Symposium: History of Nutritional Immunology
Protein-Energy Malnutrition and Immunological Responses1 RANJIT KUMAR CHANDRA2 Departments of Pediatrics and Medicine, Diuision of Immunology, Memorial Uniuersity of Newfoundland, and the World Health Organization Collaborating Centre for Research and Training in Nutritional Immunology, St. John's, Newfoundland AIA ÃŒR8, Canada
in the 12th century shows an interesting association between consecutive years of famine and epidemics of pestilence or communicable diseases (Fig. 1). Recent epidemiologie studies in the Americas and Asia have confirmed that infection, often superadded on mal nutrition, is a major cause of morbidity and is respon sible for about two-thirds of all deaths among children under 5 y of age. In 1968, Scrimshaw et al. (5) sum marized the human and animal data on interactions, often synergistic but occasionally antagonistic, be tween nutritional deficiencies and infectious illness. Careful observations showed a correlation between nutritional status and morbidity and mortality largely due to infections. It was shown that the risk of death increased from ~0.1% in the well-nourished to as much as 18% in severe malnourished infants. The number of episodes of diarrhea increased by 40% and the duration of each episode increased by more than twofold. The effect of malnutrition on different in fections is variable. For some organisms, e.g., measles, tuberculosis and Pneumocystis caiinii, there is little doubt that nutritional deficiencies enhance suscepti bility and worsen prognosis. For others, such as yellow fever and poliomyelitis, nutrition does not appear to have a major influence on natural history and outcome. On the other hand, infection leads to a number of metabolic changes that will worsen nutritional status. Infection is associated with reduced appetite, malab-
ABSTRACT Historical accounts have suggested a temporal relationship between famines and epidemics. More recently, careful epidemiologie studies have shown a relationship between nutritional deficiencies and heightened risk of morbidity and mortality due to infectious disease. These observations led to studies that examined the effect of proteion-energy malnutrition on immunocompetence. The lymphoid tissues, partic ularly the thymus, were found to be atrophied. There was a reduction in delayed cutaneous hypersensitivity, fewer T cells, especially T helper cells, decreased thymulin activity, impaired secretory immunoglobulin A antibody response, decreased antibody affinity, reduced concentration and activity of complement components and phagocyte dysfunction. These observations were then applied to the study of individual nutrient defi ciencies. The interactions of protein-energy malnutrition and the immune system have generated many practical and clinical applications. J. Nutr. 122:597-600, 1992. INDEXING KEY WORDS:
•protein-energy malnutrition •immunocompetence •cell-mediated immunity •antibody responses •phagocytes
The evolution of nutritional immunology has gone through several successive stages, from historical ac counts and anecdotal observations in the beginning to sophisticated cellular and molecular investigations in recent times (Table 1). Many investigators in several centers around the world have contributed to our cur rent knowledge in this field. In this selective review, reference is made to only a few of the early seminal works that have advanced our understanding of im munocompetence in protein-energy malnutrition (PEM). More comprehensive coverage appears in sev eral recent reviews (1-4). The association of malnutrition and infection has been recorded in ancient historical accounts. For ex ample, an examination of church records in England
' Presented as part of a symposium: History of Nutritional Im munology, given at the 75th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlanta, GA, April 23, 1991. The symposium was sponsored by the American Institute of Nutrition and the American Association of Immunologists, and was coordinated by Patricia B. Swan (Iowa State University). Guest editor for this symposium was W. R. Beisel, Department of Im munology and Infectious Diseases, The Johns Hopkins University, Baltimore, MD. 1To whom correspondence should be addressed: Dept. of Pe diatrics and Medicine, Division of Immunology, Memorial Uni versity of Newfoundland, St. John's, Newfoundland AIA 1RS, Canada.
0022-3166/92 $3.00 ©1992 American Institute of Nutrition.
