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Splitting the difference: the germline–somatic mutation debate on generating antibody diversity

Nature Immunology volume 4, pages 829–833 (2003)Cite this article

Abstract

In the debate about the mechanism for the generation of immunological diversity, the initial positions of both 'somaticists' and 'germliners' were diametrically opposed. Then, as data developed favoring first one and then the other side, concessions were made, until the final solution showed that each had been at least partially correct.

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References

  1. Capra, J.D. in The Generation of Antibody Diversity (ed. Cunningham, A.J.) 75 (Academic, New York, 1976).

    Google Scholar 

  2. However, Melvin Cohn suggests that it may be naive to conclude that here “everyone was a little bit right,” as thus everyone must have been a whole lot wrong—and it is from the latter that we learn. See Cohn, M. Annu. Rev. Immunol. 12, 41–42 (1994).

  3. Pasteur, L. C. R. Acad. Sci. 90, 239–248 (1880).

    Google Scholar 

  4. Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation (Keegan, Paul, Trench and Trübner, London, 1893). Reprinted by Dover (New York, 1968). See also Metchnikoff, E., Immunity in the Infectious Diseases (Macmillan, New York, 1905). Reprinted by Johnson Reprint (New York, 1968).

    Google Scholar 

  5. Ehrlich, P. Proc. R. Soc. Lond. 66, 424–448 (1900).

    Article  CAS  Google Scholar 

  6. Obermayer, E. & Pick, E.P. Wien. klin. Wochenschr. 19, 327–333 (1906).

    Google Scholar 

  7. Pick, E.P. in Handbuch der pathogenen Mikroorganismen 2nd edn. Vol. 1 (ed. Kolle, W. & von Wassermann, A.) 685–868 (Fischer, Jena, 1912).

    Google Scholar 

  8. Landsteiner, K. The Specificity of Serological Reactions (Dover, New York, 1962), a reprint of the 1945 2nd edn.; the original German edition was published in 1933.

    Google Scholar 

  9. Max von Gruber had challenge Ehrlich on the size of the repertoire in Gruber, M. Münch. med. Wochenschr. 48, 1214–1215 (1901) and Gruber, M. Wien. klin. Wochenschr. 16, 791–793 (1903). A sign that Ehrlich's theory was in decline was the way that it was treated, as early as 1914, as “of historical interest” by Hans Zinsser in his Infection and Resistance (Macmillan, New York, 1914) and in W.W.C. Topley and G.S. Wilson's Principles of Bacteriology and Immunity 2nd edn. (William Wood, Baltimore, 1938).

  10. Breinl, F. & Haurowitz, F. Z. Physiol. Chem. 192, 45–57 (1930).

    Article  CAS  Google Scholar 

  11. Pauling, L. J. Am. Chem. Soc. 62, 2643–2657 (1940).

    Article  CAS  Google Scholar 

  12. The role of darwinian ideas in immunological theory is outlined in Silverstein, A.M. Nat. Immunol. 4, 3–6 (2003).

  13. Jerne, N.K. Proc. Natl. Acad. Sci. USA 41, 849–857 (1955).

    Article  CAS  Google Scholar 

  14. Burnet, F.M. Austr. J. Sci. 20, 67–69 (1957). David Talmage had arrived independently at a similar idea of selection in Annu. Rev. Med. 8, 239–256 (1957).

    Google Scholar 

  15. Burnet, F.M. The Clonal Selection Theory of Antibody Formation (Cambridge University Press, London, 1959).

    Google Scholar 

  16. Lederberg, J. Science 129, 1649–1653 (1959).

    Article  CAS  Google Scholar 

  17. Talmage, D.W. Science 129, 1643–1648 (1959). See also Titani, K., Whitley, E., Avogardo, L. & Putnam, F.W. Science 152, 1513–1516 (1965).

