Advertisement

The Molecular Genetics of Phosphocholine-Binding Antibodies

  • Roger M. Perlmutter

Abstract

Early structural analyses of antibody molecules were confounded by the complex heterogeneity which typifies most humoral immune responses. The search for homogeneous antibody populations led to the use of simple bacterial vaccines as immunogens, many of which elicited quite restricted serum antibodies.In the early 1960s, a number of mineral oil- induced murine plasmacytomas were identified which secrete antibodies specific for phosphocholine(2) (PC), the immunodominant determinant on certain rough strains of Streptococcus pneumoniae (3) The murine antibody response to PC has been shown to be quite restricted in isotype(4) and idiotype.(5) In particular, the majority of induced BALB/ c anti-PC antibodies bear idiotypic determinants related to those present on a prototype PC-binding plasmacytoma protein, T15, and the expression of this idiotype is inherited as a single Mendelian allele closely linked to the immunoglobulin allotype locus. In addition, neonatal administration of anti-T15 antitypic antibodies completely abrogates the anti- R36A pneumococcal response in mice.(7) These data, coupled with the nearly homogeneous affinities of anti-PC sera as measured by hapten inhibition,(8) suggested that the murine response to PC might be essentially monoclonal.

Keywords

Heavy Chain Somatic Mutation Gene Segment Immunoglobulin Heavy Chain Antibody Population 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Krause, R. M., 1970, The search for antibodies with molecular uniformity,Adv. Immunol. 12:1–56.PubMedCrossRefGoogle Scholar
  2. 2.
    Potter, M., 1972, Immunoglobulin-producing tumors and myeloma proteins of mice, Physiol. Rev. 52:631- 719.Google Scholar
  3. 3.
    Leon, M. A., and Young, N. M., 1971, Specificity for phosphorylcholine of six murine myeloma proteins reactive with pneumococcus C polysaccharide and B-lipoprotein, Biochemistry 10:1424–1429.PubMedCrossRefGoogle Scholar
  4. 4.
    Lee, W., Cosenza, H., and Kohler, H., 1974, Clonal restriction of the immune response to phosphorylcholine, Nature 247:55–57.PubMedCrossRefGoogle Scholar
  5. 5.
    Lieberman, R., Potter, M., Mushinsky, F., Humphrey, W., and Rudikoff, S., 1974, Genetics of a new IgVH (T15 idiotype) marker in the mouse regulating natural antibody to phosphorylcholine, J. Exp. Med. 139:983–988.PubMedCrossRefGoogle Scholar
  6. 6.
    Lieberman, R., Rudikoff, S., Humphrey, W., Jr., and Potter, M., 1981, Allelic forms of anti-phosphoryl- choline antibodies,j. Immunol. 126:172–176.Google Scholar
  7. 7.
    Cosenza, H., and Kohler, H., 1972, Specific suppression of the antibody response by antibodies to receptors, Proc. Natl. Acad. Sci. USA 69:2701–2705.PubMedCrossRefGoogle Scholar
  8. 8.
    Claflin, J. L., and Davie, J. M., 1974, Clonal nature of the immune response to phosphorylcholine. III. Species-specific binding characterisitcs of rodent anti-phosphorylcholine antibodies, J. Immunol. 113:1678- 1684.PubMedGoogle Scholar
  9. 9.
    Claflin, J. L, and Rudikoff, S., 1976, Uniformity in the clonal repertoire for the immune response to phosphorylcholine in mice: A case for a germline basis of antibody diversity, Cold Spring Harbor Symp. Quant. Biol 41:725–734.CrossRefGoogle Scholar
  10. 10.
    Ruppert, V. J., Williams, K., and Claflin, J. L., 1980, Specific clonal regulation in the immune response to phosphocholine. I. Genetic analysis of the response of a distinct idiotype (M511Id), J. Immunol 124:1068–1074.PubMedGoogle Scholar
  11. 11.
    Gearhart, P., Sigal, N., and Klinman, N., 1975, Heterogeneity of the BALB/c anti-phosphorylcholine antibody response at the precursor cell level, J. Exp. Med. 141:56–74.PubMedCrossRefGoogle Scholar
  12. 12.
    Claflin, J. L., and Davie, J. M., 1974, Specific isolation and characterization of antibody directed to binding site antigenic determinants, J. Immunol 114:70–75.Google Scholar
