AQP4 Antibody Research Articles

CD58 polymorphisms associated with the risk of neuromyelitis optica in a Korean population.

BackgroundNeuromyelitis optica (NMO) is a serious inflammatory demyelinating disease (IDD), characterized by the inflammation and demyelination of optic nerves and spinal cords, which subsequently leads to the loss of function. In a previous genome-wide association study, cluster of differentiation 58 (CD58) region was found to be susceptible for the risk of multiple sclerosis (MS) in Caucasian, and the association between CD58 variants and MS was replicated in Americans. However, no study has been conducted to explore the possible association between CD58 and NMO yet. Thus, this study aimed to investigate the association of CD58 polymorphisms with the risk of NMO in a Korean population.MethodsUsing TaqMan assay, 6 single nucleotide polymorphisms (SNPs) were genotyped in 98 NMO patients and 237 normal controls (N = 336). Logistic regression analysis was conducted to find a possible association between CD58 polymorphisms and NMO.ResultsThe analysis results showed that 6 variations (rs2300747, rs1335532, rs12044852, rs1016140, CD58_ht1, and CD58_ht3) showed significant associations (P = 0.002 ~ 0.008, Pcorr = 0.01 ~ 0.04).ConclusionThe genetic variations in CD58 may be associated with the susceptibility of NMO in a Korean population. Based on previous studies, we suspect that the A allele of rs2300747 may decrease CD58 RNA expression, thus increasing NMO risk. Also, we deduced that the G allele of rs1016140 caused an increase of T cell activity, which in turn eased the access of AQP4 antibody into central nervous system (CNS) and ultimately leading to NMO development.

Brain gadolinium enhancement along the ventricular and leptomeningeal regions in patients with aquaporin-4 antibodies in cerebral spinal fluid

BackgroundAquaporin-4 (AQP4) is densely expressed in the ependymal region and leptomeninges, and it is susceptible to pathological responses triggered by antibodies from blood and cerebral spinal fluid (CSF). Therefore, enhancement of these regions may be related to neuromyelitis optica spectrum disorder (NMOSD). MethodsMRI from a consecutive cohort of 84 subjects (NMOSD=47, multiple sclerosis [MS]=37) with AQP4 antibodies in serum and CSF were analyzed retrospectively. ResultsThe brain was normal in five of the 47 patients with NMOSD and none of the MS patients showed a normal brain. Twelve patients in each group had parenchymal enhancing lesions. Of these, white matter enhancement was more frequently found in MS patients than in NMOSD patients (12/12 vs 4/12, p=0.001). “Cloud-like” enhancement was found in three NMOSD patients (3/12) and in one MS patient. Nine of the 12 NMOSD patients showed “pencil-thin” ependymal enhancement, whereas one of the 12 MS patients showed ependymal enhancement (p=0.003). Enhancement along the lateral ventricle was more frequently found in NMOSD patients than in MS patients (p=0.027), whereas enhancing lesions around the fourth ventricle tended to be more frequent in NMOSD patients than MS patients (p=0.097). Leptomeningeal enhancement around the brainstem was found in six (12.8%) NMOSD patients and in no MS patients (p=0.032). ConclusionEnhancement of the leptomeninges and ventricular ependymal region more frequently occurs in NMOSD patients than in MS patients. This may be considered as characteristic clue in the diagnosis of NMOSD.

Neuromyelitis Optica Spectrum Disorder and Neurosyphilis Coexist in A Chinese Woman

