The Experts below are selected from a list of 22782 Experts worldwide ranked by ideXlab platform
A S Verkman - One of the best experts on this subject based on the ideXlab platform.
-
the Aquaporin 4 water channel as a potential drug target in neurological disorders
Expert Opinion on Therapeutic Targets, 2017Co-Authors: A S Verkman, Lukmanee Tradtrantip, Alex J Smith, Puaywah Phuan, Marc O AndersonAbstract:Introduction: Aquaporin-4 (AQP4) is a water transporting protein expressed at the plasma membrane of astrocytes throughout the central nervous system (CNS). Analysis of AQP4 knockout mice has sugge...
-
enzymatic deglycosylation converts pathogenic neuromyelitis optica anti Aquaporin 4 immunoglobulin g into therapeutic antibody
Annals of Neurology, 2013Co-Authors: Lukmanee Tradtrantip, Julien Ratelade, Hua Zhang, A S VerkmanAbstract:Objective Neuromyelitis optica (NMO) is caused by binding of pathogenic autoantibodies (NMO-IgG) to Aquaporin-4 (AQP4) on astrocytes, which initiates complement-dependent cytotoxicity (CDC) and inflammation. We recently introduced mutated antibody (aquaporumab) and small-molecule blocker strategies for therapy of NMO, based on prevention of NMO-IgG binding to AQP4. Here, we investigated an alternative strategy involving neutralization of NMO-IgG effector function by selective IgG heavy-chain deglycosylation with bacteria-derived endoglycosidase S (EndoS).
-
Aquaporin 4 and neuromyelitis optica
Lancet Neurology, 2012Co-Authors: Marios C Papadopoulos, A S VerkmanAbstract:Summary Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS. The discovery of circulating IgG1 antibodies against the astrocyte water channel protein Aquaporin 4 (AQP4) and the evidence that AQP4-IgG is involved in the development of neuromyelitis optica revolutionised our understanding of the disease. However, important unanswered questions remain—for example, we do not know the cause of AQP4-IgG-negative disease, how astrocyte damage causes demyelination, the role of T cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters neuromyelitis optica lesions. New drug candidates have emerged, such as aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). Despite rapid progress, randomised clinical trials to test new drugs will be challenging because of the small number of individuals with the disorder.
-
orthogonal array formation by human Aquaporin 4 examination of neuromyelitis optica associated Aquaporin 4 polymorphisms
Journal of Neuroimmunology, 2011Co-Authors: Jonathan M Crane, Andrea Rossi, Tripta Gupta, Jeffrey L Bennett, A S VerkmanAbstract:Pathogenic autoantibodies target Aquaporin-4 (AQP4) water channels in individuals with neuromyelitis optica (NMO). Recently, allelic mutations were reported at residue 19 of AQP4 in three cases of NMO, and it was suggested that polymorphisms may influence disease by altering AQP4 supramolecular assembly into orthogonal arrays of particles (OAPs). We analyzed the determinants of OAP formation by human AQP4 to investigate the possible role of polymorphisms in NMO pathogenesis. NMO-associated mutations R19I and R19T in AQP4 did not affect OAP assembly, palmitoylation-dependent regulation of assembly, or NMO autoantibody binding. Residue-19 polymorphisms in AQP4 are thus unlikely to be disease relevant.
-
Aquaporin-4 and brain edema
Pediatric Nephrology, 2007Co-Authors: Marios C Papadopoulos, A S VerkmanAbstract:Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.
Marios C Papadopoulos - One of the best experts on this subject based on the ideXlab platform.
-
Aquaporin 4 and neuromyelitis optica
Lancet Neurology, 2012Co-Authors: Marios C Papadopoulos, A S VerkmanAbstract:Summary Neuromyelitis optica is an inflammatory demyelinating disorder of the CNS. The discovery of circulating IgG1 antibodies against the astrocyte water channel protein Aquaporin 4 (AQP4) and the evidence that AQP4-IgG is involved in the development of neuromyelitis optica revolutionised our understanding of the disease. However, important unanswered questions remain—for example, we do not know the cause of AQP4-IgG-negative disease, how astrocyte damage causes demyelination, the role of T cells, why peripheral AQP4-expressing organs are undamaged, and how circulating AQP4-IgG enters neuromyelitis optica lesions. New drug candidates have emerged, such as aquaporumab (non-pathogenic antibody blocker of AQP4-IgG binding), sivelestat (neutrophil elastase inhibitor), and eculizumab (complement inhibitor). Despite rapid progress, randomised clinical trials to test new drugs will be challenging because of the small number of individuals with the disorder.
