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Microbes and Metchnikoff
The American VOL.
XII
Journal MARCH,
of Medicine
1952
Editorial Microbes
and Metchnikoff
T
HE theory of cellular immunity was first championed by Metchnikoff in the early eighteen eighties1 His thesis regarding resistance to infective disease was concisely set forth in the two following statements: (1) “There is only one constant element in immunity, whether innate or acquired, and that is phagocytosis.” (2) “In general, the part played l)y the agglutinins in acquired immunity must IX regarded as of little importance, and for that reason we abstain from basing any theory of this immunity on the agglutinative property of the I)ody fluids.” Metchnikoff’s views as to the crucial role of phagocytic cells and his contention that antibodies were of little or at best of secondary importance were based upon experiments performed in the early da);s of bacteriology when such intracellular parasites as viruses and rickettsiae were unknown. Today, his original theory is wholly untenable as regards infectious agents that are able to propagate within the cytoplasm of phagocytic or other cells of the body. Rut even in the case of bacteria, such as pneumococci, that are known to be destroyed IQ phagocytosis, Metchnikoff’s cellular theory has never been accepted. Its rejection has been due primarily to an impressive body of experimental evidence which indicates that fully encapsulated pneumococci cannot bc phagocyted unless previously- opsonized with specific antibody.” The importance of type-specific immune Ijodies in pneumococcal pneumonia was clearly established by the brilliant studies of Avery, Cole, Dochez, Heidelberger, Goebel and others at the Rockefeller Hospital and of Enders and Ward at the Harvard Medical School.’ The isolation and chemical idenlification of the capsular antigen and the demonstration that
pathogenicity is directly related to the capsule of the pneumococcal cell are among the most significant achievements of contemporary microbiology. Not only did they lead to a clearer understanding of the host-parasite relationships in pneumococcal pneumonia (and certain other closely related bacterial diseases) but they resulted also in the development of a highly effective form of antipneumococcal therapy. In addition, they seemed to prove beyond the slightest doubt that antibodies play a major role in recovery. There remained, however, certain clinical and experimental observations which appeared to contradict the theory that antibodies were essential for recovery. First, it is well known that the spontaneous crisis which frequently occurs in untreated pneumococcal pneumonia does not always coincide with the appearance of circulating antibody. In fact, numerous cases have been reported in which immune bodies could not be detected in the blood until many days after the subsidence of fever and the disappearance of signs of active infection.” Secondly, Robertson clearly showed in careful histologic studies of experimental canine pneumonia that pneumococci were phagocyted and destroyed in the pneumonic exudate during the early stages of infection when no antibody was demonstrable in the circulation.5 Thirdly, early treatment with sulfonamides was shown to effect recovery in the absence of circulating immune bodies in spite of the fact that the sulfonamide drugs themselves have little if any bactericidal effect upon the pneumococcus.6 These apparently unexplained facts prompted a critical re-examination of the role of antibodies in pneumococcal pneumonia. The observations
1METCHNIKOFI;, E. Immunity in Infective Diseases. Cambridge, 1905. University Press. 2 ZINSSER,H., ENDERS,J. F. and FOTHERGILL, L. Immunity, Principles and Applications in Public Health. New York, 1939. Macmillan Co. 3 DUBOS, R. The Bacterial Cell. Cambridge, Mass., 1945. Harvard Univ. Press.
4 ROBERTSON,0. H., GRAESER, J. B., COGGESHALL, L. J. and HARRISON,M. A. 3. Clin. Investigation, 13: 633: 1934. ROBERTSON, 0. H.J. A. M. A., 111: 1932, 1938. 6 WOOD, W. B., JR. and LONO, P. H. Ann. Znt. Med., 13: 612, 1939.
