorasunclassified

“…esta positividad de la igGnMo permitió separar a la NMO y las entidades relacionadas de la EM. (2,4,7,8) › Exámenes neurofisiológicos: Los potenciales evocados son potenciales eléctricos generados en el SNC tras la estimulación de un órgano sensitivo/ sensorial periférico. Pueden usarse para evaluar la conductividad de los impulsos eléctricos a través de fibras nerviosas mielinizadas.…”

Section: Introductionunclassified

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Neuromielitis Óptica. Patología, diagnóstico y tratamiento en el siglo XXI

Pinzón¹

2015

Rev. Sal. Bosq

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La neuromielitis óptica (NMO) o enfermedad de Devic, pertenece al grupo de las enfermedades desmielinizantes del sistema nervioso central, afecta de manera significativa los nervios ópticos y la médula espinal. Desde el siglo XIX cuando Eugene Devic dio a conocer una serie de casos en los que existía asociación de lesiones en los nervios ópticos y la medula espinal, la relación de la neuromielitis óptica (NMO) y la Esclerosis Múltiple (EM) ha sido controversial, considerándose una variante de esta última; datos recientes muestran que puede ser distinguida de la Esclerosis Múltiple (EM). Los síntomas de la NMO son por lo general más agudos y severos y la presencia de un autoanticuerpo específico en sangre llamado NMO-IgG tipo acuoporina-4 (AQP4) desempeña un rol muy importante en la patogenia de esta enfermedad,asimismo se encuentran varias características entre ellas de tipo clínico, de laboratorio, neuroimágenes y en la anatomía patológica que diferencian la esclerosis múltiple (EM) de esta enfermedad. La proporción entre mujeres y hombres es mayor de 4 a 1.La presentación clínica y el curso de la enfermedad puede ser con recaídas en 80-90% y en un 10-20% curso monofásico. La manifestación distintiva de la entidad NMO es la ocurrencia ya sea consecutiva o simultánea de NO (unilateral o bilateral) y la presencia de mielitis longitudinal extensa (Mle). La terapia con corticosteroides intravenosos normalmente es el tratamiento Andrés Mauricio Álvarez Pinzón. AbstractOptic Neuromyelitis (NMO) or Devic's disease, is a demyelinating disease of central nervous system, affects the optic nerves and spinal cord. Since the nineteenth century when Eugene Devic unveiled a series of cases in which there was an association of lesions in the optic nerves and spinal cord with relation of NMO and Multiple Sclerosis (MS) has been controversial, in some cases described like a variant of the latter but recent data show that can be distinguished from multiple sclerosis (MS). Symptoms of NMO are usually more acute and severe and then we can find a presence of a specific autoantibody called NMO-IgG, it is a blood type acuoporina-4 (AQP4) and plays an important role in the pathogenesis of this disease. Also in the new millennium are various types of clinical, laboratory, neuroimaging and pathological anatomy then differentiates multiple sclerosis (MS) of this disease. In the epidemiology the ratio of women to men is greater than 4 to 1.The clinical presentation and course of the disease can be relapsing by 80-90% and 10-20% monophasic course. The distinctive manifestation is the occurrence NMO entity either consecutively or simultaneously not (unilateral or bilateral) and the presence of extensive longitudinal myelitis. Intravenous corticosteroid therapy is usually the initial therapy for acute attacks of optic neuritis or myelitis. Plasmapheresis therapy is used when the steroids therapy no work during 1. Artículo de revisión.

