AMERICAN JOURNAL OF OPHTHALMOLOGY FRANK
W.
NEWELL,
Editor-in-Chief
233 East Ontario St., Chicago, Illinois 60611 EDITORIAL BOARD Mathea Allansmith, Boston Douglas R. Anderson. Miami Crowell Beard. San Jose Bernard Becker, St. Louis Benjamin F. Boyd. Panama Charles J. Campbell. New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Sir Stewart Duke-Elder, London J. Terry Ernest, Chicago
DuPont Guerry III, Richmond Michael J. Hogan, 5Ό« Francisco Robert W. Hollenhorst, Rochester Herbert E. Kaufman. Gainesville Arthur H. Keeney. Louisville Bertha A. Klien, Tucson Carl Kupfer, Bethesda James E. Lebensohn, Chicago Irving H. Leopold, Irvine A. Edward Maumenee, Baltimore
Edward W. D. Norton, Miami Arnall Patz, Baltimore Steven M. Podos, New York Albert M. Potts, Louisville Algernon B. Reese, New York Robert D. Reinecke, Albany Marvin L. Sears, New Haven David Shoch. Chicago Bruce E. Spivey, San Francisco Bradley R. Straatsma, Los Angeles Gunter K. von Noorden, Houston
Published monthly by the Ophthalmic Publishing Company 233 East Ontario St., Chicago, Illinois 60611 Directors:
A. EDWARD MAUMENEE. President; MICHAEL J. HOGAN, Vice-President; FRANK W. NEWELL,
Secretary and Treasurer; Edward W. D. NORTON, DAVID SHOCH, BRADLEY R. STRAATSMA
T H E N E W IMMUNOLOGY The "old immunology" was about anti toxins, skin tests, complement, precipitins, and lysins. It was thought that information for an immune response was in the antigen itself, that the antigens taught or instructed the antibody-forming cell how to make an antibody exactly complementary to it. The lymphocyte was described but not under stood. The "new immunology," best described by Medawar,1 is about the molecular basis of specificity, the biology of self-recognition, and the nature of information transfer in biologic systems. The new immunology has grown up recognizing the fundamental prin ciple of molecular biology—that the in formation specifying structure can issue only from nucleic acid. Thus, a central theme in the ideologic revolution, which has transformed the old into the new immunol ogy, is the recognition that information re quired for setting off an immune response is already present in the genetic apparatus. The gene that codes for the specific response 109
is selected and switched on by contact with antigen. The basis of specificity is no longer thought to be determined by instructions from the antigen with the various com ponents of the alumnae response amorphous and undifferentiated before the antigen en ters. Evidence now indicates that the im mune system of the body is capable of re sponding to all the antigens a person could possibly encounter over a lifetime and even antigens that would be invented during the person's lifetime. An analogy adapted from Roitt2 may help in the comparison of in structional (old) and selective (new) theories of immune response. If a customer considers the purchase of a suit, two courses of action are open. The tailor may be in structed to make the suit to measure, in which case the customer acts as a template. Alternatively, the tailor may be enterprising and have already made up 104 different suits, one of which is almost certain to fit any customer ; all the customer must do is select the best fit. Although in both cases
110
AMERICAN JOURNAL OF OPHTHALMOLOGY
the know-how of making up the suits is there, in the first instance the essential in formation for the final shape is provided by the customer (antigen), whereas in the second situation the tailor had the ability to make a whole variety of differently shaped suits (information already in the DNA) before seeing the customer (antigen). Other examples of the molecular basis of specificity are the T- and B-cell systems. Each system is set off by specific messages to the cell surface, and results in produc tion of other molecules (antibodies by Bcells and lymphokines by T-cells) that initi ate other specific reactions. We have known for some time that when an antigen enters the body, two different types of immuno logie reactions may occur: one based on antibody (immediate hypersensitivity), and one on cells (delayed hypersensitivity). But now we know these two responses depend on two different lymphocyte populations al ready coded for the work they will per form: (1) T lymphocytes processed or in some way dependent on the thymus and responsible for
cell mediated
hypersensi
tivity, and (2) B lymphocytes processed by the bursa or its equivalent and responsible for antibody mediated-hypersensitivity. The thymus is a gland made up essentially of epithelial cells and large numbers of lympho cytes, many of which are dividing. Stem cells from the bone marrow must be pro cessed by the thymus to make them immunologically competent. The bursa of Fabricius is a lymphoid organ occurring in chickens. It is similar to the thymus and also embryologically derived from gut epi thelium. The equivalent of the bursa in humans and other mammals has not yet been clearly defined, although gut-associated lymphoid tissue such as the tonsil, appendix, lymphoid follicles, bone marrow, Peyer's patches, and perhaps the lacrimal gland have been named as possible candidates. Although the bursa equivalent has not been located, there is no doubt that in humans as well as in chickens and other animals the B and T
JANUARY, 1976
