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Zinc, Copper, and Iron Nutriture and Immunity12 ADRIA R. SHERMAN3 Department of Nutritional Sciences, Rutgers University, Cook College, New Brunswick, /VJ 08903 was caused by defective absorption of zinc (2). The major causes of death in this disease are all linked to immunodeficiency, which is prevented by zinc sup plementation. The first report of dietary zinc deficiency inducing thymic atrophy and loss of T helper cell function was published by Fraker et al (3). She and Luecke went on to show that it was zinc deficiency and not the reduced food intake or reduced growth associated with feeding a zinc-deficient diet that was responsible for atrophy of thymus and spleen. Their experiments also dem onstrated a decreased production of antibody to sheep red blood cells (SRBC),4 a T-dependent antigen (4). Parenteral T cell infusions corrected the defects in an tibody production (5). Additional manifestations of altered humoral re sponse include distorted serum immunoglobulin (Ig) profiles resulting from prenatal and postnatal zinc de ficiency (6). Dietary zinc deficiency in neonatal mice also impairs antibody production to sheep red blood cells (7). Repletion with zinc results in a normalization of IgM plaque response and an elevation of the IgG response. Cell-mediated immunity is also altered by zinc de ficiency. Delayed hypersensitivity to skin-test antigen is often compromised in the zinc-deficient state. Both thymic hormone and Thyl positive lymphocytes may be lowered in zinc deficiency (8). T lymphocyte pro-
ABSTRACT Inadequate nutritore of zinc, copper and iron alter immunocompetence in humans and experi mental animals. For each of these minerals deficient status leads to increased susceptibility to infectious illnesses. Specific components of the immune response may be altered in a variety of patients and models. Although many generalized functions for these nutrients could lead to altered immune function, specific functions for these minerals in immunity have not yet been iden tified. For zinc, copper and iron the importance of ad equate nutrition in maintaining immunocompetency cannot be understated. J. Nutr. 122: 604-609, 1992. INDEXING KEY WORDS:
•iron •copper •zinc •infection •immunity
In this paper the influences of zinc, copper and iron on immunity will be discussed. Deficiencies of these trace elements alter immunity and susceptibility to infection. The discussion will emphasize human nu trition, although more mechanistic research in this field has used rodent models. The intent is to highlight the major aspects of the topic rather than to present an all inclusive history.
ZINC
1 Presented as part of a symposium:
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. 2 This is New Jersey Agricultural Experiment Station publication number D-14150-1-92. 3 To whom correspondence should be addressed: Department of
The association of zinc with immunity was first documented with the discovery of human zinc defi ciency by Prasad et al. (1).Along with the characteristic hypogonadism and dwarfism, zinc-deficient adolescent males experienced increased susceptibility to infec tion. Later, a lethal mutation in Holstein-Fresian cattle was found responsible for the failure to both absorb zinc and develop a thymus. These immunodeficient cattle could be treated with zinc and symptoms could be prevented. Further evidence for zinc's role in im munity came from the discovery that the inborn error in human metabolism, acrodermatitis enteropathica, 0022-3166/92
History of Nutritional
Nutritional Sciences, Rutgers University, Cook College, P.O. Box 231, New Brunswick, NJ 08903-0231. 4 Abbreviations: SRBC, sheep red blood cells; PHA, phytohemaglutinin; NK, natural killer; DTH, delayed type hypersensitivity.
$3.00 ©1992 American Institute of Nutrition.
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liferation in response to a mitogen phytohemaglutinin (PHA) was reduced in patients maintained on parenteral hyperalimentation that did not contain zinc (9). T cell proliferation markedly improved after intra venous zinc repletion. In vitro zinc deficiency can be produced by adding EDTA to spleen cell cultures. T cell proliferation after stimulation with either PHA or concanavalin A was decreased in this zinc-deficient system, whereas no change in B cell proliferation in response to LPS B was found (10). Natural killer (NK) cells are active against tumor cells and viral infections. What effects zinc has on NK cells is unclear with both lowered (11) and increased activity reported (12). Increased attention has been focused on a number of clinical situations where zinc deficiency is likely to occur. Humans with low serum zinc levels are thought to have an increased susceptibility to a number of in fectious diseases (13). The inborn error in metabolism resulting in acrodermatitis enteropathica is an autosomal recessive impairment in zinc absorption. The disease manifests at weaning when highly bioavailable zinc in human milk is replaced with less available zinc. Defects in immunity resulting from the zinc deficiency in this disease include lowered lymphocyte response to PHA, lowered delayed type hypersensitivity and an increased incidence in infectious diseases (14). Both the zinc deficiency and immunodeficiency of acroder matitis enteropathica are corrected with zinc supple mentation. Secondary zinc deficiencies ranging from mild subclinical states to severe states have been ob served in Down syndrome, aging, sickle cell anemia and in patients on hemodialysis or total parenteral nu trition. Down syndrome patients are at risk for au toimmune diseases and often have low serum zinc levels. Some improvements in immunologie func tion occurred in Down patients supplemented with zinc (15). During aging there is a considerable loss in both immunologie function and zinc status. Several inves tigators tested the hypothesis that zinc supplementa tion can improve immune function in elderly patients. Some investigators reported improvement in cellular immunity with zinc supplementation (16, 17). A re cent report by Bogden et al. (18) however did not find a significant immunologie benefit from zinc supple mentation in an elderly population. In patients with sickle cell anemia, hypogonadism and growth retardation are associated with zinc defi ciency. Ballester and Prasad (19) reported impaired cell-mediated immunity as indicated by skin test anergy. Patients with sickle cell anemia also show de fective mitogen responsiveness in vitro and higher percentages of T suppressor cells compared with nor mal subjects (20-22). Impaired NK cell cytotoxicity found in patients with sickle cell disease is improved with zinc supplementation (23). Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/604/4755216 by guest on 07 March 2018
