Abstract
'Protective autoimmunity' refers to a well-controlled anti-self response that helps the body resist neurodegeneration. The response is mediated by autoimmune T cells, which produce cytokines and growth factors. Using an in vitro assay of hippocampal slices, we show that the cytokines interferon-gamma and (especially) interleukin-4, characteristic of pro-inflammatory and anti-inflammatory T cells, respectively, can make microglia neuroprotective. Aggregated beta-amyloid, like bacterial cell wall-derived lipopolysaccharide, rendered the microglia cytotoxic. Cytotoxicity was correlated with a signal transduction pathway that down-regulates expression of class-II major histocompatibility proteins (MHC-II) through the MHC-II-transactivator and the invariant chain. Protection by interleukin-4 was attributed to down-regulation of tumor necrosis factor-alpha and up-regulation of insulin-like growth factor I. These findings suggest that beneficial or harmful expression of the local immune response in the damaged CNS depends on how microglia interpret the threat, and that a well-regulated T-cell-mediated response enables microglia to alleviate rather than exacerbate stressful situations in the CNS.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / antagonists & inhibitors
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Amyloid beta-Peptides / immunology
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Amyloid beta-Peptides / pharmacology
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Animals
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Animals, Newborn
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Autoimmunity / drug effects
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Autoimmunity / immunology
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Cell Line
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Cells, Cultured
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Down-Regulation / drug effects
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Down-Regulation / immunology
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Encephalitis / immunology*
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Encephalitis / physiopathology
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Encephalitis / therapy
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Gliosis / immunology*
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Gliosis / physiopathology
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Gliosis / therapy
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Hippocampus / drug effects
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Hippocampus / immunology
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Hippocampus / physiopathology
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Histocompatibility Antigens Class II / drug effects
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Histocompatibility Antigens Class II / immunology*
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Insulin-Like Growth Factor I / drug effects
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Insulin-Like Growth Factor I / immunology
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Interferon-gamma / immunology*
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Interferon-gamma / pharmacology
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Interleukin-4 / immunology*
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Interleukin-4 / pharmacology
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Lipopolysaccharides / antagonists & inhibitors
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Lipopolysaccharides / immunology
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Lipopolysaccharides / pharmacology
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Lymphocyte Activation / drug effects
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Lymphocyte Activation / immunology
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Microglia / drug effects
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Microglia / immunology*
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Neurodegenerative Diseases / immunology
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Neurodegenerative Diseases / physiopathology
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Neurodegenerative Diseases / therapy
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Organ Culture Techniques
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Rats
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Rats, Sprague-Dawley
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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Transcriptional Activation / drug effects
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Transcriptional Activation / physiology
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Tumor Necrosis Factor-alpha / drug effects
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Tumor Necrosis Factor-alpha / immunology
Substances
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Amyloid beta-Peptides
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Histocompatibility Antigens Class II
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Lipopolysaccharides
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Tumor Necrosis Factor-alpha
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Interleukin-4
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Insulin-Like Growth Factor I
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Interferon-gamma