Cellular versus humoral immunology: a century-long dispute

C OMMENTARY Historical insight: Immunology’s founding fathers argued fiercely about whether Metchnikoff ’s phago-

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cytes 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.

Cellular versus humoral immunology: a century-long dispute Arthur M. Silverstein Institute of the History of Medicine, Johns Hopkins University, Baltimore, MD 21205, USA. ([email protected])

all immunity is mediated by humoral factors, or anti-bodies, specific for the disease-causing toxin or pathogenic organism. Berlin became the center of the humoralist camp. Soon scientific shots were being fired in both directions across the Franco-German border. It must not be thought that this humoralistcellularist dispute arose in a vacuum. For two thousand years medicine had been dominated by the Greek concept that all disease is based upon a disturbance of the four humors (blood, phlegm, yellow bile and black bile), and only recently had this view been challenged, primarily by Rudolph Virchow’s Cellular Pathology8. Metchnikoff’s phagocytic theory was thus breaking new ground in both pathology and immunology, and was not universally accepted. But another important contributor to the humoralist-cellularist dispute in immunology was the continuing reverberations of the FrancoPrussian war of 1870–1871, especially in the minds of the defeated French. Reports from Koch’s Institute repeatedly challenged the findings of Pasteur and the Pastorians, and these challenges were answered in kind9. Indeed, charges of “unscientific nationalism” and chauvinism were even made10. Not only did Metchnikoff fight with the Germans about antibodies (see below), but his student Jules Bordet would later engage in a long battle with Ehrlich about the nature and function of complement11.

The trans-immunologists [immunochemists] start at the end, with the structure of antibody molecules, hoping to work their way backwards, and the cis-immunologists [immunobiologists] start at the beginning, with the effect of antigenic exposure, hoping to work their way forwards ....a cis-immunologist will sometimes speak to a transimmunologist; but the latter rarely answers. Niels Jerne, 19671

From Edward Jenner’s discovery of smallpox vaccination in 1798 to Louis Pasteur’s discovery of immunization with attenuated pathogens in 1880, nothing was known of the factors that might mediate the resulting protection. Then, in 1884, expatriate Russian zoologist Ilya Metchnikoff experienced a ‘eureka moment’2. He observed that starfish and other invertebrates were able to mobilize phagocytic cells in response to insult. He first proposed that the phagocyte is crucial to an understanding of the general pathology of inflammation3 and then extended his theory to assign to this ubiquitous cell a central role in both natural and acquired immunity in vertebrates4. In 1888, Metchnikoff joined Louis Pasteur at the newly founded Pasteur Institute in Paris, and Paris thus became the intellectual center of the cellularist movement in the young field of immunology. In 1890, however, a new player Paul Ehrlich’s concept of antibody receptors on the cell surface, whose specific appeared on the immunological interaction with antigen stimulates the cell to form more of that antibody. Note the The humoralist victory way that the different specificities are indicated by different geometrical shapes. scene. Emil Behring and The battle between the cellularists Shibasaburo Kitasato of Koch’s and the humoralists was an interInstitute in Berlin reported that mice immunized with diphtheria and esting one for several reasons. First, it showed the intrinsic value of tetanus toxins develop something in their blood that seemed to medidissension in science. When everyone agrees on something, there is ate antitoxic activity, because the protection could be transferred paslittle reason for further study; when they disagree, challenges are sively to normal animals with immune serum5. Shortly thereafter, Paul made and answered, and progress is hastened. Each side in the dispute carefully scans the journals, ready to set up additional experiEhrlich, soon to become associated with Koch, showed similar ments to counter any claim made by the other side. humoral responses to the plant toxins ricin and abrin6, and then Another interesting aspect of the debate was reflected in how the Koch’s student Richard Pfeiffer showed that humoral substances biases of both sides were manifested. Metchnikoff and the cellularists could lyse typhoid and cholera organisms7. With little room for repeatedly used the anthrax bacillus in their studies, and showed that phagocytes in these systems, a school of thought arose that held that

