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Human B-cell ontogeny in humanized NOD/SCID γcnull mice generates a diverse yet auto/poly- and HIV-1-reactive antibody repertoire
- Source :
- Genes and immunity
- Publication Year :
- 2012
- Publisher :
- Springer Science and Business Media LLC, 2012.
-
Abstract
- 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.
- Subjects :
- Male
Immunology
Gene Rearrangement, B-Lymphocyte, Heavy Chain
Somatic hypermutation
Mice, SCID
Nod
HIV Antibodies
Biology
Article
Mice
03 medical and health sciences
0302 clinical medicine
Immune system
Antibody Repertoire
Mice, Inbred NOD
antibody repertoire
autoreactive
Genetics
checkpoint control
Animals
Humans
Genetics (clinical)
Autoantibodies
030304 developmental biology
B-Lymphocytes
0303 health sciences
V(D)J recombination
env Gene Products, Human Immunodeficiency Virus
Gene rearrangement
Virology
Molecular biology
V(D)J Recombination
3. Good health
single B-cell
Humanized mouse
HIV-1
biology.protein
humanized mouse
Female
Somatic Hypermutation, Immunoglobulin
Antibody
Immunoglobulin Heavy Chains
Protein Binding
030215 immunology
Subjects
Details
- ISSN :
- 14765470 and 14664879
- Volume :
- 13
- Database :
- OpenAIRE
- Journal :
- Genes & Immunity
- Accession number :
- edsair.doi.dedup.....8463b056d66e005d23e722ee8577c61d