title: Focal disturbances in the blood-brain barrier are associated with formation of neuroinflammatory lesions.
abstract: Early changes in the normal appearing white matter of multiple sclerosis (MS) patients precede the appearance of gadolinium-enhancing lesions. Although these findings suggest blood-brain barrier (BBB) breakdown as an important feature in MS pathogenesis, limited information is available on the BBB alterations during lesion genesis. Here, we perform a longitudinal characterization of the vascular, neuropathological and immunological changes before lesion formation in mice developing spontaneous relapsing-remitting experimental autoimmune encephalomyelitis (sRR-EAE). We found a significant upregulation of Th1 and Th17 cytokines in the periphery of sRR-EAE mice before any evident neuropathology. In the CNS, BBB and astroglial activations were the first pathological changes occurring after 45days of age and were followed by immune cell infiltration by day 50. These pathological alterations subsequently led to perivascular demyelination and disease onset. In MS, (p)reactive lesions mirrored the changes seen in early sRR-EAE by displaying considerable BBB disruption, perivascular astrogliosis, redistribution of junctional proteins and increased expression of endothelial cell adhesion molecules. Our findings suggest that BBB breach occurs before significant immune cell infiltration and demyelination. In addition, peripheral immune activation during sRR-EAE precedes CNS pathology, suggesting that outside in signaling mechanisms play a role in the development of neuroinflammatory lesions.
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada. Electronic address: jorge.alvarez@umontreal.ca.
authors.forename: Jorge Ivan
authors.initials: JI
authors.lastname: Alvarez
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Olivia
authors.initials: O
authors.lastname: Saint-Laurent
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Alisha
authors.initials: A
authors.lastname: Godschalk
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Simone
authors.initials: S
authors.lastname: Terouz
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Casper
authors.initials: C
authors.lastname: Briels
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Sandra
authors.initials: S
authors.lastname: Larouche
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Lyne
authors.initials: L
authors.lastname: Bourbonnière
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Catherine
authors.initials: C
authors.lastname: Larochelle
authors.affiliation: Neuroimmunology Unit, Department of Neurosciences, Centre de Recherche du Centre Hospitalier de l'Université de Montréal (CRCHUM), Montréal, Canada.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Prat
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D001253:Astrocytes / Q000378:metabolism / Q000473:pathology; D001812:Blood-Brain Barrier / Q000378:metabolism* / Q000473:pathology; D001921:Brain / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism* / Q000473:pathology; D004730:Endothelium, Vascular / Q000378:metabolism / Q000473:pathology; D005260:Female; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008137:Longitudinal Studies; D008297:Male; D008822:Mice, Transgenic; D008875:Middle Aged; D020528:Multiple Sclerosis, Chronic Progressive / Q000378:metabolism* / Q000473:pathology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000378:metabolism* / Q000473:pathology; D013601:T-Lymphocytes / Q000378:metabolism
keywords: (P)reactive lesion; Adherens junctions; Astrocytes; Blood–brain barrier; EAE; Lesion; Multiple sclerosis; Tight junctions