  13. 13.
    Early, P. W., Huang, H., Davis, M. M., Calame, K., and Hood, L., 1980, An immunoglobulin heavy chain variable region is generated from three segments of DNA: VH, D, and JH, Cell 19:981–992.PubMedCrossRefGoogle Scholar
  14. 14.
    Gearhart, P., Johnson, N., Douglas, R., and Hood, L., 1981, IgG antibodies to phosphorylcholine exhibit more diversity than their IgM counterparts, Nature 291:29–34.PubMedCrossRefGoogle Scholar
  15. 15.
    Crews, S., Griffin, J., Huang, H., Calame, K., and Hood, L., 1981, A single VH gene segment encodes the immune response to phosphorylcholine: Somatic mutation is correlated with the class of the antibody, Cell 25:59–66.PubMedCrossRefGoogle Scholar
  16. 16.
    Clarke, C., Berenson, J., Goverman, J., Boyer, P. D., Crews, S., Siu, G., and Calame, K., 1982, An immunoglobulin promoter region is unaltered by DNA rearrangement and somatic mutation during B cell development, Nucleic Acids Res. 10:7731–7749.PubMedCrossRefGoogle Scholar
  17. 17.
    Breathnach, R., and Chambon, P., 1981, Organization and expression of eukaryotic split genes coding for proteins, Annu. Rev. Biochem. 50:349–383.PubMedCrossRefGoogle Scholar
  18. 18.
    Honjo, T., 1983, Immunoglobulin genes, Annu. Rev. Immunol 1:499–528.PubMedCrossRefGoogle Scholar
  19. 19.
    Maki, R., Kearney, J., Paige, C., and Tonegawa, S., 1980, Immunoglobulin gene rearrangement in immature B cells, Science 209:1366–1369.PubMedCrossRefGoogle Scholar
  20. 20.
    Kim, S., Davis, M. M., Sinn, E., Patten, P., and Hood, L., 1981, Antibody diversity: Somatic hypermu- tation of rearranged VH genes, Cell 27:573–581.PubMedCrossRefGoogle Scholar
  21. 21.
    Kurosawa, Y., and Tonegawa, S., 1982, Organization, structure and assembly of immunoglobulin heavy chain diversity DNA segments, J. Exp. Med. 155:201–218.PubMedCrossRefGoogle Scholar
  22. 22.
    Alt, F., and Baltimore, D. 1982, Joining of immunoglobulin heavy chain gene segments: Implications from a chromosome with evidence of three D-JH fusions, Proc. Natl Acad. Sci. USA 79:4118–4122.PubMedCrossRefGoogle Scholar
  23. 23.
    Seising, E., and Storb, U., 1981, Somatic mutation of immunoglobulin light chain variable region genes, Cell 25:47–58.CrossRefGoogle Scholar
  24. 24.
    Gershenfeld, H., Tsukamoto, A., Weissman, I. L., and Joho, R., 1981, Somatic diversification is required to generate theV K genes of MOPC 511 and MOPC 167 myeloma proteins, Proc. Natl Acad. Sci. USA 78:7674–7678.PubMedCrossRefGoogle Scholar
  25. 25.
    Gearhart, P. J., and Boganhagen, D., 1983, Clusters of point mutations are found exclusively around rearranged antibody variable genes, Proc. Natl. Acad. Sci. USA 80:3439–3443.PubMedCrossRefGoogle Scholar
  26. 26.
    Padlan, E. A., Segal, D. M., Spande, T. R., Davies, D. R., Rudikoff, S., and Potter, M., 1973, Structure at 4.5 Â resolution of a phosphorylcholine-binding Fab, Nature New Biol. 245:165–167.PubMedGoogle Scholar
  27. 27.
    Gearhart, P., Sigal, N., and Klinman, N., 1975, Production of antibodies of diverse immunoglobulin classes by cells derived from a single stimulated B cell, Proc. Natl. Acad. Sci. USA 72:1707–1711.PubMedCrossRefGoogle Scholar
  28. 28.
    Rodwell, J., Gearhart, P., and Karush, F., 1983, Restriction in IgM expression. IV. Affinity analysis of monoclonal anti-phosphorylcholine antibodies, J. Immunol. 130:313–316.PubMedGoogle Scholar
  29. 29.
    Kocher, H. P., Borek, C., and Jaton, J.-C., 1981, The immune response of BABL/c mice to phosphoryl- choline is restricted to a limited number of VH and VL isotypes, Mol. Immunol. 18:1027–1033.PubMedCrossRefGoogle Scholar
  30. 30.
    Chang, S. P., Brown, M., and Rittenberg, M. B., 1982, Immunologic memory to phosphorylcholine. II. PC-KLH induces two antibody populations that dominate different isotypes,J. Immunol. 128:702–710.PubMedGoogle Scholar
  31. 31.