lymphocyte systems are present. The T and B mechanisms are not entirely independent and cooperation between them is sometimes important. By the time of birth, both Band T-cell systems are genetically coded to make all the immunologie responses the indi vidual will have through a lifetime. Self-recognition lies at the heart of im munology. The healthy body does not form immunologie reactions against itself. Why it does not and the consequences of break ing this tolerance have been the subject of much study and speculation. The ability to reject transplants of tissue from non-self may be traced far back in the evolutionary process, back even as far as the worms. Obviously this faculty did not develop in order to thwart the transplantation sur geon ; it must confer survival advantages on the host. One possibility is that the im munologie system polices the body cells, watching for altered cells that might be come neoplastic. For this immunologie sur veillance mechanism to operate, cancer cells must display new surface antigens that can be recognized by the lymphoid cells, and indeed they do. The competence of the self-recognition systems fails with age. In addition, nondebilitated cancer patients show relative de pression of their cell mediated immunity. Those who have a good immunologie re sponse to their tumors generally have a better progonsis. For example, cytotoxic antibodies have been found in the sera of a number of patients with malignant mela noma and these apparently act to prevent métastases of the tumor. Thus, while sup pression of the immune surveillance system may allow the survival of a needed trans plant, the consequence is not only lowered ability to fight off invading microbes from the outside but also lowered ability to fight off one's own newly arising cancers. Work on the nature of information trans fer in biologic systems is an important part of recent advances and has helped in under standing regulation of the immune response.
VOL. 81, NO. 1
OBITUARY
The cyclic nucleotides, cyclic A M P and cyclic GMP, appear to play a central role in the regulation of inflammation which is the final common pathway of immunologie responses. The cyclic nucleotides themselves are intracellular second messengers induced by the interaction of hormones (first mes sengers) or antigen on cell membrane bound enzymes. Neither the hormones nor the antigen enter the cells but can exert their action only at specific receptors on the cell surface. The presence of cell surface re ceptors is presumably determined by the genetic makeup of the cell. Increase in cyclic A M P is correlated with decrease in inflammatory cell activities. Increase of the complementary nucleotide, cyclic GMP, in creases inflammatory cell activity. In the last decade several changes in medi cal practice have been brought about as a result of this new immunologie knowledge. Nearly every university service has an ac tive and growing division of clinical im munology. Sufficient information is now available to evaluate patients with various inflammatory diseases as to whether or not immunologie mechanisms play a role, and if they do whether the inflammation can be controlled by various physical or pharma cologie manipulations. An accompaniment to the clinical emphasis is the growing battery of tests to measure changes in the patient's immunologie status, such as the 25 or so autoantibody measurements that can be performed on serum or on tissue, the search for various tumor-related antigens, measurement of B- and T-cell ratios in blood cells and in tumor tissue, and the in vitro laboratory measurement of delayed hypersensitivity responses of the peripheral blood lymphocytes. The old immunology counts to its credit such achievements as vaccination, the pro phylactic use of toxoids, and advances cru cial in conquering infections. The new im munology cannot yet lay claim to discoveries of equal stature, 1 but problems such as can cer, autoimmunity, and transplantation
111
should be solved or modified by the new immunology. The old immunology had its effect primarily on the lives of the young and the promise of the new immunology is for the health of the old. MATHEA ALLANSMITH REFERENCES
1. Medawar, P. B. : The new immunology. Hosp. Practice 9:48, 1974. 2. Roitt, I. : Essential Immunology, 2nd ed. London, Blackwell Scientific Publications, 1974.
OBITUARY JOHN
W. FERRÉE, M.D., M.P.H. 1904-1975
John W. Ferrée died of cancer Oct. 24, 1975, after an illness of many months. A native of Indiana, Dr. Ferrée attended the University of Pennsylvania, received his M.D. from Indiana University, and a Mas ter's in Public Health from Johns Hopkins University. He was named Indiana state health commissioner in 1940, and served as a commander in the Navy medical depart ment in World War II. Preventive medicine was a guiding pre cept throughout his career. From 1946 to 1947, he was director of education of the American Social Hygiene Association, then associate director of the National Health Council from 1947 to 1948, and associate medical director of the American Heart As sociation in charge of community service and educational activities for eight years. He was named executive director of the National Society for the Prevention of Blindness in 1959 and held the post until his retirement ten years later. During Dr. Ferree's tenure as executive director, out standing progress was achieved through his professional competence, strong leadership, wealth of knowledge about public health programs and medical research, his high
W.
