B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice
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-...
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| Veröffentlicht in: | Blood 2011-02, Vol.117 (7), p.2227-2236 |
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| creator | Chu, Yuanyuan Vahl, J. Christoph Kumar, Dilip Heger, Klaus Bertossi, Arianna Wójtowicz, Edyta Soberon, Valeria Schenten, Dominik Mack, Brigitte Reutelshöfer, Miriam Beyaert, Rudi Amann, Kerstin van Loo, Geert Schmidt-Supprian, Marc |
| description | 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. |
| doi_str_mv | 10.1182/blood-2010-09-306019 |
| format | Article |
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Christoph ; Kumar, Dilip ; Heger, Klaus ; Bertossi, Arianna ; Wójtowicz, Edyta ; Soberon, Valeria ; Schenten, Dominik ; Mack, Brigitte ; Reutelshöfer, Miriam ; Beyaert, Rudi ; Amann, Kerstin ; van Loo, Geert ; Schmidt-Supprian, Marc</creator><creatorcontrib>Chu, Yuanyuan ; Vahl, J. Christoph ; Kumar, Dilip ; Heger, Klaus ; Bertossi, Arianna ; Wójtowicz, Edyta ; Soberon, Valeria ; Schenten, Dominik ; Mack, Brigitte ; Reutelshöfer, Miriam ; Beyaert, Rudi ; Amann, Kerstin ; van Loo, Geert ; Schmidt-Supprian, Marc</creatorcontrib><description>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.</description><identifier>ISSN: 0006-4971</identifier><identifier>ISSN: 1528-0020</identifier><identifier>EISSN: 1528-0020</identifier><identifier>DOI: 10.1182/blood-2010-09-306019</identifier><identifier>PMID: 21088135</identifier><language>eng</language><publisher>Washington, DC: Elsevier Inc</publisher><subject>Aging - immunology ; Aging - pathology ; Animals ; Autoimmunity ; B-Lymphocyte Subsets - immunology ; B-Lymphocyte Subsets - pathology ; B-Lymphocytes - immunology ; B-Lymphocytes - pathology ; Biological and medical sciences ; Cell Differentiation ; Cysteine Endopeptidases - deficiency ; Cysteine Endopeptidases - genetics ; Cysteine Endopeptidases - immunology ; Gene Dosage ; Hematologic and hematopoietic diseases ; Humans ; In Vitro Techniques ; Inflammation - etiology ; Inflammation - immunology ; Inflammation - pathology ; Interleukin-6 - biosynthesis ; Intracellular Signaling Peptides and Proteins - deficiency ; Intracellular Signaling Peptides and Proteins - genetics ; Intracellular Signaling Peptides and Proteins - immunology ; Lymphocyte Activation ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Myeloid Cells - immunology ; Myeloid Cells - pathology ; NF-kappa B - metabolism ; Signal Transduction - immunology ; T-Lymphocytes, Regulatory - immunology ; T-Lymphocytes, Regulatory - pathology ; Tumor Necrosis Factor alpha-Induced Protein 3 ; Tumor Suppressor Proteins - deficiency ; Tumor Suppressor Proteins - genetics ; Tumor Suppressor Proteins - immunology</subject><ispartof>Blood, 2011-02, Vol.117 (7), p.2227-2236</ispartof><rights>2011 American Society of Hematology</rights><rights>2015 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c535t-1f53e77186790587d9673a7a5f96d9beabc6a59d06aae2cfa0b6d83185ea5b853</citedby><cites>FETCH-LOGICAL-c535t-1f53e77186790587d9673a7a5f96d9beabc6a59d06aae2cfa0b6d83185ea5b853</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=23889595$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21088135$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chu, Yuanyuan</creatorcontrib><creatorcontrib>Vahl, J. Christoph</creatorcontrib><creatorcontrib>Kumar, Dilip</creatorcontrib><creatorcontrib>Heger, Klaus</creatorcontrib><creatorcontrib>Bertossi, Arianna</creatorcontrib><creatorcontrib>Wójtowicz, Edyta</creatorcontrib><creatorcontrib>Soberon, Valeria</creatorcontrib><creatorcontrib>Schenten, Dominik</creatorcontrib><creatorcontrib>Mack, Brigitte</creatorcontrib><creatorcontrib>Reutelshöfer, Miriam</creatorcontrib><creatorcontrib>Beyaert, Rudi</creatorcontrib><creatorcontrib>Amann, Kerstin</creatorcontrib><creatorcontrib>van Loo, Geert</creatorcontrib><creatorcontrib>Schmidt-Supprian, Marc</creatorcontrib><title>B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice</title><title>Blood</title><addtitle>Blood</addtitle><description>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.