597 Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/597/4755204 by Washington University in St. Louis user on 21 May 2018
598
CHANDRA TABLE 1 Evolution of nutritional immunology
Historical accounts Anecdotal observations Immunological responses in protein-energy malnutrition Micronutrient effects on the immune system Practical, clinical and public health applications
sorption, increased catabolic activity and enhanced nutrient losses through the stools, urine and sweat. The need for rapid protein synthesis and cell prolif eration for host defense creates additional demands on the already depleted nutritional resources. These physiological changes slow growth and worsen mal nutrition. There are many causes of increased susceptibility to infection among underprivileged malnourished communities. These include poor sanitation and per sonal hygiene, inadequate supply of clean water, con taminated food and inappropriate health and nutrition education. In addition, impaired immunocompetence is an important contributing factor. However, this was not studied systematically and comprehensively until recently (6).
IMMUNE RESPONSES
IN ÃœNDERNÃœTRITION
mature demise. The tears shed on her death were not my first and would not be my last. There would be another Ramala, and another, and another. The second case was of the poor nations of the world, with high infant mortality, poor sanitation, contaminated food and water, a low literacy rate, and short life expec tancy. Widespread malnutrition and infection were obvious shackles to development. Research into their interactions became a necessity for me. Against this background in 1969,1 applied the available techniques to study immunocompetence of undernourished chil dren. To convey a sense of time, the discipline of im munology was not then even exalted by the general use of terms such as 'cell-mediated immunity,' 'Tlymphocyte subsets,' 'immunoregulation,' and so on. In malnourished patients we found impaired delayed cutaneous hypersensitivity, lymphocyte proliferation response to mitogens, complement activity, and sec ondary antibody response to certain antigens. These findings were soon confirmed by several investiga tors."
IMMUNOCOMPETENCE IN PEM Children with PEM show consistent abnormalities in immune responses. There is thy mie atrophy, re-
FAMINE
PESTILENCE YEAR
Any discussion of the effects of nutritional defi ciencies on immune responses must be prefaced by emphasizing the complexities and heterogeneity of immunocompetent cells, their subpopulations and products such as interleukins and interferons, and other inducer/regulator systems, e.g., complement, involved in immune responses. Also, malnutrition is a complex syndrome where several deficiencies exist simultaneously. Thus what is observed in an under nourished individual or a deprived animal is the sum of contributions and responses of many components of the immune system that have been altered by one or more nutrient deficiencies. The background to our work in this field has been described (7, 8). "My interest in nutrition-immunity interactions was kindled by two cases: first, the story, with an unhappy ending, of a child; second, the bleak scenario of the Third World. Eighteen-month-old Kamala was thin, her skin pale as wax, and her lungs screaming for air. She wore a spectral white deathmask in a frame of black hair. Her shrivelled body and swollen legs were typical of marasmic kwashiorkor, and she had an obvious fulminant infection. Lung as pirate revealed the opportunistic organism Pneumocystis carinii. Despite our best efforts, we lost the child. I speculated that malnutrition had robbed Kamala of her defenses against infection and led to pre Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/597/4755204 by Washington University in St. Louis user on 21 May 2018
-1100-
1115-
-1130
-
-1145
-
-1160-
-1175
-1190
-1205
-
FIGURE 1 Famine and pestilence in England in the 12th century.
