Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease
Identifieur interne : 002195 ( Istex/Corpus ); précédent : 002194; suivant : 002196Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease
Auteurs : Duncheng Wang ; Shinu A. John ; James L. Clements ; Dean H. Percy ; Kevin P. Barton ; Lee Ann Garrett-SinhaSource :
- International Immunology [ 0953-8178 ] ; 2005.
Abstract
It has been shown that mice with a targeted mutation in the Ets-1 gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this Ets-1 hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells in vitro in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, Ets-1 mutant mice develop autoimmune disease. Hence, our studies establish Ets-1 as an important regulator of peripheral B cell differentiation and B cell responses to TLR9 activation.
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DOI: 10.1093/intimm/dxh295
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Clements</name><affiliation><mods:affiliation>Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA</mods:affiliation></affiliation></author><author><name sortKey="Percy, Dean H" sort="Percy, Dean H" uniqKey="Percy D" first="Dean H." last="Percy">Dean H. Percy</name><affiliation><mods:affiliation>Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Barton, Kevin P" sort="Barton, Kevin P" uniqKey="Barton K" first="Kevin P." last="Barton">Kevin P. 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John</name><affiliation><mods:affiliation>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</mods:affiliation></affiliation></author><author><name sortKey="Clements, James L" sort="Clements, James L" uniqKey="Clements J" first="James L." last="Clements">James L. Clements</name><affiliation><mods:affiliation>Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA</mods:affiliation></affiliation></author><author><name sortKey="Percy, Dean H" sort="Percy, Dean H" uniqKey="Percy D" first="Dean H." last="Percy">Dean H. Percy</name><affiliation><mods:affiliation>Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1</mods:affiliation></affiliation></author><author><name sortKey="Barton, Kevin P" sort="Barton, Kevin P" uniqKey="Barton K" first="Kevin P." last="Barton">Kevin P. Barton</name><affiliation><mods:affiliation>Department of Medicine, Section of Hematology/Oncology, Loyola University, Chicago, IL 60611, USA</mods:affiliation></affiliation></author><author><name sortKey="Garrett Sinha, Lee Ann" sort="Garrett Sinha, Lee Ann" uniqKey="Garrett Sinha L" first="Lee Ann" last="Garrett-Sinha">Lee Ann Garrett-Sinha</name><affiliation><mods:affiliation>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</mods:affiliation></affiliation></author></analytic><monogr></monogr><series><title level="j" type="main">International Immunology</title><title level="j" type="abbrev">Int. Immunol.</title><idno type="ISSN">0953-8178</idno><idno type="eISSN">1460-2377</idno><imprint><publisher>Oxford University Press</publisher><date type="e-published" when="2005-07-28">2005</date><date when="2005-09">2005</date><biblScope unit="vol">17</biblScope><biblScope unit="issue">9</biblScope><biblScope unit="page" from="1179">1179</biblScope><biblScope unit="page" to="1191">1191</biblScope></imprint><idno type="ISSN">0953-8178</idno></series></biblStruct></sourceDesc><seriesStmt><idno type="ISSN">0953-8178</idno></seriesStmt></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en">It has been shown that mice with a targeted mutation in the Ets-1 gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this Ets-1 hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells in vitro in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, Ets-1 mutant mice develop autoimmune disease. 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John</name><affiliations><json:string>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</json:string></affiliations></json:item><json:item><name>James L. Clements</name><affiliations><json:string>Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA</json:string></affiliations></json:item><json:item><name>Dean H. Percy</name><affiliations><json:string>Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1</json:string></affiliations></json:item><json:item><name>Kevin P. Barton</name><affiliations><json:string>Department of Medicine, Section of Hematology/Oncology, Loyola University, Chicago, IL 60611, USA</json:string></affiliations></json:item><json:item><name>Lee Ann Garrett-Sinha</name><affiliations><json:string>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</json:string></affiliations></json:item></author><subject><json:item><lang><json:string>eng</json:string></lang><value>B cell activation</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CpG oligodeoxynucleotide</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>marginal zone</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Pointed domain</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CBP CREB