Purified IgG from aquaporin-4 neuromyelitis optica spectrum disorder patients alters blood-brain barrier permeability
Cobo-Calvo, Álvaro (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Ruiz, Anne (Centre de Recherche en Neurosciences de Lyon)
Richard, Chloé (Centre de Recherche en Neurosciences de Lyon)
Blondel, Sandrine (Hospital Universitari Vall d'Hebron. Institut de Recerca)
Cavagna, Sylvie (Centre de Recherche en Neurosciences de Lyon)
Strazielle, Nathalie (BIP Facility (França))
Ghersi-Egea, Jean-François (BIP Facility (França))
Giraudon, Pascale (Centre de Recherche en Neurosciences de Lyon)
Marignier, Romain (Centre de Recherche en Neurosciences de Lyon)
Universitat Autònoma de Barcelona

Fecha:	2020
Resumen:	Neuromyelitis 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. Freshly 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. We 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. Human 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.
Ayudas:	Instituto de Salud Carlos III JR19/00007
Derechos:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Lengua:	Anglès
Documento:	Article ; recerca ; Versió publicada
Publicado en:	PloS one, Vol. 15 (september 2020) , ISSN 1932-6203

DOI: 10.1371/journal.pone.0238301
PMID: 32881954

15 p, 2.0 MB

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