Cytokine-induced enhancement of autoimmune inflammation in the brain and spinal cord: implications for multiple sclerosis

Multiple sclerosis and experimental autoimmune encephalomyelitis (EAE) are autoimmune inflammatory diseases in which cytokines are intimately involved. Here we test the hypothesis that injection of pro-inflammatory cytokines, tumour necrosis factor-alpha (TNFalpha) and interferon gamma (IFNgamma) into the brain of animals in the prodromal phase of EAE significantly enhances inflammation in the central nervous system (CNS). We were particularly interested to learn whether a local increase in cytokines influenced the pathology locally, or more extensively, within the CNS. EAE was induced in female adult Lewis rats. Eight days post-inoculation, TNFalpha or INFgamma was injected into one cerebral hemisphere. Days 11 and 13 post-inoculation (3 and 5 days after the injection of cytokine) inflammation was quantified by the number of perivascular cuffs and the degree of major histocompatibility complex (MHC) class II expression by microglia. Normal animals injected with cytokines, and EAE animals with saline injection served as controls. Results: microglial activation was increased three- to fourfold in the brain and eightfold in the spinal cord (P less than or equal to 0.05); lymphocyte invasion was increased sixfold in the brain and three- to fourfold in the spinal cord (P less than or equal to 0.01) following injections of TNFalpha or INFgamma in EAE animals compared with controls. Significant axonal damage was observed in white matter associated with the perivascular cuffs. Conclusion: local changes in the release of pro-inflammatory cytokines within the brain in EAE results in the widespread enhancement of autoimmune inflammation within the brain and cord, and exacerbation of clinical symptoms.