Comparisons of the antibody repertoires of a humanized rodent and humans by high throughput sequencing.
Animals
Datasets as Topic
Genes, Immunoglobulin Heavy Chain
Genes, Immunoglobulin Light Chain
Genetic Variation
High-Throughput Nucleotide Sequencing
Humans
Immunoglobulin Class Switching
Immunoglobulin kappa-Chains
/ genetics
Lymph Nodes
/ metabolism
Organ Specificity
Rats
Rats, Transgenic
/ genetics
Sequence Alignment
Sequence Homology, Amino Acid
Software
Somatic Hypermutation, Immunoglobulin
Species Specificity
Spleen
/ metabolism
V(D)J Recombination
VDJ Exons
/ genetics
Journal
Scientific reports
ISSN: 2045-2322
Titre abrégé: Sci Rep
Pays: England
ID NLM: 101563288
Informations de publication
Date de publication:
24 01 2020
24 01 2020
Historique:
received:
22
09
2019
accepted:
12
12
2019
entrez:
26
1
2020
pubmed:
26
1
2020
medline:
21
11
2020
Statut:
epublish
Résumé
The humanization of animal model immune systems by genetic engineering has shown great promise for antibody discovery, tolerance studies and for the evaluation of vaccines. Assessment of the baseline antibody repertoires of unimmunized model animals will be useful as a benchmark for future immunization experiments. We characterized the heavy chain and kappa light chain antibody repertoires of a model animal, the OmniRat, by high throughput antibody sequencing and made use of two novel datasets for comparison to human repertoires. Intra-animal and inter-animal repertoire comparisons reveal a high level of conservation in antibody diversity between the lymph node and spleen and between members of the species. Multiple differences were found in both the heavy and kappa chain repertoires between OmniRats and humans including gene segment usage, CDR3 length distributions, class switch recombination, somatic hypermutation levels and in features of V(D)J recombination. The Inference and Generation of Repertoires (IGoR) software tool was used to model recombination in VH regions which allowed for the quantification of some of these differences. Diversity estimates of the OmniRat heavy chain repertoires almost reached that of humans, around two orders of magnitude less. Despite variation between the species repertoires, a high frequency of OmniRat clonotypes were also found in the human repertoire. These data give insights into the development and selection of humanized animal antibodies and provide actionable information for use in vaccine studies.
Identifiants
pubmed: 31980672
doi: 10.1038/s41598-020-57764-7
pii: 10.1038/s41598-020-57764-7
pmc: PMC6981180
doi:
Substances chimiques
Immunoglobulin kappa-Chains
0
Types de publication
Comparative Study
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1120Subventions
Organisme : NIAID NIH HHS
ID : U19 AI135995
Pays : United States
Organisme : NIAID NIH HHS
ID : UM1 AI144462
Pays : United States
Références
Hu, J. K. et al. Murine antibody responses to cleaved soluble HIV-1 envelope trimers are highly restricted in specificity. J. Virol. 89, 10383–10398 (2015).
doi: 10.1128/JVI.01653-15
Jardine, J. et al. Rational HIV immunogen design to target specific germline B cell receptors. Science 340, 711–716 (2013).
doi: 10.1126/science.1234150
Sok, D. et al. Priming HIV-1 broadly neutralizing antibody precursors in human ig loci transgenic mice. Science 353, 1557–1560 (2016).
doi: 10.1126/science.aah3945
Pantophlet, R. et al. Bacterially derived synthetic mimetics of mammalian oligomannose prime antibody responses that neutralize HIV infectivity. Nat. Commun. 8, 1601 (2017).
doi: 10.1038/s41467-017-01640-y
Brüggemann, M. et al. A repertoire of monoclonal antibodies with human heavy chains from transgenic mice. Proc. Natl. Acad. Sci. USA 86, 6709–6713 (1989).
doi: 10.1073/pnas.86.17.6709
Green, L. L. et al. Antigen-specific human monoclonal antibodies from mice engineered with human ig heavy and light chain YACs. Nat. Genet. 7, 13–21 (1994).
doi: 10.1038/ng0594-13
Lonberg, N. et al. Antigen-specific human antibodies from mice comprising four distinct genetic modifications. Nature 368, 856–859 (1994).
doi: 10.1038/368856a0
Brüggemann, M. et al. Human antibody production in transgenic animals. Arch. Immunol. Ther. Exp. 63, 101–108 (2015).
doi: 10.1007/s00005-014-0322-x
Green, L. L. Transgenic mouse strains as platforms for the successful discovery and development of human therapeutic monoclonal antibodies. Curr. Drug Discov. Technol. 11, 74–84 (2014).
doi: 10.2174/15701638113109990038
Nemazee, D. Mechanisms of central tolerance for B cells. Nat. Rev. Immunol. 17, 281–294 (2017).
