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Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical review of the literature.

ABSTRACT: Antibodies to aquaporin-4 (called NMO-IgG or AQP4-Ab) constitute a sensitive and highly specific serum marker of neuromyelitis optica (NMO) that can facilitate the differential diagnosis of NMO and classic multiple sclerosis. NMO-IgG/AQP4-Ab seropositive status has also important prognostic and therapeutic implications in patients with isolated longitudinally extensive myelitis (LETM) or optic neuritis (ON). In this article, we comprehensively review and critically appraise the existing literature on NMO-IgG/AQP4-Ab testing. All available immunoassays-including tissue-based (IHC), cell-based (ICC, FACS) and protein-based (RIPA, FIPA, ELISA, Western blotting) assays-and their differential advantages and disadvantages are discussed. Estimates for sensitivity, specificity, and positive and negative likelihood ratios are calculated for all published studies and accuracies of the various immunoassay techniques compared. Subgroup analyses are provided for NMO, LETM and ON, for relapsing vs. monophasic disease, and for various control groups (eg, MS vs. other controls). Numerous aspects of NMO-IgG/AQP4-Ab testing relevant for clinicians (eg, impact of antibody titers and longitudinal testing, indications for repeat testing, relevance of CSF testing and subclass analysis, NMO-IgG/AQP4-Ab in patients with rheumatic diseases) as well as technical aspects (eg, AQP4-M1 vs. AQP4-M23-based assays, intact AQP4 vs. peptide substrates, effect of storage conditions and freeze/thaw cycles) and pitfalls are discussed. Finally, recommendations for the clinical application of NMO-IgG/AQP4-Ab serology are given.

SUBMITTER: Jarius S

PROVIDER: S-EPMC8028894 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundNeuromyelitis optica spectrum disorders (NMOSD) is a primary astrocytopathy driven by antibodies directed against the aquaporin-4 water channel located at the end-feet of the astrocyte. Although blood-brain barrier (BBB) breakdown is considered one of the key steps for the development and lesion formation, little is known about the molecular mechanisms involved. The aim of the study was to evaluate the effect of human immunoglobulins from NMOSD patients (NMO-IgG) on BBB properties.MethodsFreshly isolated brain microvessels (IBMs) from rat brains were used as a study model. At first, analysis of the secretome profile from IBMs exposed to purified NMO-IgG, to healthy donor IgG (Control-IgG), or non-treated, was performed. Second, tight junction (TJ) proteins expression in fresh IBMs and primary cultures of brain microvascular endothelial cells (BMEC) was analysed by Western blotting (Wb) after exposition to NMO-IgG and Control-IgG. Finally, functional BBB properties were investigated evaluating the presence of rat-IgG in tissue lysate from brain using Wb in the rat-model, and the passage of NMO-IgG and sucrose in a bicameral model.ResultsWe found that NMO-IgG induces functional and morphological BBB changes, including: 1) increase of pro-inflammatory cytokines production (CXCL-10 [IP-10], IL-6, IL-1RA, IL-1β and CXCL-3) in IBMs when exposed to NMO-IgG; 2) decrease of Claudin-5 levels by 25.6% after treatment of fresh IBMs by NMO-IgG compared to Control-IgG (p = 0.002), and similarly, decrease of Claudin-5 by at least 20% when BMEC were cultured with NMO-IgG from five different patients; 3) a higher level of rat-IgG accumulated in periventricular regions of NMO-rats compared to Control-rats and an increase in the permeability of BBB after NMO-IgG treatment in the bicameral model.ConclusionHuman NMO-IgG induces both structural and functional alterations of BBB properties, suggesting a direct role of NMO-IgG on modulation of BBB permeability in NMOSD.

Project description:BackgroundNeuromyelitis optica (NMO) is a severe, disabling disease of the central nervous system (CNS) characterized by the formation of astrocyte-destructive, neutrophil-dominated inflammatory lesions in the spinal cord and optic nerves. These lesions are initiated by the binding of pathogenic aquaporin 4 (AQP4)-specific autoantibodies to astrocytes and subsequent complement-mediated lysis of these cells. Typically, these lesions form in a setting of CNS inflammation, where the blood-brain barrier is open for the entry of antibodies and complement. However, it remained unclear to which extent pro-inflammatory cytokines and chemokines contribute to the formation of NMO lesions. To specifically address this question, we injected the cytokines interleukin-1 beta, tumor necrosis factor alpha, interleukin-6, interferon gamma and the chemokine CXCL2 into the striatum of NMO-IgG seropositive rats and analyzed the tissue 24 hours later by immunohistochemistry.ResultsAll injected cytokines and chemokines led to profound leakage of immunoglobulins into the injected hemisphere, but only interleukin-1 beta induced the formation of perivascular, neutrophil-infiltrated lesions with AQP4 loss and complement-mediated astrocyte destruction distant from the needle tract. Treatment of rat brain endothelial cells with interleukin-1 beta, but not with any other cytokine or chemokine applied at the same concentration and over the same period of time, caused profound upregulation of granulocyte-recruiting and supporting molecules. Injection of interleukin-1 beta caused higher numbers of blood vessels with perivascular, cellular C1q reactivity than any other cytokine tested. Finally, the screening of a large sample of CNS lesions from NMO and multiple sclerosis patients revealed large numbers of interleukin-1 beta-reactive macrophages/activated microglial cells in active NMO lesions but not in MS lesions with comparable lesion activity and location.ConclusionsOur data strongly suggest that interleukin-1 beta released in NMO lesions and interleukin-1 beta-induced production/accumulation of complement factors (like C1q) facilitate neutrophil entry and BBB breakdown in the vicinity of NMO lesions, and might thus be an important secondary factor for lesion formation, possibly by paving the ground for rapid lesion growth and amplified immune cell recruitment to this site.

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Aquaporin-4 antibodies (NMO-IgG) as a serological marker of neuromyelitis optica: a critical review of the literature.

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