Generalized Resistance to Thymic Deletion in the NOD Mouse: A Polygenic Trait Characterized by Defective Induction of Bim
The cause of common polygenic autoimmune diseases is not understood because of genetic and cellular complexity. Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to D1mit181, D2mit490, D7mit101, and D15mit229, which cause a generalized resistan...
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| Veröffentlicht in: | Immunity (Cambridge, Mass.) Mass.), 2004-12, Vol.21 (6), p.817-830 |
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| creator | Liston, Adrian Lesage, Sylvie Gray, Daniel H.D. O'Reilly, Lorraine A. Strasser, Andreas Fahrer, Aude M. Boyd, Richard L. Wilson, Judith Baxter, Alan G. Gallo, Elena M. Crabtree, Gerald R. Peng, Kaiman Wilson, Susan R. Goodnow, Christopher C. |
| description | The cause of common polygenic autoimmune diseases is not understood because of genetic and cellular complexity. Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to
D1mit181,
D2mit490,
D7mit101, and
D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to
Aire-induced organ-specific gene products in the thymic medulla and to systemic antigens expressed at high levels throughout the thymus and affects CD4
+, CD4
+8
+, and CD4
+25
+ thymocytes. Resistance to thymic deletion does not reflect a general deficit in TCR signaling to calcineurin- or ERK-induced genes, imbalance in constitutive regulators of apoptosis, nor excessive signaling to prosurvival genes but is distinguished by failure to induce the proapoptotic gene and protein, Bim, during in vivo encounter with high-avidity autoantigen. These findings establish defects in thymic deletion and Bim induction as a key mechanism in the pathogenesis of autoimmunity. |
| doi_str_mv | 10.1016/j.immuni.2004.10.014 |
| format | Article |
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D1mit181,
D2mit490,
D7mit101, and
D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to
Aire-induced organ-specific gene products in the thymic medulla and to systemic antigens expressed at high levels throughout the thymus and affects CD4
+, CD4
+8
+, and CD4
+25
+ thymocytes. Resistance to thymic deletion does not reflect a general deficit in TCR signaling to calcineurin- or ERK-induced genes, imbalance in constitutive regulators of apoptosis, nor excessive signaling to prosurvival genes but is distinguished by failure to induce the proapoptotic gene and protein, Bim, during in vivo encounter with high-avidity autoantigen. These findings establish defects in thymic deletion and Bim induction as a key mechanism in the pathogenesis of autoimmunity.</description><identifier>ISSN: 1074-7613</identifier><identifier>EISSN: 1097-4180</identifier><identifier>DOI: 10.1016/j.immuni.2004.10.014</identifier><identifier>PMID: 15589170</identifier><language>eng</language><publisher>United States: Elsevier Inc</publisher><subject>Animals ; Apoptosis - genetics ; Apoptosis Regulatory Proteins ; Autoantigens - immunology ; Autoimmune diseases ; Bcl-2-Like Protein 11 ; Carrier Proteins - metabolism ; CD4 Antigens - immunology ; Defects ; Diabetes ; Female ; Gene Expression Regulation ; Lymphocytes ; MAP Kinase Signaling System ; Membrane Proteins - metabolism ; Mice ; Mice, Inbred NOD ; Multifactorial Inheritance - genetics ; Mutation ; Protein Array Analysis ; Proto-Oncogene Proteins - metabolism ; Receptors, Interleukin-2 - immunology ; RNA polymerase ; Rodents ; T-Lymphocytes - immunology ; T-Lymphocytes - pathology ; Thymus Gland - abnormalities ; Thymus Gland - immunology ; Thymus Gland - pathology</subject><ispartof>Immunity (Cambridge, Mass.), 2004-12, Vol.21 (6), p.817-830</ispartof><rights>2004 Cell Press</rights><rights>Copyright Elsevier Limited Dec 2004</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S1074761304003139$$EHTML$$P50$$Gelsevier$$Hfree_for_read</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65534</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/15589170$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Liston, Adrian</creatorcontrib><creatorcontrib>Lesage, Sylvie</creatorcontrib><creatorcontrib>Gray, Daniel H.D.