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Overzealous use of zinc supplements should be avoided, because Chandra (24) found that adult men supplemented with 150 mg of elemental zinc had re duced lymphocyte proliferation as well as lowered chemotaxic and phagocytic activities. Mulhern et al. (25) found that, in mice, antibody responsiveness to SRBC antigen is markedly impaired by excessive di etary zinc. To date the exact role of zinc in the immune re sponse is unknown. Zinc has many biochemical func tions that could contribute toward maintenance of normal immune processes. Both direct and indirect roles of zinc in immunity are possible. Direct partic ipation of zinc in regulatory activities related to im munity include its function in maintaining the bio logical activity of thymulin. The importance of zinc in DNA polymerase and RNA polymerase suggest a potential role for zinc in the regulation of gene expres sion for cellular differentiation and proliferation, for mediator factors and for regulatory compounds of the immune response. Similarly, the requirement of zinc for normal cellular replication and growth has a pro found impact on the rapidly proliferating cells of the immune system. Dozens of metalloenzymes require zinc for function. Obviously, numerous reactions contribute an effective immune response where zinc metalloenzymes could participate.
COPPER
Although copper deficiency in humans is rare, sev eral reports of increased infectious illness with copper deficiency led to the investigation of the role of copper in immunity (26). Prohaska and Lukasewycz (27) were the first to report that components of the immune re sponse are altered in experimental copper deficiency. Markedly impaired plaque formation to SRBC was shown in male and female mice fed diets low in copper. The defective antibody production of copper defi ciency has been confirmed by Prohaska and Lukase wycz (28) and others (29-32) in mice and rats treated with a variety of antigens. Cell-mediated immunity has been studied in ex perimental copper deficiency by measuring delayedtype hypersensitivity (DTH) reactions. DTH reactions have been reported to be enhanced in copper-deficient mice (33), normal in copper-deficient rats (32) or sup pressed (34). Although these in vivo indicators of cellmediated immunity have yielded contradictory re sults, Lukasewycz and Prohaska (35) found that mor tality was high when T cell-dependent immunity to syngenic malignant lymphocytes was studied. Splenic lymphocytes from copper-deficient animals have low ered proliferation in response to a variety of both T and B cell antigens (28, 29, 36-38).
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Koller et al. (32) reported that NK cell cytotoxicity, another cell-mediated function, is impaired in copperdeficient rats. This observation may in part explain the increased incidence of extrahepatic tumors seen in copper-deficient rats treated with carcinogens com pared with rats fed excessive copper (39). Impaired NK activity is not due to the immunosupressive effects of prostaglandin E2, which is normal in copper-defi cient rats (32). The lowered cell-mediated functions in copper de ficiency may be related to distorted lymphocyte pop ulations and subpopulations. Lukasewycz et al. (37) reported that spleens of copper-deficient mice have relatively higher B cells and lower T cells. The T helper cell subset seemed to be particularly effected. These observations were confirmed by Koller et al. (32). Copper deficiency, although not a serious public health problem, does occur in livestock and in some human clinical situations. Scottish Blackface lambs are genetically predisposed to low copper status and to increased mortality resulting from bacterial infections (40). Copper supplementation beginning at 6 wk markedly increases survival in these lambs. Copper supplementation is also effective in reducing the in cidence of lower respiratory tract infections in infants recovering from marasmus (41). Of clinical impor tance, use of total parenteral nutrition solutions with inadequate copper can lead to copper deficiency and immune dysfunctions. Preterm infants are also at risk for copper deficiency. Menkes Kinky Hair syndrome is an x-chromosome-linked inborn error in metabo lism that leads to copper deficiency. Menkes patients often develop pulmonary and urinary tract infections. Almost always lethal, the cause of death in Menkes syndrome is often bronchopneumonia. Patients are responsive to copper supplementation. Another situ ation where clinical copper deficiency can be problem atic is that created secondary to overzealous supple mentation with zinc. Popular self-medication with mineral supplements can thus lead to serious conse quences. Although it is clear that copper nutriture is impor tant in immunity, it is unclear what precisely is the element's biochemical role. Copper has numerous known biochemical functions, including its role in ferroxidases, cytochrome c oxidase, zinc-copper superoxide dismutase and many other metalloenzymes. Whether copper's role in immunity is via known functions of copper or in yet to be discovered capac ities is unknown at this time.
