Regulation of B cell tolerance by 129‐derived chromosome 1 loci in C57BL/6 mice
Objective Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129‐derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate...
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| Veröffentlicht in: | Arthritis and rheumatism 2008-07, Vol.58 (7), p.2131-2141 |
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| creator | Fossati‐Jimack, Liliane Cortes‐Hernandez, Josefina Norsworthy, Peter J. Cook, H. Terence Walport, Mark J. Botto, Marina |
| description | Objective
Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129‐derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.
Methods
Anti–single‐stranded DNA (anti‐ssDNA)–knockin transgenic mice (VH3H9R/Vκ8R and VH3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene‐targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.
Results
The combination of VH3H9R/Vκ8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti‐ssDNA antibodies were found in the circulation. The presence of IgG2aa anti‐ssDNA and IgMa anti‐Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene‐targeted animals showed a similar phenotype.
Conclusion
The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti‐DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains. |
| doi_str_mv | 10.1002/art.23553 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_pubme</sourceid><recordid>TN_cdi_pubmedcentral_primary_oai_pubmedcentral_nih_gov_2658014</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>69322933</sourcerecordid><originalsourceid>FETCH-LOGICAL-c5403-bd0eaf12982972767300fa02227e5c5e69e0eaa19f7d9119531a16c5042ee79d3</originalsourceid><addsrcrecordid>eNqF0d9qFDEUBvAgFruuXvgCkhsFL6Z7kkwmkxuhXfwHC8VSr0M2c6aNZCY1ma3snY_gM_okZt2l1oviVQj58Z0TPkJeMDhhAHxh03TChZTiEZkxyXUFTLDHZAYAdSWkZsfkac5fy7Uo8YQcs1aqRnA5I58v8GoT7OTjSGNPz6jDEOgUAyY7OqTrLWVc__rxs8Pkb7Gj7jrFIeY4IGU0ROepH-lSqrPVoqGDd_iMHPU2ZHx-OOfky_t3l8uP1er8w6fl6apysgZRrTtA25fslmvFVaMEQG-Bc65QOomNxgIs073qNGNaCmZZ4yTUHFHpTszJ233uzWY9YOdwnJIN5ib5waatidabf19Gf22u4q3hjWyB1SXg9SEgxW8bzJMZfN59344YN9k0WnCuhfgv5CC1UNAU-GYPXYo5J-zvtmFgdk2Z0pT501SxL--v_1ceqing1QHY7Gzod334fOc41G27S5qTxd599wG3D080pxeX-9G_AflVqMc</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>20593706</pqid></control><display><type>article</type><title>Regulation of B cell tolerance by 129‐derived chromosome 1 loci in C57BL/6 mice</title><source>MEDLINE</source><source>Wiley Online Library Journals Frontfile Complete</source><creator>Fossati‐Jimack, Liliane ; Cortes‐Hernandez, Josefina ; Norsworthy, Peter J. ; Cook, H. Terence ; Walport, Mark J. ; Botto, Marina</creator><creatorcontrib>Fossati‐Jimack, Liliane ; Cortes‐Hernandez, Josefina ; Norsworthy, Peter J. ; Cook, H. Terence ; Walport, Mark J. ; Botto, Marina</creatorcontrib><description>Objective
Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129‐derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.
Methods
Anti–single‐stranded DNA (anti‐ssDNA)–knockin transgenic mice (VH3H9R/Vκ8R and VH3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene‐targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.
Results
The combination of VH3H9R/Vκ8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti‐ssDNA antibodies were found in the circulation. The presence of IgG2aa anti‐ssDNA and IgMa anti‐Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene‐targeted animals showed a similar phenotype.