binding protein</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CFSE carboxyfluorescein diacetate succinimidyl ester</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>CpG cytosine-phosphate-guanine DNA sequence</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>Erk extracellular regulated kinase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>HA hemagglutinin</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>HEL hen egg lysozyme</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>HPRT hypoxanthine phosphoribosyl transferase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>IRAK interleukin-1 receptor associated kinase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>MFI mean fluorescent intensity</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>ODN oligodeoxynucleotide</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>RT reverse transcriptase</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>SIGIRR single Ig IL-1R-related molecule</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TLR Toll-like receptor</value></json:item><json:item><lang><json:string>eng</json:string></lang><value>TNP trinitrophenol</value></json:item></subject><arkIstex>ark:/67375/HXZ-6SD19LM9-6</arkIstex><language><json:string>eng</json:string></language><originalGenre><json:string>other</json:string></originalGenre><abstract>It has been shown that mice with a targeted mutation in the Ets-1 gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this Ets-1 hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells in vitro in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, Ets-1 mutant mice develop autoimmune disease. Hence, our studies establish Ets-1 as an important regulator of peripheral B cell differentiation and B cell responses to TLR9 activation.</abstract><qualityIndicators><score>7.484</score><pdfWordCount>8121</pdfWordCount><pdfCharCount>51170</pdfCharCount><pdfVersion>1.3</pdfVersion><pdfPageCount>13</pdfPageCount><pdfPageSize>612 x 794 pts</pdfPageSize><pdfWordsPerPage>625</pdfWordsPerPage><pdfText>true</pdfText><refBibsNative>true</refBibsNative><abstractWordCount>207</abstractWordCount><abstractCharCount>1462</abstractCharCount><keywordCount>18</keywordCount></qualityIndicators><title>Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease</title><pmid><json:string>16051621</json:string></pmid><genre><json:string>other</json:string></genre><host><title>International Immunology</title><language><json:string>unknown</json:string></language><issn><json:string>0953-8178</json:string></issn><eissn><json:string>1460-2377</json:string></eissn><publisherId><json:string>intimm</json:string></publisherId><volume>17</volume><issue>9</issue><pages><first>1179</first><last>1191</last></pages><genre><json:string>journal</json:string></genre></host><namedEntities><unitex><date><json:string>2005-07-28</json:string></date><geogName></geogName><orgName><json:string>Loyola University</json:string><json:string>Roswell Park Cancer Institute, Buffalo, NY</json:string><json:string>Sigma Chemical</json:string><json:string>Novis Research Grant</json:string><json:string>University of Texas</json:string><json:string>Anderson Cancer Center</json:string><json:string>University of Guelph</json:string><json:string>Santa Cruz Biotechnology</json:string><json:string>State University</json:string><json:string>Department Department</json:string><json:string>International Myeloma Foundation</json:string></orgName><orgName_funder><json:string>International Myeloma Foundation</json:string></orgName_funder><orgName_provider></orgName_provider><persName><json:string>Coley</json:string><json:string>Rose-Anne Romano</json:string><json:string>Ann Garrett-Sinha</json:string><json:string>Lee</json:string><json:string>Kevin P. 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All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org</licence></availability><date type="e-published" when="2005-07-28">2005</date><date when="2005-09">2005</date><date type="Copyright" when="2005">2005</date></publicationStmt><notesStmt><note type="content-type" source="other" scheme="https://content-type.data.istex.fr/ark:/67375/XTP-6N5SZHKN-D">article</note><note type="publication-type" scheme="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</note></notesStmt><sourceDesc><biblStruct type="other"><analytic><title level="a" type="main" xml:lang="en">Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease</title><author xml:id="author-0000"><persName><surname>Wang</surname><forename type="first">Duncheng</forename></persName><affiliation><orgName type="department">Department of Biochemistry</orgName><address><addrLine>State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</addrLine><country key="US" xml:lang="en">UNITED STATES</country></address></affiliation><affiliation role="corresp">Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha@buffalo.edu</affiliation></author><author xml:id="author-0001"><persName><surname>John</surname><forename type="first">Shinu A.