SYMPOSIUM: HISTORY OF NUTRITIONAL
duced frequency and magnitude of delayed cutaneous hypersensitivity responses, decreased number of ro sette-forming T lymphocytes, particularly CD4+ helper T cells and decreased natural killer cell activity. Lymphocyte stimulation responses to mitogens and allogeneic cells are decreased, especially in the pres ence of autologous plasma. This has been attributed to the presence of inhibitory factors as well as the lack of essential nutrients. PEM is associated with low total hemolytic complement activity, reduced concentra tions of complement C3 and factor B, frequent pres ence of complement C3 split products and elevated immunoconglutinin levels indicative of complement utilization. Immune complexes are often detected. Phagocytosis is intact but killing of ingested micro organisms is impaired; this has been attributed to re duced metabolic activity of several key intracellular pathways. Serum antibody response is generally nor mal, except in the case of those antigens that require T cell help. On the other hand, secretory immunoglobulin A (IgA) antibody response is blunted. Anti body affinity is decreased. The production of interleukin-1, interleukin-2 and interferon-gamma is de creased. Historical perspective. The sequential studies on immunocompetence in PEM conducted by our group are listed in Table 2. Detailed description and com plete citations to these publications are given else where (1,4,8-10). Chandra (6) showed that in children with PEM, a variety of immune responses are blunted. These include delayed hypersensitivity to common microbial antigens, lymphocyte number and response to phytohemagglutinin, antibody responses to Sal
Our group's contributions Author(s|
TABLE 2 to immunologie
investigations
PEM1
immunity,
Comprehensive study, CMI, Ab, C Phagocytosis and intracellular bacterial killing Number of T cells Complement components, immunoconglutinin, C3 conversion Secretory IgA Ab response to viral vaccines Immunocompetence in fetal malnutrition (humans) Maternal malnutrition and immunocompetence of offspring (rats) Chemotaxis of neutrophils Terminal deoxynucleotidyl transferase activity Thymulin activity (humans) Thymulin activity (rats) Immunocompetence in obesity T-cell subsets Immunocompetene of malnourished elderly T helper cell function, T and B-cell cocultures Antibody affinity Antibody response to influenza virus vaccine Bacterial binding to respiratory epithelial cells
Cytokines, natural killer cells Ab = antibody, C = complement;
Chandra (8). Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/597/4755204 by Washington University in St. Louis user on 21 May 2018
S99
monella but not to tetanus toxoid, complement C3 levels and intracellular bactericidal capacity of neutrophils. Smythe et al. (11) reported that in infants dying of kwashiorkor, the thymus was small and there was a paucity of lymphocytes. There was a reduction in skin delayed hypersensitivity responses. Edelman et al. (12) examined both the afferent and the effector limbs of delayed cutaneous hypersensitivity and found impairment in both. Sirisinha et al. (13) and Chandra (14) found the levels of several complement compo nents were decreased in PEM and there was evidence of complement activation as documented by the pres ence of C3 metabolic products and high titers of im munoconglutinin. Both Chandra (15) and Sirisinha et al. (16) showed a reduction in secretory IgA levels in PEM. In addition, the former found a decrease in nasopharyngeal secretory IgA antibody response both to measles and poliovirus vaccines. Finally, although serum antibody titer is often unchanged in PEM, the affinity of antibody was found to be decreased. These initial observations have been confirmed and extended by several investigators, including Newberne, McFarlane, Seth, Salimonu, Beatty, Coovadia, Soothill, Bhaskaram, Reddy, Keusch, Vyas, Puri, Wat son, McMurray, Hoffman-Goetz, Wade, Dardenne, Fernandes, Good and others; for want of space, their work is not cited individually here but is described in other reviews (1, 4, 8-10). With the availability of monoclonal antibodies and flow cytometry techniques, a marked reduction in the proportion of CD4+ helper T cells was found. In addition, coculture experiments employing the reverse hemolytic plaque technique showed that the major defect lies in helper T cell func-
Topic investigated
