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

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.

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

“…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.…”

Present and Future Therapies in Neuromyelitis Optica Spectrum Disorders

“…In line with these findings AQP4-IgG transiently increase after initiation of rituximab, with a subsequent decrease [107]. Lower titers of AQP4-IgG are probably associated with less disease activity but have not yet been established as a reliable biomarker of treatment response in rituximab-treated patients [74,100,101]. It is unknown whether the clinical effects of B-cell depletion are mediated by a reduction of AQP4-IgG or by inhibition of other proinflammatory B-cell functions.…”

“…Several studies including a total of almost 400 patients have shown that AZA reduces the ARR, sometimes associated with improvement of neurological disability [17,[74][75][76][77][78][79][80]. A retrospective study evaluating classical NMO and patients with AQP4-IgG-positive NMOSD reported a decrease in the mean ARR from 2.18 to 0.64 in 70 patients treated with AZA for >1 year, with or without concomitant corticosteroid therapy [77].…”

Plasma Exchange in Severe Attacks Associated with Neuromyelitis Optica Spectrum Disorder

“…NMO-IgG detection is a strong predictor of recurrence after an initial spinal or optic attack (Jarius et al, 2008(Jarius et al, , 2010b. In few patients, NMO-IgG was high during flares and became negative during the stabilized disease following treatment, and in contrary, an initially seronegative patient became positive during a further attack (Weinstock-Guttman et al, 2008).…”