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. 1997 Dec;65(12):5103–5109. doi: 10.1128/iai.65.12.5103-5109.1997

Oligoclonality of serum immunoglobulin G antibody responses to Streptococcus pneumoniae capsular polysaccharide serotypes 6B, 14, and 23F.

A H Lucas 1, D M Granoff 1, R E Mandrell 1, C C Connolly 1, A S Shan 1, D C Powers 1
PMCID: PMC175735  PMID: 9393802

Abstract

Serum antibodies (Abs) specific for the capsular polysaccharides of Streptococcus pneumoniae provide protection against invasive pneumococcal disease. Previous studies indicate that Abs to pneumococcal polysaccharide (PPS) serotypes 1 and 6B have limited clonal diversity. To determine if restricted diversity was a feature common to other PPS specificities, we examined the light (L)-chain expression and isoelectric heterogeneity of type 6B, 14, and 23F Abs elicited in 15 adults following PPS vaccination. At the population level, both PPS-6B and PPS-14 Abs expressed kappa and lambda chains, although 6B Abs more frequently expressed lambda chains lambda and 14 Abs more frequently expressed kappa chains. In individual sera, Abs were generally skewed towards either kappa or lambda expression. 23F-specific Abs had predominantly kappa chains. Isoelectric focusing analyses showed that sera contained one or at most a few immunoglobulin G Ab spectrotypes to all three respective capsular serotypes, a result indicative of oligoclonality. A sequence analysis of a purified PPS-14-specific Ab having a single spectrotype gave uniform amino-terminal sequences for both the heavy chain (V(H)III subgroup) and the L chain (kappaIII-A27 V region). From these results we conclude that within individual adults, serum Ab responses to PPS serotypes 6B, 14, and 23F derive from a small number of dominant B-cell clones, and consequently variable-region expression is probably individually limited as well. Oligoclonality appears to be a general characteristic of human PPS-specific Ab repertoires, and we suggest that this property could lead to individual differences in Ab fine specificity and/or functional activity against encapsulated pneumococci.

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Selected References

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  1. Akolkar P. N., Sikder S. K., Bhattacharya S. B., Liao J., Gruezo F., Morrison S. L., Kabat E. A. Different VL and VH germ-line genes are used to produce similar combining sites with specificity for alpha(1----6)dextrans. J Immunol. 1987 Jun 15;138(12):4472–4479. [PubMed] [Google Scholar]
  2. Amir J., Liang X., Granoff D. M. Variability in the functional activity of vaccine-induced antibody to Haemophilus influenzae type b. Pediatr Res. 1990 Apr;27(4 Pt 1):358–364. doi: 10.1203/00006450-199004000-00008. [DOI] [PubMed] [Google Scholar]
  3. Anderson E. L., Kennedy D. J., Geldmacher K. M., Donnelly J., Mendelman P. M. Immunogenicity of heptavalent pneumococcal conjugate vaccine in infants. J Pediatr. 1996 May;128(5 Pt 1):649–653. doi: 10.1016/s0022-3476(96)80130-2. [DOI] [PubMed] [Google Scholar]
  4. Atkinson M. J., Cowan M. J., Feeney A. J. New alleles of IGKV genes A2 and A18 suggest significant human IGKV locus polymorphism. Immunogenetics. 1996;44(2):115–120. [PubMed] [Google Scholar]
  5. Augustin A., Cosenza H. Expression of new idiotypes following neonatal idiotypic suppression of a dominant clone. Eur J Immunol. 1976 Jul;6(7):497–501. doi: 10.1002/eji.1830060710. [DOI] [PubMed] [Google Scholar]
  6. Austrian R. Pneumococcus: the first one hundred years. Rev Infect Dis. 1981 Mar-Apr;3(2):183–189. doi: 10.1093/clinids/3.2.183. [DOI] [PubMed] [Google Scholar]