261
Editorial of Robertson regarding the phagocytosis of pneumococci in the early stages of experimental pneumonia were confirmed and extended. Ingestion and apparent destruction of the infecting organisms were easily demonstrated at a time when no antibody could be detected either in the blood or at the site of infection in the lung.’ Later studies revealed that fully encapsulated pneumococci, contrary to the accepted teachings of immunology, were readily phagocyted by leukocytes in the complete absence of antibody, provided the phagocytic cells (1) were sufficiently numerous and (2) had access to a suitable surface upon which to operate.* Whereas the leukocytes failed to ingest the bacteria when the cell-pneumococcus suspensions were incubated on glass slides or in test tubes, phagocytosis promptly took place when the same suspensions were incubated upon the surfaces of fresh tissues, moistened filter paper, fiber glass or cloth. Microscopic study of this phagocytic process revealed that the leukocytes phagocyted the pneumococci by trapping the individual organisms against the relatively rough surfaces over which the cells moved in their ameboid migrations. When the leukocytic suspension was sufficiently concentrated, the microorganisms were frequently phagocyted by being caught between the surfaces of two or more adjacent cells.g Pneumococci caught in the interstices of fibrin clots were similarly phagocyted. lo Since in each instance the organisms were ingested only after they had been trapped against some relatively immovable surface, the process was referred to as surface phagocytosis. Both pneumococci and Friedlgnder’s bacilli thus ingested in the absence of antibody were shown to be promptly killed and eventually digested. 8,11 In none of the phagocytic preparations examined microscopically was there evidence of positive chemotaxis. Systematic histologic studies of a variety of experimental pneumococcal and FriedEinder’s bacillus infections in rats have provided ample indirect evidence that surface phagocytosis operates not only in the lungs but also in sub7 WOOD, W. B., JR., MCLEOD, 3. Exjer. Med., 84: 377, 1946.
C. and IRONS, E. N.
8 WOOD, W. B., JR., SMITH, M. R. and WATSON, B.
3. Exper. Med., 84: 387, 1946. g WOOD, 1947. 10SMITH, 187, 1949. 1’ SMITH,
W. B., JR. and M. hf.
86: 239. 1947.
SMITH,
M. R. S&me,
R. and WOOD, W.
106: 86,
B., JR. Science, 110:
R. and WOOD, W. B., JR.
3. Exjer. Med.,
cutaneous tissues,12 in the sinuses of infected lymph nodes12 and in the blood stream.13 In the latter site it has been possible by means of the Sandison rabbit ear-chamber technic to observe intravascular surface phagocytosis in the living host. The significance of surface phagocytosis lies in the fact that it takes place in the absence of antibody. It is the primary defense reaction of the host in the pre-antibody stage of infection. Admittedly less efficient than the accelerated phagocytic reaction that occurs in the presence of specific opsonins, it serves to hold the infection in check until antibodies have had time to accumulate. Occasionally it alone may effectuate recovery without the aid of immune bodies. When suitable chemotherapy is initiated, control of the infection results from the combined actions of drug and phagocytes, the latter usually operating in the absence of antibodies. In established abscesses and in suppurative lesions within the potentially “open” serous cavities and subarachnoid space, where fluid is abundant and many of the leukocytes are nonviable, phagocytosis is relatively inefficient and persistence of living organisms is the rule. For an infectious agent to cause disease it must either be capable of surviving and multiplying in an intracellular environment or else it must remain outside of phagocytic cells long enough to multiply and cause damage to the tissues of the host. Many acute bacterial infections are due to organisms that act as extracellular parasites, their protective capsules allowing them temporarily to resist phagocytosis. The body’s primary defense against such microbes is a cellular one, which depends upon the mobilization of phagocytes capable of operating in the absence of antibody. Thus in acute extracellular infections, of which pneumococcal and FriedUnder’s bacillus pneumonias are excellent examples, cellular immunity, in the Metchnikovian sense, plays a decisive role in natural resistance.14 As regards infections caused by essentially intracellular parasites, far less is known of the mechanisms of host resistance. Their elucidation would appear to depend upon future advances in a relatively unexplored field of microbiologic research-that of intracellular immunology. W. BARRY WOOD, JR., M.D. I2 SMITH, R. 0. and WOOD, W. B., JR. 3. Exper. Med., 90: 555, 1949. I3 WOOD,W.B.,JR.,%~TH,M.R., PERRY,W.D. and BERRY, J. W. 3. Exper. Med., 94: 521, 1951. I4 WOOD, W. B.,JR. Harvey Lecture (in press).