NEWELL,
Editor-in-Chief
233 East Ontario St., Chicago, Illinois 60611 EDITORIAL BOARD Mathea Allansmith, Boston Douglas R. Anderson. Miami Crowell Beard. San Jose Bernard Becker, St. Louis Benjamin F. Boyd. Panama Charles J. Campbell. New York Thomas Chalkley, Chicago Claes H. Dohlman, Boston Sir Stewart Duke-Elder, London J. Terry Ernest, Chicago
DuPont Guerry III, Richmond Michael J. Hogan, 5Ό« Francisco Robert W. Hollenhorst, Rochester Herbert E. Kaufman. Gainesville Arthur H. Keeney. Louisville Bertha A. Klien, Tucson Carl Kupfer, Bethesda James E. Lebensohn, Chicago Irving H. Leopold, Irvine A. Edward Maumenee, Baltimore
Edward W. D. Norton, Miami Arnall Patz, Baltimore Steven M. Podos, New York Albert M. Potts, Louisville Algernon B. Reese, New York Robert D. Reinecke, Albany Marvin L. Sears, New Haven David Shoch. Chicago Bruce E. Spivey, San Francisco Bradley R. Straatsma, Los Angeles Gunter K. von Noorden, Houston
Published monthly by the Ophthalmic Publishing Company 233 East Ontario St., Chicago, Illinois 60611 Directors:
A. EDWARD MAUMENEE. President; MICHAEL J. HOGAN, Vice-President; FRANK W. NEWELL,
Secretary and Treasurer; Edward W. D. NORTON, DAVID SHOCH, BRADLEY R. STRAATSMA
T H E N E W IMMUNOLOGY The "old immunology" was about anti toxins, skin tests, complement, precipitins, and lysins. It was thought that information for an immune response was in the antigen itself, that the antigens taught or instructed the antibody-forming cell how to make an antibody exactly complementary to it. The lymphocyte was described but not under stood. The "new immunology," best described by Medawar,1 is about the molecular basis of specificity, the biology of self-recognition, and the nature of information transfer in biologic systems. The new immunology has grown up recognizing the fundamental prin ciple of molecular biology—that the in formation specifying structure can issue only from nucleic acid. Thus, a central theme in the ideologic revolution, which has transformed the old into the new immunol ogy, is the recognition that information re quired for setting off an immune response is already present in the genetic apparatus. The gene that codes for the specific response 109
is selected and switched on by contact with antigen. The basis of specificity is no longer thought to be determined by instructions from the antigen with the various com ponents of the alumnae response amorphous and undifferentiated before the antigen en ters. Evidence now indicates that the im mune system of the body is capable of re sponding to all the antigens a person could possibly encounter over a lifetime and even antigens that would be invented during the person's lifetime. An analogy adapted from Roitt2 may help in the comparison of in structional (old) and selective (new) theories of immune response. If a customer considers the purchase of a suit, two courses of action are open. The tailor may be in structed to make the suit to measure, in which case the customer acts as a template. Alternatively, the tailor may be enterprising and have already made up 104 different suits, one of which is almost certain to fit any customer ; all the customer must do is select the best fit. Although in both cases
110
AMERICAN JOURNAL OF OPHTHALMOLOGY
the know-how of making up the suits is there, in the first instance the essential in formation for the final shape is provided by the customer (antigen), whereas in the second situation the tailor had the ability to make a whole variety of differently shaped suits (information already in the DNA) before seeing the customer (antigen). Other examples of the molecular basis of specificity are the T- and B-cell systems. Each system is set off by specific messages to the cell surface, and results in produc tion of other molecules (antibodies by Bcells and lymphokines by T-cells) that initi ate other specific reactions. We have known for some time that when an antigen enters the body, two different types of immuno logie reactions may occur: one based on antibody (immediate hypersensitivity), and one on cells (delayed hypersensitivity). But now we know these two responses depend on two different lymphocyte populations al ready coded for the work they will per form: (1) T lymphocytes processed or in some way dependent on the thymus and responsible for
cell mediated
hypersensi
tivity, and (2) B lymphocytes processed by the bursa or its equivalent and responsible for antibody mediated-hypersensitivity. The thymus is a gland made up essentially of epithelial cells and large numbers of lympho cytes, many of which are dividing. Stem cells from the bone marrow must be pro cessed by the thymus to make them immunologically competent. The bursa of Fabricius is a lymphoid organ occurring in chickens. It is similar to the thymus and also embryologically derived from gut epi thelium. The equivalent of the bursa in humans and other mammals has not yet been clearly defined, although gut-associated lymphoid tissue such as the tonsil, appendix, lymphoid follicles, bone marrow, Peyer's patches, and perhaps the lacrimal gland have been named as possible candidates. Although the bursa equivalent has not been located, there is no doubt that in humans as well as in chickens and other animals the B and T
JANUARY, 1976