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susceptibility to anthrax was generally unrelated to humoral factors— rather, defense against infection correlated directly with the degree of phagocytosis of the bacilli. Their experiments usually involved injecting the organisms by the intraperitoneal route and then counting the number of organisms ingested by macrophages. The humoralists, in contrast, preferred to work with bacterial toxins and with cholera organisms, whose neutralization or destruction could be demonstrated in vitro in the absence of cells, using immune serum and fresh complement. Where the evidence for circulating antibody or serum complement proved compelling, Metchnikoff would fall back on the argument that, after all, these were the products of cells. Then, in 1897, came Paul Ehrlich’s side-chain theory of antibody formation and function12, which provided a theoretical foundation for the humoralist cause. More than this, the pictures of antibody receptors that Ehrlich would soon draw13 (Fig. 1) would almost make one believe that he could see how these substances interact. Such pictures, together with the visible actions of antibody in the precipitation of antigens, the agglutination of bacteria and the hemolysis of red cells, would soon doom studies with cells. Antibodies showed impressive specificity and could be visualized and measured quantitatively; the specificity of cells was questionable, and they were extremely difficult to handle. There was little question where a new generation of immunologists would direct its attention. Two attempts were made to mediate the cellularist-humoralist dispute after the turn of the century. In 1904, Almroth Wright sought to marry the two views by suggesting that the most important role of humoral antibodies was to render the bacterium more easily phagocytized; he called them opsonins14. However, Wright’s opsonic indexes proved too difficult to use and insufficiently reproducible, and the practice was soon given up. Again, in 1908, the Swedish Academy conferred the Nobel Prize for Physiology or Medicine jointly on Paul Ehrlich, the champion of humoralism, and on Elie Metchnikoff, the champion of cellularism, “in recognition of their work in immunity.” But it was too late. Ehrlich’s (and Behring’s) antibodies became the central preoccupation of immunologists, with support from newer findings that circulating antibodies were responsible for such phenomena as anaphylaxis, the Arthus phenomenon, hay fever, asthma and serum sickness. The scientific leaders of a field choose their research problems not because they are easy, but because they are interesting and felt to be significant. During the early years of the twentieth century, the general feeling was that the explanation of the nature and functions of immunity was to be found in the study of antibodies. As a result of this humoralist victory and concentration on antibodies, the study of cell-based immunity would be inhibited for the next half-century. So preoccupied were immunologists with antibodies that any observations that might have led them to study cells (such as the absence of humoral antibody participation in the tuberculin reaction, contact sensitivity or allograft rejection) were explained by invoking putative ‘cell-bound’ antibodies15.

Antibodies, cells and the new direction There was another reason why antibodies rather than cells were studied: a general change was taking place in the young field of immunology. For the first quarter-century after Pasteur, the immune response had been studied by medical people in the context of bacteriology, vaccines and the mechanism of protection from infectious diseases. But it quickly became apparent that the startling successes of the past, of Pasteur, Behring and Ehrlich, were no longer being repeated as new pathogens were identified. Immunotherapy with 426

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antitoxins worked only with diphtheria and tetanus exotoxins; effective vaccines could not be produced to protect from many of the most serious scourges of mankind—tuberculosis, syphilis, most tropical diseases and Gram-positive infections. The cream had thus been skimmed in this field that had seemed initially to promise the eradication of all infectious disease. If medical approaches no longer stimulated investigators, another area did seem to hold promise. Paul Ehrlich had pointed the way with his chemical representations of specific interactions between antibodies, antigens and complement. This view had been endorsed, in a sense, by the Nobel Prize–winning chemist Svante Arrhenius in his book Immunochemistry16. When it was shown, therefore, that antigens could be chemically modified17, the path was opened to studying the fine specificity of antibodies. Medical immunology quickly gave way to an immunochemistry in which there was little room for the study of cells. Karl Landsteiner, discoverer of blood groups, was the first to grasp the power of these new tools. As early as 1917 he used haptenconjugated antigens to study antibody specificity and crossreactions18, an approach that would engage him productively for the rest of his career19. Then came organic chemist Michael Heidelberger with his study of pneumococcal polysaccharides and the introduction of quantitative immunochemical techniques20. Now the study of antibody structure and specificity, and the thermodynamics of antibody interactions, became the chief preoccupations of the leaders of the field, as exemplified in the work of such investigators as Marrack, Kabat, Pauling and Pressman21. This shift in emphasis from medicine to chemistry was accompanied by a decline of Ehrlich’s biological selective (Darwinian) theory of antibody formation (the side-chain theory) in favor of a more chemical (Lamarckian) concept, that of antigen-mediated instruction22.

