title: Focal transient CNS vessel leak provides a tissue niche for sequential immune cell accumulation during the asymptomatic phase of EAE induction.
abstract: Peripheral immune cells are critical to the pathogenesis of neurodegenerative diseases including multiple sclerosis (MS) (Hendriks et al., 2005; Kasper and Shoemaker, 2010). However, the precise sequence of tissue events during the early asymptomatic induction phase of experimental autoimmune encephalomyelitis (EAE) pathogenesis remains poorly defined. Due to the spatial-temporal constrains of traditional methods used to study this disease, most studies had been performed in the spine during peak clinical disease; thus the debate continues as to whether tissue changes such as vessel disruption represent a cause or a byproduct of EAE pathophysiology in the cortex. Here, we provide dynamic, high-resolution information on the evolving structural and cellular processes within the gray matter of the mouse cortex during the first 12 asymptomatic days of EAE induction. We observed that transient focal vessel disruptions precede microglia activation, followed by infiltration of and directed interaction between circulating dendritic cells and T cells. Histamine antagonist minimizes but not completely ameliorates blood vessel leaks. Histamine H1 receptor blockade prevents early microglia function, resulting in subsequent reduction in immune cell accumulation, disease incidence and clinical severity.
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Deborah S
authors.initials: DS
authors.lastname: Barkauskas
authors.affiliation: Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: R
authors.initials: R
authors.lastname: Dixon Dorand
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Jay T
authors.initials: JT
authors.lastname: Myers
authors.affiliation: Department of Neurosciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Teresa A
authors.initials: TA
authors.lastname: Evans
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University School of Engineering, Cleveland, OH 44106, USA.
authors.forename: Kestutis J
authors.initials: KJ
authors.lastname: Barkauskas
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: David
authors.initials: D
authors.lastname: Askew
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Purgert
authors.affiliation: Division of Pediatric Hematology-Oncology, Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA; Department of Pathology, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA. Electronic address: alex.y.huang@case.edu.
authors.forename: Alex Y
authors.initials: AY
authors.lastname: Huang
mesh_terms: D000818:Animals; D000938:Antigen-Presenting Cells / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D001812:Blood-Brain Barrier / Q000473:pathology; D002540:Cerebral Cortex / Q000473:pathology*; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D066128:Gray Matter / Q000473:pathology; D006634:Histamine H1 Antagonists / Q000494:pharmacology; D006919:Hydroxyzine / Q000494:pharmacology; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D037342:Pertussis Toxin; D013346:Subarachnoid Space / Q000473:pathology*; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D006634:Histamine H1 Antagonists; D006919:Hydroxyzine; D037342:Pertussis Toxin