AMERICAN
JOURNAL
OF MEDICINE
XII
Journal MARCH,
of Medicine
1952
Editorial Microbes
and Metchnikoff
T
HE theory of cellular immunity was first championed by Metchnikoff in the early eighteen eighties1 His thesis regarding resistance to infective disease was concisely set forth in the two following statements: (1) “There is only one constant element in immunity, whether innate or acquired, and that is phagocytosis.” (2) “In general, the part played l)y the agglutinins in acquired immunity must IX regarded as of little importance, and for that reason we abstain from basing any theory of this immunity on the agglutinative property of the I)ody fluids.” Metchnikoff’s views as to the crucial role of phagocytic cells and his contention that antibodies were of little or at best of secondary importance were based upon experiments performed in the early da);s of bacteriology when such intracellular parasites as viruses and rickettsiae were unknown. Today, his original theory is wholly untenable as regards infectious agents that are able to propagate within the cytoplasm of phagocytic or other cells of the body. Rut even in the case of bacteria, such as pneumococci, that are known to be destroyed IQ phagocytosis, Metchnikoff’s cellular theory has never been accepted. Its rejection has been due primarily to an impressive body of experimental evidence which indicates that fully encapsulated pneumococci cannot bc phagocyted unless previously- opsonized with specific antibody.” The importance of type-specific immune Ijodies in pneumococcal pneumonia was clearly established by the brilliant studies of Avery, Cole, Dochez, Heidelberger, Goebel and others at the Rockefeller Hospital and of Enders and Ward at the Harvard Medical School.’ The isolation and chemical idenlification of the capsular antigen and the demonstration that
pathogenicity is directly related to the capsule of the pneumococcal cell are among the most significant achievements of contemporary microbiology. Not only did they lead to a clearer understanding of the host-parasite relationships in pneumococcal pneumonia (and certain other closely related bacterial diseases) but they resulted also in the development of a highly effective form of antipneumococcal therapy. In addition, they seemed to prove beyond the slightest doubt that antibodies play a major role in recovery. There remained, however, certain clinical and experimental observations which appeared to contradict the theory that antibodies were essential for recovery. First, it is well known that the spontaneous crisis which frequently occurs in untreated pneumococcal pneumonia does not always coincide with the appearance of circulating antibody. In fact, numerous cases have been reported in which immune bodies could not be detected in the blood until many days after the subsidence of fever and the disappearance of signs of active infection.” Secondly, Robertson clearly showed in careful histologic studies of experimental canine pneumonia that pneumococci were phagocyted and destroyed in the pneumonic exudate during the early stages of infection when no antibody was demonstrable in the circulation.5 Thirdly, early treatment with sulfonamides was shown to effect recovery in the absence of circulating immune bodies in spite of the fact that the sulfonamide drugs themselves have little if any bactericidal effect upon the pneumococcus.6 These apparently unexplained facts prompted a critical re-examination of the role of antibodies in pneumococcal pneumonia. The observations
1METCHNIKOFI;, E. Immunity in Infective Diseases. Cambridge, 1905. University Press. 2 ZINSSER,H., ENDERS,J. F. and FOTHERGILL, L. Immunity, Principles and Applications in Public Health. New York, 1939. Macmillan Co. 3 DUBOS, R. The Bacterial Cell. Cambridge, Mass., 1945. Harvard Univ. Press.
4 ROBERTSON,0. H., GRAESER, J. B., COGGESHALL, L. J. and HARRISON,M. A. 3. Clin. Investigation, 13: 633: 1934. ROBERTSON, 0. H.J. A. M. A., 111: 1932, 1938. 6 WOOD, W. B., JR. and LONO, P. H. Ann. Znt. Med., 13: 612, 1939.
