Aquaporin‐4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies

Nicchia, Grazia Paola; Mastrototaro, M.; Rossi, Andrea; Pisani, Francesco; Tortorella, Carla; Ruggieri, Maddalena; Lia, Annamaria; Trojano, María; Frigeri, Antonio; Svelto, María

doi:10.1002/glia.20855

Cited by 146 publications

(167 citation statements)

References 42 publications

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“…Likewise, whole serum from a patient with NMO also stained both isoforms. This finding contradicts a recent study reporting exclusive staining of M23 by NMO-IgG (26). rAb-53 also stained AQP4 on the surface of primary glial cell cultures from mouse neonatal brain cortex (Fig.…”

Section: Diffusion Of Native Aqp4 In Primary Glial Cell Cultures Is Scontrasting

confidence: 98%

“…The majority of NMO patients contain in their serum autoantibodies (NMO-IgG) recognizing AQP4 on the surface of glial cells (12). A recent study suggested that NMO-IgG specifically targets AQP4 OAPs, based on imaging data showing preferential staining of M23-transfected cells but not M1-transfected cells (26). This finding suggests that OAPs are the site of NMO pathogenesis.…”

Section: Discussionmentioning

confidence: 99%

“…It has been speculated that OAPs might enhance AQP4 water permeability (19 -21), stabilize AQP4 polarization in glial cell foot-processes (22), and enhance glial cell-cell adhesion (23). The presence of OAPs has been correlated with neurological and neuromuscular diseases (24,25), and a recent study suggested that OAPs contribute to the pathogenesis of NMO (26).…”

Section: Aquaporin-4 (Aqp4)mentioning

confidence: 99%

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Live Cell Analysis of Aquaporin-4 M1/M23 Interactions and Regulated Orthogonal Array Assembly in Glial Cells

Crane

Bennett

Verkman

2009

Journal of Biological Chemistry

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Section: Diffusion Of Native Aqp4 In Primary Glial Cell Cultures Is Scontrasting

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Section: Aquaporin-4 (Aqp4)mentioning

confidence: 99%

See 1 more Smart Citation

Live Cell Analysis of Aquaporin-4 M1/M23 Interactions and Regulated Orthogonal Array Assembly in Glial Cells

Crane

Bennett

Verkman

2009

Journal of Biological Chemistry

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“…We previously showed that NMO patient serum and a recombinant monoclonal NMO-IgG were each able to bind to both the M23 and M1 isoforms of AQP4 (26), which contradicted an earlier study reporting undetectable binding to M1 AQP4 (28). Here, we used fluorescence ratio imaging to quantify the binding of NMO-IgG to AQP4 and to determine the role of AQP4 isoforms and OAPs in NMO-IgG binding.…”

Section: Discussionmentioning

confidence: 62%

“…A prior report that analyzed NMO sera concluded that OAPs are the exclusive target of NMO-IgG (28). However, this conclusion cannot be correct because the clinical serum assay for serum anti-AQP4 autoantibody uses M1 AQP4 (29), which does not form OAPs, and we (4,26) and others (30) reported strong binding of some NMO autoantibodies to cells expressing only M1 AQP4.…”

mentioning

confidence: 71%

Binding Affinity and Specificity of Neuromyelitis Optica Autoantibodies to Aquaporin-4 M1/M23 Isoforms and Orthogonal Arrays

Crane

Lam

Rossi

et al. 2011

Journal of Biological Chemistry

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Autoantibodies against astrocyte water channel aquaporin-4 (AQP4) are highly specific for the neuroinflammatory disease neuromyelitis optica (NMO). We measured the binding of NMO autoantibodies to AQP4 in human astrocyte-derived U87MG cells expressing M1 and/or M23 AQP4, or M23 mutants that do not form orthogonal array of particles (OAPs). Binding affinity was quantified by two-color fluorescence ratio imaging of cells stained with NMO serum or a recombinant monoclonal NMO autoantibody (NMO-rAb), together with a C terminus anti-AQP4 antibody. NMO-rAb titrations showed binding with dissociation constants down to 44 ؎ 7 nM. Different NMO-rAbs and NMO patient sera showed a wide variation in NMO-IgG binding to M1 versus M23 AQP4. Differences in binding affinity rather than stoichiometry accounted for M1 versus M23 binding specificity, with consistently greater affinity of NMO-IgG binding to M23 than M1 AQP4. Binding and OAP measurements in cells expressing different M1:M23 ratios or AQP4 mutants indicated that the differential binding of NMO-IgG to M1 versus M23 was due to OAP assembly rather than to differences in the M1 versus M23 N termini. Purified Fab fragments of NMO-IgG showed similar patterns of AQP4 isoform binding, indicating that structural changes in the AQP4 epitope upon array assembly, and not bivalent cross-linking of whole IgG, result in the greater binding affinity to OAPs. Our study establishes a quantitative assay of NMO-IgG binding to AQP4 and indicates remarkable, OAP-dependent heterogeneity in NMO autoantibody binding specificity.A defining feature of the neuroinflammatory demyelinating disease neuromyelitis optica (NMO) 2 is the presence of serum autoantibodies (NMO-IgG) against aquaporin-4 (AQP4), a water channel expressed in astrocytes throughout the central nervous system (1). The presence of NMO-IgG is specific for NMO, and in some reports serum NMO-IgG titers correlate with NMO disease activity (2, 3). Studies in rodents suggest that NMO-IgG is pathogenic in NMO. Human NMO-IgG produces many features of NMO disease in rats with preexisting experimental autoimmune encephalomyelitis (4, 5) or pretreated with complete Freund's adjuvant (6) and in naïve mice when injected together with human complement (7). These animals develop characteristic NMO lesions with neuroinflammation, perivascular deposition of activated complement, demyelination, and loss of astrocyte glial fibrillary acidic protein and AQP4 immunoreactivity.The target of the NMO autoantibody, AQP4, is involved in water balance in brain (8, 9) and spinal cord (10), sensory signal transduction (11, 12) and neuroexcitatory phenomena including seizure activity (13) and cortical spreading depression (14), and astrocyte migration and glial scarring (15, 16). AQP4 is expressed in astrocytes as two major isoforms: a long (M1) isoform with translation initiation at Met-1, and a shorter (M23) isoform with translation initiation at . M23 AQP4 assembles in membranes as regular square arrays called orthogonal arrays of particles (OAPs), whic...