</forename></persName><affiliation><orgName type="department">Department of Biochemistry</orgName><address><addrLine>State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</addrLine><country key="US" xml:lang="en">UNITED STATES</country></address></affiliation><affiliation role="corresp">Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha@buffalo.edu</affiliation></author><author xml:id="author-0002"><persName><surname>Clements</surname><forename type="first">James L.</forename></persName><affiliation><orgName type="department">Department of Immunology</orgName><address><addrLine>Roswell Park Cancer Institute, Buffalo, NY 14263, USA</addrLine><country key="US" xml:lang="en">UNITED STATES</country></address></affiliation><affiliation role="corresp">Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha@buffalo.edu</affiliation></author><author xml:id="author-0003"><persName><surname>Percy</surname><forename type="first">Dean H.</forename></persName><affiliation><orgName type="department">Department of Pathobiology</orgName><address><addrLine>Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1</addrLine></address></affiliation><affiliation role="corresp">Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha@buffalo.edu</affiliation></author><author xml:id="author-0004"><persName><surname>Barton</surname><forename type="first">Kevin P.</forename></persName><affiliation><orgName type="department">Department of Medicine</orgName><address><addrLine>Section of Hematology/Oncology, Loyola University, Chicago, IL 60611, USA</addrLine><country key="US" xml:lang="en">UNITED STATES</country></address></affiliation><affiliation role="corresp">Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha@buffalo.edu</affiliation></author><author xml:id="author-0005"><persName><surname>Garrett-Sinha</surname><forename type="first">Lee Ann</forename></persName><affiliation><orgName type="department">Department of Biochemistry</orgName><address><addrLine>State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</addrLine><country key="US" xml:lang="en">UNITED STATES</country></address></affiliation><affiliation role="corresp">Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha@buffalo.edu</affiliation></author><idno type="istex">1B727D61491D9CDCF27A1316CE4D893F1779CC4E</idno><idno type="ark">ark:/67375/HXZ-6SD19LM9-6</idno><idno type="other">dxh295</idno><idno type="DOI">10.1093/intimm/dxh295</idno></analytic><monogr><title level="j" type="main">International Immunology</title><title level="j" type="abbrev">Int. 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<ref target="http://www.tei-c.org/">We use TEI</ref></desc></application></appInfo></encodingDesc><profileDesc><abstract xml:lang="en"><p>It has been shown that mice with a targeted mutation in the <hi rend="italic">Ets-1</hi> gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this <hi rend="italic">Ets-1</hi> hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells <hi rend="italic">in vitro</hi> in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, <hi rend="italic">Ets-1</hi> mutant mice develop autoimmune disease. Hence, our studies establish Ets-1 as an important regulator of peripheral B cell differentiation and B cell responses to TLR9 activation.</p></abstract><textClass ana="subject"><keywords scheme="heading"><term>ORIGINAL RESEARCH PAPERS</term></keywords></textClass><textClass ana="keyword"><keywords scheme="KWD" xml:lang="en"><term>B cell activation</term><term>CpG oligodeoxynucleotide</term><term>marginal zone</term><term>Pointed domain</term></keywords></textClass><textClass ana="keyword"><keywords scheme="ABR" xml:lang="en"><term>CBP CREB binding protein</term><term>CFSE carboxyfluorescein diacetate succinimidyl ester</term><term>CpG cytosine-phosphate-guanine DNA sequence</term><term>Erk extracellular regulated kinase</term><term>HA hemagglutinin</term><term>HEL hen egg lysozyme</term><term>HPRT hypoxanthine phosphoribosyl transferase</term><term>IRAK interleukin-1 receptor associated kinase</term><term>MFI mean fluorescent intensity</term><term>ODN oligodeoxynucleotide</term><term>RT reverse transcriptase</term><term>SIGIRR single Ig IL-1R-related molecule</term><term>TLR Toll-like receptor</term><term>TNP trinitrophenol</term></keywords></textClass><langUsage><language ident="en"></language></langUsage></profileDesc><revisionDesc><change when="2019-12-09" who="#istex" xml:id="pub2tei">formatting</change></revisionDesc></teiHeader></istex:fulltextTEI><json:item><extension>txt</extension><original>false</original><mimetype>text/plain</mimetype><uri>https://api.istex.fr/ark:/67375/HXZ-6SD19LM9-6/fulltext.txt</uri></json:item></fulltext><metadata><istex:metadataXml wicri:clean="corpus oup, element #text not found" wicri:toSee="no header"><istex:xmlDeclaration>version="1.0" encoding="US-ASCII"</istex:xmlDeclaration><istex:docType PUBLIC="-//NLM//DTD Journal Publishing DTD v2.3 20070202//EN" URI="journalpublishing.dtd" name="istex:docType"></istex:docType><istex:document><article xml:lang="en" article-type="other"><front><journal-meta><journal-id journal-id-type="hwp">intimm</journal-id><journal-id journal-id-type="nlm-ta">Int Immunol</journal-id>
