Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation
Identifieur interne : 000B62 ( Pmc/Corpus ); précédent : 000B61; suivant : 000B63Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation
Auteurs : Ashish Jain ; Chi A. Ma ; Eduardo Lopez-Granados ; Gary Means ; William Brady ; Jordan S. Orange ; Shuying Liu ; Steven Holland ; Jonathan M. J. DerrySource :
- Journal of Clinical Investigation [ 0021-9738 ] ; 2004.
Abstract
Hypomorphic mutations in the zinc finger domain of NF-κB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iε-Cε transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-κB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-κB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-κB activation and candidate factors that may be necessary for CSR and SHM in B cells.
Url:
DOI: 10.1172/JCI200421345
PubMed: 15578091
PubMed Central: 529497
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PMC:529497Le document en format XML
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<author><name sortKey="Jain, Ashish" sort="Jain, Ashish" uniqKey="Jain A" first="Ashish" last="Jain">Ashish Jain</name>
<affiliation><nlm:aff id="N0x95f6eb8.0xa12d098">Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.</nlm:aff>
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<author><name sortKey="Ma, Chi A" sort="Ma, Chi A" uniqKey="Ma C" first="Chi A." last="Ma">Chi A. Ma</name>
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<author><name sortKey="Lopez Granados, Eduardo" sort="Lopez Granados, Eduardo" uniqKey="Lopez Granados E" first="Eduardo" last="Lopez-Granados">Eduardo Lopez-Granados</name>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation</title>
<author><name sortKey="Jain, Ashish" sort="Jain, Ashish" uniqKey="Jain A" first="Ashish" last="Jain">Ashish Jain</name>
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<author><name sortKey="Orange, Jordan S" sort="Orange, Jordan S" uniqKey="Orange J" first="Jordan S." last="Orange">Jordan S. Orange</name>
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<series><title level="j">Journal of Clinical Investigation</title>
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<front><div type="abstract" xml:lang="en"><p>Hypomorphic mutations in the zinc finger domain of NF-κB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iε-Cε transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-κB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-κB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-κB activation and candidate factors that may be necessary for CSR and SHM in B cells.</p>
</div>
</front>
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<pmc article-type="research-article"><pmc-comment>The publisher of this article does not allow downloading of the full text in XML form.</pmc-comment>
<front><journal-meta><journal-id journal-id-type="nlm-ta">J Clin Invest</journal-id>
<journal-id journal-id-type="publisher-id">J CLIN INVEST</journal-id>
<journal-title>Journal of Clinical Investigation</journal-title>
<issn pub-type="ppub">0021-9738</issn>
<publisher><publisher-name>American Society for Clinical Investigation</publisher-name>
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<article-meta><article-id pub-id-type="pmid">15578091</article-id>
<article-id pub-id-type="pmc">529497</article-id>
<article-id pub-id-type="publisher-id">21345</article-id>
<article-id pub-id-type="doi">10.1172/JCI200421345</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Article</subject>
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</article-categories>
<title-group><article-title>Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Jain</surname>
<given-names>Ashish</given-names>
</name>
<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Ma</surname>
<given-names>Chi A.</given-names>
</name>
<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Lopez-Granados</surname>
<given-names>Eduardo</given-names>
</name>
<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Means</surname>
<given-names>Gary</given-names>
</name>
<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">2</xref>
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<contrib contrib-type="author"><name><surname>Brady</surname>
<given-names>William</given-names>
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<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">2</xref>
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<contrib contrib-type="author"><name><surname>Orange</surname>
<given-names>Jordan S.</given-names>
</name>
<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">3</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Shuying</given-names>
</name>
<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Holland</surname>
<given-names>Steven</given-names>
</name>
<xref ref-type="aff" rid="N0x95f6eb8.0xa12d098">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Derry</surname>
<given-names>Jonathan M.J.</given-names>
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<aff id="N0x95f6eb8.0xa12d098"><label>1</label>
Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.<label>2</label>
Amgen Inc., Seattle, Washington, USA.<label>3</label>
Division of Immunology, Children’s Hospital Boston, Boston, Massachusetts, USA.</aff>
<author-notes><fn><p>Address correspondence to: Ashish Jain, Laboratory of Host Defense, NIAID, NIH, Bethesda, Maryland 20892, USA. Phone: (301) 594-5691; Fax: (301) 480-1753; E-mail: ajain@niaid.nih.gov. Or to: Jonathan M.J. Derry, Amgen Inc., 1201 Amgen Court West, Seattle, Washington 98119, USA. E-mail: <email>derryjmj@amgen.com</email>
.</p>
</fn>
</author-notes>
<pub-date pub-type="ppub"><day>1</day>
<month>12</month>
<year>2004</year>
</pub-date>
<volume>114</volume>
<issue>11</issue>
<fpage>1593</fpage>
<lpage>1602</lpage>
<copyright-statement>Copyright © 2004, American Society for Clinical Investigation</copyright-statement>
<copyright-year>2004</copyright-year>
<abstract><p>Hypomorphic mutations in the zinc finger domain of NF-κB essential modulator (NEMO) cause X-linked hyper-IgM syndrome with ectodermal dysplasia (XHM-ED). Here we report that patient B cells are characterized by an absence of Ig somatic hypermutation (SHM) and defective class switch recombination (CSR) despite normal induction of activation-induced cytidine deaminase (AID) and Iε-Cε transcripts. This indicates that AID expression alone is insufficient to support neutralizing antibody responses. Furthermore, we show that patient B cells stimulated with CD40 ligand are impaired in both p65 and c-Rel activation, and whereas addition of IL-4 can enhance p65 activity, c-Rel activity remains deficient. This suggests that these NF-κB components have different activation requirements and that IL-4 can augment some but not all NEMO-dependent NF-κB signaling. Finally, using microarray analysis of patient B cells we identified downstream effects of impaired NF-κB activation and candidate factors that may be necessary for CSR and SHM in B cells.</p>
</abstract>
</article-meta>
</front>
</pmc>
</record>
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