Conclusion
The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti‐DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains.</description><identifier>ISSN: 0004-3591</identifier><identifier>EISSN: 1529-0131</identifier><identifier>DOI: 10.1002/art.23553</identifier><identifier>PMID: 18576325</identifier><identifier>CODEN: ARHEAW</identifier><language>eng</language><publisher>Hoboken: Wiley Subscription Services, Inc., A Wiley Company</publisher><subject>Animals ; Autoantibodies ; Autoimmunity - immunology ; B-Lymphocytes - immunology ; Biological and medical sciences ; Chromosomes, Human, Pair 1 - immunology ; Diseases of the osteoarticular system ; DNA, Single-Stranded ; Humans ; Immunoglobulin Class Switching - immunology ; Immunoglobulin G ; Immunoglobulin M ; Lupus Erythematosus, Systemic - immunology ; Medical sciences ; Mice ; Mice, Inbred C57BL ; Mice, Knockout ; Mice, Transgenic ; Phenotype ; Systemic Lupus Erythematosus Basic Science Studies</subject><ispartof>Arthritis and rheumatism, 2008-07, Vol.58 (7), p.2131-2141</ispartof><rights>Copyright © 2008 by the American College of Rheumatology</rights><rights>2008 INIST-CNRS</rights><rights>Copyright © 2008 American College of Rheumatology 2008</rights><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c5403-bd0eaf12982972767300fa02227e5c5e69e0eaa19f7d9119531a16c5042ee79d3</citedby><cites>FETCH-LOGICAL-c5403-bd0eaf12982972767300fa02227e5c5e69e0eaa19f7d9119531a16c5042ee79d3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://onlinelibrary.wiley.com/doi/pdf/10.1002%2Fart.23553$$EPDF$$P50$$Gwiley$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://onlinelibrary.wiley.com/doi/full/10.1002%2Fart.23553$$EHTML$$P50$$Gwiley$$Hfree_for_read</linktohtml><link.rule.ids>230,314,776,780,881,1411,27901,27902,45550,45551</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=20488355$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/18576325$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Fossati‐Jimack, Liliane</creatorcontrib><creatorcontrib>Cortes‐Hernandez, Josefina</creatorcontrib><creatorcontrib>Norsworthy, Peter J.</creatorcontrib><creatorcontrib>Cook, H. Terence</creatorcontrib><creatorcontrib>Walport, Mark J.</creatorcontrib><creatorcontrib>Botto, Marina</creatorcontrib><title>Regulation of B cell tolerance by 129‐derived chromosome 1 loci in C57BL/6 mice</title><title>Arthritis and rheumatism</title><addtitle>Arthritis Rheum</addtitle><description>Objective
Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129‐derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.
Methods
Anti–single‐stranded DNA (anti‐ssDNA)–knockin transgenic mice (VH3H9R/Vκ8R and VH3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene‐targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.
Results
The combination of VH3H9R/Vκ8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti‐ssDNA antibodies were found in the circulation. The presence of IgG2aa anti‐ssDNA and IgMa anti‐Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene‐targeted animals showed a similar phenotype.
Conclusion
The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti‐DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains.</description><subject>Animals</subject><subject>Autoantibodies</subject><subject>Autoimmunity - immunology</subject><subject>B-Lymphocytes - immunology</subject><subject>Biological and medical sciences</subject><subject>Chromosomes, Human, Pair 1 - immunology</subject><subject>Diseases of the osteoarticular system</subject><subject>DNA, Single-Stranded</subject><subject>Humans</subject><subject>Immunoglobulin Class Switching - immunology</subject><subject>Immunoglobulin G</subject><subject>Immunoglobulin M</subject><subject>Lupus Erythematosus, Systemic - immunology</subject><subject>Medical sciences</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mice, Knockout</subject><subject>Mice, Transgenic</subject><subject>Phenotype</subject><subject>Systemic Lupus Erythematosus Basic Science Studies</subject><issn>0004-3591</issn><issn>1529-0131</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2008</creationdate><recordtype>article</recordtype><sourceid>24P</sourceid><sourceid>EIF</sourceid><recordid>eNqF0d9qFDEUBvAgFruuXvgCkhsFL6Z7kkwmkxuhXfwHC8VSr0M2c6aNZCY1ma3snY_gM_okZt2l1oviVQj58Z0TPkJeMDhhAHxh03TChZTiEZkxyXUFTLDHZAYAdSWkZsfkac5fy7Uo8YQcs1aqRnA5I58v8GoT7OTjSGNPz6jDEOgUAyY7OqTrLWVc__rxs8Pkb7Gj7jrFIeY4IGU0ROepH-lSqrPVoqGDd_iMHPU2ZHx-OOfky_t3l8uP1er8w6fl6apysgZRrTtA25fslmvFVaMEQG-Bc65QOomNxgIs073qNGNaCmZZ4yTUHFHpTszJ233uzWY9YOdwnJIN5ib5waatidabf19Gf22u4q3hjWyB1SXg9SEgxW8bzJMZfN59344YN9k0WnCuhfgv5CC1UNAU-GYPXYo5J-zvtmFgdk2Z0pT501SxL--v_1ceqing1QHY7Gzod334fOc41G27S5qTxd599wG3D080pxeX-9G_AflVqMc</recordid><startdate>200807</startdate><enddate>200807</enddate><creator>Fossati‐Jimack, Liliane</creator><creator>Cortes‐Hernandez, Josefina</creator><creator>Norsworthy, Peter J.</creator><creator>Cook, H. Terence</creator><creator>Walport, Mark J.