<journal-id journal-id-type="publisher-id">intimm</journal-id><journal-title>International Immunology</journal-title><abbrev-journal-title abbrev-type="publisher">Int. Immunol.</abbrev-journal-title><issn pub-type="ppub">0953-8178</issn><issn pub-type="epub">1460-2377</issn><publisher><publisher-name>Oxford University Press</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="other">dxh295</article-id><article-id pub-id-type="doi">10.1093/intimm/dxh295</article-id><article-categories><subj-group subj-group-type="heading"><subject>ORIGINAL RESEARCH PAPERS</subject></subj-group></article-categories><title-group><article-title>Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease</article-title></title-group><contrib-group>
<contrib contrib-type="author"><name><surname>Wang</surname><given-names>Duncheng</given-names></name>
<xref rid="AFF1">
<sup>1</sup>
</xref>
<xref rid="FN1">
<sup>*</sup>
</xref>
</contrib><contrib contrib-type="author"><name><surname>John</surname><given-names>Shinu A.</given-names></name>
<xref rid="AFF1">
<sup>1</sup>
</xref>
<xref rid="FN1">
<sup>*</sup>
</xref>
</contrib><contrib contrib-type="author"><name><surname>Clements</surname><given-names>James L.</given-names></name>
<xref rid="AFF2">
<sup>2</sup>
</xref>
</contrib><contrib contrib-type="author"><name><surname>Percy</surname><given-names>Dean H.</given-names></name>
<xref rid="AFF3">
<sup>3</sup>
</xref>
</contrib><contrib contrib-type="author"><name><surname>Barton</surname><given-names>Kevin P.</given-names></name>
<xref rid="AFF4">
<sup>4</sup>
</xref>
</contrib><contrib contrib-type="author"><name><surname>Garrett-Sinha</surname><given-names>Lee Ann</given-names></name>
<xref rid="AFF1">
<sup>1</sup>
</xref>
</contrib><aff id="AFF1"><label>1</label>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</aff><aff id="AFF2"><label>2</label>Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA</aff><aff id="AFF3"><label>3</label>Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1</aff><aff id="AFF4"><label>4</label>Department of Medicine, Section of Hematology/Oncology, Loyola University, Chicago, IL 60611, USA</aff></contrib-group><author-notes><corresp><italic>Correspondence to</italic>: L. A. Garrett-Sinha; E-mail: <ext-link xlink:href="leesinha@buffalo.edu" ext-link-type="email">leesinha@buffalo.edu</ext-link></corresp></author-notes><pub-date pub-type="epub"><day>28</day><month>7</month><year>2005</year></pub-date><pub-date pub-type="ppub"><month>September</month><year>2005</year></pub-date><volume>17</volume><issue>9</issue><fpage>1179</fpage><lpage>1191</lpage><history><date date-type="accepted"><day>13</day><month>6</month><year>2005</year></date><date date-type="received"><day>16</day><month>2</month><year>2005</year></date></history><permissions><copyright-statement>© The Japanese Society for Immunology. 2005. All rights reserved. For permissions, please e-mail: journals.permissions@oupjournals.org</copyright-statement><copyright-year>2005</copyright-year></permissions><abstract xml:lang="en">
<p>It has been shown that mice with a targeted mutation in the <italic>Ets-1</italic> gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this <italic>Ets-1</italic> hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells <italic>in vitro</italic> in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, <italic>Ets-1</italic> mutant mice develop autoimmune disease. Hence, our studies establish Ets-1 as an important regulator of peripheral B cell differentiation and B cell responses to TLR9 activation.</p>
</abstract><kwd-group kwd-group-type="KWD" xml:lang="en">
<kwd>B cell activation</kwd>
<kwd>CpG oligodeoxynucleotide</kwd>
<kwd>marginal zone</kwd>
<kwd>Pointed domain</kwd>
</kwd-group><kwd-group kwd-group-type="ABR" xml:lang="en">
<kwd>CBP CREB binding protein</kwd>
<kwd>CFSE carboxyfluorescein diacetate succinimidyl ester</kwd>
<kwd>CpG cytosine-phosphate-guanine DNA sequence</kwd>
<kwd>Erk extracellular regulated kinase</kwd>
<kwd>HA hemagglutinin</kwd>
<kwd>HEL hen egg lysozyme</kwd>
<kwd>HPRT hypoxanthine phosphoribosyl transferase</kwd>
<kwd>IRAK interleukin-1 receptor associated kinase</kwd>
<kwd>MFI mean fluorescent intensity</kwd>
<kwd>ODN oligodeoxynucleotide</kwd>
<kwd>RT reverse transcriptase</kwd>
<kwd>SIGIRR single Ig IL-1R-related molecule</kwd>
<kwd>TLR Toll-like receptor</kwd>
<kwd>TNP trinitrophenol</kwd>