  7. Barington T., Hougs L., Juul L., Madsen H. O., Ryder L. P., Heilmann C., Svejgaard A. The progeny of a single virgin B cell predominates the human recall B cell response to the capsular polysaccharide of Haemophilus influenzae type b. J Immunol. 1996 Nov 1;157(9):4016–4027. [PubMed] [Google Scholar]
  8. Bona C. Molecular characteristics of anti-polysaccharide antibodies. Springer Semin Immunopathol. 1993;15(2-3):103–118. doi: 10.1007/BF00201095. [DOI] [PubMed] [Google Scholar]
  9. Borgoño J. M., McLean A. A., Vella P. P., Woodhour A. F., Canepa I., Davidson W. L., Hilleman M. R. Vaccination and revaccination with polyvalent pneumococcal polysaccharide vaccines in adults and infants. Proc Soc Exp Biol Med. 1978 Jan;157(1):148–154. doi: 10.3181/00379727-157-40010. [DOI] [PubMed] [Google Scholar]
  10. Bruyn G. A., Zegers B. J., van Furth R. Mechanisms of host defense against infection with Streptococcus pneumoniae. Clin Infect Dis. 1992 Jan;14(1):251–262. doi: 10.1093/clinids/14.1.251. [DOI] [PubMed] [Google Scholar]
  11. Butler J. C., Breiman R. F., Campbell J. F., Lipman H. B., Broome C. V., Facklam R. R. Pneumococcal polysaccharide vaccine efficacy. An evaluation of current recommendations. JAMA. 1993 Oct 20;270(15):1826–1831. [PubMed] [Google Scholar]
  12. Chen C., Bruderer U., Rittenberg M. B. The developmental patterns of B cell precursors distinguishing between environmental and nonenvironmental forms of phosphocholine. Cell Immunol. 1992 Sep;143(2):378–388. doi: 10.1016/0008-8749(92)90034-m. [DOI] [PubMed] [Google Scholar]
  13. Claflin J. L., Rudikoff S. Uniformity in a clonal repertoire: a case for a germ-line basis of antibody diversity. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 2):725–734. doi: 10.1101/sqb.1977.041.01.083. [DOI] [PubMed] [Google Scholar]
  14. Emara M. G., Tout N. L., Kaushik A., Lam J. S. Diverse VH and V kappa genes encode antibodies to Pseudomonas aeruginosa LPS. J Immunol. 1995 Oct 15;155(8):3912–3921. [PubMed] [Google Scholar]
  15. Geckeler W., Blomberg B., de Preval C., Cohn M. On the genetic dissection of a specific humoral immune response to alpha(1,3) dextran. Cold Spring Harb Symp Quant Biol. 1977;41(Pt 2):743–748. doi: 10.1101/sqb.1977.041.01.085. [DOI] [PubMed] [Google Scholar]
  16. Granoff D. M., Lucas A. H. Laboratory correlates of protection against Haemophilus influenzae type b disease. Importance of assessment of antibody avidity and immunologic memory. Ann N Y Acad Sci. 1995 May 31;754:278–288. doi: 10.1111/j.1749-6632.1995.tb44461.x. [DOI] [PubMed] [Google Scholar]
  17. Granoff D. M., Shackelford P. G., Holmes S. J., Lucas A. H. Variable region expression in the antibody responses of infants vaccinated with Haemophilus influenzae type b polysaccharide-protein conjugates. Description of a new lambda light chain-associated idiotype and the relation between idiotype expression, avidity, and vaccine formulation. The Collaborative Vaccine Study Group. J Clin Invest. 1993 Mar;91(3):788–796. doi: 10.1172/JCI116298. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Hansburg D., Briles D. E., Davie J. M. Analysis of the diversity of murine antibodies to dextran B1355. I. Generation of a larger, pauci-clonal response by a bacterial vaccine. J Immunol. 1976 Aug;117(2):569–575. [PubMed] [Google Scholar]
  19. Insel R. A., Anderson P. W. Oligosaccharide-protein conjugate vaccines induce and prime for oligoclonal IgG antibody responses to the Haemophilus influenzae b capsular polysaccharide in human infants. J Exp Med. 1986 Feb 1;163(2):262–269. doi: 10.1084/jem.163.2.262. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Insel R. A., Kittelberger A., Anderson P. Isoelectric focusing of human antibody to the Haemophilus influenzae b capsular polysaccharide: restricted and identical spectrotypes in adults. J Immunol. 1985 Oct;135(4):2810–2816. [PubMed] [Google Scholar]
