Abstract
T cells from lupus patients have hypomethylated DNA and overexpress genes normally suppressed by DNA methylation that contribute to disease pathogenesis. We found that stimulatory and inhibitory killer cell Ig-like receptor (KIR) genes are aberrantly overexpressed on experimentally demethylated T cells. We therefore asked if lupus T cells also overexpress KIR, and if the proteins are functional. T cells from lupus patients were found to overexpress KIR genes, and expression was proportional to disease activity. Abs to the stimulatory molecule KIR2DL4 triggered IFN-gamma release by lupus T cells, and production was proportional to disease activity. Similarly, cross-linking the inhibitory molecule KIR3DL1 prevented the autoreactive macrophage killing that characterizes lupus T cells. These results indicate that aberrant T cell KIR expression may contribute to IFN overproduction and macrophage killing in human lupus, and they suggest that Abs to inhibitory KIR may be a treatment for this disease.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Autoantigens / immunology
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Autoantigens / metabolism
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CD4-Positive T-Lymphocytes / immunology
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CD4-Positive T-Lymphocytes / metabolism
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Cross-Linking Reagents / metabolism
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Cytotoxicity Tests, Immunologic
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DNA Methylation
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Female
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Humans
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Interferon-gamma / biosynthesis
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Interferon-gamma / metabolism
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Lupus Erythematosus, Systemic / diagnosis
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Lupus Erythematosus, Systemic / immunology*
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Lupus Erythematosus, Systemic / pathology
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Macrophages / immunology
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Macrophages / metabolism
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Male
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Receptors, KIR / biosynthesis*
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Receptors, KIR / genetics*
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Receptors, KIR / physiology
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Receptors, KIR2DL4 / physiology
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Receptors, KIR3DL1 / physiology
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T-Lymphocyte Subsets / immunology*
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T-Lymphocyte Subsets / metabolism*
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T-Lymphocyte Subsets / pathology
Substances
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Autoantigens
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Cross-Linking Reagents
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KIR2DL4 protein, human
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KIR3DL1 protein, human
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Receptors, KIR
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Receptors, KIR2DL4
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Receptors, KIR3DL1
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Interferon-gamma