</creator><creator>Botto, Marina</creator><general>Wiley Subscription Services, Inc., A Wiley Company</general><general>Wiley</general><scope>24P</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>7T5</scope><scope>8FD</scope><scope>FR3</scope><scope>H94</scope><scope>P64</scope><scope>RC3</scope><scope>7X8</scope><scope>5PM</scope></search><sort><creationdate>200807</creationdate><title>Regulation of B cell tolerance by 129‐derived chromosome 1 loci in C57BL/6 mice</title><author>Fossati‐Jimack, Liliane ; Cortes‐Hernandez, Josefina ; Norsworthy, Peter J. ; Cook, H. Terence ; Walport, Mark J. ; Botto, Marina</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c5403-bd0eaf12982972767300fa02227e5c5e69e0eaa19f7d9119531a16c5042ee79d3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2008</creationdate><topic>Animals</topic><topic>Autoantibodies</topic><topic>Autoimmunity - immunology</topic><topic>B-Lymphocytes - immunology</topic><topic>Biological and medical sciences</topic><topic>Chromosomes, Human, Pair 1 - immunology</topic><topic>Diseases of the osteoarticular system</topic><topic>DNA, Single-Stranded</topic><topic>Humans</topic><topic>Immunoglobulin Class Switching - immunology</topic><topic>Immunoglobulin G</topic><topic>Immunoglobulin M</topic><topic>Lupus Erythematosus, Systemic - immunology</topic><topic>Medical sciences</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mice, Knockout</topic><topic>Mice, Transgenic</topic><topic>Phenotype</topic><topic>Systemic Lupus Erythematosus Basic Science Studies</topic><toplevel>online_resources</toplevel><creatorcontrib>Fossati‐Jimack, Liliane</creatorcontrib><creatorcontrib>Cortes‐Hernandez, Josefina</creatorcontrib><creatorcontrib>Norsworthy, Peter J.</creatorcontrib><creatorcontrib>Cook, H. Terence</creatorcontrib><creatorcontrib>Walport, Mark J.</creatorcontrib><creatorcontrib>Botto, Marina</creatorcontrib><collection>Wiley Online Library Open Access</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Immunology Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>AIDS and Cancer Research Abstracts</collection><collection>Biotechnology and BioEngineering Abstracts</collection><collection>Genetics Abstracts</collection><collection>MEDLINE - Academic</collection><collection>PubMed Central (Full Participant titles)</collection><jtitle>Arthritis and rheumatism</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Fossati‐Jimack, Liliane</au><au>Cortes‐Hernandez, Josefina</au><au>Norsworthy, Peter J.</au><au>Cook, H. Terence</au><au>Walport, Mark J.</au><au>Botto, Marina</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Regulation of B cell tolerance by 129‐derived chromosome 1 loci in C57BL/6 mice</atitle><jtitle>Arthritis and rheumatism</jtitle><addtitle>Arthritis Rheum</addtitle><date>2008-07</date><risdate>2008</risdate><volume>58</volume><issue>7</issue><spage>2131</spage><epage>2141</epage><pages>2131-2141</pages><issn>0004-3591</issn><eissn>1529-0131</eissn><coden>ARHEAW</coden><abstract>Objective
Systemic lupus erythematosus is a multifactorial disease with a strong genetic component. Previous studies have shown that a 129‐derived chromosome 1 interval (Sle16) on the C57BL/6 (B6) background is sufficient to induce humoral autoimmunity. The aim of the present study was to elucidate the mechanisms by which this locus contributes to the loss of peripheral tolerance.
Methods
Anti–single‐stranded DNA (anti‐ssDNA)–knockin transgenic mice (VH3H9R/Vκ8R and VH3H9R) were crossed with a B6 congenic line named B6.129chr1b that carries the Sle16 locus. A parallel study of a gene‐targeted animal, whose mutated gene is located within the 129chr1b interval on chromosome 1, was also performed.
Results
The combination of VH3H9R/Vκ8R with the 129chr1b interval resulted in impaired B cell anergy, and transgenic IgM and IgG anti‐ssDNA antibodies were found in the circulation. The presence of IgG2aa anti‐ssDNA and IgMa anti‐Sm antibodies in sera indicated that the autoreactive transgenic B cells underwent class switching and epitope spreading. The 129chr1b locus appeared to have a dominant effect, since transgenic antibodies were also detected in mice carrying a single allele. The gene‐targeted animals showed a similar phenotype.
Conclusion
The presence of a single 129chr1b locus on the B6 background impaired B cell anergy, prevented deletion of anti‐DNA transgenic B cells, and induced receptor revision. The findings of this study also emphasize that the autoimmune phenotype observed in mice with targeted genes located on chromosome 1 may simply arise from epistatic interactions between the 129 and B6 parental strains.</abstract><cop>Hoboken</cop><pub>Wiley Subscription Services, Inc., A Wiley Company</pub><pmid>18576325</pmid><doi>10.1002/art.23553</doi><tpages>11</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Animals Autoantibodies Autoimmunity - immunology B-Lymphocytes - immunology Biological and medical sciences Chromosomes, Human, Pair 1 - immunology Diseases of the osteoarticular system DNA, Single-Stranded Humans Immunoglobulin Class Switching - immunology Immunoglobulin G Immunoglobulin M Lupus Erythematosus, Systemic - immunology Medical sciences Mice Mice, Inbred C57BL Mice, Knockout Mice, Transgenic Phenotype Systemic Lupus Erythematosus Basic Science Studies |
| title | Regulation of B cell tolerance by 129‐derived chromosome 1 loci in C57BL/6 mice |
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