    Chang, S. P., Perlmutter, R. M., Brown, M., Heusser, C. H., Rittenberg, M. B., and Hood, L., 1984, Immunologic memory to phosphorylcholine. IV. Hybridomas representative of group I and group II antibodies utilize distinct VH genes, J. Immunol. 132:1550–1555.PubMedGoogle Scholar
  32. 32.
    Todd, I., Chang, S. P., Perlmutter, R. M., Aebersold, R., Heusser, C., Hood, L., and Rittenberg, M. B., 1984, Immunologic memory to phosphorylcholine V. Hybridomas representative of group II antibodies utilize F,l-3 gene(s), J. Immunol. 132:1556–1560.PubMedGoogle Scholar
  33. 34.
    Perlmutter, R. M., Hansburg, D., Briles, D. E., Nicolotti, R. A., and Davie, J. M., 1978, Subclass restriction of murine anti-carbohydrate antibodies, J. Immunol. 121:566–572.PubMedGoogle Scholar
  34. 34.
    Briles, D. E., Forman, C., Hudak, S., and Claflin, J. L., 1982, Antiphosphorylcholine antibodies of the T15 idiotype are optimally protective against Streptococcus pneumoniae, f. Exp. Med. 156:1177–1185.Google Scholar
  35. 35.
    Perlmutter, R. M., and Davie, J. M., 1977, Characterization of molecular heterogeneity and multispecific- ity in homologous idiotypic antisera, J. Immunol. 118:769–774.PubMedGoogle Scholar
  36. 36.
    Clarke, S. H., Claflin, J. L., and Rudikoff, S., 1982, Polymorphisms in immunoglobulin heavy chains suggesting gene conversion,Proc. Natl. Acad. Sci. USA 79:3280–3284.PubMedCrossRefGoogle Scholar
  37. 37.
    Bottomly, K., Mathieson, B., and Mosier, D., 1978, Anti-idiotype regulation of helper cell function for the response to phosphorylcholine in adult BALB/c mice, J. Exp. Med. 148:1216–1227.PubMedCrossRefGoogle Scholar
  38. 38.
    Pillemer, E., and Weissman, I. L., 1981, A monoclonal antibody that detects a V-TEPC 15 idiotypic determinant cross-reactive with a Thy-1 determinant, J. Exp. Med. 153:1068–1079.PubMedCrossRefGoogle Scholar
  39. 39.
    Rabat, E. A., Wu, T. T., Bilofsky, H., Reid-Miller, M., and Perry, H., 1983,Sequences of Proteins of Immunological Interest U.S. Department of Health and Human Services, Public Health Service, National Institutes of Health.Google Scholar
  40. 40.
    Huang, H., Crews, S., and Hood, L., 1918, An immunoglobulin VH pseudogene, f. Mol. Appl. Genet. 1:93–101.Google Scholar
  41. 41.
    Clarke, S. H., Claflin, J. L., Potter, M., and Rudikoff, S., 1983, Polymorphisms in anti-phosphorylcholine antibodies reflecting evolution of immunoglobulin families, f. Exp. Med. 157:98–113.CrossRefGoogle Scholar
  42. 42.
    Riesen, W., Braun, D., and Jaton, J.-C., 1976, Human and murine phosphorylcholine-binding immunoglobulins: Conserved subgroup and first hypervariable region of heavy chains, Proc. Natl. Acad. Sci. USA 73:2096–2100.PubMedCrossRefGoogle Scholar
  43. 43.
    Bothwell, A. L. M., Paskind, M., Reth, M., Imanishi-Kari, T., Rajewsky, K., and Baltimore, D., 1981, Heavy chain variable region contribution to the NPb family of antibodies: Somatic mutation evident in a 72a variable region, Cell 24:625–637.PubMedCrossRefGoogle Scholar
  44. 44.
    Sims, J., Rabbitts, T. H., Estess, P., Slaughter, C., Tucker, P. W., and Capra, J. D., 1982, Somatic mutation in genes for the variable portion of the immunoglobulin heavy chain, Science 216:309–311.PubMedCrossRefGoogle Scholar
  45. 45.
    Kaartinen, M., Griffiths, G. M., Hamlyn, P. H., Markham, A. F., Karjalainen, K., Pelkonen, J. L. T., Mâkelâ, O., and Milstein, C., 1983, Anti-oxazolone hybridomas and the structure of the oxazolone idiotype, J. Immunol. 130:937–945.PubMedGoogle Scholar
  46. Perlmutter, R. M., Briles, D. E., and Davie, J. M., 1977, Complete sharing of light chain spectrotypes by murine IgM and IgG anti-streptococcal antibodies, f. Immunol. 118:2161–2166.Google Scholar

Copyright information

© Plenum Press, New York 1984

Authors and Affiliations

  • Roger M. Perlmutter
    • 1
  1. 1.Division of BiologyCalifornia Institute of TechnolgyPasadenaUSA

Personalised recommendations