The specificity of phagocytosis The study of cells (and of the biomedical aspects of immunology) may have been out of favor during the period when antibodies dominated, but that does not mean that all work in these areas stopped— just that some results may not have been given the importance that they might later seem to have merited. Thus, for example, James Murphey’s work during the first quarter of the twentieth century on the role of lymphoid cells in protection from infection and in transplantation23 went substantially unnoticed at the time, as did Louis Dienes’ work on cellular immunity24, the early reports of experimental allergic encephalomyelitis25 and even Landsteiner and Chase’s report on the passive transfer of delayed hypersensitivity with cells26. So long as Metchnikoff argued for an important role for phagocytes in natural immunity, he had little opposition, and in general his views have been upheld. But his attempt to extend his theory to include acquired immunity would encounter difficulties, especially in the face of the readily demonstrable specificity of humoral antibodies. Metchnikoff would occasionally speak27 of “leukocytes impressed with a special sensitiveness,” but he generally begged the question of specificity. Others, however, pursued the idea of a ‘specific macrophage’ during this period. One observation that strongly reinforced the idea that macrophages might interact specifically with antigen came from an observation in 1932 by Rich and Lewis28. These investigators found that tuberculin specifically inhibited the normal migration of macrophages from lymphoid tissue explants taken from tuberculous but not from normal animals; they supposed that the cells were specifically killed. (It took a quarter-century for Waksman and Matoltsy to show that these cells do not die29; David, and Bloom and Bennett, would later show that it was lymphoid cells that responded may 2003

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to antigen with the release of a factor that inhibits the migration of macrophages—the first lymphokine30.) Then Lurie, Elberg and others31 advanced the cause of the ‘immune macrophage’, primarily by suggesting that those from immune animals would ingest the pertinent bacteria more efficiently than those from normal animals, a view contested by Mackaness32. As late as 1964, Granger and Weiser could attribute the rejection of allografts to the action of immune macrophages33, and Suter and Ramseier could include a 21-page section entitled “The Immune Phagocyte” in a broad review of cellular reactions to infection34. Perhaps the final chapter in the story suggesting that infection or immunization might alter the macrophage and endow it with specific properties came in the work of Fishman and Adler35. These authors claimed that antigen induces the formation, in the macrophage, of a specific RNA that is able to transfer specific information to antibodyforming lymphoid cells. Askonas and Rhodes, however, found traces of antigen in these RNA preparations36, and suggested that the nonspecific association of macrophage RNA with protein antigens might enhance their immunogenicity, forming a sort of ‘superantigen’. The work of Askonas and Rhodes appeared in the context of an increasing appreciation of another important, if nonspecific, role for phagocytic cells in acquired immunity37. This ultimately was resolved with recognition of the collaboration of the antigen-presenting cell (APC), whose processing of ingested protein antigens is especially crucial to the preparation of specific, antigen-derived peptide-MHC complexes for the activation of T cells38.

The rebirth of cellular immunology We come now to the period after World War II, when a number of observations challenged the dominant immunochemistry of the preceding decades39. Now medicine and pathophysiological processes came to the fore. The use of Freund’s adjuvant simplified the induction of autoimmune diseases, a variety of other immunopathologies, and delayed hypersensitivities in animal models. The demonstration of clinical immunodeficiencies, the experimental effects of thymectomy and bursectomy, and developments in transplantation immunology40 cast a new light on the workings of the immune apparatus. Immunological tolerance was predicted41 and verified42. A new generation of biologically oriented scientists were entering the field of immunology, and for the first time in some 60 years, texts and guides were written for clinicians and biologists43. A theoretical underpinning for the new immunology came with Macfarlane Burnet’s clonal selection theory; for the first time he, together with David Talmage, placed emphasis on the cellular dynamics of the immune response44. Cellular immunology now came to dominate the field. But this was not the cellular immunology of a Metchnikoff, based upon phagocytes45; it was the cellular immunology of a Gowans, based upon lymphocytes. It would define T and B cells, their functions and collaborations; it would explain the pathogenesis of many autoimmune diseases and the mechanisms of allograft rejection; and it would clarify the complicated mechanisms of immunoregulation, among others46. This is not to say that the humoralists were inactive during this period. They were still studying the antibody chemically and physically47, defining its structure48 and isolating and characterizing the many components of complement49. But, as we noted above, even as early as 1967, the Cold Spring Harbor symposium could be almost equally divided between ‘humoralists’ and ‘cellularists’, and Niels Jerne could draw his sharp line between the cis- and trans-immunologists—between biologically and chemically oriented investigators. It www.nature.com/natureimmunology

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was not so much that they were still arguing against one another, as they had earlier in the century; it was just that a broad gulf still existed between the two traditions, and they tended still to ask different questions, to employ different methodologies and to speak different, and often mutually unintelligible, languages.