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Aquaporin 4 Expression and Tissue Susceptibility to Neuromyelitis Optica

et al. 2013

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N euromyelitis optica (NMO) is an autoimmune, relapsing inflammatory disease of the central nervous system (CNS) with a predilection for optic neuritis and myelitis associated with long spinal cord lesions. 1 Other brain structures with high levels of aquaporin 4 (AQP4) immunoreactivity are also preferentially targeted. 2 A pathogenic autoantibody specific for extracellular epitopes of the transmembrane CNS-predominant water channel protein, AQP4 is detectable in most patients. 3 This antibody reproduces many aspects of NMO-specific pathologic changes when injected directly into the CNS in the presence of human complement or when injected intravenously in the setting of a disrupted blood-brain barrier resulting from prior induction of experimental autoimmune encephalomyelitis or injection of a Freund adjuvant. [4][5][6][7] The relative predilection of this disease for the optic nerve and spinal cord remains poorly understood, as are the reasons why other AQP4-expressing tissues are not targeted.Aquaporin 4 protein is expressed in humans as 2 isoforms that result from alternative transcription initiation and alternative splicing of the same gene encoded on chromosome 18. M23, the shorter isoform, lacks 22 N-terminus amino acid residues of the longer M1 isoform. 8 The basic unit of AQP4 assembly is a heterotetramer. Heterotetramers with a high proportion of M23 isoform aggregate as supramolecular complexes 9,10 that lead to formation of orthogonal arrays of IMPORTANCE To understand the predilection for optic nerve and spinal cord pathologic changes in neuromyelitis optica (NMO). OBJECTIVE To evaluate tissue-specific expression (RNA and protein) and supramolecular aggregation of aquaporin 4 (AQP4) in mouse, rat, and human tissues. DESIGN Quantitative polymerase chain reaction, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and blue native polyacrylamide gel electrophoresis. SETTING Laboratory analysis of mouse, rat, and human tissue. PARTICIPANTS Tissues from control individuals and 1 patient with NMO obtained at autopsy. EXPOSURE Neuromyelitis optica in the patient. MAIN OUTCOMES AND MEASURES Tissue-specific messenger RNA and protein expression and supramolecular aggregation of AQP4. RESULTSThe AQP4 messenger RNA and proteins were much more highly expressed in the optic nerve and spinal cord relative to other regions of the brain and to non-central nervous system tissues in all species evaluated. Large supramolecular aggregates of AQP4 were overrepresented in the optic nerve and spinal cord relative to other central nervous system tissue. There was no difference in AQP4 expression between an individual with NMO and the control samples.CONCLUSIONS AND RELEVANCE Optic nerve tissue from an individual with NMO did not differ in AQP4 expression from control samples. The relatively high levels of expression and of supramolecular aggregation in the optic nerve and spinal cord may contribute to the predilection of these structures to NMO pathologic changes.

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Aquaporin‐4 orthogonal arrays of particles are the target for neuromyelitis optica autoantibodies

Cited by 146 publications

References 42 publications

Live Cell Analysis of Aquaporin-4 M1/M23 Interactions and Regulated Orthogonal Array Assembly in Glial Cells

Live Cell Analysis of Aquaporin-4 M1/M23 Interactions and Regulated Orthogonal Array Assembly in Glial Cells

Binding Affinity and Specificity of Neuromyelitis Optica Autoantibodies to Aquaporin-4 M1/M23 Isoforms and Orthogonal Arrays

Aquaporin 4 Expression and Tissue Susceptibility to Neuromyelitis Optica

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