Abstract
Here we show that mice lacking the zinc finger transcription factor Aiolos develop the symptoms of human systemic lupus erythematosus (SLE), which is characterized by the production of anti-dsDNA Ab and immune complex-mediated glomerulonephritis. This finding indicates that normal Aiolos function is necessary to maintain immune homeostasis and suppress the development of systemic autoimmune disease and implicates Aiolos as a possible candidate gene for SLE. Interestingly, Aiolos-null mice can no longer mount autoimmune reactions and completely fail to develop SLE when they are deficient for the B cell-specific transcription coactivator OBF-1. The lack of OBF-1 reverses several Aiolos mutant mouse phenotypes, such as B cell hyperproliferation, high expression of activation marker on B cells, and spontaneous germinal center formation. Unexpectedly, B cell development at the immature B cell stage is severely impaired in the bone marrow of Aiolos/OBF-1 double-deficient mice, demonstrating the key role of these factors in the transition from pre-B to immature B cells. Our results indicate that B cells play a crucial role in the development of SLE in Aiolos mutant mice and might be useful for the strategy of SLE treatment.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antibodies, Antinuclear / biosynthesis
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Antibodies, Antinuclear / blood
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Antibodies, Antinuclear / metabolism
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B-Lymphocytes / immunology
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B-Lymphocytes / pathology
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Bone Marrow Cells / immunology
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Bone Marrow Cells / pathology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Division / genetics
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Cell Division / immunology
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Cells, Cultured
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Female
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Germinal Center / immunology
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Germinal Center / pathology
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Humans
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Ikaros Transcription Factor
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Immune Complex Diseases / genetics
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Immune Complex Diseases / immunology
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Immune Complex Diseases / metabolism
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Immunoglobulins / biosynthesis
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Lupus Erythematosus, Systemic / genetics*
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Lupus Erythematosus, Systemic / immunology
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Lupus Erythematosus, Systemic / prevention & control*
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Lymphocyte Activation / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Phenotype
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Stem Cells / immunology
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Stem Cells / pathology
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Trans-Activators / deficiency*
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Trans-Activators / genetics*
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Trans-Activators / physiology
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Transcription Factors
Substances
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Antibodies, Antinuclear
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IKZF3 protein, human
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Ikzf3 protein, mouse
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Immunoglobulins
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POU2AF1 protein, human
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Pou2af1 protein, mouse
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Trans-Activators
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Transcription Factors
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Ikaros Transcription Factor