Somatic Hypermutation and Diverse Immunoglobulin Gene Usage in the Human Antibody Response to the Capsular Polysaccharide of Streptococcus Pneumoniae Type 6B

Overview

Journal Infect Immun

Publisher American Society for Microbiology

Specialty Allergy & Immunology

Date 2004 May 25

PMID 15155658

Citations 35

Authors

Jianhui Zhou

Kathleen R Lottenbach

Stephen J Barenkamp

Donald C Reason

Affiliations

Soon will be listed here.

Abstract

Combinatorial cloning and expression library analysis were used to determine the expressed human antibody repertoire specific for the capsular polysaccharide (PS) of Streptococcus pneumoniae serotype 6B. Sequence analysis of 55 6B-specific antibody Fab fragments isolated from six vaccinated donors reveal that different individuals used a variety of heavy and light chain germ line variable (V) region genes to form pneumococcal capsular PS (PPS) 6B-specific paratopes. Within each donor, however, the response was more restricted, with five of the six donors using at most one or two gene pairs to form combining sites. Analysis also indicated that although the response in each donor was oligoclonal in terms of variable gene usage, the combination of extensive somatic hypermutation, deletion of germ line-encoded residues, insertion of non-germ line-encoded residues, and intraclonal isotype switching generated a surprising degree of paratope diversity within the individuals analyzed. In contrast to previously studied PS-specific responses, we find that the PPS 6B repertoire makes use of a diverse collection of heavy-chain and light-chain V region gene products to form specific paratopes, with no apparent tendency for conservation of immunoglobulin gene usage between individuals.

Citing Articles

Fast clonal family inference from large-scale B cell repertoire sequencing data.

Wang K, Hu X, Zhang J Cell Rep Methods. 2023; 3(10):100601.

PMID: 37788671 PMC: 10626204. DOI: 10.1016/j.crmeth.2023.100601.

The 15-valent pneumococcal conjugate vaccine V114 induces cross-reactive antibodies against pneumococcal serotype 6C.

Shi Y, Nolan K, Burton R, Shekar T, Murphy R, Banniettis N Hum Vaccin Immunother. 2023; 19(2):2235238.

PMID: 37529944 PMC: 10399465. DOI: 10.1080/21645515.2023.2235238.

T-independent responses to polysaccharides in humans mobilize marginal zone B cells prediversified against gut bacterial antigens.

Weller S, Sterlin D, Fadeev T, Coignard E, Verge de Los Aires A, Goetz C Sci Immunol. 2023; 8(79):eade1413.

PMID: 36706172 PMC: 7614366. DOI: 10.1126/sciimmunol.ade1413.

Learning the statistics and landscape of somatic mutation-induced insertions and deletions in antibodies.

Lupo C, Spisak N, Walczak A, Mora T PLoS Comput Biol. 2022; 18(6):e1010167.

PMID: 35653375 PMC: 9197026. DOI: 10.1371/journal.pcbi.1010167.

Isolation and Characterization of Human Monoclonal Antibodies to Pneumococcal Capsular Polysaccharide 3.

Babb R, Doyle C, Pirofski L Microbiol Spectr. 2021; 9(3):e0144621.

PMID: 34756090 PMC: 8579928. DOI: 10.1128/Spectrum.01446-21.

References

Scott M, Zachau H, Nahm M . The human antibody V region repertoire to the type B capsular polysaccharide of Haemophilus influenzae. Int Rev Immunol. 1992; 9(1):45-55. DOI: 10.3109/08830189209061782. View

Mills F, Thyphronitis G, Finkelman F, Max E . Ig mu-epsilon isotype switch in IL-4-treated human B lymphoblastoid cells. Evidence for a sequential switch. J Immunol. 1992; 149(3):1075-85. View

Park M, Sun Y, Olander J, Hoffmann J, Nahm M . The repertoire of human antibodies to the carbohydrate capsule of Streptococcus pneumoniae 6B. J Infect Dis. 1996; 174(1):75-82. DOI: 10.1093/infdis/174.1.75. View

Boswell C, STEIN K . Avidity maturation, repertoire shift, and strain differences in antibodies to bacterial levan, a type 2 thymus-independent polysaccharide antigen. J Immunol. 1996; 157(5):1996-2005. View