Background: Neuromyelitisoptica spectrum disorder (NMOSD) is a series of central nervous system diseases with positive aquaporin-4 antibody. And neurosyphilis is a manifestation of the late syphilis. Although Neuromyelitisoptica (NMO) following syphilis has been previously reported, transverse myelitis and neurosyphilis in the same patient with positive aquaporin-4 antibody has never been mentioned. Method: We presented the coexistence of NMOSD and syphilis in a 72-year-oldChinese woman and analyzed the relationship of these two diseases. The pertinent literatures were also reviewed. Result: Previous studies showed that syphilitic myelitis might be more frequent in male than in female and it tended to be asymptomatic. However our case was a woman who experienced acute attack, with positive AQP4 antibody. Therefore, her myelitis occurrence mainly associated with AQP4 antibodies autoimmunity, and neurosyphilis might be an asymptomatic episode in our case. Although there was no evidence that treponema pallidum subspecies pallidum involved in the pathogenesis of NMO, it seemed that anti-syphilitic treatment was helpful to attenuate disability in our present case. Conclusion: Anti-NMO and anti-syphilitic treatment should be used together to treat the patient with both NMOSD and neurosyphilis.

PAIN IN NEUROMYELITIS OPTICA IS AN UNDER–RECOGNISED BUT DISABLING SYMPTOM

BackgroundNeuromyelitis Optica (NMO) is an autoimmune inflammatory demyelinating disorder of the central nervous system that affects the optic nerve and spinal cord: frequent relapses and the absence of full remission...

Antibodies identified by cell‐based assays in myasthenia gravis and associated diseases

We have established cell-based assays for the improved detection of acetylcholine receptor (AChR) and muscle-specific kinase (MuSK) antibodies in myasthenia gravis. This approach has enabled us to demonstrate antibodies to "clustered" AChRs in patients who were previously AChR antibody negative and can also be used to distinguish between adult and fetal AChR antibodies in mothers of babies with arthrogryposis multiplex congenita. We summarize our recent evidence for the pathogenicity of MuSK and clustered AChR antibodies using in vivo models. Cell-based assays are now also being used for the detection of other antibodies, such as those directed to components of the VGKC/CASPR2/LGI1 complex in Morvan's syndrome, and to AQP4 antibodies in neuromyelitis optica; both of these diseases can be associated with MG and sometimes thymoma. The cell-based method is time consuming but has many advantages and may provide a gold standard for the future in the detection of pathogenic autoantibodies in patients with immune-mediated diseases.

149 The national diagnostic and advisory service for NMO: an overview of the service

In April 2010, a Nationally Commissioned Neuromyelitis Optica (NMO) service was set up as a joint venture between Liverpool and Oxford. This service covers neurological specialist care to patients with...

162 The association of two rare neurological diseases: a multicentre study of 16 patients with AChR antibody myasthenia gravis and AQP4 antibody neuromyelitis optica spectrum disorder

Aquaporin-4 antibody-mediated neuromyelitis optica spectrum disorders (AQP4-NMOSD) and acetylcholine receptor antibody-mediated myasthenia gravis (AChR-MG) are rare neurological autoimmune diseases. We describe the largest cohort of patients with both conditions. The...

Aquaporin-4 antibodies and idiopathic intracranial hypertension: the jury is in and the channels are out