doi: 10.1038/nri.2017.19
Osborn, M. J. et al. High-affinity IgG antibodies develop naturally in ig-knockout rats carrying germline human IgH/Igκ/Igλ loci bearing the rat CH region. J. Immunol. 190, 1481–1490 (2013).
doi: 10.4049/jimmunol.1203041
Ma, B. et al. Human antibody expression in transgenic rats: comparison of chimeric IgH loci with human VH, D and JH but bearing different rat c-gene regions. J. Immunol. Methods 400–401, 78–86 (2013).
doi: 10.1016/j.jim.2013.10.007
Briney, B., Inderbitzin, A., Joyce, C. & Burton, D. R. Commonality despite exceptional diversity in the baseline human antibody repertoire. Nature 566, 393–397 (2019).
doi: 10.1038/s41586-019-0879-y
Briney, B., Le, K., Zhu, J. & Burton, D. R. Clonify: unseeded antibody lineage assignment from next-generation sequencing data. Sci. Rep. 6, 23901 (2016).
doi: 10.1038/srep23901
Vollmers, C., Sit, R. V., Weinstein, J. A., Dekker, C. L. & Quake, S. R. Genetic measurement of memory b-cell recall using antibody repertoire sequencing. Proc. Natl. Acad. Sci. USA 110, 13463–13468 (2013).
doi: 10.1073/pnas.1312146110
He, L. et al. Toward a more accurate view of human b-cell repertoire by next-generation sequencing, unbiased repertoire capture and single-molecule barcoding. Sci. Rep. 4, 6778 (2014).
doi: 10.1038/srep06778
Briney, B. & Burton, D. R. Massively scalable genetic analysis of antibody repertoires, Preprint at https://www.biorxiv.org/content/early/2018/10/19/447813 (2018).
Umotoy, J. et al. Rapid and focused maturation of a VRC01-Class HIV broadly neutralizing antibody lineage involves both binding and accommodation of the N276-Glycan. Immunity 51, 141–154.e6 (2019).
doi: 10.1016/j.immuni.2019.06.004
Jardine, J. G. et al. HIV-1 VACCINES. priming a broadly neutralizing antibody response to HIV-1 using a germline targeting immunogen. Science 349, 156–161 (2015).
doi: 10.1126/science.aac5894
Andrabi, R. et al. Identification of common features in prototype broadly neutralizing antibodies to HIV envelope V2 apex to facilitate vaccine design. Immunity 43, 959–973 (2015).
doi: 10.1016/j.immuni.2015.10.014
Marcou, Q., Mora, T. & Walczak, A. M. High-throughput immune repertoire analysis with IGoR. Nat. Commun. 9, 561 (2018).
doi: 10.1038/s41467-018-02832-w
Chao, A. Estimating the population size for capture-recapture data with unequal catchability. Biometrics 43, 783–791 (1987).
doi: 10.2307/2531532
Mora, T. & Walczak, A. M. How many different clonotypes do immune repertoires contain? Curr. Opin. Syst. Biol. (2019).
Kaplinsky, J. & Arnaout, R. Robust estimates of overall immune-repertoire diversity from high-throughput measurements on samples. Nat. Commun. 7, 11881 (2016).
doi: 10.1038/ncomms11881
Lee, E.-C. et al. Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery. Nat. Biotechnol. 32, 356–363 (2014).
doi: 10.1038/nbt.2825
Longo, N. S., Rogosch, T., Zemlin, M., Zouali, M. & Lipsky, P. E. Mechanisms that shape human antibody repertoire development in mice transgenic for human ig H and L chain loci. J. Immunol. 198, 3963–3977 (2017).
doi: 10.4049/jimmunol.1700133
Briney, B. S., Willis, J. R., Finn, J. A., McKinney, B. A. & Crowe, J. E. Jr. Tissue-specific expressed antibody variable gene repertoires. PLoS One 9, e100839 (2014).
doi: 10.1371/journal.pone.0100839
Hoi, K. H. & Ippolito, G. C. Intrinsic bias and public rearrangements in the human immunoglobulin Vλ light chain repertoire. Genes Immun. 14, 271–276 (2013).
doi: 10.1038/gene.2013.10
Collins, A. M. & Watson, C. T. Immunoglobulin light chain gene rearrangements, receptor editing and the development of a Self-Tolerant antibody repertoire. Front. Immunol. 9, 2249 (2018).
doi: 10.3389/fimmu.2018.02249
Chen, Y. et al. Microbial symbionts regulate the primary ig repertoire. J. Exp. Med. 215, 1397–1415 (2018).
doi: 10.1084/jem.20171761
Bunker, J. J. et al. B cell superantigens in the human intestinal microbiota. Sci. Transl. Med. 11 (2019).
Soto, C. et al. High frequency of shared clonotypes in human B cell receptor repertoires. Nature 566, 398–402 (2019).
pubmed: 30760926
pmcid: 6949180
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq. 2. Genome Biol. 15, 550 (2014).
doi: 10.1186/s13059-014-0550-8