</creatorcontrib><creatorcontrib>O'Reilly, Lorraine A.</creatorcontrib><creatorcontrib>Strasser, Andreas</creatorcontrib><creatorcontrib>Fahrer, Aude M.</creatorcontrib><creatorcontrib>Boyd, Richard L.</creatorcontrib><creatorcontrib>Wilson, Judith</creatorcontrib><creatorcontrib>Baxter, Alan G.</creatorcontrib><creatorcontrib>Gallo, Elena M.</creatorcontrib><creatorcontrib>Crabtree, Gerald R.</creatorcontrib><creatorcontrib>Peng, Kaiman</creatorcontrib><creatorcontrib>Wilson, Susan R.</creatorcontrib><creatorcontrib>Goodnow, Christopher C.</creatorcontrib><title>Generalized Resistance to Thymic Deletion in the NOD Mouse: A Polygenic Trait Characterized by Defective Induction of Bim</title><title>Immunity (Cambridge, Mass.)</title><addtitle>Immunity</addtitle><description>The cause of common polygenic autoimmune diseases is not understood because of genetic and cellular complexity. Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to
D1mit181,
D2mit490,
D7mit101, and
D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to
Aire-induced organ-specific gene products in the thymic medulla and to systemic antigens expressed at high levels throughout the thymus and affects CD4
+, CD4
+8
+, and CD4
+25
+ thymocytes. Resistance to thymic deletion does not reflect a general deficit in TCR signaling to calcineurin- or ERK-induced genes, imbalance in constitutive regulators of apoptosis, nor excessive signaling to prosurvival genes but is distinguished by failure to induce the proapoptotic gene and protein, Bim, during in vivo encounter with high-avidity autoantigen. These findings establish defects in thymic deletion and Bim induction as a key mechanism in the pathogenesis of autoimmunity.</description><subject>Animals</subject><subject>Apoptosis - genetics</subject><subject>Apoptosis Regulatory Proteins</subject><subject>Autoantigens - immunology</subject><subject>Autoimmune diseases</subject><subject>Bcl-2-Like Protein 11</subject><subject>Carrier Proteins - metabolism</subject><subject>CD4 Antigens - immunology</subject><subject>Defects</subject><subject>Diabetes</subject><subject>Female</subject><subject>Gene Expression Regulation</subject><subject>Lymphocytes</subject><subject>MAP Kinase Signaling System</subject><subject>Membrane Proteins - metabolism</subject><subject>Mice</subject><subject>Mice, Inbred NOD</subject><subject>Multifactorial Inheritance - genetics</subject><subject>Mutation</subject><subject>Protein Array Analysis</subject><subject>Proto-Oncogene Proteins - metabolism</subject><subject>Receptors, Interleukin-2 - immunology</subject><subject>RNA polymerase</subject><subject>Rodents</subject><subject>T-Lymphocytes - immunology</subject><subject>T-Lymphocytes - pathology</subject><subject>Thymus Gland - abnormalities</subject><subject>Thymus Gland - immunology</subject><subject>Thymus Gland - pathology</subject><issn>1074-7613</issn><issn>1097-4180</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2004</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkV9rFDEUxYMo9p_fQCQg9G3WZJJMJj4Idau1UG2R9TlkMzdulplMTTKF6advtltf-tKne7n87oFzDkLvKVlQQptP24Ufhin4RU0IL6cFofwVOqREyYrTlrze7ZJXsqHsAB2ltCWFEIq8RQdUiFZRSQ7RfAEBoun9PXT4NySfsgkWcB7xajMP3uJz6CH7MWAfcN4A_nV9jn-OU4LP-AzfjP38F0LBVtH4jJcbE43NEB_11nP5dmCzvwN8GbrJPgqNDn_1wwl640yf4N3TPEZ_vn9bLX9UV9cXl8uzqwpYzXIlVWOc4MQQDkwoB8y2RjZOCcuNM7VyjjrR1BZot26kMF3LGWsbx1XbUavYMTrd697G8d8EKevBJwt9bwIUG7qRVHJevwxS2TIiVF3Aj8_A7TjFUExoKgivGWF1W6gPT9S0HqDTt9EPJs76f_YF-LIHoLi_8xB1sh5K-J2PJTPdjV5Tondl663el613Ze-upUr2AEt5nJw</recordid><startdate>20041201</startdate><enddate>20041201</enddate><creator>Liston, Adrian</creator><creator>Lesage, Sylvie</creator><creator>Gray, Daniel H.D.