IRON The earliest research on iron and immunity showed that iron deficiency is associated with increased infec Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/604/4755216 by guest on 07 March 2018
tious diseases in infancy. Mackay (42) was the first to observe that infants given iron supplements had 50% fewer respiratory and gastrointestinal infections than infants given no iron. Andelman and Sered (43) fed either iron-fortified formula or evaporated milk for mula to term infants of lower socioeconomic status during their first 18 mo of life. The incidence of both iron-deficiency anemia and respiratory infections was highest in the group fed the evaporated milk with lower iron content. A number of field studies conducted in the 1970s suggested that iron deficiency provides a protection from infection and that iron repletion reverses this protection (44-46). Although these reports are often cited in support of a protection against infection af forded by mild iron deficiency, a more plausible al ternate interpretation of the observations is that ex cessive iron is associated with increased infectious illness. For example, the Murrays (46) repleted irondeficient Somali nomads, whose diet is all milk, with 900 mg of ferrous sulfate daily. The reported increase in infections after iron treatment may in fact be due to the hyperferremia associated with iron intakes 10fold greater than required. Prophylactic administration of large doses of parenteral iron to iron-deficient Poly nesian infants in New Zealand has also been associated with increased infection (47). A delicate balance exists between the need for iron for host defense mechanisms and the need for iron to sustain microbial growth (48). Most research in the late 1970s and 1980s focused on the role of iron in components of the host immune response. Anatomical and structural changes in immunologically important tissues have been found in experi mental iron deficiency. In iron deficiency there is thymic atrophy (49) and reduced cellularity of the thy mus (50), which is not reversed with iron repletion (51). In neonates, splenic development is retarded in iron deficiency (49), but in adult rats fed an iron-de ficient diet after weaning, splenomegaly is often ob served (52). Circulating T lymphocytes are reduced in iron deficiency (53). Humoral immunity has been studied in both irondeficient humans and iron-deficient animals. Circu lating Ig levels in children with iron-deficiency anemia appear to be unaffected (54-56). Serum levels of IgG and IgM have been reported to actually increase slightly in iron deficiency in adult rats (57). The level of circulating Ig, however, is not a reflection of recent, specific antibody production. When humoral immu nity is measured as antibody titers in response to an immunization (58) or as plaque formation in response to SRBC antigens (59, 60), iron-deficient rats do not mount a normal response. Components of nonspecific immunity may be al tered by iron deficiency. Milk and salivary secretory IgA levels are protected in iron-deficient rat pups and
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dams (61). Lysozyme is another component of secre tory immunity with bactericidal activity. Increased levels of lysozyme have been found in serum and spleen of iron-deficient rat pups (62) and in kidney of iron-deficient adult rats (63). Phagocytosis by granulocytes is a cellular component of nonspecific immu nity, which is altered in iron-deficient rat pups (64). Iron deficiency has a marked effect on cell-mediated immunity. Lymphocyte blastogenesis is impaired in splenocytes of iron-deficient weanling mice (65). Irondeficient children also have lower lymphocyte blas togenesis (54, 66-68). Delayed type hypersensitivity reactions to skin test antigens may be low in irondeficient children (54, 55, 69). NK cell activity is depressed in iron-deficient rats (52, 70). The mechanism responsible for lowered NK activity is not known. Because interferon stimulates NK cytotoxicity, defective responsiveness to inter feron may explain the observed NK activity in iron deficiency. NK cytotoxicity was not fully restored by addition in vitro of either alpha/beta interferon (71) or addition of interferon containing supernatants from macrophages (52). This suggests that in iron deficiency there may be a limited capacity in NK cells to be stim ulated by interferon. Several soluble proteinous mediators of immunity are lowered by dietary iron deficiency in rodents. Interleukin 1, produced by activated macrophages, in duces the fever of infection and also intensifies the activity of T helper cells to produce interleukin 2. In iron-deficient rats, peritoneal macrophage production of interleukin 1 is impaired (72). Interleukin 2 activity is lowered in iron-deficient rats (unpublished data). Whether the role of iron in immunity is distinct from the more general biochemical functions of iron is unknown at the present time. As part of the cytochromes, hemoglobin and myoglobin, iron plays an important role in energy metabolism of all cells. Spe cific iron metalloenzymes that play roles in immunity include catalase and peroxidases. In addition, iron is part of dozens of other metalloproteins important to cellular metabolism. Iron deficiency may result in