Antibody to Aquaporin 4 in the Diagnosis of Neuromyelitis Optica

Friedemann Paul,Frauke Zipp,Edward Littleton,Martin Bluthner,Reinhard Hohlfeld,Roberto Bergamaschi,Sven Jarius,Jacqueline Palace,Heribert Appelhans,Hans-Peter Seelig,Diego Franciotta,Angela Vincent,Oliver Bauer,Orhan Aktas,Hans Lassmann

doi:10.1371/journal.pmed.0040133

Abstract

BackgroundNeuromyelitis optica (NMO) is a demyelinating disease of the central nervous system (CNS) of putative autoimmune aetiology. Early discrimination between multiple sclerosis (MS) and NMO is important, as optimum treatment for both diseases may differ considerably. Recently, using indirect immunofluorescence analysis, a new serum autoantibody (NMO-IgG) has been detected in NMO patients. The binding sites of this autoantibody were reported to colocalize with aquaporin 4 (AQP4) water channels. Thus we hypothesized that AQP4 antibodies in fact characterize NMO patients.Methods and FindingsBased on these observations we cloned human water channel AQP4, expressed the protein in a eukaryotic transcription/translation system, and employed the recombinant AQP4 to establish a new radioimmunoprecipitation assay (RIPA). Indeed, application of this RIPA showed that antibodies against AQP4 exist in the majority of patients with NMO (n = 37; 21 positive) as well as in patients with isolated longitudinally extensive transverse myelitis (n = 6; six positive), corresponding to a sensitivity of 62.8% and a specificity of 98.3%. By contrast, AQP4 antibodies were virtually absent in 291 other participants, which included patients with MS (n = 144; four positive), patients with other inflammatory and noninflammatory neurological diseases (n = 73; one positive), patients with systemic autoimmune diseases (n = 45; 0 positive), and healthy participants (n = 29; 0 positive).ConclusionsIn the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the aquaporin 4 water channel is a target antigen in a majority of patients with NMO. The newly developed assay represents a highly specific, observer-independent, and easily reproducible detection method facilitating clinically relevant discrimination between NMO, MS, and other inflammatory diseases.

Highlights

Neuromyelitis optica (NMO, Devic syndrome) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), mainly affecting the optic nerves and the spinal cord [1,2,3,4]
In the largest series reported so far to our knowledge, we quantified AQP4 antibodies in patients with NMO versus various other diseases, and showed that the aquaporin 4 water channel is a target antigen in a majority of patients with NMO
It is still unclear whether antibodies to AQP4 are specific for NMO and whether testing for these antibodies may be useful for its diagnosis and its distinction from diseases with similar clinical and neuroradiological patterns, such as multiple sclerosis (MS) and other autoimmune diseases with involvement of the CNS

Summary

Introduction

Neuromyelitis optica (NMO, Devic syndrome) is a chronic inflammatory demyelinating disease of the central nervous system (CNS), mainly affecting the optic nerves and the spinal cord [1,2,3,4]. It is still a matter of debate whether NMO represents a disease entity in itself or whether it is a subform of multiple sclerosis (MS). The researchers have developed a new assay for antibodies to AQP4 and quantified the antibodies in patients with NMO and other demyelinating diseases

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