    Article  CAS  Google Scholar 

  18. This argument was advanced in Hood, L. & Talmage, D.W. Science 168, 325–334 (1970) in the context of two genes, not for entire light or heavy chains, but for their respective variable regions. They would calculate that no more than 0.2% of the total DNA in the genome would suffice.

  19. Klinman showed that as many as 5,000 different clonotypes reactive with the dinitrophenyl group could be found in the mouse, in Klinman, N.R. J. Exp. Med. 136, 241–260 (1972) and Sigal, N.H. & Klinman, N.R. Adv. Immunol. 26, 255–337 (1978), and Kreth and Williamson calculated that the mouse can produce some 8,000–15,000 individual clones reactive with the o-nitro-p-iodophenyl (NIP) hapten, in Kreth, H.W. & Williamson, A.R. Eur. J. Immunol. 3, 141–146 (1973). See also Pink, J.R.L. & Askonas, B. Eur. J. Immunol. 4, 426–430 (1974).

  20. According to Hood, L. & Prahl, J. Adv. Immunol. 14, 291–351 (1971), a new antibody gene develops by a slow process of mutation and selection in evolutionary time.

  21. Kindt, T.J. & Capra, J.D. The Antibody Enigma (Plenum, New York, 1984). These authors present in detail all of the data (except for the ontogenetic data) that contributed to the original debate and then to the ultimate molecular biological solution to the problem of the generation of diversity.

    Book  Google Scholar 

  22. See, for example, Cohn, M. Cell. Immunol. 1, 461–467 (1970) and Jerne, N.K. Ann. Inst. Pasteur 125C, 373–389 (1974).

  23. However, Melvin Cohn, in Cell. Immunol. 1, 461–467 (1970), calculated that there is indeed enough time.

  24. Brenner, S. & Milstein, C. Nature 211, 242–243 (1966).

    Article  CAS  Google Scholar 

  25. Smithies, O. Science 157, 267–273 (1967) and Smithies, O. Nature 199, 1231–1236 (1963). See also Smithies, O. Cold Spring Harb. Symp. Quant. Biol. 32, 161–166 (1967).

    Article  CAS  Google Scholar 

  26. Edelman, G.M. & Gally, J.A. Proc. Natl. Acad. Sci. USA 57, 353–358 (1967).

    Article  CAS  Google Scholar 

  27. See šterzl, J. & Silverstein, A.M. Adv. Immunol. 6, 337–459 (1967) and Solomon, J.B. Foetal and Neonatal Immunology (North Holland, Amsterdam, 1971).

  28. Thus, the tadpole does reasonably well with fewer than one million lymphocytes: Du Pasquier, L. Immunology 19, 353–362 (1970); Du Pasquier, L. & Wabl, M.R. in The Generation of Antibody Diversity (ed. Cunningham, A.J.) 151–164 (Academic, New York, 1976). The very young fetal lamb does equally well: Silverstein, A.M. & Prendergast, R.A. in Developmental Aspects of Antibody Formation and Structure Vol. I (eds. šterzl, J. & Řiha, I.) 69–77 (Czech Academy of Sciences, Prague, 1970).

  29. Thus, the fetal lamb, in Silverstein, A.M. & Prendergast, R.A. in Developmental Aspects of Antibody Formation and Structure Vol. I (eds. šterzl, J. & Řiha, I.) 69–77 (Czech Academy of Sciences, Prague, 1970); the mouse, in Yung, L. et al. Eur. J. Immunol. 3, 224–228 (1973); and the opossum, in Sherwin, W.K. & Rowlands, D.T. J. Immunol. 113, 1353–1360 (1974). These data were used to argue in favor of the germline side of the multigene/paucigene debate by Silverstein, A.M. in Phylogenic and Ontogenic Study of the Immune Response and its Contribution to the Immunological Theory (eds. Liacopoulos, P & Panijel, J.) 221–227 (INSERM, Paris, 1973).