-
Aquaporin-4 and brain edema
Pediatric Nephrology, 2007Co-Authors: Marios C Papadopoulos, A S VerkmanAbstract:Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.
-
Aquaporin 4 and brain edema
Pediatric Nephrology, 2007Co-Authors: Marios C Papadopoulos, A S VerkmanAbstract:Aquaporin-4 (AQP4) is a water-channel protein expressed strongly in the brain, predominantly in astrocyte foot processes at the borders between the brain parenchyma and major fluid compartments, including cerebrospinal fluid (CSF) and blood. This distribution suggests that AQP4 controls water fluxes into and out of the brain parenchyma. Experiments using AQP4-null mice provide strong evidence for AQP4 involvement in cerebral water balance. AQP4-null mice are protected from cellular (cytotoxic) brain edema produced by water intoxication, brain ischemia, or meningitis. However, AQP4 deletion aggravates vasogenic (fluid leak) brain edema produced by tumor, cortical freeze, intraparenchymal fluid infusion, or brain abscess. In cytotoxic edema, AQP4 deletion slows the rate of water entry into brain, whereas in vasogenic edema, AQP4 deletion reduces the rate of water outflow from brain parenchyma. AQP4 deletion also worsens obstructive hydrocephalus. Recently, AQP4 was also found to play a major role in processes unrelated to brain edema, including astrocyte migration and neuronal excitability. These findings suggest that modulation of AQP4 expression or function may be beneficial in several cerebral disorders, including hyponatremic brain edema, hydrocephalus, stroke, tumor, infection, epilepsy, and traumatic brain injury.
-
greatly impaired migration of implanted Aquaporin 4 deficient astroglial cells in mouse brain toward a site of injury
The FASEB Journal, 2007Co-Authors: Kurtis I Auguste, Geoffrey T Manley, Marios C Papadopoulos, Donghong Yan, Songwan Jin, Kazunori Uchida, A S VerkmanAbstract:We reported previously that astroglia cultured from Aquaporin-4-deficient (AQP4−/−) mice migrate more slowly in vitro than those from wild-type (AQP4+/+) mice (J. Cell Sci. 2005;118, 5691–5698). He...
-
involvement of Aquaporin 4 in astroglial cell migration and glial scar formation
Journal of Cell Science, 2005Co-Authors: Samira Saadoun, Geoffrey T Manley, Marios C Papadopoulos, Hiroyuki Watanabe, Donghong Yan, A S VerkmanAbstract:Aquaporin-4, the major water-selective channel in astroglia throughout the central nervous system, facilitates water movement into and out of the brain. Here, we identify a novel role for Aquaporin-4 in astroglial cell migration, as occurs during glial scar formation. Astroglia cultured from the neocortex of Aquaporin-4-null mice had similar morphology, proliferation and adhesion, but markedly impaired migration determined by Transwell migration efficiency (18+/-2 vs 58+/-4% of cells migrated towards 10% serum in 8 hours; P<0.001) and wound healing rate (4.6 vs 7.0 microm/hour speed of wound edge; P<0.001) compared with wild-type mice. Transwell migration was similarly impaired (25+/-4% migrated cells) in wild-type astroglia after approximately 90% reduction in Aquaporin-4 protein expression by RNA inhibition. Aquaporin-4 was polarized to the leading edge of the plasma membrane in migrating wild-type astroglia, where rapid shape changes were seen by video microscopy. Astroglial cell migration was enhanced by a small extracellular osmotic gradient, suggesting that Aquaporin-4 facilitates water influx across the leading edge of a migrating cell. In an in vivo model of reactive gliosis and astroglial cell migration produced by cortical stab injury, glial scar formation was remarkably impaired in Aquaporin-4-null mice, with reduced migration of reactive astroglia towards the site of injury. Our findings provide evidence for the involvement of Aquaporin-4 in astroglial cell migration, which occurs during glial scar formation in brain injury, stroke, tumor and focal abscess.
Vanda A Lennon - One of the best experts on this subject based on the ideXlab platform.
