Blood–brain barrier changes and cell invasion differ between therapeutic immune clearance of neurotrophic virus and CNS autoimmunity

Abstract

CNS tissues are protected from circulating cells and factors by the blood-brain barrier (BBB), a specialization of the neurovasculature. Outcomes of the loss of BBB integrity and cell infiltration into CNS tissues can differ vastly. For example, elevated BBB permeability is closely associated with the development of neurological disease in experimental allergic encephalomyelitis (EAE) but not during clearance of the attenuated rabies virus CVS-F3 from the CNS tissues. To probe whether differences in the nature of BBB permeability changes may contribute to the pathogenesis of acute neuroinflammatory disease, we compared the characteristics of BBB permeability changes in mice with EAE and in mice clearing CVS-F3. BBB permeability changes are largely restricted to the cerebellum and spinal cord in both models but differ in the extent of leakage of markers of different size and in the nature of cell accumulation in the CNS tissues. The accumulation in the CNS tissues of CD4 T cells expressing mRNAs specific for IFN-gamma and IL-17 is common to both, but iNOS-positive cells invade into the CNS parenchyma only in EAE. Mice that have been immunized with myelin basic protein (MBP) and infected exhibit the features of EAE. Treatment with the peroxynitrite-dependent radical scavenger urate inhibits the invasion of iNOS-positive cells into the CNS tissues and the development of clinical signs of EAE without preventing the loss of BBB integrity in immunized/infected animals. These findings indicate that BBB permeability changes can occur in the absence of neuropathology provided that cell invasion is restricted.