Elsevier

Clinica Chimica Acta

Volume 415, 16 January 2013, Pages 350-360
Clinica Chimica Acta

Invited critical review
Aquaporins, anti-aquaporin-4 autoantibodies and neuromyelitis optica

https://doi.org/10.1016/j.cca.2012.04.027Get rights and content

Abstract

The classification, distribution and functions of the different molecules of aquaporins (AQPs), including aquaporins, aquaglyceroporins and superaquaporins are reviewed together with their potential diagnostic and therapeutic uses. We analyzed the pathogenic importance of anti-AQP4 autoantibodies in neuromyelitis optica and related syndromes, as well as their diagnostic and predictive potential, prognosis, and monitoring of the disease. Finally, the analytical methods and current recommendations for testing anti-AQP4 autoantibodies in clinical practice are described.

Highlights

► Aquaporins are protein channels that allow the movement of water and other molecules. ► Aquaporin-4 is the target of an autoimmune response in neuromyelitis optica. ► Anti-AQP4 autoantibodies have diagnostic usefulness with reasonable sensitivity and high specificity. ► Anti-AQP4 can be measured, although there is no standard method.

Introduction

The diffusion of water across biological membranes has long been known. It occurs across all lipid bilayers and is a slow and low-capacity bidirectional process. However, many physiological processes require rapid movement of water. More than 30 years ago, it was considered that in certain specialized epithelia (renal tubules, red cells, secretory glands) there should be an additional system for the rapid movement of large masses of water. This system would possess high capacity for water and be specific, not allowing the passage of other substances, such as hydronium ions (H3O+). Water would move according to the saline osmotic gradient and the system could be modified or inhibited by various substances. The evidence pointed to the notion that it might be a membrane channel for water.

Section snippets

Membrane channels for water

In 1988, in studies addressing Rh cell antigens, a 28 kDa protein shared by red cells from different species that participated in the movement of water across biological membranes was found unexpectedly [1]. Later, coding DNA was isolated and a membrane polypeptide with several transmembrane domains with repeated amino acid sequences in the amino and carboxyl ends were identified. Its structure suggested that it might be part of a channel and that it could correspond to a component of water

The aquaporin family of proteins

Aquaporin-1 (AQP1) was the first aquaporin described in humans. Currently, for aquaporins at least 13 physiological sequences have been described (Table 1), which can be divided into two broad groups. On one hand, there are the channels that transport water exclusively, and on the other there are the aquaglyceroporins, which transport water and glycerol. A third group of aquaporins called super-AQP, with less homology with the above, has been proposed.

Clinical applications of aquaporin measurements

The current and potential usefulness of aquaporin measurements can be divided into two major diagnostic and therapeutic areas.

Neuromyelitis optica

Neuromyelitis optica (NMO), also known as Devic's disease, is a severe immune-mediated demyelinating and necrotizing disease that predominantly affects the optic nerves and spinal cord. It has been considered a form of multiple sclerosis in which inflammatory lesions are restricted to the optic nerve and spinal cord, but currently it is considered a distinct clinical entity. NMO causes acute eye pain with loss of function and myelitis with symmetric paraplegia, sensory loss, and sphincter

Anti-AQP4 antibodies

In 2004, Lennon et al. found anti-AQP4 antibodies in the serum of individuals with NMO and related disorders, but not in the serum of subjects with multiple sclerosis and normal individuals. Therefore, these antibodies are also called anti-NMO [120]. Anti-AQP4 antibodies are directed against epitopes located in extracellular loops of AQP4 (Fig. 2) [121]. Specifically, anti-AQP4 antibodies recognize an epitope located in the E outer loop of AQP4, which is considered the major epitope of

Anti-AQP4 assays

At least 15 methods for assaying anti-AQP4 antibodies have been reported. The sensitivity varies widely between 33 and 91% (median 63%), while the overall specificity remains high (85% to 100% with a median of 99%) [119]. Methods depending on the substrate can be divided into indirect immunofluorescence or immunohistochemistry using tissue sections as substrate. Sensitivity is variable (38–87%); the methods are semiquantitative (titres) and depend on the observer's experience. These methods can

Conclusion

AQPs are a family of protein channels that allow the movement of water, gas, glycerol and other molecules. AQP4 is the one that has gained the greatest clinical relevance; it is abundantly expressed in the brain, where it regulates the movement of water into and out of it, and it is the target of an autoimmune response in NMO and other related syndromes. NMO is a rare disease that is difficult to diagnose and has atypical partially clinical forms. Differential diagnostic problems with multiple

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