</description><subject>Aging - immunology</subject><subject>Aging - pathology</subject><subject>Animals</subject><subject>Autoimmunity</subject><subject>B-Lymphocyte Subsets - immunology</subject><subject>B-Lymphocyte Subsets - pathology</subject><subject>B-Lymphocytes - immunology</subject><subject>B-Lymphocytes - pathology</subject><subject>Biological and medical sciences</subject><subject>Cell Differentiation</subject><subject>Cysteine Endopeptidases - deficiency</subject><subject>Cysteine Endopeptidases - genetics</subject><subject>Cysteine Endopeptidases - immunology</subject><subject>Gene Dosage</subject><subject>Hematologic and hematopoietic diseases</subject><subject>Humans</subject><subject>In Vitro Techniques</subject><subject>Inflammation - etiology</subject><subject>Inflammation - immunology</subject><subject>Inflammation - pathology</subject><subject>Interleukin-6 - biosynthesis</subject><subject>Intracellular Signaling Peptides and Proteins - deficiency</subject><subject>Intracellular Signaling Peptides and Proteins - genetics</subject><subject>Intracellular Signaling Peptides and Proteins - immunology</subject><subject>Lymphocyte Activation</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Myeloid Cells - immunology</subject><subject>Myeloid Cells - pathology</subject><subject>NF-kappa B - metabolism</subject><subject>Signal Transduction - immunology</subject><subject>T-Lymphocytes, Regulatory - immunology</subject><subject>T-Lymphocytes, Regulatory - pathology</subject><subject>Tumor Necrosis Factor alpha-Induced Protein 3</subject><subject>Tumor Suppressor Proteins - deficiency</subject><subject>Tumor Suppressor Proteins - genetics</subject><subject>Tumor Suppressor Proteins - immunology</subject><issn>0006-4971</issn><issn>1528-0020</issn><issn>1528-0020</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkc1u1DAURi0EokPhDRDyBrEKvU7Gib1Bmlb0R6qARVlbN_ZNa4iTYDuV5lV4WjLMwOxgZevTudfWdxh7LeC9EKo8a_txdEUJAgrQRQU1CP2ErYQsVQFQwlO2AoC6WOtGnLAXKX0DEOuqlM_ZSSlAKVHJFft5zi31feI92u9-uOf5gXiewxh5mqcpUkrL9e7T5ebmS3W2KYE7n6Yet9yHCX0ktwRdR5GG7DH7ceA4OP6wnSiizf7xmFmcE3E_dD2GcIxxzqMPYR58XpYu2f2yM3hLL9mzDvtErw7nKft6-fHu4rq4_Xx1c7G5LaysZC5EJytqGqHqRoNUjdN1U2GDstO10y1ha2uU2kGNSKXtENraqUooSShbJatT9m6_d4rjj5lSNsGnXSk40Dgno6HZlSrr_5JKlhq0Fs1CrvekjWNKkTozRR8wbo0As9NnfuszO30GtNnrW8beHB6Y20Du79AfXwvw9gBgsth3EQfr05GrlNJS77gPe46W4h49RZOsp8GSW5TZbNzo__2TX5Miuyg</recordid><startdate>20110217</startdate><enddate>20110217</enddate><creator>Chu, Yuanyuan</creator><creator>Vahl, J. Christoph</creator><creator>Kumar, Dilip</creator><creator>Heger, Klaus</creator><creator>Bertossi, Arianna</creator><creator>Wójtowicz, Edyta</creator><creator>Soberon, Valeria</creator><creator>Schenten, Dominik</creator><creator>Mack, Brigitte</creator><creator>Reutelshöfer, Miriam</creator><creator>Beyaert, Rudi</creator><creator>Amann, Kerstin</creator><creator>van Loo, Geert</creator><creator>Schmidt-Supprian, Marc</creator><general>Elsevier Inc</general><general>Americain Society of Hematology</general><scope>6I.</scope><scope>AAFTH</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7T5</scope><scope>7TO</scope><scope>H94</scope></search><sort><creationdate>20110217</creationdate><title>B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice</title><author>Chu, Yuanyuan ; Vahl, J. Christoph ; Kumar, Dilip ; Heger, Klaus ; Bertossi, Arianna ; Wójtowicz, Edyta ; Soberon, Valeria ; Schenten, Dominik ; Mack, Brigitte ; Reutelshöfer, Miriam ; Beyaert, Rudi ; Amann, Kerstin ; van Loo, Geert ; Schmidt-Supprian, Marc</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c535t-1f53e77186790587d9673a7a5f96d9beabc6a59d06aae2cfa0b6d83185ea5b853</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>Aging - immunology</topic><topic>Aging - pathology</topic><topic>Animals</topic><topic>Autoimmunity</topic><topic>B-Lymphocyte Subsets - immunology</topic><topic>B-Lymphocyte Subsets - pathology</topic><topic>B-Lymphocytes - immunology</topic><topic>B-Lymphocytes - pathology</topic><topic>Biological and medical sciences</topic><topic>Cell Differentiation</topic><topic>Cysteine Endopeptidases - deficiency</topic><topic>Cysteine Endopeptidases - genetics</topic><topic>Cysteine Endopeptidases - immunology</topic><topic>Gene Dosage</topic><topic>Hematologic and hematopoietic diseases</topic><topic>Humans</topic><topic>In Vitro Techniques</topic><topic>Inflammation - etiology</topic><topic>Inflammation - immunology</topic><topic>Inflammation - pathology</topic><topic>Interleukin-6 - biosynthesis</topic><topic>Intracellular Signaling Peptides and Proteins - deficiency</topic><topic>Intracellular Signaling Peptides and Proteins - genetics</topic><topic>Intracellular Signaling Peptides and Proteins - immunology</topic><topic>Lymphocyte Activation</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Myeloid Cells - immunology</topic><topic>Myeloid Cells - pathology</topic><topic>NF-kappa B - metabolism</topic><topic>Signal Transduction - immunology</topic><topic>T-Lymphocytes, Regulatory - immunology</topic><topic>T-Lymphocytes, Regulatory - pathology</topic><topic>Tumor Necrosis Factor alpha-Induced Protein 3</topic><topic>Tumor Suppressor Proteins - deficiency</topic><topic>Tumor Suppressor Proteins - genetics</topic><topic>Tumor Suppressor Proteins - immunology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Chu, Yuanyuan</creatorcontrib><creatorcontrib>Vahl, J. 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Christoph</au><au>Kumar, Dilip</au><au>Heger, Klaus</au><au>Bertossi, Arianna</au><au>Wójtowicz, Edyta</au><au>Soberon, Valeria</au><au>Schenten, Dominik</au><au>Mack, Brigitte</au><au>Reutelshöfer, Miriam</au><au>Beyaert, Rudi</au><au>Amann, Kerstin</au><au>van Loo, Geert</au><au>Schmidt-Supprian, Marc</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice</atitle><jtitle>Blood</jtitle><addtitle>Blood</addtitle><date>2011-02-17</date><risdate>2011</risdate><volume>117</volume><issue>7</issue><spage>2227</spage><epage>2236</epage><pages>2227-2236</pages><issn>0006-4971</issn><issn>1528-0020</issn><eissn>1528-0020</eissn><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.</abstract><cop>Washington, DC</cop><pub>Elsevier Inc</pub><pmid>21088135</pmid><doi>10.1182/blood-2010-09-306019</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Aging - immunology Aging - pathology Animals Autoimmunity B-Lymphocyte Subsets - immunology B-Lymphocyte Subsets - pathology B-Lymphocytes - immunology B-Lymphocytes - pathology Biological and medical sciences Cell Differentiation Cysteine Endopeptidases - deficiency Cysteine Endopeptidases - genetics Cysteine Endopeptidases - immunology Gene Dosage Hematologic and hematopoietic diseases Humans In Vitro Techniques Inflammation - etiology Inflammation - immunology Inflammation - pathology Interleukin-6 - biosynthesis Intracellular Signaling Peptides and Proteins - deficiency Intracellular Signaling Peptides and Proteins - genetics Intracellular Signaling Peptides and Proteins - immunology Lymphocyte Activation Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Myeloid Cells - immunology Myeloid Cells - pathology NF-kappa B - metabolism Signal Transduction - immunology T-Lymphocytes, Regulatory - immunology T-Lymphocytes, Regulatory - pathology Tumor Necrosis Factor alpha-Induced Protein 3 Tumor Suppressor Proteins - deficiency Tumor Suppressor Proteins - genetics Tumor Suppressor Proteins - immunology |
| title | B cells lacking the tumor suppressor TNFAIP3/A20 display impaired differentiation and hyperactivation and cause inflammation and autoimmunity in aged mice |
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