Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection

Abstract

Cytokines are important mediators in the pathogenesis of central nervous system (CNS) inflammatory diseases including multiple sclerosis (MS), experimental allergic encephalomyelitis (EAE), viral encephalitis and virus induced demyelinating diseases. We have used immunohistochemical techniques to characterize the mononuclear cell infiltrate and cytokine profiles in the CNS following infection of mice with the demyelinating A7(74) strain of Semliki Forest virus (SFV), an important viral model of MS. Mononuclear cell infiltrates in the CNS, first observed at 3 days and maximal during clearance of infectious virus, were comprised predominantly of CD8 + lymphocytes. F4/80 + macrophage/microglia and CD45/B220 + B lymphocytes were most numerous during the subsequent phase of demyelination. CD4 + T-lymphocytes were observed at low levels throughout infection. By immunostaining MHC class I, IL-1 β, IL-3 and TGF β1 were constitutively expressed in normal mice and were upregulated following infection. MHC class II, IL-1 α, IL-2, IL-2R, TNF- α and IL-6 were strongly upregulated in the CNS of SFV-infected mice and mice with chronic relapsing EAE. The spatial and temporal distribution of these cytokines during the course of disease was analysed. Whereas IL-1 α, IL-1 β, IL-10, and TGF β1 were observed on day 3 following infection GMCSF, IL-2 and TNF α were first apparent at day 7 when the cellular infiltration in the CNS was most intense. In contrast IFN γ and IL-6 were first observed on day 10 prior to the demyelination phase of disease. Cytokines in the lesions of demyelination suggest a role in the pathogeneisis of myelin damage. Based on cytokine profiles no clear bias of either a Th1 or Th2 response was observed in the CNS during infection.