Jarius, S. et al. Antibody to aquaporin-4 in the long-term course of neuromyelitis optica. Brain 131, 3072-3080

Neurosciences Group, Weatherall Institute of Molecular Medicine, and Department of Neurology, John Radcliffe Hospital, University of Oxford, UK.
Brain (Impact Factor: 9.2). 11/2008; 131(Pt 11):3072-80. DOI: 10.1093/brain/awn240
Source: PubMed


Neuromyelitis optica (NMO) is a severe inflammatory CNS disorder of putative autoimmune aetiology, which predominantly affects the spinal cord and optic nerves. Recently, a highly specific serum reactivity to CNS microvessels, subpia and Virchow-Robin spaces was described in patients with NMO [called NMO-IgG (NMO-immunoglobulin G)]. Subsequently, aquaporin-4 (AQP4), the most abundant water channel in the CNS, was identified as its target antigen. Strong support for a pathogenic role of the antibody would come from studies demonstrating a correlation between AQP4-Ab (AQP4-antibody) titres and the clinical course of disease. In this study, we determined AQP4-Ab serum levels in 96 samples from eight NMO-IgG positive patients (median follow-up 62 months) in a newly developed fluorescence-based immunoprecipitation assay employing recombinant human AQP4. We found that AQP4-Ab serum levels correlate with clinical disease activity, with relapses being preceded by an up to 3-fold increase in AQP4-Ab titres, which was not paralleled by a rise in other serum autoantibodies in one patient. Moreover, AQP4-Ab titres were found to correlate with CD19 cell counts during therapy with rituximab. Treatment with immunosuppressants such as rituximab, azathioprine and cyclophosphamide resulted in a marked reduction in antibody levels and relapse rates. Our results demonstrate a strong relationship between AQP4-Abs and clinical state, and support the hypothesis that these antibodies are involved in the pathogenesis of NMO.

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    • "It cannot be excluded that the rituximab therapy affected the detectability of these antibodies [2] [22]. Thus, the first measurement should be performed before treatment is initiated; this was not done in our patient's case [23]. In one study the connection between brainstem symptoms and seropositivity was found [16]. "
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    ABSTRACT: Aim Neuromyelitis optica is an autoimmune disorder connected with the effect of IgG antibodies against water channels (aquaporin-4) in the central nervous system. In the course of the disease, there is the involvement of the optic nerves and the spinal cord, resulting in a progressive disability. In the treatment, immunosuppressive agents are used as well as monoclonal antibodies such as rituximab (anti-CD20). According to the results, rituximab is the most effective, safe and recommended as a first-line treatment. Until now the duration and frequency of this therapy has not been established. The aim of this report is to provide the information necessary to create the optimal rituximab dosing regimen. Case An NMO patient, who was treated with rituximab for 6 years depending on the blood CD19+ B lymphocytes titres, is presented here. The complete relapse restrain and clinical stabilisation were achieved, with beneficial effect remaining even after the rituximab treatment was terminated – present observation period is almost 4 years without any immunosuppressive or immunomodulating treatment. Since the treatment was stopped, the CD19+ B lymphocyte population tends to rise, but the neurological state has not changed. The most recent magnetic resonance imaging (MRI) of the cervical spine, from 2014, showed a post-inflammatory lesion between the medulla and the cervical spine, which had been present before, without any new inflammatory lesions. The IgG antibodies against AQP-4 assays were performed in 2013 for the first time and were negative. Comment Temporary rituximab therapy in neuromyelitis optica may lead to a prolonged remission lasting some years.
    Full-text · Article · Nov 2015
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    • "However, as mentioned above, AECA were negative also in a relevant number of samples taken from untreated patients or taken during active disease. Moreover, several of our AECA-positive patients had very high titers also during remission (similarly, autoantibodies remain detectable during remission in many neurological and non-neurological autoimmune disorders such as AQP4-Ab-positive NMO [15,29], myasthenia gravis [30] or SLE [31]. These findings suggest that treatment and disease activity are not the only factor determining AECA serostatus; instead, AECA may be truly absent in some cases of SuS as discussed above. "
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    ABSTRACT: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed.Objectives: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS.Patients and methods: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections. IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. Ten IgG-AECA-positive samples (90.9%), were positive also for IgA-AECA and 5 (45.5%) for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed. SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS.
    Full-text · Article · Mar 2014 · Journal of Neuroinflammation
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    • "In addition, good network communication is provided by the Austrian Society of Neurology and by the National Task Force for NMO (‘ARGE NMO’ [ARbeitsGEmeinschaft NeuroMyelitis Optica], A nationwide collaboration was initiated by ARGE NMO and has already resulted in the publication of several studies [6-11]. The vigilance of Austrian neurologists for NMO and NMO-SD is considered to be high (see methods below). "
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    ABSTRACT: In 2008 the Austrian Task Force for Neuromyelitis Optica (NMO) started a nation-wide network for information exchange and multi-centre collaboration. Their aim was to detect all patients with NMO or NMO spectrum disorders (NMO-SD) in Austria and to analyse their disease courses and response to treatment. (1) As of March 2008, 1957 serum samples (of 1557 patients) have been tested with an established cell based immunofluorescence aquaporin-4 antibody (AQP4-ab) assay with a high sensitivity and specificity (both >95%). All tests were performed in a single reference laboratory (Clinical Dept. of Neurology of the Innsbruck Medical University). (2) A nation-wide survey with several calls for participation (via email newsletters, articles in the official journal of the Austrian Society of Neurology, and workshops) was initiated in 2008. All collected data will be presented in a way that allows that every individual patient can be traced back in order to ensure transparency and to avoid any data distortion in future meta-analyses. The careful and detailed presentation allows the visualization and comparison of the different disease courses in real time span. Failure and response to treatment are made visible at one glance. Database closure was 31 December 2011. All co-operators were offered co-authorship. All 71 NMO- or NMO-SD patients with AQP4-ab positivity (age range 12.3 to 79.6 years) were analysed in detail. Sex ratio (m:f = 1:7) and the proportion of patients without oligoclonal bands in cerebrospinal fluid (86.6%) were in line with previously published results. All identified patients were Caucasians. A nationwide collaboration amongst Austrian neurologists with good network communications made it possible to establish a database of 71 AQP4-ab positive patients with NMO/NMO-SD. This database is presented in detail and provides the basis for further studies and international cooperation in order to investigate this rare disease.
    Full-text · Article · Nov 2013 · PLoS ONE
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