The aquaporins are transmembrane water channel proteins that regulate water homeostasis in the body; of the many aquaporin (AQP) subtypes, AQP-4 is the predominant channel expressed in brain, with expression localized to astrocytic foot processes surrounding capillary endothelium (1). We generally think of AQP-4 in the context of cerebral edema. AQP-4 appears to be important in the development of cellular (cytoxic) edema in response to ischemic and toxic injuries (1), as high levels of AQP-4 expression correlate with sites of early cellular edema. Moreover, mice that are deficient in AQP-4 are more resistant both to cellular edema that is induced experimentally by water loading and to ischemia (2,3). On the other hand, AQP-4 does not appear to influence the rate of extracellular (vasogenic) edema formation. Extracellular edema results from processes that interrupt the blood-brain barrier (BBB), such as tumors, intracranial hemorrhage and brain infections (1). AQP-4 may be involved in fluid clearance resulting from extracellular edema, and it has been hypothesized that ‘normal’ clearance of proteins through the ventricles and CSF pathways is reversed when the intracranial pressure (ICP) is elevated. According to this theory, when the system becomes overwhelmed in the setting of intracranial hypertension/hydrocephalus, extracellular fluid is absorbed via the brain parenchyma via capillary clearance (4). AQP-4-deficient mice, studied under conditions known to provoke BBB disruption and edema formation, developed greater increases in water content and ICP than wild-type mice (5). Idiopathic intracranial hypertension (IIH) is characterized by increased ICP without ventriculomegaly, occurring predominantly in obese females in their child-bearing years. The absence of hydrocephalus makes IIH somewhat more usual than other disorders causing increased ICP, and this aspect of IIH has confounded clinicians and researchers since the disease was first described. A disorder of cerebrospinal fluid regulation is implicit but the pathogenesis of IIH remains elusive. Ekizoglu and colleagues measured serum anti-AQP4-antibody levels in subjects with IIH, neuromyelitis optica and controls with encephalitis and report their findings in the current issue of Cephalalgia (6). AQP-4 antibodies were not detected in any patients with IIH. Their study has potential limitations, as not all patients were studied at the onset of their disease and those with ongoing chronic headaches may have had normal intracranial pressure at the time they were studied. Nonetheless, the results were consistent with those of Dhungana et al, who did not detect anti-AQP-4-antibody levels in the serum and CSF of participants with IIH or in control participants being investigated for acute headache conditions (7). AQP-4 antibodies are commonly (but not ubiquitously) found in patients with neuromyelitis optica (NMO), a demyelinating disorder ascribed to inflammatory and autoimmune processes and not associated with increased ICP. These antibodies are fairly specific for the diagnosis of NMO. The NMO immunoglobulin G binding pattern was also assessed in the current study (6); serum from four of the 29 patients with IIH showed cytoplasmic cerebellar Purkinje cell immunoreactivity and four showed diffuse neuronal nuclear staining that is typically associated with NMO. The significance of this pattern is uncertain, as it was also present in serum from patients with encephalitis and other inflammatory/demyelinating disorders. Is it possible that inflammation has a role in the development or

Comparison of the Cytokine Profiles of Patients With Neuronal-Antibody-Associated Central Nervous System Disorders

ABSTRACTLevels of several cytokines were evaluated in the sera of patients with neuromyelitis optica (NMO) and paraneoplastic or nonparaneoplastic autoimmune encephalitis (AE) and healthy controls (HC). AE patients had higher serum interleukin-17 (IL-17), interferon-gamma (IFN-γ), and IL-12 levels than NMO patients and HC. Also, AE patients with antibodies to cell surface antigens (voltage-gated potassium channel, N-methyl-d-aspartate receptor) displayed increased serum Th17 cytokine (IL-17, IL-23) levels as compared with AE patients with antibodies to intracellular antigens (Hu, Yo), NMO patients, and HC. Aquaporin-4 (Aqp-4) antibody positive NMO patients had higher serum IL-9 levels than Aqp-4 antibody negative NMO patients. IL-17, IL-23, IL-12, and antibody levels were significantly correlated in AE patients with antibodies to cell surface antigens. Our results support the notion that different pathogenic mechanisms are involved in central nervous system diseases associated with antibodies to intracellular and cell surface neuronal antigens. T helper 1 (Th1)-/Th17-type immunities and IL-9 might be important therapeutic targets in AE and NMO, respectively.

Aquaporin-4 antibodies are not present in patients with idiopathic intracranial hypertension

We aimed to investigate anti-aquaporin-4 (AQP-4) water channel antibodies, affecting cerebrospinal fluid (CSF) secretion and absorption, in idiopathic intracranial hypertension (IIH) patients. Patients fulfilling the modified Dandy's diagnostic criteria for IIH were included and their clinical features and CSF findings were reviewed. Their serum samples and control groups were investigated by immunofluorescence and a cell-based assay for anti-AQP-4 antibodies and by immunohistochemistry for IgG binding patterns. Twenty-nine patients diagnosed with IIH were investigated. We could not detect any anti-AQP-4 antibodies in our series. However, we identified different serum IgG binding patterns in 11 IIH patients. There is only one report investigating the anti-AQP4 antibodies in IIH. Our study with a larger sample confirmed the results of this report and indicated that AQP4 antibodies did not have a primary role in IIH pathogenesis, but provided some support for the contribution of inflammatory mechanisms in IIH.

