Article

Antibody to aquaporin-4 in the long-term course of neuromyelitis optica

Neurosciences Group, Weatherall Institute of Molecular Medicine, and Department of Neurology, John Radcliffe Hospital, University of Oxford, UK.
Brain (Impact Factor: 10.23). 11/2008; 131(Pt 11):3072-80. DOI: 10.1093/brain/awn240
Source: PubMed

ABSTRACT 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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    • "between high anti-AQP4 Ab serum concentration and both transverse myelitis lesion length and disease activity [15]. Accordingly, Jarius et al. [16] and Waters et al. [17] described increased anti-AQP4 serum concentration during clinical relapses and a decrease following immunosuppressive therapy . Kim et al. suggested that anti-AQP4 Ab levels correlate with disease activity but noted that rising of anti-AQP4-Ab levels did not always lead to acute exacerbation [18]. "
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    ABSTRACT: Neuromyelitis optica (NMO) is an autoimmune disease in which a specific biomarker named NMO-IgG and directed against aquaporin-4 (AQP4) has been found. A correlation between disease activity and anti-AQP4 antibody (Ab) serum concentration or complement-mediated cytotoxicity has been reported, but the usefulness of longitudinal evaluation of these parameters remains to be evaluated in actual clinical practice. Thirty serum samples from 10 NMO patients positive for NMO-IgG were collected from 2006 to 2011. Anti-AQP4 Ab serum concentration and complement-mediated cytotoxicity were measured by flow cytometry using two quantitative cell-based assays (CBA) and compared with clinical parameters. We found a strong correlation between serum anti-AQP4 Ab concentration and complement-mediated cytotoxicity (P < 0.0001). Nevertheless, neither relapse nor worsening of impairment level was closely associated with a significant increase in serum Ab concentration or cytotoxicity. These results suggest that complement-mediated serum cytotoxicity assessment does not provide extra insight compared to anti-AQP4 Ab serum concentration. Furthermore, none of these parameters appears closely related to disease activity and/or severity. Therefore, in clinical practice, serum anti-AQP4 reactivity seems not helpful as a predictive biomarker in the followup of NMO patients as a means of predicting the onset of a relapse and adapting the treatment accordingly.
    Clinical and Developmental Immunology 04/2013; 2013:146219. DOI:10.1155/2013/146219 · 2.93 Impact Factor
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    • "In addition, a longitudinal study of eight NMO-IgG positive patients reported a correlation of serum anti-AQP4 Ig with clinical disease activity (Jarius et al., 2008a), demonstrating a threefold intra-individual increase of AQP4 IgG titers during relapse, which was not accompanied by other serum antibodies (Takahashi et al., 2006). Some papers suggest an effect of treatment on antibody titers, showing a reduction of NMO antibody titer levels after immunosuppressive treatment (Takahashi et al., 2006; Jarius et al., 2008a). Recently, an increase of anti-AQP4 antibody titers was described in one NMO patient following immunomodulatory treatment with IFN-ß (Palace et al., 2010). "
    Autoimmune Disorders - Current Concepts and Advances from Bedside to Mechanistic Insights, 11/2011; , ISBN: 978-953-307-653-9
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    • "Interestingly, the interruption of therapy in these patients was followed by a clinical relapse and an increase in anti-AQP4 values [Jarius et al. 2008]. However, whether or not the antibody level is correlated with disease activity in NMO remains a subject of debate. "
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    ABSTRACT: Neuromyelitis optica (NMO) is an inflammatory disease of the central nervous system (CNS) characterized by severe attacks of optic neuritis and myelitis, and which, unlike multiple sclerosis (MS), commonly spares the brain in the early stages. NMO used to be considered as a special form of MS. During the past 10 years, however, the two diseases have been shown to be clearly different. NMO is a B-cell-mediated disease associated with anti-aquaporin-4 antibodies in many cases and its pathophysiology seems to be near the acute lesion of necrotizing vasculitis. Assessment of prevalence shows that NMO is far less frequent than MS, which explains the absence of randomized clinical trials and NMO treatment strategies validated by evidence-based medicine. Recently, many data have been published that suggest that the therapeutic option in NMO should be immunosuppressive rather than immunomodulatory drugs. In the present study, after a brief overview of NMO, we review therapeutic studies and propose new therapeutic strategies in the relapse and disease-modifying fields.
    Therapeutic Advances in Neurological Disorders 03/2011; 4(2):111-21. DOI:10.1177/1756285611398939
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