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Cellular versus humoral immunology: a century-long dispute

Nature Immunology volume 4, pages 425–428 (2003)Cite this article

Historical insight: Immunology's founding fathers argued fiercely about whether Metchnikoff's phagocytes or Ehrlich's antibodies were the most important mediators of immunity. Antibodies won out, but even after lymphocytes re-established cellular immunology, the humoralist-cellularist divide persisted.

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References

  1. Jerne, N.K. Waiting for the end. Cold Spring Harbor Symposium “Antibodies” 37, 591–603 (1967).

    Google Scholar 

  2. Metchnikov, E. Virchows Archiv. 96, 177–195 (1884). The founding myth of discovery is described in Metchnikoff, O., Life of Elie Metchnikoff, 116–117 (Houghton, Mifflin, Boston, 1921).

    Google Scholar 

  3. Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation (Keegan, Paul, Trench, Trübner, London, 1893). Reprinted by Dover (New York, 1968).

    Google Scholar 

  4. Metchnikoff, E. Immunity in the Infectious Diseases (Macmillan, New York, 1905). Reprinted by Johnson Reprint Corp. (New York, 1968).

    Google Scholar 

  5. Behring, E. & Kitasato, S. Deutsch. med. Wochenschr. 16, 1113–1114 (1890); Behring, E. & Wernicke, E. Z. Hyg. 12, 10–44; 45–57 (1892).

    Article  Google Scholar 

  6. Ehrlich, P. Deutsch. med. Wochenschr. 17, 976–979; 1218–1219 (1891).

    Article  Google Scholar 

  7. Pfeiffer, R.Z. Hyg. Infektskr. 18, 1–16 (1895). Jules Bordet would later show that both bacteriolysis and hemolysis are due to the action of two substances, humoral antibody and complement; Ann. Inst. Pasteur 12, 688–695 (1989).

    Google Scholar 

  8. Virchow, R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre (Hirschwald, Berlin, 1858). English edition: Cellular Pathology (Dover, New York, 1971).

    Google Scholar 

  9. See also Baxter, A.G. Nature Rev. Immunol. 1, 229–232 (2001).

    Article  CAS  Google Scholar 

  10. The cellular-humoral debate, including its political aspects, is discussed at greater length in Silverstein, A.M. A History of Immunology, 38–58 (Academic Press, San Diego, 1989).

  11. See Silverstein, A.M. Paul Ehrlich's Receptor Immunology: The Magnificent Obsession, 95–122 (San Diego, Academic Press, 2002).

    Book  Google Scholar 

  12. Ehrlich, P. Klin. Jahrb. 6, 299–333 (1897).

    Google Scholar 

  13. Ehrlich, P. Proc. Roy. Soc. Ser. B 66, 424–448 (1900); see also Cambrosio, A., Jacobi, D. & Keating, P. Ehrlich's 'beautiful pictures' and the controversial beginnings of immunological imagery. Isis, 84, 662–699 (1993).

    Article  CAS  Google Scholar 

  14. Wright, A.E. & Douglas, S.R. Proc. Roy. Soc. Ser. B 73, 128–142 (1904). Bernard Shaw would take up Wright's suggestion in his play A Doctor's Dilemma, suggesting that the opsonins “butter the disease germs appetizingly for [the phagocytes].”

    Article  Google Scholar 

  15. For the history of the idea of cell-bound antibodies, see Silverstein, A.M. Nature Immunol. 3, 105–108 (2002).

    Article  CAS  Google Scholar 

  16. Arrhenius, S. Immunochemistry (Macmillan, New York, 1907).

    Google Scholar 

  17. Pick, E.P. in Handbuch der pathogenen Mikroorganismen, edn. 2 vol. 1 (W. Kolle & A. von Wassermann, eds.) 685–868 (Fischer, Jena, 1912).

    Google Scholar 

  18. Landsteiner, K. and Lampl, H. Z. Immunitätsforsch. 26, 258–276; 293–304 (1917).

    CAS  Google Scholar 

  19. Landsteiner's work in this area is summarized in his classic The Specificity of Serological Reactions (Dover, New York, 1962). This was a reprint of edn. 2, of 1945; the original German edition was published in 1933.