-
Aquaporin 4 and myelin oligodendrocyte glycoprotein autoantibody status predict outcome of recurrent optic neuritis
Ophthalmology, 2018Co-Authors: Jiraporn Jitprapaikulsan, Brian G. Weinshenker, Vanda A Lennon, John J Chen, Eoin P Flanagan, Oliver W Tobin, J P Fryer, Andrew Mckeon, Jacqueline A Leavitt, Janmendelt TillemaAbstract:Purpose To determine the Aquaporin-4 and myelin oligodendrocyte glycoprotein (MOG) immunoglobulin G (IgG) serostatus and visual outcomes in patients with recurrent optic neuritis (rON) initially seeking treatment. Design Cross-sectional cohort study. Participants The study identified patients by searching the Mayo Clinic computerized central diagnostic index (January 2000–March 2017). The 246 eligible patients fulfilled the following criteria: (1) initially seeking treatment for at least 2 consecutive episodes of optic neuritis (ON) and (2) serum available for testing. Methods Serum was tested for Aquaporin-4 IgG and MOG IgG1 using an in-house validated flow cytometric assay using live HEK293 cells transfected with M1 Aquaporin-4 or full-length MOG. Main Outcomes Measures Aquaporin-4 IgG and MOG IgG1 serostatus, clinical characteristics, and visual outcomes. Results Among 246 patients with rON at presentation, glial autoantibodies were detected in 32% (Aquaporin-4 IgG, 19%; MOG IgG1, 13%); 186 patients had rON only and 60 patients had rON with subsequent additional inflammatory demyelinating attacks (rON-plus group). The rON-only cohort comprised the following: double seronegative (idiopathic), 110 patients (59%); MOG IgG1 positive, 27 patients (15%; 4 with chronic relapsing inflammatory optic neuropathy); multiple sclerosis (MS), 25 patients (13%); and Aquaporin-4 IgG positive, 24 patients (13%). The rON-plus cohort comprised the following: Aquaporin-4 IgG positive, 23 patients (38%); MS, 22 patients (37%); double seronegative, 11 patients (18%); and MOG IgG1 positive, 4 patients (7%). The annualized relapse rate for the rON-only group was 1.2 for MOG IgG1−positive patients, 0.7 for double-seronegative patients, 0.6 for Aquaporin-4 IgG−positive patients, and 0.4 for MS patients ( P = 0.005). The median visual acuity (VA) of patients with the worst rON-only attack at nadir were hand movements in Aquaporin-4 IgG−positive patients, between counting fingers and hand movements in MOG IgG1−positive patients, 20/800 in idiopathic patients, and 20/100 in MS patients ( P = 0.02). The median VA at last follow-up for affected eyes of the rON-only cohort were counting fingers for Aquaporin-4 IgG−positive patients, 20/40 for idiopathic patients, 20/25 for MS patients and MOG IgG1−positive patients ( P = 0.006). At 5 years after ON onset, 59% of Aquaporin-4 IgG−positive patients, 22% of idiopathic patients, 12% of MOG IgG1−positive patients, and 8% of MS patients were estimated to have severe visual loss. Conclusions Glial autoantibodies (MOG IgG1 or Aquaporin-4 IgG) are found in one third of all patients with rON. Aquaporin-4 IgG seropositivity predicts a worse visual outcome than MOG IgG1 seropositivity, double seronegativity, or MS diagnosis. Myelin oligodendrocyte glycoprotein IgG1 is associated with a greater relapse rate but better visual outcomes.
-
Aquaporin 4 autoimmunity
Neuroimmunology and Neuroinflammation, 2015Co-Authors: Anastasia Zekeridou, Vanda A LennonAbstract:Neuromyelitis optica (NMO) and a related spectrum of inflammatory CNS disorders are unified by detection of a serum autoantibody specific for the Aquaporin-4 (AQP4) water channel, which is abundant in astrocytic foot processes. The classic clinical manifestations of NMO are optic neuritis and longitudinally extensive transverse myelitis. Newly recognized manifestations of AQP4 autoimmunity include lesions of circumventricular organs and skeletal muscle. NMO is commonly relapsing, is frequently accompanied by other autoimmune disorders, and sometimes occurs in a paraneoplastic context. The goals of treatment are to minimize neurologic disability in the acute attack and thereafter to prevent relapses and cumulative disability. The disease specificity of AQP4 immunoglobulin (Ig) G approaches 100% using optimized molecular-based detection assays. Clinical, immunohistopathologic, and in vitro evidence support this antibody being central to NMO pathogenesis. Current animal models yield limited histopathologic characteristics of NMO, with no clinical deficits to date. Recent descriptions of a myelin oligodendrocyte glycoprotein autoantibody in a minority of patients with NMO spectrum phenotype who lack AQP4-IgG predict serologic delineation of additional distinctive disease entities.