261
Editorial of Robertson regarding the phagocytosis of pneumococci in the early stages of experimental pneumonia were confirmed and extended. Ingestion and apparent destruction of the infecting organisms were easily demonstrated at a time when no antibody could be detected either in the blood or at the site of infection in the lung.’ Later studies revealed that fully encapsulated pneumococci, contrary to the accepted teachings of immunology, were readily phagocyted by leukocytes in the complete absence of antibody, provided the phagocytic cells (1) were sufficiently numerous and (2) had access to a suitable surface upon which to operate.* Whereas the leukocytes failed to ingest the bacteria when the cell-pneumococcus suspensions were incubated on glass slides or in test tubes, phagocytosis promptly took place when the same suspensions were incubated upon the surfaces of fresh tissues, moistened filter paper, fiber glass or cloth. Microscopic study of this phagocytic process revealed that the leukocytes phagocyted the pneumococci by trapping the individual organisms against the relatively rough surfaces over which the cells moved in their ameboid migrations. When the leukocytic suspension was sufficiently concentrated, the microorganisms were frequently phagocyted by being caught between the surfaces of two or more adjacent cells.g Pneumococci caught in the interstices of fibrin clots were similarly phagocyted. lo Since in each instance the organisms were ingested only after they had been trapped against some relatively immovable surface, the process was referred to as surface phagocytosis. Both pneumococci and Friedlgnder’s bacilli thus ingested in the absence of antibody were shown to be promptly killed and eventually digested. 8,11 In none of the phagocytic preparations examined microscopically was there evidence of positive chemotaxis. Systematic histologic studies of a variety of experimental pneumococcal and FriedEinder’s bacillus infections in rats have provided ample indirect evidence that surface phagocytosis operates not only in the lungs but also in sub7 WOOD, W. B., JR., MCLEOD, 3. Exjer. Med., 84: 377, 1946.
C. and IRONS, E. N.
8 WOOD, W. B., JR., SMITH, M. R. and WATSON, B.
3. Exper. Med., 84: 387, 1946. g WOOD, 1947. 10SMITH, 187, 1949. 1’ SMITH,
W. B., JR. and M. hf.
86: 239. 1947.
SMITH,
M. R. S&me,
R. and WOOD, W.
106: 86,
B., JR. Science, 110:
R. and WOOD, W. B., JR.
3. Exjer. Med.,
cutaneous tissues,12 in the sinuses of infected lymph nodes12 and in the blood stream.13 In the latter site it has been possible by means of the Sandison rabbit ear-chamber technic to observe intravascular surface phagocytosis in the living host. The significance of surface phagocytosis lies in the fact that it takes place in the absence of antibody. It is the primary defense reaction of the host in the pre-antibody stage of infection. Admittedly less efficient than the accelerated phagocytic reaction that occurs in the presence of specific opsonins, it serves to hold the infection in check until antibodies have had time to accumulate. Occasionally it alone may effectuate recovery without the aid of immune bodies. When suitable chemotherapy is initiated, control of the infection results from the combined actions of drug and phagocytes, the latter usually operating in the absence of antibodies. In established abscesses and in suppurative lesions within the potentially “open” serous cavities and subarachnoid space, where fluid is abundant and many of the leukocytes are nonviable, phagocytosis is relatively inefficient and persistence of living organisms is the rule. For an infectious agent to cause disease it must either be capable of surviving and multiplying in an intracellular environment or else it must remain outside of phagocytic cells long enough to multiply and cause damage to the tissues of the host. Many acute bacterial infections are due to organisms that act as extracellular parasites, their protective capsules allowing them temporarily to resist phagocytosis. The body’s primary defense against such microbes is a cellular one, which depends upon the mobilization of phagocytes capable of operating in the absence of antibody. Thus in acute extracellular infections, of which pneumococcal and FriedUnder’s bacillus pneumonias are excellent examples, cellular immunity, in the Metchnikovian sense, plays a decisive role in natural resistance.14 As regards infections caused by essentially intracellular parasites, far less is known of the mechanisms of host resistance. Their elucidation would appear to depend upon future advances in a relatively unexplored field of microbiologic research-that of intracellular immunology. W. BARRY WOOD, JR., M.D. I2 SMITH, R. 0. and WOOD, W. B., JR. 3. Exper. Med., 90: 555, 1949. I3 WOOD,W.B.,JR.,%~TH,M.R., PERRY,W.D. and BERRY, J. W. 3. Exper. Med., 94: 521, 1951. I4 WOOD, W. B.,JR. Harvey Lecture (in press).
AMERICAN
JOURNAL
OF MEDICINE