Chandra R. K. Seth V., Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. et al. Chandra R. K. Chandra R. K. Heresi G., Chandra R. K. Chandra R. K., Kutty K. M. Chandra R. K. et al. Chandra R. K. et al. Chandra R. K. Chandra R. K. et al. Chandra R. K., Puri S. Chandra R. K., Gupta S. P. Chandra R. K. 1CMI = cell-mediated
IMMUNOLOGY
Year of publication 1972 1972 1974 1975 1975 1975 1975 1976 1979 1979 1980 1980 1982 1982 1983 1984 1985 1990 1991
complete citations are given in Chandra and Newberne
(1) and in
600
CHANDRA
tion. There was an increase in the level of leukocyte terminal deoxynucleotidyl transferase enzyme, an in dication of impaired maturation of T cells. This was in part due to decreased activity of thymic inductive factors, such as thymulin. Natural killer cell activity was decreased. The sera of children with PEM inhibit T cell rosette formation and do not support optimal lymphocyte proliferation in vitro. There is a reduction in interleukin-1 and lysozyme production and release. Animal models of energy restriction show a reduction in selective immunologie functions and, in some in stances, improved resistance to tumors. Energy excess also decreases phagocyte and lymphocyte functions in humans and animals. The pioneering studies on immunocompetence in PEM have led to several practical applications. These include the use of immunologie tests as prognostic indices in patients undergoing surgery, and the use of immunologie methods to assess nutritional status and to judge the adequacy of nutritional therapy, immu nologie response to and protective efficacy of vaccines. Finally, the new knowledge has permitted the devel opment of designer formulas with selective ingredients in specified amounts; these feeding formulas have been shown to reduce the risk of infection in immunocompromised hosts. Clearly, the early work on PEM and immunity reviewed above has had a significant and crucial influence on public health and clinical medi cine. LITERATURE CITED 1. Chandra, R. K. & Newberne, P. M. (1977) Nutrition, Immunity and Infection; Mechanisms of Interactions. Plenum Press, New York, NY.
Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/597/4755204 by Washington University in St. Louis user on 21 May 2018
2. Watson, R. R., ed. (1984) Nutrition, Disease Resistance, and Immune Function. Marcel Dekker, New York, NY. 3. Gershwin M. E., Beach, R. S. & Hurley, L. S. (1984) Nutrition and Immunity. Academic Press, New York, NY. 4. Chandra, R. K. (1983) Nutrition, immunity and infection. Present knowledge and future directions. Lancet I: 688-691. 5. Scrimshaw, N. S., Taylor, C. E. &. Gordon, J. E. (1968) Interactions of nutrition and infection. WHO Monograph Series 57. World Health Organization, Geneva, Switzerland. 6. Chandra, R. K. (1972) Immunocompetence in undernutrition. J. Pediatr. 81: 1194-1200. 7. This week's citation classic. (1987) Current Contents 30: 15. 8. Chandra, R. K. (1991) Nutrition and Immunology. Lessons from the past and visions of the future. Am. J. Clin. Nutr. 53: 1087-1101. 9. Chandra, R. K. (1989) Heath Clarke Lecture. Immune re sponses in undernutrition and overnutrition. Basic considera tions and applied significance. Nutrition 5: 297-302. 10. Chandra, R. K. (1989) Nutritional regulation of immunity and risk of infection in old age. Immunology 67: 141-147. 11. Smythe, P. M., Schonland, M., Brerton-Stiles, G. G., Grace, H. J., Coovadia, H. M., Loennig, W. E. K., Mafoyane, A., Parent, M. A. & Vos, G. H. (1971) Thymolymphatic deficiency and depression of cell-mediated immunity in protein-calorie mal nutrition. Lancet II: 939-944. 12. Edelman, R., Suskind, R. M., Olson, R. E. & Sirisinha, S. (1973) Mechanisms of defective delayed cutaneous hypersensitivity in children with protein-calorie malnutrition. Lancet II: 506-508. 13. Sirisinha, S., Suskind, R. M., Edelman, R., Charupatana, C. & Olson, R. E. 11973) Complement and C3-proactivator levels in children with protein-calorie malnutrition and effect of dietary treatment. Lancet I: 1016-1018. 14. Chandra, R. K. (1975) Serum complement and immunoconglutinin in malnutrition. Arch. Dis. Child. 50: 225-228. 15. Chandra, R. K. (1975) Reduced secretory antibody response to live attenuated measles and poliovirus vaccines in malnourished children. Br. Med. J. 2: 583-585. lé.Sirisinha, S., Suskind, S., Edelman, R., Asvapaka, C. & Olsen, R. E. (1975) Secretory and serum IgA in children with proteinenergy malnutrition. Pediatrics 55: 166-170.
