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Genes Immun. 2012 Jul;13(5):399-410. doi: 10.1038/gene.2012.16. Epub 2012 May 17.

Human B-cell ontogeny in humanized NOD/SCID γc(null) mice generates a diverse yet auto/poly- and HIV-1-reactive antibody repertoire.

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Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Boston, MA 02115, USA.


Characterization 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) (hNSG) mice at 8-10 months post engraftment with human cord blood-derived CD34(+) stem cells. Human IG 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 Abs (scFvFcs) and functional studies were performed. Although overall distribution of V(H) genes approximated the normal human Ab repertoire, analysis of the V(H)-third complementarity-determining regions in the mature B-cell subset demonstrated an increase in length and positive charges, suggesting autoimmune characteristics. Additionally, >70% of V(κ) 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 Abs. These data lend support to the hypothesis that anti-HIV broadly neutralizing antibodies 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.

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