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

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


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / blood
  • Autoantibodies / immunology*
  • B-Lymphocytes / immunology*
  • B-Lymphocytes / metabolism
  • Female
  • Gene Rearrangement, B-Lymphocyte, Heavy Chain
  • HIV Antibodies / blood
  • HIV Antibodies / immunology*
  • HIV Antibodies / metabolism
  • HIV-1 / immunology*
  • Humans
  • Immunoglobulin Heavy Chains / chemistry
  • Immunoglobulin Heavy Chains / genetics
  • Male
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Protein Binding / immunology
  • Somatic Hypermutation, Immunoglobulin
  • V(D)J Recombination
  • env Gene Products, Human Immunodeficiency Virus / immunology
  • env Gene Products, Human Immunodeficiency Virus / metabolism


  • Autoantibodies
  • HIV Antibodies
  • Immunoglobulin Heavy Chains
  • env Gene Products, Human Immunodeficiency Virus
  • gp140 envelope protein, Human immunodeficiency virus 1