</creator><creator>O'Reilly, Lorraine A.</creator><creator>Strasser, Andreas</creator><creator>Fahrer, Aude M.</creator><creator>Boyd, Richard L.</creator><creator>Wilson, Judith</creator><creator>Baxter, Alan G.</creator><creator>Gallo, Elena M.</creator><creator>Crabtree, Gerald R.</creator><creator>Peng, Kaiman</creator><creator>Wilson, Susan R.</creator><creator>Goodnow, Christopher C.</creator><general>Elsevier Inc</general><general>Elsevier Limited</general><scope>6I.</scope><scope>AAFTH</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7QL</scope><scope>7QP</scope><scope>7QR</scope><scope>7T5</scope><scope>7T7</scope><scope>7TK</scope><scope>7TM</scope><scope>7U9</scope><scope>8FD</scope><scope>C1K</scope><scope>FR3</scope><scope>H94</scope><scope>K9.</scope><scope>M7N</scope><scope>NAPCQ</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope></search><sort><creationdate>20041201</creationdate><title>Generalized Resistance to Thymic Deletion in the NOD Mouse: A Polygenic Trait Characterized by Defective Induction of Bim</title><author>Liston, Adrian ; 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Here, we pinpoint the action of a subset of autoimmune susceptibility loci in the NOD mouse strain linked to
D1mit181,
D2mit490,
D7mit101, and
D15mit229, which cause a generalized resistance to thymic deletion in vivo that applies equally to
Aire-induced organ-specific gene products in the thymic medulla and to systemic antigens expressed at high levels throughout the thymus and affects CD4
+, CD4
+8
+, and CD4
+25
+ thymocytes. Resistance to thymic deletion does not reflect a general deficit in TCR signaling to calcineurin- or ERK-induced genes, imbalance in constitutive regulators of apoptosis, nor excessive signaling to prosurvival genes but is distinguished by failure to induce the proapoptotic gene and protein, Bim, during in vivo encounter with high-avidity autoantigen. These findings establish defects in thymic deletion and Bim induction as a key mechanism in the pathogenesis of autoimmunity.</abstract><cop>United States</cop><pub>Elsevier Inc</pub><pmid>15589170</pmid><doi>10.1016/j.immuni.2004.10.014</doi><tpages>14</tpages><oa>free_for_read</oa></addata></record> |
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| source | MEDLINE; Elsevier ScienceDirect Journals Complete; Cell Press Free Archives; Elektronische Zeitschriftenbibliothek - Frei zugängliche E-Journals |
| subjects | Animals Apoptosis - genetics Apoptosis Regulatory Proteins Autoantigens - immunology Autoimmune diseases Bcl-2-Like Protein 11 Carrier Proteins - metabolism CD4 Antigens - immunology Defects Diabetes Female Gene Expression Regulation Lymphocytes MAP Kinase Signaling System Membrane Proteins - metabolism Mice Mice, Inbred NOD Multifactorial Inheritance - genetics Mutation Protein Array Analysis Proto-Oncogene Proteins - metabolism Receptors, Interleukin-2 - immunology RNA polymerase Rodents T-Lymphocytes - immunology T-Lymphocytes - pathology Thymus Gland - abnormalities Thymus Gland - immunology Thymus Gland - pathology |
| title | Generalized Resistance to Thymic Deletion in the NOD Mouse: A Polygenic Trait Characterized by Defective Induction of Bim |
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