  30. Klinman, N.R., Press, J.L., Sigal, N.H. & Gearhart, P.J. in The Generation of Antibody Diversity (ed. Cunningham, A.J.) 127–149 (Academic Press, New York, 1976); Klinman, N.R. et al. Cold Spring Harb. Symp. Quant. Biol. 41, 165–173 (1976).

    Google Scholar 

  31. Such a theory of antigen-enhanced generation of diversity was advanced by Cunningham, A.J. & Pilarsky, L.M. Scand. J. Immunol. 3, 5–10 (1974).

  32. Porter, R.R. Biochem. J. 46, 479–484 (1950); Fried, M. & Putnam, F.W. J. Biol. Chem. 193, 1086–1087 (1960); Nisonoff, A., Wissler, F.C. & Woernley, D.L. Biochem. Biophys. Res. Commun. 1, 318–322 (1959).

    Article  CAS  Google Scholar 

  33. Edelman, G.M. J. Am. Chem. Soc. 81, 3155–3156 (1959); Fraňek, F. Biochem. Biophys. Res. Commun. 4, 28–32 (1961).

    Article  CAS  Google Scholar 

  34. Slater, R.J., Ward, S.M. & Kunkel, H.G. J. Exp. Med. 101, 85–108 (1955); Kunkel, H.G. Harvey Lect. 59, 219–242 (1965). Potter's discovery that myelomas can be induced in mice by intraperitoneal injection of mineral oil provided extensive material for sequencing: Potter, M. & Boyce, C. Nature 193, 1086–1087 (1962) and Potter, M. Physiol. Rev. 52, 631–719 (1972).

    Article  CAS  Google Scholar 

  35. Edelman, G.M. & Gally, J.A. J. Exp. Med. 116, 207–227 (1962); see also Putnam, F.W. & Hardy, S. J. Biol. Chem. 212, 361–369 (1955).

    Article  CAS  Google Scholar 

  36. Hilschmann, N. & Craig, L.C. Proc. Natl. Acad. Sci. USA 53, 1403–1409 (1965); Putnam, F.W. et al. Cold Spring Harb. Symp. Quant. Biol. 32, 9–29 (1967).

    Article  CAS  Google Scholar 

  37. Dreyer, W.J. & Bennet, J.C. Proc. Natl. Acad. Sci. USA 54, 864–869 (1965).

    Article  CAS  Google Scholar 

  38. Wu, T.T. & Kabat, E.A. J. Exp. Med. 132, 211–250 (1970).

    Article  CAS  Google Scholar 

  39. Kehoe, J.M. & Capra, J.D. Proc. Natl. Acad. Sci. USA 68, 2019–2021 (1971).

    Article  CAS  Google Scholar 

  40. A variant of this gene segment idea was taken up by Capra, J.D. & Kindt, T.J. Immunogenetics 1, 417–427 (1975).

  41. Hood, L. & Talmage, D.W. Science 168, 325–334 (1970).

    Article  CAS  Google Scholar 

  42. Fitch, W.M. & Margoliash, E. Science 155, 279–284 (1967).

    Article  CAS  Google Scholar 

  43. See Weigert, M.G. et al. Nature 228, 1045–1047 (1970).

  44. Oudin, J. C. R. Acad. Sci. 242, 2606–2608 (1956). See also Grubb, R. Acta Pathol. Microbiol. Scand. 39, 195–197 (1956).

    CAS  Google Scholar 

  45. Todd, C.W. Biochem. Biophys. Res. Commun. 11, 170–175 (1963); Feinstein, A. Nature 199, 1197–1199 (1963).

    Article  CAS  Google Scholar 

  46. Pernis, B. et al. J. Exp. Med. 122, 853–876 (1965); Weiler, E. Proc. Natl. Acad. Sci. USA 54, 1765–1772 (1965).

    Article  CAS  Google Scholar 

  47. Oudin, J. & Michel, M. C. R. Acad. Sci. 257, 805–808 (1963); Kunkel, H.G., Mannick, M. & Williams, R.C. Science 140, 1218–1219 (1963); Gell, P.G.H. & Kelus, A. Nature 201, 687–689 (1964).