lymphocyte systems are present. The T and B mechanisms are not entirely independent and cooperation between them is sometimes important. By the time of birth, both Band T-cell systems are genetically coded to make all the immunologie responses the indi vidual will have through a lifetime. Self-recognition lies at the heart of im munology. The healthy body does not form immunologie reactions against itself. Why it does not and the consequences of break ing this tolerance have been the subject of much study and speculation. The ability to reject transplants of tissue from non-self may be traced far back in the evolutionary process, back even as far as the worms. Obviously this faculty did not develop in order to thwart the transplantation sur geon ; it must confer survival advantages on the host. One possibility is that the im munologie system polices the body cells, watching for altered cells that might be come neoplastic. For this immunologie sur veillance mechanism to operate, cancer cells must display new surface antigens that can be recognized by the lymphoid cells, and indeed they do. The competence of the self-recognition systems fails with age. In addition, nondebilitated cancer patients show relative de pression of their cell mediated immunity. Those who have a good immunologie re sponse to their tumors generally have a better progonsis. For example, cytotoxic antibodies have been found in the sera of a number of patients with malignant mela noma and these apparently act to prevent métastases of the tumor. Thus, while sup pression of the immune surveillance system may allow the survival of a needed trans plant, the consequence is not only lowered ability to fight off invading microbes from the outside but also lowered ability to fight off one's own newly arising cancers. Work on the nature of information trans fer in biologic systems is an important part of recent advances and has helped in under standing regulation of the immune response.
VOL. 81, NO. 1
OBITUARY
The cyclic nucleotides, cyclic A M P and cyclic GMP, appear to play a central role in the regulation of inflammation which is the final common pathway of immunologie responses. The cyclic nucleotides themselves are intracellular second messengers induced by the interaction of hormones (first mes sengers) or antigen on cell membrane bound enzymes. Neither the hormones nor the antigen enter the cells but can exert their action only at specific receptors on the cell surface. The presence of cell surface re ceptors is presumably determined by the genetic makeup of the cell. Increase in cyclic A M P is correlated with decrease in inflammatory cell activities. Increase of the complementary nucleotide, cyclic GMP, in creases inflammatory cell activity. In the last decade several changes in medi cal practice have been brought about as a result of this new immunologie knowledge. Nearly every university service has an ac tive and growing division of clinical im munology. Sufficient information is now available to evaluate patients with various inflammatory diseases as to whether or not immunologie mechanisms play a role, and if they do whether the inflammation can be controlled by various physical or pharma cologie manipulations. An accompaniment to the clinical emphasis is the growing battery of tests to measure changes in the patient's immunologie status, such as the 25 or so autoantibody measurements that can be performed on serum or on tissue, the search for various tumor-related antigens, measurement of B- and T-cell ratios in blood cells and in tumor tissue, and the in vitro laboratory measurement of delayed hypersensitivity responses of the peripheral blood lymphocytes. The old immunology counts to its credit such achievements as vaccination, the pro phylactic use of toxoids, and advances cru cial in conquering infections. The new im munology cannot yet lay claim to discoveries of equal stature, 1 but problems such as can cer, autoimmunity, and transplantation
111
should be solved or modified by the new immunology. The old immunology had its effect primarily on the lives of the young and the promise of the new immunology is for the health of the old. MATHEA ALLANSMITH REFERENCES
1. Medawar, P. B. : The new immunology. Hosp. Practice 9:48, 1974. 2. Roitt, I. : Essential Immunology, 2nd ed. London, Blackwell Scientific Publications, 1974.
OBITUARY JOHN
W. FERRÉE, M.D., M.P.H. 1904-1975
John W. Ferrée died of cancer Oct. 24, 1975, after an illness of many months. A native of Indiana, Dr. Ferrée attended the University of Pennsylvania, received his M.D. from Indiana University, and a Mas ter's in Public Health from Johns Hopkins University. He was named Indiana state health commissioner in 1940, and served as a commander in the Navy medical depart ment in World War II. Preventive medicine was a guiding pre cept throughout his career. From 1946 to 1947, he was director of education of the American Social Hygiene Association, then associate director of the National Health Council from 1947 to 1948, and associate medical director of the American Heart As sociation in charge of community service and educational activities for eight years. He was named executive director of the National Society for the Prevention of Blindness in 1959 and held the post until his retirement ten years later. During Dr. Ferree's tenure as executive director, out standing progress was achieved through his professional competence, strong leadership, wealth of knowledge about public health programs and medical research, his high