-
evolution of longitudinally extensive transverse myelitis in an Aquaporin 4 igg positive patient
Neurology, 2013Co-Authors: Nasrin Asgari, Hanne Pernille Bro Skejoe, Vanda A LennonAbstract:A 36-year-old woman presented with hemiplegia and loss of pain and temperature sensation 1 day after the subacute onset of intractable vomiting. Paresthesia followed. She was tetraplegic at day 12. Initial MRI revealed a lesion in the medulla oblongata, involving primarily the area postrema (figure). The lesion progressively extended into the upper cervical cord. Forebrain MRI was normal. CSF contained 11 leukocytes/mm3. Brainstem tumor and multiple sclerosis were early diagnostic considerations. Aquaporin-4 immunoglobulin (Ig)G was detected in serum. This case supports the concept that fenestrated capillaries in the area postrema are an important initial CNS entry site for pathogenic neuromyelitis optica–IgG in neuromyelitis optica spectrum disorders.1,2
-
neuromyelitis optica igg Aquaporin 4 autoantibodies in immune mediated optic neuritis
Journal of Neurology Neurosurgery and Psychiatry, 2010Co-Authors: Axel Petzold, Sean J Pittock, Vanda A Lennon, Cosimo Maggiore, B G Weinshenker, Gordon T PlantAbstract:The clinical course of immune mediated optic neuritis (ON) will depend on the specific underlying inflammatory disease. These disorders have traditionally been classified according to clinical and MRI findings. Aquaporin-4 (AQP4) autoantibodies (neuromyelitis optica-IgG (NMO-IgG)) may have diagnostic and prognostic value in patients who present with isolated ON. In this prospective study, NMO-IgG was evaluated in 114 patients with ON in the following contexts: neuromyelitis optica (NMO), multiple sclerosis (MSON), chronic relapsing inflammatory ON (CRION), relapsing isolated ON (RION) and single isolated ON (SION). The proportion seropositive was 56% for NMO (n = 9), 0% for MSON (n = 28) and 5% for the remaining diagnostic categories (CRION (n = 19), RION (n = 17) and SION (n = 41)). Testing for NMO-IgG in patients with recurrent or severe ON who lack convincing evidence of MS may identify patients who would benefit from immunosuppression rather than MS directed immunomodulatory therapies.
-
cns Aquaporin 4 autoimmunity in children
Neurology, 2008Co-Authors: Andrew Mckeon, Vanda A Lennon, Timothy Lotze, S Tenenbaum, Jayne Ness, Mary Rensel, Nancy L Kuntz, Jim Fryer, Henry A Homburger, Jill V HunterAbstract:Background: In adult patients, autoantibodies targeting the water channel Aquaporin-4 (AQP4) are a biomarker for a spectrum of CNS inflammatory demyelinating disorders with predilection for optic nerves and spinal cord (neuromyelitis optica [NMO]). Here we describe the neurologic, serologic, and radiographic findings associated with CNS AQP4 autoimmunity in childhood. Methods: A total of 88 consecutive seropositive children were identified through service evaluation for NMO-IgG. Sera of 75 were tested for coexisting autoantibodies. Clinical information was available for 58. Results: Forty-two patients (73%) were non-Caucasian, and 20 (34%) had African ethnicity. Median age at symptom onset was 12 years (range 4–18). Fifty-seven (98%) had attacks of either optic neuritis (n = 48; 83%) or transverse myelitis (n = 45; 78%), or both. Twenty-six (45%) had episodic cerebral symptoms (encephalopathy, ophthalmoparesis, ataxia, seizures, intractable vomiting, or hiccups). Thirty-eight (68%) had brain MRI abnormalities, predominantly involving periventricular areas (in descending order of frequency): the medulla, supratentorial and infratentorial white matter, midbrain, cerebellum, thalamus, and hypothalamus. Additional autoantibodies were detected in 57 of 75 patients (76%), and 16 of 38 (42%) had a coexisting autoimmune disorder recorded (systemic lupus erythematosus, Sjogren syndrome, juvenile rheumatoid arthritis, Graves disease). Attacks were recurrent in 54 patients (93%; median follow-up, 12 months). Forty-three of 48 patients (90%) had residual disability: 26 (54%) visual impairment and 21 (44%) motor deficits (median Expanded Disability Status Scale 4.0 at 12 months). Conclusions: Aquaporin-4 autoimmunity is a distinctive recurrent and widespread inflammatory CNS disease in children.
