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dc.contributor.authorChang, Hong
dc.contributor.authorBiswas, Subhabrata
dc.contributor.authorTallarico, Aimee St. Clair
dc.contributor.authorSarkis, Phuong Thi Nguyen
dc.contributor.authorGeng, Shusheng
dc.contributor.authorPanditrao, Madhura M.
dc.contributor.authorZhu, Quan Karen
dc.contributor.authorMarasco, Wayne A.
dc.date.accessioned2013-05-07T16:08:41Z
dc.date.issued2012
dc.identifier.citationChang, Hong, Subhabrata Biswas, Aimee St. Clair Tallarico, Phuong Thi Nguyen Sarkis, Shusheng Geng, Madhura M. Panditrao, Quan Zhu, and Wayne A. Marasco. 2012. Human B-cell ontogeny in humanized NOD/SCID γc\(^{null}\) mice generates a diverse yet auto/poly- and HIV-1 reactive antibody repertoire. Genes and Immunity 13(5): 399-410.en_US
dc.identifier.issn1466-4879en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:10611741
dc.description.abstractCharacterization of the human antibody (Ab) repertoire in mouse models of the human immune system is essential to establish their relevance in translational studies. Single human B-cells were sorted from bone marrow and periphery of humanized NOD/SCID γc\(^{null}\) mice at 8–10 months post-engraftment with human cord blood-derived CD34\(^+\) stem cells. Human immunoglobulin variable heavy (V\(_H\)) and kappa (V\(_κ\)) genes were amplified, cognate V\(_H\)-V\(_κ\) gene-pairs assembled as single-chain variable fragment-Fc antibodies (scFvFcs) and functional studies performed. Although overall distribution of V\(_H\) genes approximated the normal human Ab repertoire, analysis of the V\(_H\)-third complementarity determining regions (H-CDR3) in the mature B-cell subset demonstrated an increase in length and positive charges suggesting autoimmune characteristics. Additionally, >70% of Vκ sequences utilized V\(_κ\)4-1, a germline gene associated with autoimmunity. The mature B-cell subset-derived scFvFcs displayed the highest frequency of autoreactivity and polyspecificity, suggesting defects in checkpoint control mechanisms. Furthermore, these scFvFcs demonstrated binding to recombinant HIV envelope corroborating previous observations of poly/autoreactivity in anti-HIVgp140 antibodies. These data lend support to the hypothesis that anti-HIV BnAbs may be derived from auto/polyspecific Abs that escaped immune elimination and that the hNSG mouse could provide a new experimental platform for studying the origin of anti-HIV neutralizing Ab responses.en_US
dc.language.isoen_USen_US
dc.publisherNature Publishing Groupen_US
dc.relation.isversionofdoi:10.1038/gene.2012.16en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC3411862/pdf/en_US
dash.licenseLAA
dc.subjecthumanized mouseen_US
dc.subjectsingle B-cellen_US
dc.subjectantibody repertoireen_US
dc.subjectautoreactiveen_US
dc.subjectcheckpoint controlen_US
dc.titleHuman B-cell Ontogeny in Humanized NOD/SCID γc\(^{null}\) Mice Generates a Diverse Yet Auto/Poly- and HIV-1 Reactive Antibody Repertoireen_US
dc.typeJournal Articleen_US
dc.description.versionAccepted Manuscripten_US
dc.relation.journalGenes and Immunityen_US
dash.depositing.authorMarasco, Wayne A.
dc.date.available2013-05-07T16:08:41Z
dc.identifier.doi10.1038/gene.2012.16*
dash.contributor.affiliatedBiswas, Subhabrata
dash.contributor.affiliatedTallarico, Aimee S.
dash.contributor.affiliatedMarasco, Wayne
dash.contributor.affiliatedZhu, Quan


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