Protein-Energy Malnutrition and Immunological Responses1 RANJIT KUMAR CHANDRA2 Departments of Pediatrics and Medicine, Diuision of Immunology, Memorial Uniuersity of Newfoundland, and the World Health Organization Collaborating Centre for Research and Training in Nutritional Immunology, St. John's, Newfoundland AIA ÃŒR8, Canada
in the 12th century shows an interesting association between consecutive years of famine and epidemics of pestilence or communicable diseases (Fig. 1). Recent epidemiologie studies in the Americas and Asia have confirmed that infection, often superadded on mal nutrition, is a major cause of morbidity and is respon sible for about two-thirds of all deaths among children under 5 y of age. In 1968, Scrimshaw et al. (5) sum marized the human and animal data on interactions, often synergistic but occasionally antagonistic, be tween nutritional deficiencies and infectious illness. Careful observations showed a correlation between nutritional status and morbidity and mortality largely due to infections. It was shown that the risk of death increased from ~0.1% in the well-nourished to as much as 18% in severe malnourished infants. The number of episodes of diarrhea increased by 40% and the duration of each episode increased by more than twofold. The effect of malnutrition on different in fections is variable. For some organisms, e.g., measles, tuberculosis and Pneumocystis caiinii, there is little doubt that nutritional deficiencies enhance suscepti bility and worsen prognosis. For others, such as yellow fever and poliomyelitis, nutrition does not appear to have a major influence on natural history and outcome. On the other hand, infection leads to a number of metabolic changes that will worsen nutritional status. Infection is associated with reduced appetite, malab-
ABSTRACT Historical accounts have suggested a temporal relationship between famines and epidemics. More recently, careful epidemiologie studies have shown a relationship between nutritional deficiencies and heightened risk of morbidity and mortality due to infectious disease. These observations led to studies that examined the effect of proteion-energy malnutrition on immunocompetence. The lymphoid tissues, partic ularly the thymus, were found to be atrophied. There was a reduction in delayed cutaneous hypersensitivity, fewer T cells, especially T helper cells, decreased thymulin activity, impaired secretory immunoglobulin A antibody response, decreased antibody affinity, reduced concentration and activity of complement components and phagocyte dysfunction. These observations were then applied to the study of individual nutrient defi ciencies. The interactions of protein-energy malnutrition and the immune system have generated many practical and clinical applications. J. Nutr. 122:597-600, 1992. INDEXING KEY WORDS:
•protein-energy malnutrition •immunocompetence •cell-mediated immunity •antibody responses •phagocytes
The evolution of nutritional immunology has gone through several successive stages, from historical ac counts and anecdotal observations in the beginning to sophisticated cellular and molecular investigations in recent times (Table 1). Many investigators in several centers around the world have contributed to our cur rent knowledge in this field. In this selective review, reference is made to only a few of the early seminal works that have advanced our understanding of im munocompetence in protein-energy malnutrition (PEM). More comprehensive coverage appears in sev eral recent reviews (1-4). The association of malnutrition and infection has been recorded in ancient historical accounts. For ex ample, an examination of church records in England
' Presented as part of a symposium: History of Nutritional Im munology, given at the 75th Annual Meeting of the Federation of American Societies for Experimental Biology, Atlanta, GA, April 23, 1991. The symposium was sponsored by the American Institute of Nutrition and the American Association of Immunologists, and was coordinated by Patricia B. Swan (Iowa State University). Guest editor for this symposium was W. R. Beisel, Department of Im munology and Infectious Diseases, The Johns Hopkins University, Baltimore, MD. 1To whom correspondence should be addressed: Dept. of Pe diatrics and Medicine, Division of Immunology, Memorial Uni versity of Newfoundland, St. John's, Newfoundland AIA 1RS, Canada.
0022-3166/92 $3.00 ©1992 American Institute of Nutrition.
