Abstract
BackgroundThe 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.MethodsPIFS 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.ResultsC57BL/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.ConclusionC57BL/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.
Highlights
Unregulated permeability of the blood-brain barrier (BBB) is a feature of many neurological diseases as diverse as stroke, viral hemorrhagic fevers, HIV dementia, shock, cerebral malaria, multiple sclerosis, acute hemorrhagic leukoencephalitis and epilepsy [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]
129 SvIm mouse strains Seven days post-intracranial infection with Theiler’s murine encephalomyelitis virus (TMEV), C57BL/6 mice developed a robust central nervous system (CNS)-infiltrating CD8 T-cell response toward the virus peptide VP2121-130 presented in the context of the Db class I molecule
Using Db: VP2121-130 peptide major histocompatibility complex (MHC) tetramers, we determined that 50% to 70% of CNS-infiltrating CD8 T cells are specific for the Db: VP2121-130 epitope (Figures 1A and 1D) [36,39]
Summary
Unregulated permeability of the blood-brain barrier (BBB) is a feature of many neurological diseases as diverse as stroke, viral hemorrhagic fevers, HIV dementia, shock, cerebral malaria, multiple sclerosis, acute hemorrhagic leukoencephalitis and epilepsy [1,2,3,4,5,6,7,8,9,10,11,12,13,14,15,16]. The extent to which susceptibility to brain hemorrhage is due to blood-derived factors or stromal tissue remains unknown. 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. We hypothesize that hematopoietic factors contribute to susceptibility to brain hemorrhage, CNS vascular permeability and death following induction of PIFS
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