Publications (2)2.42 Total impact
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Article: Axonal sprouting regulates myelin basic protein gene expression in denervated mouse hippocampus
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ABSTRACT: The regulation of oligodendrocyte gene expression and myelination in vivo in the normal and injured adult CNS is still poorly understood. We have analyzed the effects of axotomy-induced axonal sprouting and microglial activation, on oligodendrocyte myelin basic protein (MBP) gene expression from 2 to 35 days after transection of the entorhino-hippocampal perforant path axonal projection. In situ hybridization analysis showed that anterograde axonal and terminal degeneration lead to upregulated oligodendrocyte MBP mRNA expression starting between day 2 and day 4, in (1) the deep part of stratum radiatum of CA3 and the dentate hilus, which display axonal sprouting but no degenerative changes or microglial activation, and (2) the outer part of the molecular layer of the fascia dentata, and in stratum moleculare of CA3 and stratum lacunosum-moleculare of CA1, areas that display dense anterograde axonal and terminal degeneration, myelin degenerative changes, microglial activation and axotomi-induced axonal sprouting. Oligodendrocyte MBP mRNA expression reached maximum in both these areas at day 7. MBP gene transcription remained constant in stratum radiatum, stratum pyramidale and stratum oriens of CA1, areas that were unaffected by perforant path transection. These results provide strong evidence that oligodendrocyte MBP gene expression can be regulated by axonal sprouting independently of microglial activation in the injured adult CNS.International Journal of Developmental Neuroscience · 2.42 Impact Factor -
Article: The pathogenesis of encephalitis
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ABSTRACT: One of the most fundamental neuroimmune interactions is that involving immune responses in and against the brain. Although the CNS is immunologically-privileged relative to other organs, activated T lymphocytes are known to cross the blood-brain barrier. Entry of virusspecific T cells, usually a host-protective event, can induce encephalitis. The pathology of viral encephalitis is associated with inflammatory (Th1) immune responses against infected cells, such as in Theiler's virus infection of oligodendrocytes. Myelin reactivity can occur as a consequence of epitope spreading from anti-viral responses. Myelin-specific CD4+ T cells induce autoimmune encephalomyelitis. The inflammatory, demyelinating pathology of experimental autoimmune encephalomyelitis (EAE) is similar in many respects to that of Multiple Sclerosis, including axonal damage. We find that naive T cells can enter the CNS during EAE, and may become activated there if costimulator molecules such as B7 are expressed on MHC II+ microglia. Indeed, B7 is known to be induced by viral infection, thus linking infection to CNS autommunity. Although initiated by infiltrating T cells, many of the inflammatory mediators detected in the CNS in MS or EAE are produced by CNS-resident glial cells. Interferon-gamma (IFNγ), an immune cytokine not normally expressed in the adult CNS, can induce glial cells to produce a variety of mediators, including tumor necrosis factor (TNF) and nitric oxide, that are cytopathic for oligodendrocytes in vitro. TNF is also implicated in repair/regenerative responses, in vivo. We find that IFNγ amplified but did not affect the kinetics of microglial TNF production, induced in response to axonal lesioning in MBP promoter/IFNγ transgenic mice. TNF, whether induced by EAE or by axonal damage, was nevertheless produced in IFNγ-deficient mice. This indicates that there are endogenous programs of glial response, which are amplified by IFNγ. The macrophage-dominated, perivascular infiltrates that are characteristic of EAE were replaced by a disseminated, invasive neutrophilia in IFNγ-deficient mice, with lethal consequence. The EAE-associated enzyme NOS2, the cytokine interleukin-10, and chemokines MCP-1 and RANTES were undetectable in IFNγ-deficient mice with EAE, whereas the neutrophil-attractant chemokines MIP2 and TCA3 became prominent. CNS glia may interact with immune cells via chemokines to redirect further infiltration. Restriction of NOS2 expression to parenchymal glia, in chimeric mice reconstituted with NOS2-/- bone marrow, conferred protection against EAE. Nitric oxide may play distinct roles when made by microglia/macrophages versus astrocytes. Our observations demonstrate the capacity of the CNS to mediate and direct protective and inflammatory responses, and of the immune system to interpret and amplify CNS-derived signals.NeuroImmune Biology.
