title: A hematopoietic contribution to microhemorrhage formation during antiviral CD8 T cell-initiated blood-brain barrier disruption.
abstract: BACKGROUND
  The extent to which susceptibility to brain hemorrhage is derived from blood-derived factors or stromal tissue remains largely unknown. We have developed an inducible model of CD8 T cell-initiated blood-brain barrier (BBB) disruption using a variation of the Theiler's murine encephalomyelitis virus (TMEV) model of multiple sclerosis. This peptide-induced fatal syndrome (PIFS) model results in severe central nervous system (CNS) vascular permeability and death in the C57BL/6 mouse strain, but not in the 129 SvIm mouse strain, despite the two strains' having indistinguishable CD8 T-cell responses. Therefore, we hypothesize that hematopoietic factors contribute to susceptibility to brain hemorrhage, CNS vascular permeability and death following induction of PIFS.
  
  
  METHODS
  PIFS was induced by intravenous injection of VP2121-130 peptide at 7 days post-TMEV infection. We then investigated brain inflammation, astrocyte activation, vascular permeability, functional deficit and microhemorrhage formation using T2*-weighted magnetic resonance imaging (MRI) in C57BL/6 and 129 SvIm mice. To investigate the contribution of hematopoietic cells in this model, hemorrhage-resistant 129 SvIm mice were reconstituted with C57BL/6 or autologous 129 SvIm bone marrow. Gadolinium-enhanced, T1-weighted MRI was used to visualize the extent of CNS vascular permeability after bone marrow transfer.
  
  
  RESULTS
  C57BL/6 and 129 SvIm mice had similar inflammation in the CNS during acute infection. After administration of VP2121-130 peptide, however, C57BL/6 mice had increased astrocyte activation, CNS vascular permeability, microhemorrhage formation and functional deficits compared to 129 SvIm mice. The 129 SvIm mice reconstituted with C57BL/6 but not autologous bone marrow had increased microhemorrhage formation as measured by T2*-weighted MRI, exhibited a profound increase in CNS vascular permeability as measured by three-dimensional volumetric analysis of gadolinium-enhanced, T1-weighted MRI, and became moribund in this model system.
  
  
  CONCLUSIONS
  C57BL/6 mice are highly susceptible to microhemorrhage formation, severe CNS vascular permeability and morbidity compared to the 129 SvIm mouse. This susceptibility is transferable with the bone marrow compartment, demonstrating that hematopoietic factors are responsible for the onset of brain microhemorrhage and vascular permeability in immune-mediated fatal BBB disruption.
authors.affiliation: Department of Neurology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Holly L
authors.initials: HL
authors.lastname: Johnson
authors.forename: Yi
authors.initials: Y
authors.lastname: Chen
authors.forename: Georgette L
authors.initials: GL
authors.lastname: Suidan
authors.forename: Jeremiah R
authors.initials: JR
authors.lastname: McDole
authors.forename: Anne K
authors.initials: AK
authors.lastname: Lohrey
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Hanson
authors.forename: Fang
authors.initials: F
authors.lastname: Jin
authors.forename: Istvan
authors.initials: I
authors.lastname: Pirko
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Johnson
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D001812:Blood-Brain Barrier; D016026:Bone Marrow Transplantation / Q000379:methods; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D002199:Capillary Permeability / Q000187:drug effects; D036022:Capsid Proteins / Q000009:adverse effects; D018188:Cardiovirus Infections / Q000150:complications*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005904:Glial Fibrillary Acidic Protein / Q000378:metabolism; D006397:Hematinics; D020300:Intracranial Hemorrhages / Q000209:etiology* / Q000601:surgery / Q000821:virology; D008279:Magnetic Resonance Imaging; D051379:Mice; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000502:physiology; D045442:Rotarod Performance Test; D017945:Theilovirus / Q000472:pathogenicity; D014764:Viral Proteins / Q000009:adverse effects
chemical_list: D036022:Capsid Proteins; D005904:Glial Fibrillary Acidic Protein; D006397:Hematinics; C442553:VP2 protein, Dependovirus; D014764:Viral Proteins; D016650:Fluorescein-5-isothiocyanate