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

Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, Lang W, Reindl M, Vincent A, Kristoferitsch W - Brain (2008)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neurosciences Group, Weatherall Institute of Molecular Medicine, and Department of Neurology, John Radcliffe Hospital, University of Oxford, UK.

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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AQP4-Ab serum levels before and after (values refer to Nadir values) eight applications of rituximab in four patients with NMO/LETM (P = 0.0156; Wilcoxon matched-pairs rank sum test).
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Figure 4: AQP4-Ab serum levels before and after (values refer to Nadir values) eight applications of rituximab in four patients with NMO/LETM (P = 0.0156; Wilcoxon matched-pairs rank sum test).

Mentions: CD19 cell numbers declined after treatment with rituximab following a protocol proposed by Cree and co-workers (Cree et al., 2005). They reappeared after 251, 258, 265, 272 and 350 days, respectively, following the last application of rituximab, with slight rises in cell counts being associated with a strong increase in AQP4-Ab values (Fig. 2A, day 3168; Fig. 2B, day 1392). Although application of the drug was followed by a prompt and marked decline in titres (51–90%; P = 0.02, Wilcoxon's matched-pairs rank sum test; Fig. 4), AQP4-Ab remained detectable during therapy with rituximab in 29/30 samples. Moreover, AQP4-Ab was still positive despite the cell numbers being below the detection limit in 16/17 samples. No correlation between CD19 cell count and AQP4-Ab values was found in those patients not treated with rituximab (data not shown).Fig. 4


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

Jarius S, Aboul-Enein F, Waters P, Kuenz B, Hauser A, Berger T, Lang W, Reindl M, Vincent A, Kristoferitsch W - Brain (2008)

AQP4-Ab serum levels before and after (values refer to Nadir values) eight applications of rituximab in four patients with NMO/LETM (P = 0.0156; Wilcoxon matched-pairs rank sum test).
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2577801&req=5

Figure 4: AQP4-Ab serum levels before and after (values refer to Nadir values) eight applications of rituximab in four patients with NMO/LETM (P = 0.0156; Wilcoxon matched-pairs rank sum test).
Mentions: CD19 cell numbers declined after treatment with rituximab following a protocol proposed by Cree and co-workers (Cree et al., 2005). They reappeared after 251, 258, 265, 272 and 350 days, respectively, following the last application of rituximab, with slight rises in cell counts being associated with a strong increase in AQP4-Ab values (Fig. 2A, day 3168; Fig. 2B, day 1392). Although application of the drug was followed by a prompt and marked decline in titres (51–90%; P = 0.02, Wilcoxon's matched-pairs rank sum test; Fig. 4), AQP4-Ab remained detectable during therapy with rituximab in 29/30 samples. Moreover, AQP4-Ab was still positive despite the cell numbers being below the detection limit in 16/17 samples. No correlation between CD19 cell count and AQP4-Ab values was found in those patients not treated with rituximab (data not shown).Fig. 4

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Neurosciences Group, Weatherall Institute of Molecular Medicine, and Department of Neurology, John Radcliffe Hospital, University of Oxford, UK.

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.

Show MeSH
Related in: MedlinePlus