    CAS  Google Scholar 

  48. Kuettner, M.G., Wang, A. & Nisonoff, A. J. Exp. Med. 135, 579–595 (1972).

    Article  CAS  Google Scholar 

  49. Eichmann, K. Eur. J. Immunol. 2, 301–307 (1972).

    Article  CAS  Google Scholar 

  50. Lieberman, R. et al. J. Exp. Med. 139, 983–1001 (1974).

    Article  CAS  Google Scholar 

  51. See, for example, Eichmann, K. & Kindt, T.J. J. Exp. Med. 134, 532–552 (1971) and Eichmann, K. Immunogenetics 2, 491–506 (1975).

  52. The history of the cellularist/humoralist debate is described in Silverstein, A.M. Cell. Immunol. 48, 208–221 (1979).

  53. See, for example, Cantor, H., Chess, L. & Sercarz, E. (eds.) Regulation of the Immune System (Alan Liss, New York, 1984) and Bock, G.R. & Goode, J.A. (eds.) Immunological Tolerance (Wiley, New York, 1997). In his introduction to the latter volume, Avrion Mitchison concludes (on page 4), “The problem posed by Ehrlich turns out to be far, far more complex than the pioneers had imagined.”

  54. See, for example, Delovitch, T.L. & Baglioni, C. Proc. Natl. Acad. Sci. USA 70, 173–178 (1973); Premkumar, E., Shoyab, M. & Williamson, A.R. Proc. Natl. Acad. Sci. USA 71, 99–103 (1974); Leder, P. et al. Proc. Natl. Acad. Sci. USA 71, 5109–5114 (1974); Tonegawa, S. et al. FEBS Lett. 40, 92–96 (1974).

  55. Leder, P. Sci. Am. 246, 102–115 (1982).

    Article  CAS  Google Scholar 

  56. Tonegawa, S. et al. Cold Spring Harb. Symp. Quant. Biol. 41, 877–889 (1976).

    Article  Google Scholar 

  57. Weigert, M. et al. Nature 276, 785–790 (1978).

    Article  CAS  Google Scholar 

  58. For a full review of the molecular genetics of immunoglobulin formation, see Max, E.E. in Fundamental Immunology 4th edn. (ed. Paul, W.E.) 111–182 (Lippincott-Raven, New York, 1998).

  59. See Langman, R.E. & Cohn, M. Semin. Immunol. 14, 153–162 (2002).

  60. For example, Cohn, M., Langman, R.E. & Geckeler, W. Progr. Immunol. 4, 153–201 (1980); Janeway, C.A. Immunol. Today 13, 11–16 (1992). Briles and colleagues have been more specific, suggesting that the germline contains genes encoding the antibody of the T15 idiotype specific for the ubiquitous bacterial component phosphoryl choline, in Briles, D.E. et al. Exp. Med. 156, 1177–1185 (1982).

  61. Langman, R.E. & Cohn, M. Mol. Immunol. 24, 675–697 (1987). They suggested that the problem of natural selection is simpler, in that the critical germline specificities maintained by selection are formed by the unique pairing of the germline VH and VL segments.

    Article  CAS  Google Scholar 

  62. Ohno, S. Perspect. Biol. Med. 19, 527–532 (1976) and Ohno, S. Progr. Immunol. 4, 577–598 (1980).

    Article  CAS  Google Scholar 

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  1. Institute of the History of Medicine, Johns Hopkins School of Medicine, 1900 East Monument Street, Baltimore, 21205, Maryland, USA

    Arthur M Silverstein

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Silverstein, A. Splitting the difference: the germline–somatic mutation debate on generating antibody diversity. Nat Immunol 4, 829–833 (2003). https://doi.org/10.1038/ni0903-829

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