Title
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The ubiquitin-editing protein A20 prevents dendritic cell activation, recognition of apoptotic cells, and systemic autoimmunity
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Author
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Abstract
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Dendritic cells (DCs) regulate both immunity and tolerance. Here we have shown that the ubiquitin editing enzyme A20 (Tnfaip3) determines the activation threshold of DCs, via control of canonical NF-kappa B activation. Tnfaip3(fl)/(fl)Cd11c-cre(+) mice lacking A20 in DCs demonstrated spontaneous proliferation of conventional and double-negative T cells, their conversion to interferon-gamma (IFN-gamma)-producing effector cells, and expansion of plasma cells. They developed ds-DNA antibodies, nephritis, the antiphospholipid syndrome, and lymphosplenomegaly-features of systemic lupus erythematosus-and extramedullary hematopoiesis. A20-deficient DCs were resistant to apoptosis, caused by increased sensitivity to CD40L and RANKL prosurvival signals and upregulation of antiapoptotic proteins Bcl-2 and Bcl-x. They captured injected apoptotic cells more efficiently, resisted the inhibitory effects of apoptotic cells, and induced self-reactive effector lymphocytes. Because genetic polymorphisms in TNFAIP3 are associated with human autoimmune disorders, these findings identify A20-mediated control of DC activation as a crucial checkpoint in the development of systemic autoimmunity. |
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Language
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English
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Source (journal)
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Immunity. - Cambridge, Mass.
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Publication
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Cambridge, Mass.
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2011
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ISSN
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1074-7613
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DOI
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10.1016/J.IMMUNI.2011.05.013
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Volume/pages
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35
:1
(2011)
, p. 82-96
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ISI
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000293107300012
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Full text (Publisher's DOI)
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Full text (publisher's version - intranet only)
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