Abstract
The ubiquitin-editing enzyme A20/TNFAIP3 is essential for controlling signals inducing the activation of nuclear factor-κB transcription factors. Polymorphisms and mutations in the TNFAIP3 gene are linked to various human autoimmune conditions, and inactivation of A20 is a frequent event in human B-cell lymphomas characterized by constitutive nuclear factor-κB activity. Through B cell-specific ablation in the mouse, we show here that A20 is required for the normal differentiation of the marginal zone B and B1 cell subsets. However, loss of A20 in B cells lowers their activation threshold and enhances proliferation and survival in a gene-dose-dependent fashion. Through the expression of proinflammatory cytokines, most notably interleukin-6, A20-deficient B cells trigger a progressive inflammatory reaction in naive mice characterized by the expansion of myeloid cells, effector-type T cells, and regulatory T cells. This culminates in old mice in an autoimmune syndrome characterized by splenomegaly, plasma cell hyperplasia, and the presence of class-switched, tissue-specific autoantibodies.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Aging / immunology
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Aging / pathology
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Animals
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Autoimmunity
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B-Lymphocyte Subsets / immunology
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B-Lymphocyte Subsets / pathology
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B-Lymphocytes / immunology*
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B-Lymphocytes / pathology*
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Cell Differentiation
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Cysteine Endopeptidases / deficiency*
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Cysteine Endopeptidases / genetics
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Cysteine Endopeptidases / immunology*
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Gene Dosage
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Humans
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In Vitro Techniques
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Inflammation / etiology
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Inflammation / immunology
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Inflammation / pathology
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Interleukin-6 / biosynthesis
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Intracellular Signaling Peptides and Proteins / deficiency*
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Intracellular Signaling Peptides and Proteins / genetics
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Intracellular Signaling Peptides and Proteins / immunology*
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Lymphocyte Activation
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Myeloid Cells / immunology
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Myeloid Cells / pathology
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NF-kappa B / metabolism
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Signal Transduction / immunology
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T-Lymphocytes, Regulatory / immunology
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T-Lymphocytes, Regulatory / pathology
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Tumor Necrosis Factor alpha-Induced Protein 3
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Tumor Suppressor Proteins / deficiency
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Tumor Suppressor Proteins / genetics
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Tumor Suppressor Proteins / immunology
Substances
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Interleukin-6
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Intracellular Signaling Peptides and Proteins
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NF-kappa B
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Tumor Suppressor Proteins
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Tumor Necrosis Factor alpha-Induced Protein 3
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Cysteine Endopeptidases
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Tnfaip3 protein, mouse