Where Do AQP4 Antibodies Fit in the Pathogenesis of NMO?

Recent advances in the field of neuromyelitis optica (NMO) research provided convincing evidence that anti-AQP4 antibody (AQP4-Ab) not only serves as a highly specific disease marker, but also plays an essential role in the pathogenesis of the disease. Although it is now widely recognized that AQP4-Ab induces astrocytic necrosis in a complement-dependent manner, additional triggers are also suspected as a prerequisite for the development of the disease. Unraveling these unresolved aspects of the disease will provide substantial insight into still controversial issues in the pathogenesis of NMO.

Does detection of anti-AQP4 antibodies trump clinical criteria for neuromyelitis optica?

Neuromyelitis optica (NMO) is a common or even predominant form of CNS demyelinating disease in Asian and African countries, but controversy as to how it can be distinguished from multiple sclerosis (MS) in Asian countries persists. In this issue of Neurology ®, Siritho et al.1 report a retrospective analysis of 135 consecutive Thai patients with idiopathic inflammatory CNS demyelinating disease. These patients were categorized sequentially by satisfying the most specific to least specific clinical criteria, as follows: NMO, based on Wingerchuk et al. 2006 criteria2 (excluding anti-aquaporin 4 [AQP4] seropositivity); NMO spectrum disorder (limited forms of myelitis or optic neuritis syndromes, in some cases with brain lesions now regarded as suggestive of NMO); optic-spinal MS (dominant optic neuritis and myelitis but lacking a longitudinally extensive spinal cord lesion [LESCL], precluding a diagnosis of definite NMO); classic MS; and indeterminate clinically isolated syndromes. Serum was tested blind in Japan for AQP4 autoantibodies using a sensitive cell-based immunofluorescence assay; 40% were seropositive. Although the proportion of seropositive cases in each category declined from NMO (78%) to clinically isolated syndrome (6.3%), the proportion of seropositive cases among the total study population was equally distributed among 3 categories: 34% NMO, 36% NMO spectrum disorder, and 30% others, including classic MS. Considering the specificity of AQP4 antibodies as demonstrated worldwide, at first glance …

A population-based study of neuromyelitis optica in Caucasians

Epidemiologic studies have suggested different prevalence of neuromyelitis optica (NMO) in different ethnic groups. However, data on the incidence and prevalence of NMO in Caucasians are scarce. To estimate the incidence and prevalence of NMO in a predominantly Caucasian population based on the Wingerchuk 2006 criteria. The study was a population-based retrospective case series with longitudinal follow-up. Patients with multiple sclerosis (MS), optic neuritis (ON), acute transverse myelitis (TM), and NMO from the 4 neurology and 3 ophthalmology departments in the Region of Southern Denmark having been diagnosed between 1998 and 2008 were investigated. Patients were included based on 1) episodes of ON or TM and 2) an initial brain MRI not diagnostic for MS. An immunofluorescence assay was used to determine aquaporin-4 (AQP-4) antibodies. A total of 477 patients with MS, TM, or ON were evaluated: 163 fulfilled the inclusion criteria, 42 (26%) qualified for the diagnosis of NMO, 26 (62.0%) of these were AQP4 antibody positive. All except one were Caucasian, the female:male ratio was 2.8:1, and mean age at onset was 35.6 years (range 15-64 years). The clinical presentation was heterogeneous including TM, longitudinally extensive TM, ON, and brainstem syndromes. The yearly incidence rate of NMO in the population was estimated to be 0.4 per 10(5) person-years (95% confidence interval [CI] 0.30-0.54) and the prevalence was 4.4 per 10(5) (95% CI 3.1-5.7). Despite being a rare disease, NMO is more common in a Caucasian population than earlier believed.

PAW33 Aquaporin-4 M 23 isoform provides a more sensitive assay for aquaporin-4 antibodies

Neuromyelitis optica (NMO) is a serious inflammatory, demyelinating disease affecting the spinal cord and optic nerves. IgG antibodies to aquaporin-4 (AQP4) in patients' sera are now taken as evidence for...