597 Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/597/4755204 by Washington University in St. Louis user on 21 May 2018
598
CHANDRA TABLE 1 Evolution of nutritional immunology
Historical accounts Anecdotal observations Immunological responses in protein-energy malnutrition Micronutrient effects on the immune system Practical, clinical and public health applications
sorption, increased catabolic activity and enhanced nutrient losses through the stools, urine and sweat. The need for rapid protein synthesis and cell prolif eration for host defense creates additional demands on the already depleted nutritional resources. These physiological changes slow growth and worsen mal nutrition. There are many causes of increased susceptibility to infection among underprivileged malnourished communities. These include poor sanitation and per sonal hygiene, inadequate supply of clean water, con taminated food and inappropriate health and nutrition education. In addition, impaired immunocompetence is an important contributing factor. However, this was not studied systematically and comprehensively until recently (6).
IMMUNE RESPONSES
IN ÃœNDERNÃœTRITION
mature demise. The tears shed on her death were not my first and would not be my last. There would be another Ramala, and another, and another. The second case was of the poor nations of the world, with high infant mortality, poor sanitation, contaminated food and water, a low literacy rate, and short life expec tancy. Widespread malnutrition and infection were obvious shackles to development. Research into their interactions became a necessity for me. Against this background in 1969,1 applied the available techniques to study immunocompetence of undernourished chil dren. To convey a sense of time, the discipline of im munology was not then even exalted by the general use of terms such as 'cell-mediated immunity,' 'Tlymphocyte subsets,' 'immunoregulation,' and so on. In malnourished patients we found impaired delayed cutaneous hypersensitivity, lymphocyte proliferation response to mitogens, complement activity, and sec ondary antibody response to certain antigens. These findings were soon confirmed by several investiga tors."
IMMUNOCOMPETENCE IN PEM Children with PEM show consistent abnormalities in immune responses. There is thy mie atrophy, re-
FAMINE
PESTILENCE YEAR
Any discussion of the effects of nutritional defi ciencies on immune responses must be prefaced by emphasizing the complexities and heterogeneity of immunocompetent cells, their subpopulations and products such as interleukins and interferons, and other inducer/regulator systems, e.g., complement, involved in immune responses. Also, malnutrition is a complex syndrome where several deficiencies exist simultaneously. Thus what is observed in an under nourished individual or a deprived animal is the sum of contributions and responses of many components of the immune system that have been altered by one or more nutrient deficiencies. The background to our work in this field has been described (7, 8). "My interest in nutrition-immunity interactions was kindled by two cases: first, the story, with an unhappy ending, of a child; second, the bleak scenario of the Third World. Eighteen-month-old Kamala was thin, her skin pale as wax, and her lungs screaming for air. She wore a spectral white deathmask in a frame of black hair. Her shrivelled body and swollen legs were typical of marasmic kwashiorkor, and she had an obvious fulminant infection. Lung as pirate revealed the opportunistic organism Pneumocystis carinii. Despite our best efforts, we lost the child. I speculated that malnutrition had robbed Kamala of her defenses against infection and led to pre Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/597/4755204 by Washington University in St. Louis user on 21 May 2018
-1100-
1115-
-1130
-
-1145
-
-1160-
-1175
-1190
-1205
-
FIGURE 1 Famine and pestilence in England in the 12th century.