  21. Kenne L., Lindberg B., Madden J. K. Structural studies of the capsular antigen from Streptococcus pneumoniae type 26. Carbohydr Res. 1979 Aug;73:175–182. doi: 10.1016/s0008-6215(00)85487-7. [DOI] [PubMed] [Google Scholar]
  22. Konradsen H. B., Hahn-Zoric M., Nagao A. T., Hanson L. A. Differences within mono- and dizygotic twin-pairs in spectrotypes and clones of IgG2 antibodies to pneumococcal polysaccharide type 1 and C-polysaccharide after vaccination. Scand J Immunol. 1994 Oct;40(4):423–428. doi: 10.1111/j.1365-3083.1994.tb03484.x. [DOI] [PubMed] [Google Scholar]
  23. Käyhty H., Ahman H., Rönnberg P. R., Tillikainen R., Eskola J. Pneumococcal polysaccharide-meningococcal outer membrane protein complex conjugate vaccine is immunogenic in infants and children. J Infect Dis. 1995 Nov;172(5):1273–1278. doi: 10.1093/infdis/172.5.1273. [DOI] [PubMed] [Google Scholar]
  24. Käyhty H., Eskola J. New vaccines for the prevention of pneumococcal infections. Emerg Infect Dis. 1996 Oct-Dec;2(4):289–298. doi: 10.3201/eid0204.960404. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Lindberg B., Lönngren J., Powell D. A. Structural studies on the specific type-14 pneumococcal polysaccharide. Carbohydr Res. 1977 Sep;58(1):177–186. doi: 10.1016/s0008-6215(00)83413-8. [DOI] [PubMed] [Google Scholar]
  26. Lucas A. H., Azmi F. H., Mink C. M., Granoff D. M. Age-dependent V region expression in the human antibody response to the Haemophilus influenzae type b polysaccharide. J Immunol. 1993 Mar 1;150(5):2056–2061. [PubMed] [Google Scholar]
  27. Lucas A. H., Granoff D. M. Functional differences in idiotypically defined IgG1 anti-polysaccharide antibodies elicited by vaccination with Haemophilus influenzae type B polysaccharide-protein conjugates. J Immunol. 1995 Apr 15;154(8):4195–4202. [PubMed] [Google Scholar]
  28. Lucas A. H., Langley R. J., Granoff D. M., Nahm M. H., Kitamura M. Y., Scott M. G. An idiotypic marker associated with a germ-line encoded kappa light chain variable region that predominates the vaccine-induced human antibody response to the Haemophilus influenzae b polysaccharide. J Clin Invest. 1991 Dec;88(6):1811–1818. doi: 10.1172/JCI115502. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Lucas A. H., Larrick J. W., Reason D. C. Variable region sequences of a protective human monoclonal antibody specific for the Haemophilus influenzae type b capsular polysaccharide. Infect Immun. 1994 Sep;62(9):3873–3880. doi: 10.1128/iai.62.9.3873-3880.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Morrow C. D., Macy E. M., Stevens R. H. Analysis of human anti-diphtheria antibodies by isoelectric focusing: evidence for restricted clonal heterogeneity of anti-fragment A antibodies. Infect Immun. 1981 Mar;31(3):1132–1137. doi: 10.1128/iai.31.3.1132-1137.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Mukherjee J., Nussbaum G., Scharff M. D., Casadevall A. Protective and nonprotective monoclonal antibodies to Cryptococcus neoformans originating from one B cell. J Exp Med. 1995 Jan 1;181(1):405–409. doi: 10.1084/jem.181.1.405. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Musher D. M., Groover J. E., Watson D. A., Pandey J. P., Rodriguez-Barradas M. C., Baughn R. E., Pollack M. S., Graviss E. A., de Andrade M., Amos C. I. Genetic regulation of the capacity to make immunoglobulin G to pneumococcal capsular polysaccharides. J Investig Med. 1997 Feb;45(2):57–68. [PubMed] [Google Scholar]
