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Anti-aquaporin-4 antibodies in Devic's neuromyelitis optica: therapeutic implications.

ABSTRACT: Devic's neuromyelitis optica (DNMO) is a demyelinating and inflammatory disease of the central nervous system (CNS) essentially restricted to the spinal cord and the optic nerves. It is a rare disorder with a prevalence estimated at less than 1/100,000 in Western countries. Since the first description by Eugène Devic in 1894, the relationship between DNMO and multiple sclerosis (MS) has been controversial. Recent clinical, epidemiological, pathological and immunological data demonstrate that MS and DNMO are distinct entities. This distinction between DNMO and MS is crucial, as prognosis and treatment are indeed different. DNMO is now considered to be an autoimmune, antibody-mediated disease especially since the identification of a specific serum autoantibody, named NMO-IgG and directed against the main water channel of the CNS, aquaporin-4 (AQP4). The assessment of AQP4 antibodies (Abs) has initially been proposed to differentiate DNMO and MS. It has also enlarged the clinical spectrum of DNMO and proved to be helpful in predicting relapses and conversion to DNMO after a first episode of longitudinally extensive transverse myelitis or isolated optic neuritis. Lastly, the discovery of the pathogenic role of AQP4 Abs in DNMO leads to a better understanding of detailed DNMO immunopathology and the elaboration of relevant novel treatment strategies specific to DNMO. In this review, we summarize the present and future therapeutic implications generated by the discovery of the various pathogenic mechanisms of AQP4 Abs in DNMO pathophysiology.

SUBMITTER: Marignier R

PROVIDER: S-EPMC3002663 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Anti-aquaporin-4 antibodies in Devic's neuromyelitis optica: therapeutic implications.

Marignier Romain R Giraudon Pascale P Vukusic Sandra S Confavreux Christian C Honnorat Jérôme J

Therapeutic advances in neurological disorders 20100901 5

Devic's neuromyelitis optica (DNMO) is a demyelinating and inflammatory disease of the central nervous system (CNS) essentially restricted to the spinal cord and the optic nerves. It is a rare disorder with a prevalence estimated at less than 1/100,000 in Western countries. Since the first description by Eugène Devic in 1894, the relationship between DNMO and multiple sclerosis (MS) has been controversial. Recent clinical, epidemiological, pathological and immunological data demonstrate that MS ...[more]

PMID: 21179621

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Project description:BackgroundRecognizing the predictors of disease relapses in patients with anti-aquaporin-4 antibody (AQP4-ab)-positive neuromyelitis optica spectrum disorder (NMOSD) is essential for individualized treatment strategy. We aimed to identify the factors that predicted relapses among patients with AQP4-ab-positive NMOSD, develop outcome prediction models, and validate them in a multicenter validation cohort.MethodsBetween January 2015 and December 2020, 820 patients with NMOSD were registered at Huashan Hospital. We retrospectively reviewed their medical records, and included 358 AQP4-ab-positive patients with 1135 treatment episodes. Univariate and multivariate analyses were used to explore the predictors of relapse, severe visual or motor disability during follow-up. A model predicting the 1- and 2-year relapse-free probability was developed and validated in an external validation cohort of 92 patients with 213 treatment episodes.ResultsLower serum AQP4-ab titer (< 1:100), higher Expanded Disability Status Scale (EDSS) score at onset (≥ 2.5), and use of intravenous methylprednisolone (IVMP) at the first attack predicted an overall lower annualized relapse rate. Older age (> 48 years), optic neuritis at onset, and higher onset EDSS score (≥ 2.5) significantly increased the risk for blindness, while IVMP at the first attack and maintenance therapy reduced the risk for blindness. Myelitis at onset increased the possibility of motor disability (EDSS ≥ 6.0), severe motor disability or death (EDSS ≥ 8.0), while maintenance therapy reduced these possibilities. Anderson and Gill model identified that the risk factors predicting recurrent relapses under certain treatment status were female gender, high AQP4-ab titer (≥ 1:100), previous attack under same therapy, lower EDSS score at treatment initiation (< 2.5), and no maintenance therapy or oral prednisone lasting less than 6 months. A nomogram using the above factors showed good discrimination and calibration abilities. The concordance indexes in the primary and validation cohort were 0.66 and 0.65, respectively.ConclusionThis study reports the demographic, clinical and therapeutic predictors of relapse, and severe visual or motor disability in NMOSD. Early identification of patients at risk of unfavorable outcomes is of paramount importance to inform treatment decisions.