  20. See the definitive work of its day by Heidelberger's students: Kabat, E.A. & Mayer, M.M. Experimental Immunochemistry (Thomas, Springfield, Illinois, 1948).

    Google Scholar 

  21. See, for example, Marrack, J.R. The Chemistry of Antigens and Antibodies (HM Stationery Office, London, 1934); Pressman, D.P. & Grossberg, A. The Structural Basis of Antibody Specificity (Benjamin, New York, 1968); Kabat, E.A. Structural Concepts in Immunology and Immunochemistry (Rinehart & Winston, New York, 1968).

    Google Scholar 

  22. Breinl, F. & Haurowitz, F. Z. Physiol. Chem. 192, 45–57 (1930); Pauling, L.J. Am. Chem. Soc. 62, 2643–2657 (1940). The comings and goings of Darwinism in immunology are discussed in Silverstein, A.M. Nature Immunol. 4, 3–6 (2003).

    Article  CAS  Google Scholar 

  23. Murphy, J.B. Monographs of the Rockefeller Institute for Medical Research 21 (1926); see also Silverstein, A.M., Nature Immunol. 2, 569–571 (2001).

    Google Scholar 

  24. Dienes, L. J. Immunol. 17, 531–538 (1929); Dienes, L. & Schoenheit, E.W. Am. Rev. Tuberc. 20, 92–105 (1929).

    Google Scholar 

  25. Rivers, T.M. & Schwentker, E.F. J. Exp. Med. 61, 689–702 (1935); Kabat, E.A., Wolfe, A. & Bezer, A.E. J. Exp. Med. 85, 117–130 (1947); 89, 395–398 (1949).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Landsteiner, K. & Chase, M.W. Proc. Soc. Exp. Biol. Med. 49, 688–690 (1942).

    Article  CAS  Google Scholar 

  27. Metchnikoff, E. Immunity in the Infectious Diseases, p. 306 (Macmillan, New York, 1905).

    Google Scholar 

  28. Rich, A.R. & Lewis, M.R. Bull. Johns Hopkins Hosp. 50, 115–131 (1932).

  29. Waksman, B.H. & Matoltsy, M.J. J. Immunol. 81, 220–234 (1958).

    CAS  PubMed  Google Scholar 

  30. Bloom, B.R. & Bennett, B. Science 153, 80–82 (1966); David, J.R. Proc. Natl. Acad. Sci. USA 56, 72–77 (1966).

    Article  CAS  PubMed  Google Scholar 

  31. Lurie, M.B. J. Exp. Med. 75, 247–268 (1942); Elberg, S.S. Bacteriol. Rev. 24, 67–95 (1960). See also Rowley, D. Adv. Immunol. 2, 241–264 (1962).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Mackaness, G.B. & Blanden, R.V. Progr. Allergy 11, 89–140 (1967). They were willing to concede that if macrophages do indeed exhibit specificity of action, it is probably due to adherent antibody.

    CAS  Google Scholar 

  33. Granger, G.A. & Weiser, R.S. Science 145, 1427–1429 (1964).

    Article  CAS  PubMed  Google Scholar 

  34. Suter, E. & Ramseier, H. Adv. Immunol. 4, 117–173 (1964).

    Article  CAS  Google Scholar 

  35. Fishman, M. & Adler, F.L. J. Exp. Med. 117, 595–602 (1963); see also Fong, J., Chen, D. & Elberg, S.S. J. Exp. Med. 118, 371–386 (1963).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Askonas, B.A. & Rhodes, J.M. Nature 205, 470–474 (1965).

    Article  CAS  PubMed  Google Scholar 

  37. See, for example, Möller, G. (ed.) Immunol. Rev. 40 (1978); Unanue, E.R. & Rosenthal, A.S. (eds.). Macrophage Regulation of Immunity (Academic Press, New York, 1980).

    Google Scholar 

  38. Zinkernagel, R.M. & Doherty, P.C. J. Exp. Med. 141, 1427–1436 (1975); Zinkernagel, R.M. & Doherty, P.C. Adv. Immunol. 27, 51–177 (1979).