  33. Musher D. M., Johnson B., Jr, Watson D. A. Quantitative relationship between anticapsular antibody measured by enzyme-linked immunosorbent assay or radioimmunoassay and protection of mice against challenge with Streptococcus pneumoniae serotype 4. Infect Immun. 1990 Dec;58(12):3871–3876. doi: 10.1128/iai.58.12.3871-3876.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Nahm M. H., Kim K. H., Anderson P., Hetherington S. V., Park M. K. Functional capacities of clonal antibodies to Haemophilus influenzae type b polysaccharide. Infect Immun. 1995 Aug;63(8):2989–2994. doi: 10.1128/iai.63.8.2989-2994.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Nahm M. H., Siber G. R., Olander J. V. A modified Farr assay is more specific than ELISA for measuring antibodies to Streptococcus pneumoniae capsular polysaccharides. J Infect Dis. 1996 Jan;173(1):113–118. doi: 10.1093/infdis/173.1.113. [DOI] [PubMed] [Google Scholar]
  36. Pargent W., Schäble K. F., Zachau H. G. Polymorphisms and haplotypes in the human immunoglobulin kappa locus. Eur J Immunol. 1991 Aug;21(8):1829–1835. doi: 10.1002/eji.1830210808. [DOI] [PubMed] [Google Scholar]
  37. Park M. K., Sun Y., Olander J. V., Hoffmann J. W., Nahm M. H. The repertoire of human antibodies to the carbohydrate capsule of Streptococcus pneumoniae 6B. J Infect Dis. 1996 Jul;174(1):75–82. doi: 10.1093/infdis/174.1.75. [DOI] [PubMed] [Google Scholar]
  38. Powers D. C., Anderson E. L., Lottenbach K., Mink C. M. Reactogenicity and immunogenicity of a protein-conjugated pneumococcal oligosaccharide vaccine in older adults. J Infect Dis. 1996 Apr;173(4):1014–1018. doi: 10.1093/infdis/173.4.1014. [DOI] [PubMed] [Google Scholar]
  39. Pricop L., Hatakeyama A., Moran T., Bona C. Antibody response against poly (Glu60Ala30Tyr10) terpolymer and bacterial levan in kappa-deficient mice. Eur J Immunol. 1995 Apr;25(4):1039–1043. doi: 10.1002/eji.1830250427. [DOI] [PubMed] [Google Scholar]
  40. Quataert S. A., Kirch C. S., Wiedl L. J., Phipps D. C., Strohmeyer S., Cimino C. O., Skuse J., Madore D. V. Assignment of weight-based antibody units to a human antipneumococcal standard reference serum, lot 89-S. Clin Diagn Lab Immunol. 1995 Sep;2(5):590–597. doi: 10.1128/cdli.2.5.590-597.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  41. Reason D. C., Lucas A. H. Functional expression of the IGKV A18b gene and its idiotypic cross-reactivity with the A2 variable region. Immunogenetics. 1997;45(5):343–344. doi: 10.1007/s002510050214. [DOI] [PubMed] [Google Scholar]
  42. Richards J. C., Perry M. B. Structure of the specific capsular polysaccharide of Streptococcus pneumoniae type 23F (American type 23). Biochem Cell Biol. 1988 Jul;66(7):758–771. doi: 10.1139/o88-087. [DOI] [PubMed] [Google Scholar]
  43. Riesen W. F., Skvaril F., Braun D. G. Natural infection of man with group A streptococci. Levels; restriction in class, subclass, and type; and clonal appearance of polysaccharide-group-specific antibodies. Scand J Immunol. 1976;5(4):383–390. doi: 10.1111/j.1365-3083.1976.tb00292.x. [DOI] [PubMed] [Google Scholar]
  44. Robbins J. B., Austrian R., Lee C. J., Rastogi S. C., Schiffman G., Henrichsen J., Mäkelä P. H., Broome C. V., Facklam R. R., Tiesjema R. H. Considerations for formulating the second-generation pneumococcal capsular polysaccharide vaccine with emphasis on the cross-reactive types within groups. J Infect Dis. 1983 Dec;148(6):1136–1159. doi: 10.1093/infdis/148.6.1136. [DOI] [PubMed] [Google Scholar]
  45. Rosén A., Ek K., Aman P. Agarose isoelectric focusing of native human immunoglobulin M and alpha 2-macroglobulin. J Immunol Methods. 1979;28(1-2):1–11. doi: 10.1016/0022-1759(79)90322-3. [DOI] [PubMed] [Google Scholar]