Sven Jarius - One of the best experts on this subject based on the ideXlab platform.
-
Aquaporin 4 autoimmunity in patients with systemic lupus erythematosus a predominantly population based study
Multiple Sclerosis Journal, 2018Co-Authors: Nasrin Asgari, Brian G. Weinshenker, Sven Jarius, Helle Laustrup, Hanne Pernille Bro Skejoe, Soeren Thue Lillevang, Anne VossAbstract:Background:Serum immunoglobulin G targeting the astrocyte water channel Aquaporin-4 (AQP4) in the central nervous system (CNS) is a biomarker for neuromyelitis optica spectrum disease (NMOSD). Co-e...
-
contribution of spinal cord biopsy to diagnosis of Aquaporin 4 antibody positive neuromyelitis optica spectrum disorder
Multiple Sclerosis Journal, 2014Co-Authors: Marius Ringelstein, Sven Jarius, Imke Metz, Klemens Ruprecht, Arend Koch, J Rappold, Jens Ingwersen, Christian Mathys, Wolfgang Bruck, H P HartungAbstract:Longitudinally extensive transverse myelitis is characteristic but not pathognomonic for neuromyelitis optica spectrum disorders (NMOSDs) and may mimic local tumors. In this retrospective study based on a cohort of 175 NMOSD patients we identified seven patients who initially presented with a longitudinally extensive spinal cord lesion and underwent spinal cord biopsy due to magnetic resonance imaging (MRI)-suspected malignancies. Remarkably, routine neuropathology was inconclusive and did not guide the diagnostic process to anti-Aquaporin-4 (AQP4)-seropositive NMOSD. Serious postoperative complications occurred in 5/7 patients and persisted during follow-up in 2/7 patients (29%). Considering these sequelae, AQP4-antibody testing should be mandatory in patients with inconclusive longitudinally extensive spinal cord lesions prior to biopsy.
-
prognostic implications of Aquaporin 4 antibody status in neuromyelitis optica patients
Journal of Neurology, 2011Co-Authors: Gulsen Akmandemir, Sema İçöz, Patrick Waters, Sven Jarius, Murat Kurtuncu, Zuhal Yapici, Melike Mutlu, Nilufer Yesilot, Angela VincentAbstract:Neuromyelitis optica (NMO) is an inflammatory/demyelinating disorder predominantly affecting the optic nerves and spinal cord. Recent findings showed an underlying humoral abnormality in NMO, characterized by a serum antibody against Aquaporin-4 (Aqp-4-Ab). In this study, we evaluated the Aqp-4-Ab status among Turkish patients with NMO to determine the clinical and prognostic relevance. Serum samples from 35 consecutive patients with NMO followed at a single center and diagnosed according to the 2006 revised criteria, were evaluated for Aqp-4-Ab. All samples were obtained during a relapse prior to any immunosuppressive treatment. Aqp-4-Ab was positive in 21/35 (60%) patients. Among these cases, 11 had an EDSS of 6.0 or more, whereas only two patients in the seronegative group had such severe disability (p < 0.05). Overall, seropositive cases had a mean EDSS score of 5.1 ± 2.2 compared with 3.5 ± 1.7 in seronegative cases (p < 0.01). There were trends towards female predominance in seropositive cases and a monophasic course predominance in seronegative cases. Disease duration, age at onset, number of attacks and time to definite NMO did not differ between groups. Our findings in this single-center cohort suggest that the presence of Aqp-4-Ab might have a prognostic significance indicating a more severe disease course.
-
patterns of antibody binding to Aquaporin 4 isoforms in neuromyelitis optica
PLOS ONE, 2010Co-Authors: Simone Mader, Sven Jarius, Kathrin Schanda, Andreas Lutterotti, Franziska Di Pauli, Bettina Kuenz, Fahmy Aboulenein, Michael Khalil, Maria K Storch, Wolfgang KristoferitschAbstract:Background Neuromyelitis optica (NMO), a severe demyelinating disease, represents itself with optic neuritis and longitudinally extensive transverse myelitis. Serum NMO-IgG autoantibodies (Abs), a specific finding in NMO patients, target the water channel protein Aquaporin-4 (AQP4), which is expressed as a long (M-1) or a short (M-23) isoform.