SYMPOSIUM: HISTORY OF NUTRITIONAL
duced frequency and magnitude of delayed cutaneous hypersensitivity responses, decreased number of ro sette-forming T lymphocytes, particularly CD4+ helper T cells and decreased natural killer cell activity. Lymphocyte stimulation responses to mitogens and allogeneic cells are decreased, especially in the pres ence of autologous plasma. This has been attributed to the presence of inhibitory factors as well as the lack of essential nutrients. PEM is associated with low total hemolytic complement activity, reduced concentra tions of complement C3 and factor B, frequent pres ence of complement C3 split products and elevated immunoconglutinin levels indicative of complement utilization. Immune complexes are often detected. Phagocytosis is intact but killing of ingested micro organisms is impaired; this has been attributed to re duced metabolic activity of several key intracellular pathways. Serum antibody response is generally nor mal, except in the case of those antigens that require T cell help. On the other hand, secretory immunoglobulin A (IgA) antibody response is blunted. Anti body affinity is decreased. The production of interleukin-1, interleukin-2 and interferon-gamma is de creased. Historical perspective. The sequential studies on immunocompetence in PEM conducted by our group are listed in Table 2. Detailed description and com plete citations to these publications are given else where (1,4,8-10). Chandra (6) showed that in children with PEM, a variety of immune responses are blunted. These include delayed hypersensitivity to common microbial antigens, lymphocyte number and response to phytohemagglutinin, antibody responses to Sal
Our group's contributions Author(s|
TABLE 2 to immunologie
investigations
PEM1
immunity,
Comprehensive study, CMI, Ab, C Phagocytosis and intracellular bacterial killing Number of T cells Complement components, immunoconglutinin, C3 conversion Secretory IgA Ab response to viral vaccines Immunocompetence in fetal malnutrition (humans) Maternal malnutrition and immunocompetence of offspring (rats) Chemotaxis of neutrophils Terminal deoxynucleotidyl transferase activity Thymulin activity (humans) Thymulin activity (rats) Immunocompetence in obesity T-cell subsets Immunocompetene of malnourished elderly T helper cell function, T and B-cell cocultures Antibody affinity Antibody response to influenza virus vaccine Bacterial binding to respiratory epithelial cells
Cytokines, natural killer cells Ab = antibody, C = complement;
Chandra (8). Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/597/4755204 by Washington University in St. Louis user on 21 May 2018
S99
monella but not to tetanus toxoid, complement C3 levels and intracellular bactericidal capacity of neutrophils. Smythe et al. (11) reported that in infants dying of kwashiorkor, the thymus was small and there was a paucity of lymphocytes. There was a reduction in skin delayed hypersensitivity responses. Edelman et al. (12) examined both the afferent and the effector limbs of delayed cutaneous hypersensitivity and found impairment in both. Sirisinha et al. (13) and Chandra (14) found the levels of several complement compo nents were decreased in PEM and there was evidence of complement activation as documented by the pres ence of C3 metabolic products and high titers of im munoconglutinin. Both Chandra (15) and Sirisinha et al. (16) showed a reduction in secretory IgA levels in PEM. In addition, the former found a decrease in nasopharyngeal secretory IgA antibody response both to measles and poliovirus vaccines. Finally, although serum antibody titer is often unchanged in PEM, the affinity of antibody was found to be decreased. These initial observations have been confirmed and extended by several investigators, including Newberne, McFarlane, Seth, Salimonu, Beatty, Coovadia, Soothill, Bhaskaram, Reddy, Keusch, Vyas, Puri, Wat son, McMurray, Hoffman-Goetz, Wade, Dardenne, Fernandes, Good and others; for want of space, their work is not cited individually here but is described in other reviews (1, 4, 8-10). With the availability of monoclonal antibodies and flow cytometry techniques, a marked reduction in the proportion of CD4+ helper T cells was found. In addition, coculture experiments employing the reverse hemolytic plaque technique showed that the major defect lies in helper T cell func-
Topic investigated