AQP4 antibodies in neuromyelitis optica: diagnostic and pathogenetic relevance

Antibodies to aquaporin-4 (also known as AQP4-Ab or NMO-IgG) are sensitive and highly specific serum markers of autoimmune neuromyelitis optica (NMO). Second-generation recombinant diagnostic assays can detect AQP4-Ab in >or=80% of patients with NMO, and a role for AQP4-Ab in the pathophysiology of this condition was corroborated by a series of in vitro studies that demonstrated disruption of the blood-brain barrier, impairment of glutamate homeostasis and induction of necrotic cell death by AQP4-Ab-positive serum. Additional evidence for such a role has emerged from clinical observations, including the demonstration of a correlation between serum levels of AQP4-Ab and disease activity. The finding of NMO-like CNS lesions and clinical disease following passive transfer of AQP4-Ab-positive serum in several independent animal studies provided definitive proof for a pathogenic role of AQP4-Ab in vivo. Together, these findings provide a strong rationale for the use of therapies targeted against B cells or antibodies in the treatment of NMO. In this Review, we summarize the latest evidence in support of a direct involvement of AQP4-Ab in the immunopathogenesis of NMO, and critically appraise the diagnostic tests currently available for the detection of this serum reactivity.

Absence of aquaporin-4 antibodies in patients with idiopathic intracranial hypertension

The pathophysiology of abnormal cerebrospinal fluid (CSF) dynamics in idiopathic intracranial hypertension (IIH) is not clear [1]. In healthy individuals, CSF is mostly formed in the choroid plexus with small contributions from extrachoroidal tissues, including ependymal surfaces of the brain and the capillary–astrocyte complex in the blood-brain barrier. It is reabsorbed into the dural venous sinuses through the arachnoid villi, although other sites are increasingly being recognised [10]. Several theories have been suggested to explain the aetiology of raised CSF pressure in IIH, including increased CSF production, impaired CSF absorption, obstruction of dural venous sinuses and increased brain volume due to cerebral oedema [6]. More recently, the potential role of proinflammatory CSF profiles have been suggested in some studies [2, 5]. Aquaporins are a recently discovered family of transmembrane water channels which play an important role in water homeostasis in the central nervous system (CNS) and are thought to be involved in the pathophysiologic mechanisms of cerebral oedema [3]. Aquaporin (AQP)-1 is natively expressed in the choroid plexus and contributes to water transport across the choroidal epithelium during CSF secretion. AQP-4 is more widely distributed within the CNS, including the choroid plexus [13] and ependymal cells of the ventricles [9]. Bloch et al. [4] suggested that AQP-4 could facilitate CSF absorption in hydrocephalus. Recently, antibodies to AQP-4 have been suggested to play a role in the pathogenesis of neuromyelitis optica (NMO) [11]. We hypothesised that a dysfunction of AQP-4 expression could affect CSF secretion or absorption and potentially contribute to the pathogenesis of IIH. In this study, we utilised a recently described anti-AQP-4 antibody assay [14] to look for AQP-4 antibodies in the serum and CSF of patients with IIH. We were not able to investigate the role of anti-AQP-1 antibodies because such an assay is currently not available. Paired CSF and serum samples from 10 female symptomatic IIH patients [mean age 31.8 ± 7.8 years; mean body mass index (BMI) 33.4 ± 6.9 kg/m] who were diagnosed according to the updated modified Dandy criteria [8] and 10 female control subjects (mean age: 35.8 ± 12.1 years; mean BMI: 31.7 ± 8.8 kg/m) were examined for anti-AQP-4 antibodies. Control subjects were patients who presented with headache and had lumbar puncture to exclude subarachnoid haemorrhage or raised intracranial pressure, and who were subsequently diagnosed with migraine or tension-type headache. The study was approved by South Yorkshire research ethics committee and all participants provided written informed consent. S. Dhungana A. Ismail B. Sharrack Department of Neurology, Sheffield Teaching Hospitals NHS Trust, University of Sheffield, Sheffield, UK

Immunoglobulin M antibodies to aquaporin-4 in neuromyelitis optica and related disorders

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. 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. 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. 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.