-
immunoglobulin m antibodies to Aquaporin 4 in neuromyelitis optica and related disorders
Clinical Chemistry and Laboratory Medicine, 2010Co-Authors: Sven Jarius, Diego Franciotta, Roberto Bergamaschi, Brigitte Wildemann, Klauspeter WandingerAbstract:Background Neuromyelitis optica (NMO, Devic syndrome) is an inflammatory disorder of the central nervous system of putative autoimmune etiology that primarily affects the optic nerves and spinal cord. NMO is frequently associated with immunoglobulin G (IgG) antibodies to Aquaporin-4 (AQP4-IgG), which are thought to be involved in the patho-genesis of the disease. The frequency and diagnostic relevance of immunoglobulin M (IgM) antibodies to Aquaporin-4 (AQP4-IgM) in patients with NMO is essentially not known. Testing for AQP4-IgM may be of importance since 20%-30% of patients with NMO are negative for AQP4-IgG. Moreover, IgM antibodies are more potent activators of complement compared with IgG, and are detectable at NMO lesional sites. Methods Serum samples from 42 patients with NMO spectrum disorders (NMOSD) and from 66 controls were tested for IgM AQP4-Ab using a cell-based assay employing HEK293 cells transfected with human full length AQP4. To control for possible interactions between IgG and IgM, serum was depleted of IgG prior to testing by indirect immunofluorescence. Results IgM AQP4-Ab were detectable in 4/42 samples from patients with NMOSD, but in none of the 66 control samples. In three patients, titers were higher following depletion of total IgG from the samples. One sample was positive only after precipitation of total IgG. Conclusions AQP4 antibodies of the IgM class exist in almost 10% of patients with NMO and might contribute to lesion pathology. Routine testing for AQP4-IgM appears to not be justified, as all AQP4-IgM positive patients were also positive for AQP4-IgG, and none of the AQP4-IgG negative samples were positive for AQP4-IgM.
Diego Franciotta - One of the best experts on this subject based on the ideXlab platform.
-
systemic sclerosis in Aquaporin 4 antibody positive longitudinally extensive transverse myelitis
Journal of the Neurological Sciences, 2011Co-Authors: Diego Franciotta, Elisabetta Zardini, Roberto Caporali, Laura Piccolo, Elisa Alberici, A Romani, Roberto Bergamaschi, Enrico Marchioni, Mauro Ceroni, G PiccoloAbstract:We report on the first patient with a relapsing, anti-Aquaporin-4 (AQP-4) antibody-positive, longitudinally extensive transverse myelitis (LETM) who developed systemic sclerosis (SSc). A 62-year-old woman, who presented with bilateral, distal lower limb and perineal numbness, developed clinical manifestations and paraclinical features of SSc. Spinal cord imaging revealed lesions that were consistent with LETM. Patient's serum was positive for neuromyelitis optica (NMO)-IgG/AQP-4 antibodies. High-dose intravenous corticosteroids improved the neurological symptoms. The present case expands the list of autoimmune systemic diseases that occur in neuromyelitis optica spectrum disorders associated with NMO-IgG/AQP-4 antibodies.
-
immunoglobulin m antibodies to Aquaporin 4 in neuromyelitis optica and related disorders
Clinical Chemistry and Laboratory Medicine, 2010Co-Authors: Sven Jarius, Diego Franciotta, Roberto Bergamaschi, Brigitte Wildemann, Klauspeter WandingerAbstract:Background Neuromyelitis optica (NMO, Devic syndrome) is an inflammatory disorder of the central nervous system of putative autoimmune etiology that primarily affects the optic nerves and spinal cord. NMO is frequently associated with immunoglobulin G (IgG) antibodies to Aquaporin-4 (AQP4-IgG), which are thought to be involved in the patho-genesis of the disease. The frequency and diagnostic relevance of immunoglobulin M (IgM) antibodies to Aquaporin-4 (AQP4-IgM) in patients with NMO is essentially not known. Testing for AQP4-IgM may be of importance since 20%-30% of patients with NMO are negative for AQP4-IgG. Moreover, IgM antibodies are more potent activators of complement compared with IgG, and are detectable at NMO lesional sites. Methods Serum samples from 42 patients with NMO spectrum disorders (NMOSD) and from 66 controls were tested for IgM AQP4-Ab using a cell-based assay employing HEK293 cells transfected with human full length AQP4. To control for possible interactions between IgG and IgM, serum was depleted of IgG prior to testing by indirect immunofluorescence. Results IgM AQP4-Ab were detectable in 4/42 samples from patients with NMOSD, but in none of the 66 control samples. In three patients, titers were higher following depletion of total IgG from the samples. One sample was positive only after precipitation of total IgG. Conclusions AQP4 antibodies of the IgM class exist in almost 10% of patients with NMO and might contribute to lesion pathology. Routine testing for AQP4-IgM appears to not be justified, as all AQP4-IgM positive patients were also positive for AQP4-IgG, and none of the AQP4-IgG negative samples were positive for AQP4-IgM.