Discussion We may reasonably suspect that had antibodies not become the center of attention around a century ago, more attention might have been paid to cell function in the immune response and its more biomedical manifestations. Before the triumph of antibodies over phagocytes around the turn of the twentieth century, the debate between the two camps had moved immunology forward by stimulating experiments. Afterward, new experiments with cells seem to have been discouraged, as was early appreciation of the significance of certain studies that would only later be put into context. This is surely not the first time in science that commitment to a Kuhnian paradigm50 (in this instance, antibody as the be-all and end-all of immunology) would inhibit work and speculation. We saw in an earlier Commentary51 how antibodies were bent into service as mediators of tuberculin, poison ivy and other delayed hypersensitivities; of many autoimmune diseases; and of allograft rejection. We may appear, in the discussion above, to have relegated the macrophage to the role of a nonspecific and even passive collaborator in immune responses, but this may be a premature judgment. A more Metchnikovian view of their importance may be revived, if the views of Charles Janeway and his colleagues are confirmed. These investigators suggest that innate immunity (what was formerly called ‘natural’ immunity) is far more important than previously realized. They propose that the immune system evolved to discriminate self from infectious nonself and that the initial response to infection is initiated by the interaction of pathogen-associated molecular patterns (PAMPs) with pattern recognition receptors (PRRs) on the surface of macrophages and other professional antigen-presenting cells52. This interaction would then signal immunocyte activity. If confirmed, this would assign to macrophage function a degree of specificity heretofore unrecognized, and thus a more active and significant a role in the workings of cellular immunology. 1. Jerne, N.K.Waiting for the end. Cold Spring Harbor Symposium “Antibodies” 37, 591–603 (1967). 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). 3. Metchnikoff, E. Lectures on the Comparative Pathology of Inflammation (Keegan, Paul,Trench,Trübner, London, 1893). Reprinted by Dover (New York, 1968). 4. Metchnikoff, E. Immunity in the Infectious Diseases (Macmillan, New York, 1905). Reprinted by Johnson Reprint Corp. (New York, 1968). 5. Behring, E. & Kitasato, S. Deutsch. med.Wochenschr. 16, 1113–1114 (1890); Behring, E. & Wernicke, E. Z. Hyg. 12, 10–44; 45–57 (1892). 6. Ehrlich, P. Deutsch. med.Wochenschr. 17, 976–979; 1218–1219 (1891). 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). 8. Virchow, R. Die Cellularpathologie in ihrer Begründung auf physiologische und pathologische Gewebelehre (Hirschwald, Berlin, 1858). English edition: Cellular Pathology (Dover, New York, 1971). 9. See also Baxter, A.G. Nature Rev. Immunol. 1, 229–232 (2001). 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). 12. Ehrlich, P. Klin. Jahrb. 6, 299–333 (1897). 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). 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].” 15. For the history of the idea of cell-bound antibodies, see Silverstein, A.M. Nature Immunol. 3, 105–108 (2002). 16. Arrhenius, S. Immunochemistry (Macmillan, New York, 1907). 17. Pick, E.P. in Handbuch der pathogenen Mikroorganismen, edn. 2 vol. 1 (W. Kolle & A. von Wassermann, eds.) 685– 868 (Fischer, Jena, 1912).

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18 Landsteiner, K. and Lampl, H. Z. Immunitätsforsch. 26, 258–276; 293–304 (1917). 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). 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). 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). 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). 24. Dienes, L. J. Immunol. 17, 531–538 (1929); Dienes, L. & Schoenheit, E.W. Am. Rev.Tuberc. 20, 92–105 (1929). 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). 26. Landsteiner, K. & Chase, M.W. Proc. Soc. Exp. Biol. Med. 49, 688–690 (1942). 27. Metchnikoff, E. Immunity in the Infectious Diseases, p. 306 (Macmillan, New York, 1905). 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). 30. Bloom, B.R. & Bennett, B. Science 153, 80–82 (1966); David, J.R. Proc. Natl.Acad. Sci. USA 56, 72–77 (1966). 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). 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. 33. Granger, G.A. & Weiser, R.S. Science 145, 1427–1429 (1964). 34. Suter, E. & Ramseier, H. Adv. Immunol. 4, 117–173 (1964). 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). 36. Askonas, B.A. & Rhodes, J.M. Nature 205, 470–474 (1965).

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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). 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). 39. This paradigm shift in immunology is discussed at length by Silverstein, A.M. Cell. Immunol. 132, 515–531 (1991). 40. See Brent, L. A History of Transplantation Immunology (Academic Press, San Diego, 1997). 41. Burnet, F.M. & Fenner, F. The Production of Antibodies, edn. 2 (Macmillan, New York, 1949). 42. Billingham, R.E., Brent, L. & Medawar, P.B. Nature 172, 603–606 (1953). 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). 44. Burnet, F.M. Austral. J. Sci. 20, 67–69 (1957);Talmage, D.W. Annu. Rev. Med. 8, 239–257 (1957). 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). 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). 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). 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). 49. Müller-Eberhard, H.J. Adv. Immunol. 8, 1–80 (1968); Mayer, M.M., Proc. Natl. Acad. Sci. USA 69, 2954–2958 (1972). 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). 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).

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