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Functional Consequences of Neuromyelitis Optica-IgG Astrocyte Interactions on Blood-Brain Barrier Permeability and Granulocyte Recruitment¹

Thierry Vincent^*,, Philippe Saikali, Romain Cayrol, Alejandro D. Roth^,, Amit Bar-Or, Alexandre Prat and Jack P. Antel^2,

^* Laboratoire d’Immunologie, Hôpital Saint-Eloi-CHU Montpellier, Montpellier, France; Neuroimmunology Unit, and Experimental Therapeutics Program, Montreal Neurological Institute, McGill University, and Neuroimmunology Research Laboratory, Centre Hospitalier de l’Université de Montréal–Notre-Dame Hospital, Université de Montréal, Montréal, Québec, Canada; and Department of Biology, Faculty of Science, Universidad de Chile, Santiago, Chile

Autoantibody neuromyelitis optica-IgG (NMO-IgG) recognizing aquaporin-4 (AQP4) is implicated as playing a central role in the physiopathology of NMO. The aim of this in vitro-based study was to characterize functional consequences of interaction between NMO-IgG and cells of the neurovascular unit (astrocytes and brain endothelium) that would provide insight into recognized features of NMO, namely altered blood-brain barrier (BBB) permeability and granulocyte recruitment. We used sera from NMO and longitudinally extensive transverse myelitis cases shown to bind in a characteristic perivascular pattern to primate cerebellar slices. Using flow cytometry, we found that sera from NMO-IgG-positive patients reacted with CNS-derived human fetal astrocytes, whereas sera from multiple sclerosis patients did not. We demonstrated that NMO-IgG binding to astrocytes alters aquaporin-4 polarized expression and increases permeability of a human BBB endothelium/astrocyte barrier. We further demonstrated that NMO-IgG binding to human fetal astrocytes can result in NK cell degranulation, astrocyte killing by Ab-dependent cellular cytotoxicity and complement-dependent granulocyte attraction through the BBB model. Our study highlights important functional roles for NMO-IgG that could account for pathological lesions and BBB dysfunction observed in NMO.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by grants from the Canadian Institutes of Health Research, by the Multiple Sclerosis Society of Canada (MSSC) and by the Canadian Foundation for Innovation (to A.P., A.B.-O., and J.P.A.). A.B.-O. is recipient of the MSSC Don Paty Award and McGill Dawson Scholar. A.P. holds a Donald Paty Career Development Award of the MSSC and is a Research scholar from the Fond de la Recherche en Santé du Québec. P.S. and R.C. hold studentships from the MSSC and from the Neuroinflammation Training Program of the Canadian Institutes for Health Research.

² Address correspondence and reprint requests Dr. Jack P. Antel, Neuroimmunology Unit, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada; E-mail address: jack.antel{at}mcgill.ca

³ Abbreviations used in this paper: NMO, neuromyelitis optica; MS, multiple sclerosis; AQP4, aquaporin-4; HFA, human fetal astrocyte; BBB, blood-brain barrier; EC, endothelial cell; GFAP, glial fibrillary acidic protein; ADCC, Ab-dependent cellular cytotoxicity.

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