Enhanced IL-6 Production in Aquaporin-4 Antibody Positive Neuromyelitis Optica Patients

ABSTRACTAnti-aquaporin-4 (Aqp-4) antibody and complement system have emerged as major pathogenic factors in neuromyelitis optica (NMO). To test the significance of interleukin-6 (IL-6), another important humoral immunity factor, in NMO pathogenesis, we measured serum and cerebrospinal fluid (CSF) IL-6 levels of 23 NMO, 11 transverse myelitis, 16 optic neuritis, 27 relapsing remitting multiple sclerosis patients, and 20 neurologically normal controls. NMO and transverse myelitis patients had higher serum and CSF IL-6 levels than other groups. Particularly, anti-Aqp-4 positive NMO patients (n == 12) had higher serum/CSF IL-6 levels than anti-Aqp-4 negative patients (n == 11) and CSF IL-6 levels correlated with anti-Aqp-4 levels and disease severity of the NMO patients. Our results suggest that IL-6 is involved in NMO pathogenesis presumably via anti-Aqp-4 associated mechanisms.

Sjögren’s syndrome myelopathy: spinal cord involvement in Sjögren’s syndrome might be a manifestation of neuromyelitis optica

Objective To evaluate clinical characteristics, aquaporin (AQP)-4 antibody results, and probability of developing symptoms of neuromyelitis optica (NMO) in patients with Sjögren’s syndrome myelopathy (SSM). Methods We identified eight patients with spinal cord involvement from 112 patients with Sjögren’s syndrome (SS) referred to the neurology department. The clinical characteristics and AQP-4 antibody status, based on immunoprecipitation of EGFP-tagged AQP-4, of the patients with SSM were assessed. Results All patients with SSM had extensive spinal cord lesions, high mean annual relapse rates, and poor response to steroid treatment. Of the eight patients with SSM, seven patients satisfied the revised diagnostic criteria for NMO or showed positive results from AQP-4 antibody testing; one patient had incomplete follow-up. The clinical manifestations and AQP-4 autoantibody status of patients with SSM did not differ significantly from those of NMO patients without SS. Conclusion All patients with SSM had poor prognosis with high mean annual relapse rates, and most seemed to have the clinical and immunological characteristics of NMO. Early aggressive immune therapies should be considered in patients with SSM irrespective of the presence or absence of optic neuritis.

High-salt loading exacerbates increased retinal content of aquaporins AQP1 and AQP4 in rats with diabetic retinopathy

In the neural retina, glial cells control formation of ionic gradients by mediating transmembrane water fluxes through aquaporin (AQP) water channels. Retinal content and immunolocalization of two water channels, AQP1 and AQP4, in the diabetic rat retinas during high-salt loading were examined in this study. Diabetes was induced by an intraperitoneal injection of streptozotocin. Diabetic and control animals were observed after varying lengths of exposure to normal- and high-salt conditions. Ultrathin sections of retinal tissue, stained with uranyl acetate and lead citrate, were photographed using a transmission electron microscope (TEM). Retinal wholemounts were immunostained with AQP1 and AQP4 antibody to detect the immunolocalization changes by confocal microscopy. AQP1 and AQP4 content were evaluated by Western blot analysis. In the retinas of high-salt loading diabetic animals, obviously increased intracellular edema was observed by TEM in ganglion cells and mitochondrial swelling was observed in glial cells. Immunolocalization of AQP1 increased from the posterior to peripheral retina. Western blot results indicated that a high-salt diet may cause increased retinal content of AQP4 and may exacerbate increased retinal content of AQP1 caused by diabetic retinopathy. High-salt loading may increase neural retinal edema in rats with diabetic retinopathy, and altered glial cell mediated water transport via AQP channels in the retina may play an important role in the neural retinal edema formation and resolution.