lowered protein synthesis in immunologically impor tant issues (73). Impaired protein synthesis could be a mechanism of central importance whereby iron de ficiency impairs the immune response system. Because iron deficiency is the most prevalent nu tritional disorder in the world and because it is most common in women of reproductive age and their chil dren, the implications of dysfunctional immunity re sulting from iron deficiency are vast. Although the history of nutritional immunology is recent and mechanistic information pertaining to the role of trace elements in immunity is scant, it is clear that adequate status of zinc, copper and iron is essen tial for maintaining immunocompetence. Challenges for the future include elucidation of the roles of these Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/604/4755216 by guest on 07 March 2018
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trace elements in immune processes, specific roles in disease states and, most importantly, prevention of deficiency states. LITERATURE CITED 1. Prasad, A. S., Miale, A., Farid, Z., Sandstead, H. H. & Schulen, A. R. (1963| Zinc metabolism in normals and patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarh'sm and hepogonadism. J. Lab. Clin. Med. 61: 537-549. 2. Moynahan, E. J. & Barnes, P. M. (1973) Zinc deficiency and a synthetic diet for lactose intolerance. Lancet I: 676-677. 3. Fraker, P. J., Haas, S. M. & Leucke, R. W. (1977] Effect of zinc deficiency on the immune response of the young adult A/J mouse. J. Nutr. 107: 1889-1895. 4. Luecke, R. W., Simonel, C. E. & Fraker, P. J. (1978) The effect of restricted dietary intake on the antibody mediated response of the zinc deficient A/J mouse. J. Nutr. 108: 881-887. 5. Fraker, P. J., dePasquale-Jardieu, P., Zwickl, C. M. &. Leuke, R. W. (1978) Regeneration of T-cell helper function in zinc deficient adult mice. Proc. Nati. Acad. Sci. USA 75: 5660-5664. b. Beach, R. S., Gershwin, M. E. & Hurley, L. S. (1982) Gestational zinc deprivation in mice: persistence of immunodeficiency for three generations. Science 218: 469-471. 7. Zwickl, C.M. & Fraker, P. J. (1980) Restoration of the antibody mediated response of zinc/caloric deficient neonatal mice. Immunol. Commun. 9: 611-626. 8. Bach, J. F., Dardenne, M., Pleau, J. M. & Bach, M. (1975) Isolation, biochemical characteristics and biological activity of a circulation thymic hormone in the mouse and in the human. Ann. N.Y. Acad. Sci. 249: 186-210. 9. Allen, J. I., Kay, N. E. & McClain, C. J. (1981) Severe zinc de ficiency in humans: association with a reversible T-lymphocyte dysfunction. Ann. Intern. Med. 95: 154-157. 10. Zanzonico, P., Fernandes, G. & Good, R. A. (1981) The dif ferential sensitivity of T-cell and B-cell mitogenesis to in vitro zinc deficiency. Cell. Immunol. 60: 203-211. 11. Fernandes, G., Nair, M., Onoe, K., Tanaka, T., Floyd, R. & Good, R. A. (1979) Impairment of cell-mediated functions by dietary zinc deficiency in mice. Proc. Nati. Acad. Sci. USA 76: 457461. 12. Chandra, R. K. & Au, B. (1980) Single nutrient deficiency and cell-mediated immune responses. I. Zinc. Am. J. Clin. Nutr. 33: 736-738. 13. Hambidge, K. M., Casey, C. E. & Krebs, N. F. (1986) Zinc. In: Trace Elements in Human Health and Animal Nutrition (Mertz, W., ed.), 5th éd.,pp. 1-137, Academic Press, New York, NY. 14. Moynahan, E. J. (1981) Acrodermatitis enteropathica and the immunological role of zinc. Immunodermatology 30: 437-447. 15. Lockitch, G., Singh, V. K., Puterman, M. L., Godolophin, W. L., Sheps, A. S., Tingle, A. J., Wong, F. & Quigley, G. (1987) Age-related changes in humoral and cell-mediated immunity in Down syndrome children living at home. Pediatr. Res. 22: 536540. lé.Duchateau, J., Delepesse, G., Vrijens, R. & Collet, H. (1981) Beneficial effects of oral zinc supplementation on the immune response of old people. Am. J. Med. 70: 10011004. 17. Wagner, P. A., Jernigan, J. A., Bailey, L. B., Nickens, C. & Brazzi G. A. (1983) Zinc nutriture and cell-mediated immunity in the aged. Int. J. Vitam. Nutr. Res. 53: 94-101. 18. Bogden, J. D., Oleske, J. M., Lavenhar, M. A., Munves, E. M., Kemp, P. W., Bruening, K. S., Holding, K. J., Denny, T. N., Guarino, M. A., Krieger, L. M. & Holland, B. K. (1988) Zinc and immunocompetence in elderly people: effects of zinc sup plementation for 3 months. Am. J. Clin. Nutr. 48: 655-663.
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19. Ballester, O. F. & Prasad, A. S. (1983) Anergy, zinc deficiency, and decreased nucleoside phosphorylase activity in patients with sickle cell anemia. Ann. Intern. Med. 98: 180-182. 20. Ades, E. W., Hirson, A. & Morgan, S. K. (1980| Immunological studies in sickle cell disease. I. Analyses of circulating T-lymphocyte subpopulations. Clin. Immunol. Immunopathol. 14: 459-462. 21. Classman, A. B., Deas, D. V., Berlinsky, F. S. & Benne«, C.E. (1980) Lymphocyte blast transformation and peripheral lymphocytes percentages in patients with sickle cell disease. Ann. Clin. Lab. Sci. 10:9-12. 22. Hernandez, P., Cruz, C., Santos, M. N. &.Ballester, J. M. (1980) Immunologie dysfunction in sickle cell anemia. Acta Haematol. (Basel) 63: 156-161. 23. Tapazoglou, E., Prasad, A. S., Hill, G., Brewer, G. J. &. Kaplan, J. (1985) Decreased natural killer cell activity in patients with zinc deficiency and sickle cell disease. J. Lab. Clin. Med. 105: 19-22. 