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Section: Papel De Los Eosinófilosunclassified

Section: Papel De Las Células T Reguladorasunclassified

Section: Introductionunclassified

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Neuromielitis Óptica. Patología, diagnóstico y tratamiento en el siglo XXI

Pinzón¹

2015

Rev. Sal. Bosq

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Anti–Aquaporin‐4 monoclonal antibody blocker therapy for neuromyelitis optica

Tradtrantip

Zhang

Saadoun

et al. 2012

Annals of Neurology

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232

187

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Objective Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system. Circulating autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4) cause complement- and cell-mediated astrocyte damage with consequent neuroinflammation and demyelination. Current NMO therapies, which have limited efficacy, include immunosuppression and plasma exchange. The objective of this study was to develop a potential new NMO therapy based on blocking of pathogenic NMO-IgG to its target, AQP4. Methods We generated non-pathogenic recombinant monoclonal anti-AQP4 antibodies that selectively block NMO-IgG binding to AQP4. These antibodies comprise a tight-binding anti-AQP4 Fab and a mutated Fc that lacks functionality for complement- and cell-mediated cytotoxicity. The efficacy of the blocking antibodies was studied using cell culture, spinal cord slice and in vivo mouse models of NMO. Results In AQP4-expressing cell cultures, the non-pathogenic competing antibodies blocked binding of NMO-IgG in human sera, reducing to near zero complement- and cell-mediated cytotoxicity. The antibodies prevented the development of NMO lesions in an ex vivo spinal cord slice model of NMO and in an in vivo mouse model, without causing cytotoxicity. Interpretation Our results provide proof-of-concept for therapy of NMO with blocking antibodies. The broad efficacy of antibody inhibition is likely due to steric competition because of its large physical size compared to AQP4. Blocker therapy to prevent binding of pathogenic autoantibodies to their targets may be useful for treatment of other autoimmune diseases as well.

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Neuromyelitis optica IgG does not alter aquaporin‐4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly

Rossi

Ratelade

Papadopoulos

et al. 2012

Glia

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Neuromyelitis optica (NMO) is thought to be caused by immunoglobulin G autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4). A recent study (Hinson et al. (2012) Proc Natl Acad Sci USA 109:1245- 1250) reported that NMO-IgG inhibits AQP4 water permeability directly and causes rapid cellular internalization of the M1 but not M23 isoform of AQP4, resulting in AQP4 clustering, enhanced complement-dependent cytotoxicity, and tissue swelling. Here, we report evidence challenging this proposed mechanism of NMO-IgG-mediated pathology. We measured osmotic water permeability by stopped-flow light scattering on plasma membrane vesicles isolated from AQP4-expressing CHO cells, an approach that can detect changes in water permeability as small as 5% and is not confounded by internalization effects. We found similar single- molecule water permeability for M1-AQP4 tetramers and M23-AQP4 clusters (orthogonal arrays of particles, OAPs). Exposure of AQP4 to high concentrations of NMOIgG from six seropositive NMO patients, and to high-affinity recombinant monoclonal NMO antibodies, did not reduce AQP4 water permeability. Also, NMO-IgG did not reduce water permeability in AQP4-reconstituted proteoliposomes. In transfected cells expressing M1- or M23-AQP4 individually, NMO-IgG caused more rapid internalization of M23- than M1-AQP4. In cells coexpressing both isoforms, M1- and M23-AQP4 comingled in OAPs that were internalized together in response to NMO-IgG. Super-resolution imaging and native gel electrophoresis showed that the size of AQP4 OAPs was not altered by NMO sera or recombinant NMO antibodies. We conclude that NMO-IgG does not: (i) inhibit AQP4 water permeability, (ii) cause preferential internalization of M1-AQP4, or (iii) cause intramembrane AQP4 clustering.

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Evidence against Cellular Internalization in Vivo of NMO-IgG, Aquaporin-4, and Excitatory Amino Acid Transporter 2 in Neuromyelitis Optica

Cited by 63 publications

References 29 publications

Neuromielitis Óptica. Patología, diagnóstico y tratamiento en el siglo XXI

Neuromielitis Óptica. Patología, diagnóstico y tratamiento en el siglo XXI

Anti–Aquaporin‐4 monoclonal antibody blocker therapy for neuromyelitis optica

Neuromyelitis optica IgG does not alter aquaporin‐4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly

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