Reason D, Wagner T, Lucas A . Human Fab fragments specific for the Haemophilus influenzae b polysaccharide isolated from a bacteriophage combinatorial library use variable region gene combinations and express an idiotype that mirrors in vivo expression. Infect Immun. 1997; 65(1):261-6. PMC: 174585. DOI: 10.1128/iai.65.1.261-266.1997. View

Kawasaki K, Minoshima S, Nakato E, Shibuya K, Shintani A, Schmeits J . One-megabase sequence analysis of the human immunoglobulin lambda gene locus. Genome Res. 1997; 7(3):250-61. DOI: 10.1101/gr.7.3.250. View

Foster S, Brezinschek H, Brezinschek R, Lipsky P . Molecular mechanisms and selective influences that shape the kappa gene repertoire of IgM+ B cells. J Clin Invest. 1997; 99(7):1614-27. PMC: 507981. DOI: 10.1172/JCI119324. View

Altschul S, Madden T, Schaffer A, Zhang J, Zhang Z, Miller W . Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Res. 1997; 25(17):3389-402. PMC: 146917. DOI: 10.1093/nar/25.17.3389. View

Nahm M, Olander J, Magyarlaki M . Identification of cross-reactive antibodies with low opsonophagocytic activity for Streptococcus pneumoniae. J Infect Dis. 1997; 176(3):698-703. DOI: 10.1086/514093. View

10.

Lucas A, Granoff D, Mandrell R, Connolly C, Shan A, Powers D . Oligoclonality of serum immunoglobulin G antibody responses to Streptococcus pneumoniae capsular polysaccharide serotypes 6B, 14, and 23F. Infect Immun. 1997; 65(12):5103-9. PMC: 175735. DOI: 10.1128/iai.65.12.5103-5109.1997. View

11.

Wilson P, Liu Y, Banchereau J, Capra J, Pascual V . Amino acid insertions and deletions contribute to diversify the human Ig repertoire. Immunol Rev. 1998; 162:143-51. DOI: 10.1111/j.1600-065x.1998.tb01437.x. View

12.

Lucas A, Moulton K, Reason D . Role of kappa II-A2 light chain CDR-3 junctional residues in human antibody binding to the Haemophilus influenzae type b polysaccharide. J Immunol. 1998; 161(7):3776-80. View

13.

Sverremark E, Fernandez C . Role of T cells and germinal center formation in the generation of immune responses to the thymus-independent carbohydrate dextran B512. J Immunol. 1998; 161(9):4646-51. View

14.

Matsuda F, Ishii K, Bourvagnet P, Kuma K, Hayashida H, Miyata T . The complete nucleotide sequence of the human immunoglobulin heavy chain variable region locus. J Exp Med. 1998; 188(11):2151-62. PMC: 2212390. DOI: 10.1084/jem.188.11.2151. View

15.

Lefranc M, Giudicelli V, Ginestoux C, Bodmer J, Muller W, Bontrop R . IMGT, the international ImMunoGeneTics database. Nucleic Acids Res. 1998; 27(1):209-12. PMC: 148137. DOI: 10.1093/nar/27.1.209. View

16.

Sun Y, Park M, Kim J, Diamond B, Solomon A, Nahm M . Repertoire of human antibodies against the polysaccharide capsule of Streptococcus pneumoniae serotype 6B. Infect Immun. 1999; 67(3):1172-9. PMC: 96443. DOI: 10.1128/IAI.67.3.1172-1179.1999. View

17.

Usinger W, Lucas A . Avidity as a determinant of the protective efficacy of human antibodies to pneumococcal capsular polysaccharides. Infect Immun. 1999; 67(5):2366-70. PMC: 115979. DOI: 10.1128/IAI.67.5.2366-2370.1999. View

18.

Lucas A, Reason D . Polysaccharide vaccines as probes of antibody repertoires in man. Immunol Rev. 1999; 171:89-104. DOI: 10.1111/j.1600-065x.1999.tb01343.x. View

19.

de Wildt R, van Venrooij W, Winter G, Hoet R, Tomlinson I . Somatic insertions and deletions shape the human antibody repertoire. J Mol Biol. 1999; 294(3):701-10. DOI: 10.1006/jmbi.1999.3289. View

20.

Baxendale H, Davis Z, White H, Spellerberg M, Stevenson F, Goldblatt D . Immunogenetic analysis of the immune response to pneumococcal polysaccharide. Eur J Immunol. 2000; 30(4):1214-23. DOI: 10.1002/(SICI)1521-4141(200004)30:4<1214::AID-IMMU1214>3.0.CO;2-D. View