    Article  CAS  PubMed  Google Scholar 

  39. This paradigm shift in immunology is discussed at length by Silverstein, A.M. Cell. Immunol. 132, 515–531 (1991).

    Article  CAS  PubMed  Google Scholar 

  40. See Brent, L. A History of Transplantation Immunology (Academic Press, San Diego, 1997).

    Google Scholar 

  41. Burnet, F.M. & Fenner, F. The Production of Antibodies, edn. 2 (Macmillan, New York, 1949).

    Google Scholar 

  42. Billingham, R.E., Brent, L. & Medawar, P.B. Nature 172, 603–606 (1953).

    Article  CAS  PubMed  Google Scholar 

  43. For example, Humphrey, J.H. & White, R.G. Immunology for Students of Medicine (Davis, Philadelphia, 1963); Gell, P.G.H. & Coombs, R.R.A. (eds.). Clinical Aspects of Immunology (Blackwell, Oxford, 1963); Mackay, I.R. & Burnet, F.M. Autoimmune Diseases (Thomas, Springfield, IL, 1963).

    Google Scholar 

  44. Burnet, F.M. Austral. J. Sci. 20, 67–69 (1957); Talmage, D.W. Annu. Rev. Med. 8, 239–257 (1957).

    Google Scholar 

  45. See, however, the attempts by Tauber and colleagues to align Metchnikoff more closely to the context of contemporary immunology. Thus: Tauber, A.I. Cell Immunol. 139, 505–530 (1992); Tauber, A.I. & Chernyak, L. Metchnikoff and the Origins of Immunology (Oxford University Press, New York, 1991); Tauber, A.I. The Immune Self: Theory or Metaphor? (Cambridge University Press, Cambridge, 1994).

    Google Scholar 

  46. The most comprehensive summary of these and other modern advances may perhaps be found in Paul, W.E. (ed.). Fundamental Immunology edn. 4 (Lippincott-Raven, Philadelphia, 1999).

    Google Scholar 

  47. Karush, F. Adv. Immunol. 2, 1–40 (1962); Fahey, J.L. Adv. Immunol. 2, 41–109 (1962); Edelman, G.M. & Gall, W.E. Ann. Rev. Biochem. 38, 415–466 (1969); Poljak, R.J. et al. Proc. Natl. Acad. Sci. USA 70, 3305–3310 (1973); 71, 1427–1430 (1974).

    CAS  Google Scholar 

  48. Porter, R.R. Brit. Med. Bull. 19, 197–201 (1963); Edelman, G.M. Biochemistry 9, 3197–3205 (1970); Kunkel, H.G. Harvey Lect. 59, 219–242 (1965); Wu, T.T. & Kabat, E.A. J. Exp. Med. 132, 211–250 (1970).

    Article  CAS  PubMed  Google Scholar 

  49. Müller-Eberhard, H.J. Adv. Immunol. 8, 1–80 (1968); Mayer, M.M., Proc. Natl. Acad. Sci. USA 69, 2954–2958 (1972).

    Article  PubMed  Google Scholar 

  50. Thomas Kuhn defined a paradigm as the set of understandings and assumptions about a field that guide the contemporary design of experiments and interpretation of results, The Structure of Scientific Revolutions 2nd ed. (University of Chicago Press, Chicago, 1970).

  51. Silverstein, A.M., Nature Immunol. 3, 105–108 (2002).

    Article  CAS  Google Scholar 

  52. Janeway, C.J. Jr. Immunol. Today 13, 11–16 (1992); Medzhitov, R. & Janeway, C.A. Jr. Curr. Opin. Immunol. 9, 9 (1997); Janeway, C.A. Jr. Proc. Natl. Acad. Sci. USA 98, 7461–7468 (2001).

    Article  CAS  PubMed  Google Scholar 

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  1. Institute of the History of Medicine, Johns Hopkins University, Baltimore, 21205, MD, USA

    Arthur M. Silverstein

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Silverstein, A. Cellular versus humoral immunology: a century-long dispute. Nat Immunol 4, 425–428 (2003). https://doi.org/10.1038/ni0503-425

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