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</article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo lang="en"><title>Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease</title></titleInfo><titleInfo type="alternative" lang="en" contentType="CDATA"><title>Ets-1 deficiency leads to altered B cell differentiation, hyperresponsiveness to TLR9 and autoimmune disease</title></titleInfo><name type="personal"><namePart type="given">Duncheng</namePart><namePart type="family">Wang</namePart><affiliation>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Shinu A.</namePart><namePart type="family">John</namePart><affiliation>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">James L.</namePart><namePart type="family">Clements</namePart><affiliation>Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Dean H.</namePart><namePart type="family">Percy</namePart><affiliation>Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, Ontario, Canada N1G 2W1</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Kevin P.</namePart><namePart type="family">Barton</namePart><affiliation>Department of Medicine, Section of Hematology/Oncology, Loyola University, Chicago, IL 60611, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Lee Ann</namePart><namePart type="family">Garrett-Sinha</namePart><affiliation>Department of Biochemistry, State University of New York at Buffalo, 3435 Main Street, Buffalo, NY 14214, USA</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="other" displayLabel="other" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-7474895G-0">other</genre><originInfo><publisher>Oxford University Press</publisher><dateIssued encoding="w3cdtf">2005-09</dateIssued><dateCreated encoding="w3cdtf">2005-06-13</dateCreated><copyrightDate encoding="w3cdtf">2005</copyrightDate></originInfo><language><languageTerm type="code" authority="iso639-2b">eng</languageTerm><languageTerm type="code" authority="rfc3066">en</languageTerm></language><abstract lang="en">It has been shown that mice with a targeted mutation in the Ets-1 gene exhibit increased B cell terminal differentiation to IgM-secreting plasma cells. Here, we show that mice, formerly described to lack Ets-1 protein, actually express low levels of an internally deleted Ets-1 protein. Mice harboring this Ets-1 hypomorphic allele possess very few marginal zone B cells and have increased expression of activation markers on follicular B cells. Adoptive transfer experiments indicate that this activated phenotype can be reversed upon transfer of Ets-1-deficient B cells to a wild-type host, suggesting a role for B cell-extrinsic factors in regulating the activated state. Supporting this observation, the reverse transfer experiment of wild-type B cells into an Ets-1-deficient host resulted in increased expression of activation markers on the transferred B cells. However, there are also cell-intrinsic changes in Ets-1-deficient B cells as demonstrated by their increased differentiation to plasma cells in vitro in response to stimulation with cytosine-phosphate-guanine DNA sequence-containing oligodeoxynucleotide [CpG DNA, a Toll-like receptor (TLR) 9 ligand]. Consistent with the activated phenotype and increased terminal differentiation of Ets-1-deficient B cells, Ets-1 mutant mice develop autoimmune disease. Hence, our studies establish Ets-1 as an important regulator of peripheral B cell differentiation and B cell responses to TLR9 activation.</abstract><note type="author-notes">Correspondence to: L. A. Garrett-Sinha; E-mail: leesinha@buffalo.edu</note><subject lang="en"><genre>KWD</genre><topic>B cell activation</topic><topic>CpG oligodeoxynucleotide</topic><topic>marginal zone</topic><topic>Pointed domain</topic></subject><subject lang="en"><genre>ABR</genre><topic>CBP CREB binding protein</topic><topic>CFSE carboxyfluorescein diacetate succinimidyl ester</topic><topic>CpG cytosine-phosphate-guanine DNA sequence</topic><topic>Erk extracellular regulated kinase</topic><topic>HA hemagglutinin</topic><topic>HEL hen egg lysozyme</topic><topic>HPRT hypoxanthine phosphoribosyl transferase</topic><topic>IRAK interleukin-1 receptor associated kinase</topic><topic>MFI mean fluorescent intensity</topic><topic>ODN oligodeoxynucleotide</topic><topic>RT reverse transcriptase</topic><topic>SIGIRR single Ig IL-1R-related molecule</topic><topic>TLR Toll-like receptor</topic><topic>TNP trinitrophenol</topic></subject><relatedItem type="host"><titleInfo><title>International Immunology</title></titleInfo><titleInfo type="abbreviated"><title>Int. Immunol.</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0953-8178</identifier><identifier type="eISSN">1460-2377</identifier><identifier type="PublisherID">intimm</identifier><identifier type="PublisherID-hwp">intimm</identifier><identifier type="PublisherID-nlm-ta">Int Immunol</identifier><part><date>2005</date><detail type="volume"><caption>vol.</caption><number>17</number></detail><detail type="issue"><caption>no.</caption><number>9</number></detail><extent unit="pages"><start>1179</start><end>1191</end></extent></part></relatedItem><relatedItem type="references" displayLabel="BIB1"><titleInfo><title>J. Exp. Med.</title></titleInfo><note>Reljic, R., Wagner, S. D., Peakman, L. J. and Fearon, D. T. 2000. 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