Project description:Objective Neuromyelitis optica and its spectrum disorders (NMOSD) are inflammatory demyelinating diseases (IDD) with a specific biomarker, aquaporin-4-IgG. Prior NMO/NMOSD epidemiological studies are limited by lack of aquaporin-4-IgG seroprevalence assessment, absence of population-based USA studies and under-representation of blacks. To overcome these limitations, we sought to compare NMO/NMOSD seroepidemiology across two ethnically divergent populations. Methods We performed a population-based comparative study of the incidence (2003-2011) and prevalence (on December 31, 2011) of NMO/NMOSD and aquaporin-4-IgG seroincidence and seroprevalence (sera collected in 80-84% of IDD) among patients with IDD diagnosis in Olmsted County, USA (82% white [Caucasian]) and Martinique (90% black [Afro-Caribbean]). Aquaporin-4-IgG was measured by M1-isoform-fluorescent-activated-cell-sorting assays. Results The age and sex adjusted incidence (7.3 vs 0.7/1,000,000 person-years [p<0.01]) and prevalence (10 vs 3.9/100,000[p=0.01]) in Martinique exceeded that in Olmsted County. The AQP4-IgG age and sex-adjusted seroincidence (6.5 vs 0.7/1,000,000 person-years [p<0.01]) and seroprevalence (7.9 vs 3.3/100,000[p=0.04]) were also higher in Martinique than Olmsted County. The ethnicity-specific prevalence was similar in Martinique and Olmsted County: 11.5 and 13/100,000 in blacks, and 6.1 and 4.0/100,000 in whites, respectively. NMO/NMOSD represented a higher proportion of IDD in Martinique than Olmsted County (16% vs 1.4%; p<0.01). The onset age (median, 35-37 years) and female:male distribution (8-9:1) were similar across both populations; 60% of prevalent cases were either blind in one eye, dependent on a gait aid or both. Interpretation This study reports the highest prevalence of NMO/NMOSD in any population (10/100,000 in Martinique), estimates it affects 16,000-17,000 in the USA (higher than previous predictions) and demonstrates it disproportionately affects blacks. This article is protected by copyright. All rights reserved.

Project description:Autoantibodies to aquaporin-4 (AQP4) are pathogenic in neuromyelitis optica spectrum disorder (NMOSD). However, it is not known which B cells are the major contributors to circulating AQP4 antibodies nor which conditions promote their generation. Our experiments showed CD19+CD27++CD38++ circulating ex vivo antibody-secreting cells did not produce AQP4 antibodies under several culture conditions. To question whether other cells in circulation were capable of AQP4 antibody production, B cells were differentiated into antibody-secreting cells in vitro. Unfractionated peripheral blood mononuclear cells, isolated from 12 patients with NMOSD and a wide range of serum AQP4 antibody levels (91-26 610 units), were cultured with factors that mimicked established associations of NMOSD including T cell help, concurrent infections and cytokines reported to be elevated in NMOSD. Overall, the in vitro generation of CD19+CD27++CD38++ cells across several culture conditions correlated closely with the total IgG secreted (P < 0.0001, r = 0.71), but not the amount of AQP4 antibody. AQP4 antibody production was enhanced by CD40-ligand (P = 0.005), and by interleukin-2 plus toll-like receptor stimulation versus interleukin-21-predominant conditions (P < 0.0001), and did not require antigen. Across NMOSD patients, this in vitro generation of AQP4 antibodies correlated well with serum AQP4 antibody levels (P = 0.0023, r = 0.81). To understand how early within B cell lineages this AQP4 specificity was generated, purified B cell subsets were activated under these optimized conditions. Naïve pre-germinal centre B cells (CD19+CD27-IgD+) differentiated to secrete AQP4 antibodies as frequently as post-germinal centre cells (CD19+CD27+). Taken together, these human cell-culture experiments demonstrate that preformed B cells, rather than ex vivo circulating antibody-secreting cells, possess AQP4 reactivity. Their differentiation and AQP4 antibody secretion is preferentially driven by select cytokines and these cells may make the dominant contribution to serum AQP4 antibodies. Furthermore, as AQP4-specific B cells can derive from likely autoreactive naïve populations an early, pre-germinal centre loss of immunological tolerance appears present in some patients with NMOSD. This study has implications for understanding mechanisms of disease perpetuation and for rational choice of immunotherapies in NMOSD. Furthermore, the in vitro model presents an opportunity to apply condition-specific approaches to patients with NMOSD and may be a paradigm to study other antibody-mediated diseases.awy010media15732448284001.

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Anti-aquaporin-4 antibodies in Devic's neuromyelitis optica: therapeutic implications.

Publications

Anti-aquaporin-4 antibodies in Devic's neuromyelitis optica: therapeutic implications.

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