Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation
Identifieur interne : 008712 ( Main/Exploration ); précédent : 008711; suivant : 008713Specific NEMO mutations impair CD40-mediated c-Rel activation and B cell terminal differentiation
Auteurs : Ashish Jain [États-Unis] ; Chi A. Ma [États-Unis] ; Eduardo Lopez-Granados [États-Unis] ; Gary Means [États-Unis] ; William Brady [États-Unis] ; Jordan S. Orange [États-Unis] ; Shuying Liu [États-Unis] ; Steven Holland [États-Unis] ; Jonathan M. J. Derry [États-Unis]Source :
- 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
Affiliations:
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Ma</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Lopez Granados, Eduardo" sort="Lopez Granados, Eduardo" uniqKey="Lopez Granados E" first="Eduardo" last="Lopez-Granados">Eduardo Lopez-Granados</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Means, Gary" sort="Means, Gary" uniqKey="Means G" first="Gary" last="Means">Gary Means</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Amgen Inc., Seattle, Washington, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Amgen Inc., Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region></placeName></affiliation></author><author><name sortKey="Brady, William" sort="Brady, William" uniqKey="Brady W" first="William" last="Brady">William Brady</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Amgen Inc., Seattle, Washington, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Amgen Inc., Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region></placeName></affiliation></author><author><name sortKey="Orange, Jordan S" sort="Orange, Jordan S" uniqKey="Orange J" first="Jordan S." last="Orange">Jordan S. Orange</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Division of Immunology, Children’s Hospital Boston, Boston, Massachusetts, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Division of Immunology, Children’s Hospital Boston, Boston, Massachusetts</wicri:regionArea><placeName><region type="state">Massachusetts</region></placeName></affiliation></author><author><name sortKey="Liu, Shuying" sort="Liu, Shuying" uniqKey="Liu S" first="Shuying" last="Liu">Shuying Liu</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Holland, Steven" sort="Holland, Steven" uniqKey="Holland S" first="Steven" last="Holland">Steven Holland</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Laboratory of Host Defense, National Institute of Allergy and Infectious Diseases (NIAID), NIH, Bethesda, Maryland</wicri:regionArea><placeName><region type="state">Maryland</region></placeName></affiliation></author><author><name sortKey="Derry, Jonathan M J" sort="Derry, Jonathan M J" uniqKey="Derry J" first="Jonathan M. J." last="Derry">Jonathan M. J. Derry</name><affiliation wicri:level="2"><nlm:aff id="N0x95f6eb8.0xa12d098">Amgen Inc., Seattle, Washington, USA.</nlm:aff><country xml:lang="fr" wicri:curation="lc">États-Unis</country><wicri:regionArea>Amgen Inc., Seattle, Washington</wicri:regionArea><placeName><region type="state">Washington (État)</region></placeName></affiliation></author></analytic><series><title level="j">Journal of Clinical Investigation</title><idno type="ISSN">0021-9738</idno><imprint><date when="2004">2004</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><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></TEI><affiliations><list><country><li>États-Unis</li></country><region><li>Maryland</li><li>Massachusetts</li><li>Washington (État)</li></region></list><tree><country name="États-Unis"><region name="Maryland"><name sortKey="Jain, Ashish" sort="Jain, Ashish" uniqKey="Jain A" first="Ashish" last="Jain">Ashish Jain</name></region><name sortKey="Brady, William" sort="Brady, William" uniqKey="Brady W" first="William" last="Brady">William Brady</name><name sortKey="Derry, Jonathan M J" sort="Derry, Jonathan M J" uniqKey="Derry J" first="Jonathan M. J." last="Derry">Jonathan M. J. Derry</name><name sortKey="Holland, Steven" sort="Holland, Steven" uniqKey="Holland S" first="Steven" last="Holland">Steven Holland</name><name sortKey="Liu, Shuying" sort="Liu, Shuying" uniqKey="Liu S" first="Shuying" last="Liu">Shuying Liu</name><name sortKey="Lopez Granados, Eduardo" sort="Lopez Granados, Eduardo" uniqKey="Lopez Granados E" first="Eduardo" last="Lopez-Granados">Eduardo Lopez-Granados</name><name sortKey="Ma, Chi A" sort="Ma, Chi A" uniqKey="Ma C" first="Chi A." last="Ma">Chi A. Ma</name><name sortKey="Means, Gary" sort="Means, Gary" uniqKey="Means G" first="Gary" last="Means">Gary Means</name><name sortKey="Orange, Jordan S" sort="Orange, Jordan S" uniqKey="Orange J" first="Jordan S." last="Orange">Jordan S. Orange</name></country></tree></affiliations></record>Pour manipuler ce document sous Unix (Dilib)
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