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The Susceptibility of Mice to Immune-Mediated Neurologic Disease Correlates with the Degree to Which Their Lymphocytes Resist the Effects of Brain-Derived Gangliosides¹

Department of Neurology, Johns Hopkins University School of Medicine, and Department of Molecular Microbiology and Immunology, Johns Hopkins University School of Hygiene and Public Health, Baltimore, MD 21205

SJL mice develop immune-mediated disorders of the central nervous system (CNS) when infected with certain neurotropic viruses or when immunized with myelin Ags. Other strains including BALB/c are more resistant to these diseases. During Sindbis virus-induced encephalitis, both mice are easily infected and elicit rapid mononuclear cell inflammation in the brain. However, only SJL mice develop immune-mediated paralysis; BALB/c mice remain asymptomatic. To understand how the same stimulus produces such divergent immunologic effects on the host, the present study investigated lymphocytes that were isolated from the brains of Sindbis virus-infected animals. Cells from the brains of SJL mice exhibited more proliferation, produced more IL-2, maintained a higher viability, and expressed less bax mRNA (a proapoptotic mediator) than did lymphocytes from the brains of BALB/c mice. Since the central nervous system is enriched in gangliosides that regulate T cell proliferation and IL-2 production in vitro, purified brain-derived gangliosides were tested on peripheral lymphocytes from both strains. These lipids had less of an effect on the mitogen-induced proliferation, IL-2 production, activation-induced cell death, and up-regulation of bax mRNA in lymphocytes from SJL mice compared with those from BALB/c mice. Thus, gangliosides may inhibit various T cell effector functions and induce T cell apoptosis to a greater degree in the brains of BALB/c mice compared with the brains of SJL mice. This relative deficiency in local lymphocyte regulation may enhance the susceptibility of SJL mice to immune-mediated neurologic disease.

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