24. Chandra, R. K. (1984) Excessive intake of zinc impairs immune responses. J. Am. Med. Assoc. 252: 1443-1446. 25. Mulhern, S. A., Vessey, A. R., Taylor, G. L. & Magruder, L. E. (1985) Suppression of antibody response by excess dietary zinc exposure during certain stages of ontogeny. Proc. Soc. Exp. Biol. Med. 180: 453-461. 26. Prohaska, J. R. & Lukasewycz, O. A. (1990) Effects of copper deficiency on the immune system. Adv. Exp. Med. Biol. 262: 123-143. 27. Prohaska, J. R. & Lukasewycz, O. A. (1981) Copper deficiency suppresses the immune response of mice. Science 213: 559561. 28. Prohaska, J. R. & Lukasewycz, O. A. (1989) Biochemical and immunological changes in mice following postweaning copper deficiency. Biol. Trace Elem. Res. 22: 101-112. 29. Blakly, B. R. & Hamilton, D. L. (1987) The effect of copper deficiency on the immune response in mice. Drug-Nutr. Interact. 5: 103-111. 30. Vyas, D. & Chandra, R. K. (1983) Thymic factor activity, lym phocyte stimulation response and antibody producing cells in copper deficiency Nutr. Res. 3: 343-349. 31. Failla, M. L., Babu, U. a Seidel, K. E. (1988) Use of immunoresponsiveness to demonstrate that the dietary requirement for copper in young rats is greater with dietary fructose than dietary starch. J. Nutr. 118: 487-496. 32. Koller, L. D., Mulhern, S. A., Frankel, N. C., Steven, M. G. & Williams J. R. (1987) Immune dysfunction in rats fed a diet deficient in copper. Am. J. Clin. Nutr. 45: 997-1006. 33. Jones, D. G. (1984) Effects of dietary copper depletion on acute and delayed inflammatory responses in mice. Res. Vet. Sci. 37: 205-210. 34. Kishore, V., Latman, N., Roberts, D. W., Barnett, J. B. & Sorenson, J. R. (1984) Effect of nutritional copper deficiency on ad juvant arthritis and immunocompetence in the rat. Agents Ac tions 14: 274-282. 35. Lukasewycz, O. A. & Prohaska, J. R. (1982) Immunization against transplantable leukemia impaired in copper deficient mice. J. Nati. Cancer Inst. 69: 489-493. 36. Lukasewycz, O. A. & Prohaska, J. R. (1983) Lymphocytes from copper-deficient mice exhibit decreased mitogen reactivity. Nutr. Res. 3:335-341. 37. Lukasewycz, O. A., Prohaska, J. R., Meyer, S. G., Schmidtke, J. R., Hatfield, S. M. & Marder, P. (1985) Alterations in lym phocyte subpopulations in copper-deficient mice. Infect. Immun. 48: 644-647. 38. Davis, M. A., Johnson, W. T., Briske-Anderson, M. &. Kramer, T. R. (1987) Lymphoid cell functions during copper deficiency. Nutr. Res. 7:211-222. 39. Carelton, W. W. &. Price, P. S. (1983) Dietary copper and the induction of neoplasms in the rat by acetylaminofluorene and dimethylnitrosamine. Food Cosmet. Toxicol. 11: 827-840.
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40. Suttle, N. F. &. Jones, D. G. (1986) Copper and disease resis tance in sheep: a rare natural confirmation of interaction between a specific nutrient and infection. Proc. Nutr. Soc. 45: 317-325. 41. Castollo-Duran, C., Fisberg, A., Vanlenzuela, J. I., Egana, J. I. & Uauay, R. (1983) Controlled trial copper supplementation during the recovery from marasmus. Am. J. Clin. Nutr. 37: 898920. 42. Mackay, H. M. M. (1928) Anaemia in infancy: Its prevalence and prevention. Arch. Dis. Child. 3: 117-147. 43. Andelman, M. B. & Sered, B. R. (1966) Utilization of dietary iron by term infants. Am. J. Dis. Child. 3: 45-55. 44. Masawe, A. E., Muindi, J. M. a Swai, G. B. (1974) Infections in iron deficiency and other types of anaemia in the tropics. Lancet II: 314-317. 45. Murray, M. J., Murray, A. B., Murray, N. J. & Murray, M. B. (1975) Refeeding-malaria and hyperferraemia. Lancet I: 653654. 46. Murray, M. J., Murray, A. B., Murray, M. B. & Murray, C. J. (1978) The adverse effect of iron repletion on the course of certain infections. Br. Med. J. 2: 1113-1115. 47. Barry, D. M. J. & Reeve, A. W. (1977) Increased incidence of gram-negative neonatal sepsis with intramuscular iron admin istration. Pediatrics 60: 908-912. 48. Sherman, A. R. (1984) Iron, infection, and immunity. In: Mal nutrition, Disease Resistance, and Immune Function (Watson, R. R., ed.), Marcel Dekker, New York, NY. 49. Rothenbacher, H. & Sherman, A. R. (1980) Target organ pa thology in iron-deficient suckling rats. J. Nutr. 110: 1648-1654. 50. Kochanowski, B. A. &.Sherman, A. R. (1982) Cellular growth in iron-deficient rat pups. Growth 46: 126-134. 51. Kochanowski, B. A. & Sherman, A. R. (1985) Cellular growth in iron-deficient rats: effect of pre- and postweaning iron reple tion. J. Nutr. 115: 279-287. 52. Hallquist, N. A. Si Sherman, A. R. (1989) Effect of iron defi ciency on the stimulation of natural killer cells by macrophageproduced interferon. Nutr. Res. 9: 282-292. 53. Skikantia, S. G., Bhaskaram, C., Prasad, J. S. &.Krishnamachari, K. A. V. R. (1976) Anaemia and immune response. Lancet II: 1307-1309. 54. Macdougall, L. G., Anderson, R., McNab, G. M. & Katz, J. (1975) The immune response in iron-deficient children: Im paired cellular defense mechanisms with altered humoral com ponents. J. Pediatr. 86: 833-843. 55. Chandra, R. K. (1975) Impaired immunocompetence associated with iron deficiency. J. Pediatr. 86: 899-902. 56. Bagchi, K., Mohanram, M. & Reddy, V. (1980) Humoral im mune response in children with iron-deficiency anaemia. Br. Med. J. 280: 1249-1251. 