  46. Rubinstein L. J., Stein K. E. Murine immune response to the Neisseria meningitidis group C capsular polysaccharide. II. Specificity. J Immunol. 1988 Dec 15;141(12):4357–4362. [PubMed] [Google Scholar]
  47. Sasso E. H., Buckner J. H., Suzuki L. A. Ethnic differences of polymorphism of an immunoglobulin VH3 gene. J Clin Invest. 1995 Sep;96(3):1591–1600. doi: 10.1172/JCI118198. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Schlesinger Y., Granoff D. M. Avidity and bactericidal activity of antibody elicited by different Haemophilus influenzae type b conjugate vaccines. The Vaccine Study Group. JAMA. 1992 Mar 18;267(11):1489–1494. [PubMed] [Google Scholar]
  49. Scott M. G., Crimmins D. L., McCourt D. W., Chung G., Schäble K. F., Thiebe R., Quenzel E. M., Zachau H. G., Nahm M. H. Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. IV. The less frequently expressed VL are heterogeneous. J Immunol. 1991 Dec 1;147(11):4007–4013. [PubMed] [Google Scholar]
  50. Scott M. G., Crimmins D. L., McCourt D. W., Zocher I., Thiebe R., Zachau H. G., Nahm M. H. Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. III. A single VKII gene and one of several JK genes are joined by an invariant arginine to form the most common L chain V region. J Immunol. 1989 Dec 15;143(12):4110–4116. [PubMed] [Google Scholar]
  51. Scott M. G., Tarrand J. J., Crimmins D. L., McCourt D. W., Siegel N. R., Smith C. E., Nahm M. H. Clonal characterization of the human IgG antibody repertoire to Haemophilus influenzae type b polysaccharide. II. IgG antibodies contain VH genes from a single VH family and VL genes from at least four VL families. J Immunol. 1989 Jul 1;143(1):293–298. [PubMed] [Google Scholar]
  52. Sell S. H., Wright P. F., Vaughn W. K., Thompson J., Schiffman G. Clinical studies of pneumococcal vaccines in infants. I. Reactogenicity and immunogenicity of two polyvalent polysaccharide vaccines. Rev Infect Dis. 1981 Mar-Apr;3 (Suppl):S97–107. doi: 10.1093/clinids/3.supplement_1.s97. [DOI] [PubMed] [Google Scholar]
  53. Shackelford P. G., Nelson S. J., Palma A. T., Nahm M. H. Human antibodies to group A streptococcal carbohydrate. Ontogeny, subclass restriction, and clonal diversity. J Immunol. 1988 May 1;140(9):3200–3205. [PubMed] [Google Scholar]
  54. Shaw D. R., Kirkham P., Schroeder H. W., Jr, Roben P., Silverman G. J. Structure-function studies of human monoclonal antibodies to pneumococcus type 3 polysaccharide. Ann N Y Acad Sci. 1995 Sep 29;764:370–373. doi: 10.1111/j.1749-6632.1995.tb55849.x. [DOI] [PubMed] [Google Scholar]
  55. Shelly M. A., Jacoby H., Riley G. J., Graves B. T., Pichichero M., Treanor J. J. Comparison of pneumococcal polysaccharide and CRM197-conjugated pneumococcal oligosaccharide vaccines in young and elderly adults. Infect Immun. 1997 Jan;65(1):242–247. doi: 10.1128/iai.65.1.242-247.1997. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. Smit P., Oberholzer D., Hayden-Smith S., Koornhof H. J., Hilleman M. R. Protective efficacy of pneumococcal polysaccharide vaccines. JAMA. 1977 Dec 12;238(24):2613–2616. [PubMed] [Google Scholar]
  57. Steinhoff M. C., Edwards K., Keyserling H., Thoms M. L., Johnson C., Madore D., Hogerman D. A randomized comparison of three bivalent Streptococcus pneumoniae glycoprotein conjugate vaccines in young children: effect of polysaccharide size and linkage characteristics. Pediatr Infect Dis J. 1994 May;13(5):368–372. doi: 10.1097/00006454-199405000-00007. [DOI] [PubMed] [Google Scholar]
  58. Weng N. P., Yu-Lee L. Y., Sanz I., Patten B. M., Marcus D. M. Structure and specificities of anti-ganglioside autoantibodies associated with motor neuropathies. J Immunol. 1992 Oct 1;149(7):2518–2529. [PubMed] [Google Scholar]

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