-
antibody to Aquaporin 4 in the diagnosis of neuromyelitis optica
PLOS Medicine, 2007Co-Authors: Friedemann Paul, Sven Jarius, Diego Franciotta, Orhan Aktas, Martin Bluthner, Oliver Bauer, Heribert Appelhans, R Bergamaschi, E Littleton, J PalaceAbstract:Background Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) of putative autoimmune aetiology. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. Recently, using indirect immunofluorescence analysis, a new serum autoantibody (NMO-IgG) has been detected in NMO patients. The binding sites of this autoantibody were reported to colocalize with Aquaporin 4 (AQP4) water channels. Thus we hypothesized that AQP4 antibodies in fact characterize NMO patients. Methods and Findings Based on these observations we cloned human water channel AQP4, expressed the protein in a eukaryotic transcription/translation system, and employed the recombinant AQP4 to establish a new radioimmunoprecipitation assay (RIPA). Indeed, application of this RIPA showed that antibodies against AQP4 exist in the majority of patients with NMO (n = 37; 21 positive) as well as in patients with isolated longitudinally extensive transverse myelitis (n = 6; six positive), corresponding to a sensitivity of 62.8% and a specificity of 98.3%. By contrast, AQP4 antibodies were virtually absent in 291 other participants, which included patients with MS (n = 144; four positive), patients with other inflammatory and noninflammatory neurological diseases (n = 73; one positive), patients with systemic autoimmune diseases (n = 45; 0 positive), and healthy participants (n = 29; 0 positive). Conclusions In the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the Aquaporin 4 water channel is a target antigen in a majority of patients with NMO. The newly developed assay represents a highly specific, observer-independent, and easily reproducible detection method facilitating clinically relevant discrimination between NMO, MS, and other inflammatory diseases.
-
antibody to Aquaporin 4 in the diagnosis of neuromyelitis optica
PLOS Medicine, 2007Co-Authors: Friedemann Paul, Sven Jarius, Diego Franciotta, Orhan Aktas, Martin Bluthner, Oliver Bauer, Heribert Appelhans, R Bergamaschi, E Littleton, J PalaceAbstract:Background Neuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) of putative autoimmune aetiology. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. Recently, using indirect immunofluorescence analysis, a new serum autoantibody (NMO-IgG) has been detected in NMO patients. The binding sites of this autoantibody were reported to colocalize with Aquaporin 4 (AQP4) water channels. Thus we hypothesized that AQP4 antibodies in fact characterize NMO patients. Methods and Findings Based on these observations we cloned human water channel AQP4, expressed the protein in a eukaryotic transcription/translation system, and employed the recombinant AQP4 to establish a new radioimmunoprecipitation assay (RIPA). Indeed, application of this RIPA showed that antibodies against AQP4 exist in the majority of patients with NMO (n = 37; 21 positive) as well as in patients with isolated longitudinally extensive transverse myelitis (n = 6; six positive), corresponding to a sensitivity of 62.8% and a specificity of 98.3%. By contrast, AQP4 antibodies were virtually absent in 291 other participants, which included patients with MS (n = 144; four positive), patients with other inflammatory and noninflammatory neurological diseases (n = 73; one positive), patients with systemic autoimmune diseases (n = 45; 0 positive), and healthy participants (n = 29; 0 positive). Conclusions In the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the Aquaporin 4 water channel is a target antigen in a majority of patients with NMO. The newly developed assay represents a highly specific, observer-independent, and easily reproducible detection method facilitating clinically relevant discrimination between NMO, MS, and other inflammatory diseases.