57. Sherman, A. R. (1984) Immunoglobulins and lysozyme in irondeficient and iron-overloaded rats. Nutr. Rep. Int. 29: 859-868. 58. Nalder, B. N., Wahoney, A. W., Ramakrishnan, R. &.Hendricks, D. G. (1972) Sensitivity of the immunological response to the nutritional status of rats. J. Nutr. 102: 535-542. 59. Kochanowski, B. A. & Sherman, A. R. (1985) Decreased an tibody formation in iron-deficient rat pups—effect of iron re pletion. Am. J. Clin. Nutr. 41: 278-284. 60. Sherman, A. R. (1990) Influence of iron on immunity and dis ease resistance. Ann. N.Y. Acad. Sci. 587: 140-146. 61. Kochanowski, B. A. &. Sherman, A. R. (1982) Serum and se cretory proteins in iron-deficient rat pups and dams. Nutr. Res. 2: 689-698. 62. Sherman, A. R. &.Wolinsky, I. (1978) Lysozyme levels in tis sues of iron-deficient rats. Experientia 34: 367-368. 63. Wolinsky, I. & Sherman, A. R. (1979) Maternal and neo-natal tissue lysozyme levels: Effects of iron nutriture in rats. Proc. Soc. Exp. Biol. Med. 162: 369-373.
SYMPOSIUM: HISTORY OF NUTRITIONAL 64. Kochanowski, B. A. & Sherman, A. R. (1984) Phagocytosis and lysozyme activity in granulocytes from iron-deficient rat dams and pups. Nutr. Res. 4: 511-520. 65. Kuvibidila, S., Nauss, K. M., Baliga, B. S. & Suskind, R. M. j 1983| Impairment of blastogenic response of splenic lympho cytes from iron-deficient mice: In vivo repletion. Am. J. Clin. Nutr. 37: 15-25. 66. Buckley, R. H. (1975) Iron deficiency anemia: Its relationship to infection susceptibility and host defense. J. Pediatr. 86: 993995. 67. Chandra, R. K. (1976) Immune response in iron-deficient chil dren. J. Pediatr. 88: 698-699. 68. Chandra, R. K. (1976) Iron-deficiency anaemia and immunological responses. Lancet II: 1200-1201.
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69. Krantman,
70.
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609 C. M.,
Rachelefsky, G. S. & Stiehm, E. R. (1982) Immune function in pure iron deficiency. Am. J. Dis. Child. 136: 840-844. Sherman, A. R. & Lockwood, J. (1987) Impaired natural killer cell activity in iron-deficient rat pups. J. Nutr. 117: 567571. Lockwood, J. & Sherman, A. R. (1988) Spleen natural killer cells from iron-deficient rat pups manifest an altered ability to be stimulated by interferon. J. Nutr. 118: 1558-1563. Helyar, L. & Sherman, A. R. (1987) The effect of iron deficiency on interleukin 1 production by rat leukocytes. Am. J. Clin. Nutr. 46: 346-452. Rosch, L. M., Sherman, A. R. & Layman, D. K. (1987) Iron deficiency impairs protein synthesis in immune tissues of rat pups. J. Nutr. 117: 1475-1481.
History of Nutritional Immunology
Zinc, Copper, and Iron Nutriture and Immunity12 ADRIA R. SHERMAN3 Department of Nutritional Sciences, Rutgers University, Cook College, New Brunswick, /VJ 08903 was caused by defective absorption of zinc (2). The major causes of death in this disease are all linked to immunodeficiency, which is prevented by zinc sup plementation. The first report of dietary zinc deficiency inducing thymic atrophy and loss of T helper cell function was published by Fraker et al (3). She and Luecke went on to show that it was zinc deficiency and not the reduced food intake or reduced growth associated with feeding a zinc-deficient diet that was responsible for atrophy of thymus and spleen. Their experiments also dem onstrated a decreased production of antibody to sheep red blood cells (SRBC),4 a T-dependent antigen (4). Parenteral T cell infusions corrected the defects in an tibody production (5). Additional manifestations of altered humoral re sponse include distorted serum immunoglobulin (Ig) profiles resulting from prenatal and postnatal zinc de ficiency (6). Dietary zinc deficiency in neonatal mice also impairs antibody production to sheep red blood cells (7). Repletion with zinc results in a normalization of IgM plaque response and an elevation of the IgG response. Cell-mediated immunity is also altered by zinc de ficiency. Delayed hypersensitivity to skin-test antigen is often compromised in the zinc-deficient state. Both thymic hormone and Thyl positive lymphocytes may be lowered in zinc deficiency (8). T lymphocyte pro-
ABSTRACT Inadequate nutritore of zinc, copper and iron alter immunocompetence in humans and experi mental animals. For each of these minerals deficient status leads to increased susceptibility to infectious illnesses. Specific components of the immune response may be altered in a variety of patients and models. Although many generalized functions for these nutrients could lead to altered immune function, specific functions for these minerals in immunity have not yet been iden tified. For zinc, copper and iron the importance of ad equate nutrition in maintaining immunocompetency cannot be understated. J. Nutr. 122: 604-609, 1992. INDEXING KEY WORDS:
•iron •copper •zinc •infection •immunity
In this paper the influences of zinc, copper and iron on immunity will be discussed. Deficiencies of these trace elements alter immunity and susceptibility to infection. The discussion will emphasize human nu trition, although more mechanistic research in this field has used rodent models. The intent is to highlight the major aspects of the topic rather than to present an all inclusive history.