Chandra R. K. Seth V., Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. Chandra R. K. et al. Chandra R. K. Chandra R. K. Heresi G., Chandra R. K. Chandra R. K., Kutty K. M. Chandra R. K. et al. Chandra R. K. et al. Chandra R. K. Chandra R. K. et al. Chandra R. K., Puri S. Chandra R. K., Gupta S. P. Chandra R. K. 1CMI = cell-mediated
IMMUNOLOGY
Year of publication 1972 1972 1974 1975 1975 1975 1975 1976 1979 1979 1980 1980 1982 1982 1983 1984 1985 1990 1991
complete citations are given in Chandra and Newberne
(1) and in
600
CHANDRA
tion. There was an increase in the level of leukocyte terminal deoxynucleotidyl transferase enzyme, an in dication of impaired maturation of T cells. This was in part due to decreased activity of thymic inductive factors, such as thymulin. Natural killer cell activity was decreased. The sera of children with PEM inhibit T cell rosette formation and do not support optimal lymphocyte proliferation in vitro. There is a reduction in interleukin-1 and lysozyme production and release. Animal models of energy restriction show a reduction in selective immunologie functions and, in some in stances, improved resistance to tumors. Energy excess also decreases phagocyte and lymphocyte functions in humans and animals. The pioneering studies on immunocompetence in PEM have led to several practical applications. These include the use of immunologie tests as prognostic indices in patients undergoing surgery, and the use of immunologie methods to assess nutritional status and to judge the adequacy of nutritional therapy, immu nologie response to and protective efficacy of vaccines. Finally, the new knowledge has permitted the devel opment of designer formulas with selective ingredients in specified amounts; these feeding formulas have been shown to reduce the risk of infection in immunocompromised hosts. Clearly, the early work on PEM and immunity reviewed above has had a significant and crucial influence on public health and clinical medi cine. LITERATURE CITED 1. Chandra, R. K. & Newberne, P. M. (1977) Nutrition, Immunity and Infection; Mechanisms of Interactions. Plenum Press, New York, NY.
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2. Watson, R. R., ed. (1984) Nutrition, Disease Resistance, and Immune Function. Marcel Dekker, New York, NY. 3. Gershwin M. E., Beach, R. S. & Hurley, L. S. (1984) Nutrition and Immunity. Academic Press, New York, NY. 4. Chandra, R. K. (1983) Nutrition, immunity and infection. Present knowledge and future directions. Lancet I: 688-691. 5. Scrimshaw, N. S., Taylor, C. E. &. Gordon, J. E. (1968) Interactions of nutrition and infection. WHO Monograph Series 57. World Health Organization, Geneva, Switzerland. 6. Chandra, R. K. (1972) Immunocompetence in undernutrition. J. Pediatr. 81: 1194-1200. 7. This week's citation classic. (1987) Current Contents 30: 15. 8. Chandra, R. K. (1991) Nutrition and Immunology. Lessons from the past and visions of the future. Am. J. Clin. Nutr. 53: 1087-1101. 9. Chandra, R. K. (1989) Heath Clarke Lecture. Immune re sponses in undernutrition and overnutrition. Basic considera tions and applied significance. Nutrition 5: 297-302. 10. Chandra, R. K. (1989) Nutritional regulation of immunity and risk of infection in old age. Immunology 67: 141-147. 11. Smythe, P. M., Schonland, M., Brerton-Stiles, G. G., Grace, H. J., Coovadia, H. M., Loennig, W. E. K., Mafoyane, A., Parent, M. A. & Vos, G. H. (1971) Thymolymphatic deficiency and depression of cell-mediated immunity in protein-calorie mal nutrition. Lancet II: 939-944. 12. Edelman, R., Suskind, R. M., Olson, R. E. & Sirisinha, S. (1973) Mechanisms of defective delayed cutaneous hypersensitivity in children with protein-calorie malnutrition. Lancet II: 506-508. 13. Sirisinha, S., Suskind, R. M., Edelman, R., Charupatana, C. & Olson, R. E. 11973) Complement and C3-proactivator levels in children with protein-calorie malnutrition and effect of dietary treatment. Lancet I: 1016-1018. 14. Chandra, R. K. (1975) Serum complement and immunoconglutinin in malnutrition. Arch. Dis. Child. 50: 225-228. 15. Chandra, R. K. (1975) Reduced secretory antibody response to live attenuated measles and poliovirus vaccines in malnourished children. Br. Med. J. 2: 583-585. lé.Sirisinha, S., Suskind, S., Edelman, R., Asvapaka, C. & Olsen, R. E. (1975) Secretory and serum IgA in children with proteinenergy malnutrition. Pediatrics 55: 166-170.