ZINC
1 Presented as part of a symposium:
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. 2 This is New Jersey Agricultural Experiment Station publication number D-14150-1-92. 3 To whom correspondence should be addressed: Department of
The association of zinc with immunity was first documented with the discovery of human zinc defi ciency by Prasad et al. (1).Along with the characteristic hypogonadism and dwarfism, zinc-deficient adolescent males experienced increased susceptibility to infec tion. Later, a lethal mutation in Holstein-Fresian cattle was found responsible for the failure to both absorb zinc and develop a thymus. These immunodeficient cattle could be treated with zinc and symptoms could be prevented. Further evidence for zinc's role in im munity came from the discovery that the inborn error in human metabolism, acrodermatitis enteropathica, 0022-3166/92
History of Nutritional
Nutritional Sciences, Rutgers University, Cook College, P.O. Box 231, New Brunswick, NJ 08903-0231. 4 Abbreviations: SRBC, sheep red blood cells; PHA, phytohemaglutinin; NK, natural killer; DTH, delayed type hypersensitivity.
$3.00 ©1992 American Institute of Nutrition.
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liferation in response to a mitogen phytohemaglutinin (PHA) was reduced in patients maintained on parenteral hyperalimentation that did not contain zinc (9). T cell proliferation markedly improved after intra venous zinc repletion. In vitro zinc deficiency can be produced by adding EDTA to spleen cell cultures. T cell proliferation after stimulation with either PHA or concanavalin A was decreased in this zinc-deficient system, whereas no change in B cell proliferation in response to LPS B was found (10). Natural killer (NK) cells are active against tumor cells and viral infections. What effects zinc has on NK cells is unclear with both lowered (11) and increased activity reported (12). Increased attention has been focused on a number of clinical situations where zinc deficiency is likely to occur. Humans with low serum zinc levels are thought to have an increased susceptibility to a number of in fectious diseases (13). The inborn error in metabolism resulting in acrodermatitis enteropathica is an autosomal recessive impairment in zinc absorption. The disease manifests at weaning when highly bioavailable zinc in human milk is replaced with less available zinc. Defects in immunity resulting from the zinc deficiency in this disease include lowered lymphocyte response to PHA, lowered delayed type hypersensitivity and an increased incidence in infectious diseases (14). Both the zinc deficiency and immunodeficiency of acroder matitis enteropathica are corrected with zinc supple mentation. Secondary zinc deficiencies ranging from mild subclinical states to severe states have been ob served in Down syndrome, aging, sickle cell anemia and in patients on hemodialysis or total parenteral nu trition. Down syndrome patients are at risk for au toimmune diseases and often have low serum zinc levels. Some improvements in immunologie func tion occurred in Down patients supplemented with zinc (15). During aging there is a considerable loss in both immunologie function and zinc status. Several inves tigators tested the hypothesis that zinc supplementa tion can improve immune function in elderly patients. Some investigators reported improvement in cellular immunity with zinc supplementation (16, 17). A re cent report by Bogden et al. (18) however did not find a significant immunologie benefit from zinc supple mentation in an elderly population. In patients with sickle cell anemia, hypogonadism and growth retardation are associated with zinc defi ciency. Ballester and Prasad (19) reported impaired cell-mediated immunity as indicated by skin test anergy. Patients with sickle cell anemia also show de fective mitogen responsiveness in vitro and higher percentages of T suppressor cells compared with nor mal subjects (20-22). Impaired NK cell cytotoxicity found in patients with sickle cell disease is improved with zinc supplementation (23). Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/604/4755216 by guest on 07 March 2018
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Overzealous use of zinc supplements should be avoided, because Chandra (24) found that adult men supplemented with 150 mg of elemental zinc had re duced lymphocyte proliferation as well as lowered chemotaxic and phagocytic activities. Mulhern et al. (25) found that, in mice, antibody responsiveness to SRBC antigen is markedly impaired by excessive di etary zinc. To date the exact role of zinc in the immune re sponse is unknown. Zinc has many biochemical func tions that could contribute toward maintenance of normal immune processes. Both direct and indirect roles of zinc in immunity are possible. Direct partic ipation of zinc in regulatory activities related to im munity include its function in maintaining the bio logical activity of thymulin. The importance of zinc in DNA polymerase and RNA polymerase suggest a potential role for zinc in the regulation of gene expres sion for cellular differentiation and proliferation, for mediator factors and for regulatory compounds of the immune response. Similarly, the requirement of zinc for normal cellular replication and growth has a pro found impact on the rapidly proliferating cells of the immune system. Dozens of metalloenzymes require zinc for function. Obviously, numerous reactions contribute an effective immune response where zinc metalloenzymes could participate.
COPPER
Although copper deficiency in humans is rare, sev eral reports of increased infectious illness with copper deficiency led to the investigation of the role of copper in immunity (26). Prohaska and Lukasewycz (27) were the first to report that components of the immune re sponse are altered in experimental copper deficiency. Markedly impaired plaque formation to SRBC was shown in male and female mice fed diets low in copper. The defective antibody production of copper defi ciency has been confirmed by Prohaska and Lukase wycz (28) and others (29-32) in mice and rats treated with a variety of antigens. Cell-mediated immunity has been studied in ex perimental copper deficiency by measuring delayedtype hypersensitivity (DTH) reactions. DTH reactions have been reported to be enhanced in copper-deficient mice (33), normal in copper-deficient rats (32) or sup pressed (34). Although these in vivo indicators of cellmediated immunity have yielded contradictory re sults, Lukasewycz and Prohaska (35) found that mor tality was high when T cell-dependent immunity to syngenic malignant lymphocytes was studied. Splenic lymphocytes from copper-deficient animals have low ered proliferation in response to a variety of both T and B cell antigens (28, 29, 36-38).
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Koller et al. (32) reported that NK cell cytotoxicity, another cell-mediated function, is impaired in copperdeficient rats. This observation may in part explain the increased incidence of extrahepatic tumors seen in copper-deficient rats treated with carcinogens com pared with rats fed excessive copper (39). Impaired NK activity is not due to the immunosupressive effects of prostaglandin E2, which is normal in copper-defi cient rats (32). The lowered cell-mediated functions in copper de ficiency may be related to distorted lymphocyte pop ulations and subpopulations. Lukasewycz et al. (37) reported that spleens of copper-deficient mice have relatively higher B cells and lower T cells. The T helper cell subset seemed to be particularly effected. These observations were confirmed by Koller et al. (32). Copper deficiency, although not a serious public health problem, does occur in livestock and in some human clinical situations. Scottish Blackface lambs are genetically predisposed to low copper status and to increased mortality resulting from bacterial infections (40). Copper supplementation beginning at 6 wk markedly increases survival in these lambs. Copper supplementation is also effective in reducing the in cidence of lower respiratory tract infections in infants recovering from marasmus (41). Of clinical impor tance, use of total parenteral nutrition solutions with inadequate copper can lead to copper deficiency and immune dysfunctions. Preterm infants are also at risk for copper deficiency. Menkes Kinky Hair syndrome is an x-chromosome-linked inborn error in metabo lism that leads to copper deficiency. Menkes patients often develop pulmonary and urinary tract infections. Almost always lethal, the cause of death in Menkes syndrome is often bronchopneumonia. Patients are responsive to copper supplementation. Another situ ation where clinical copper deficiency can be problem atic is that created secondary to overzealous supple mentation with zinc. Popular self-medication with mineral supplements can thus lead to serious conse quences. Although it is clear that copper nutriture is impor tant in immunity, it is unclear what precisely is the element's biochemical role. Copper has numerous known biochemical functions, including its role in ferroxidases, cytochrome c oxidase, zinc-copper superoxide dismutase and many other metalloenzymes. Whether copper's role in immunity is via known functions of copper or in yet to be discovered capac ities is unknown at this time.
IRON The earliest research on iron and immunity showed that iron deficiency is associated with increased infec Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/604/4755216 by guest on 07 March 2018
tious diseases in infancy. Mackay (42) was the first to observe that infants given iron supplements had 50% fewer respiratory and gastrointestinal infections than infants given no iron. Andelman and Sered (43) fed either iron-fortified formula or evaporated milk for mula to term infants of lower socioeconomic status during their first 18 mo of life. The incidence of both iron-deficiency anemia and respiratory infections was highest in the group fed the evaporated milk with lower iron content. A number of field studies conducted in the 1970s suggested that iron deficiency provides a protection from infection and that iron repletion reverses this protection (44-46). Although these reports are often cited in support of a protection against infection af forded by mild iron deficiency, a more plausible al ternate interpretation of the observations is that ex cessive iron is associated with increased infectious illness. For example, the Murrays (46) repleted irondeficient Somali nomads, whose diet is all milk, with 900 mg of ferrous sulfate daily. The reported increase in infections after iron treatment may in fact be due to the hyperferremia associated with iron intakes 10fold greater than required. Prophylactic administration of large doses of parenteral iron to iron-deficient Poly nesian infants in New Zealand has also been associated with increased infection (47). A delicate balance exists between the need for iron for host defense mechanisms and the need for iron to sustain microbial growth (48). Most research in the late 1970s and 1980s focused on the role of iron in components of the host immune response. Anatomical and structural changes in immunologically important tissues have been found in experi mental iron deficiency. In iron deficiency there is thymic atrophy (49) and reduced cellularity of the thy mus (50), which is not reversed with iron repletion (51). In neonates, splenic development is retarded in iron deficiency (49), but in adult rats fed an iron-de ficient diet after weaning, splenomegaly is often ob served (52). Circulating T lymphocytes are reduced in iron deficiency (53). Humoral immunity has been studied in both irondeficient humans and iron-deficient animals. Circu lating Ig levels in children with iron-deficiency anemia appear to be unaffected (54-56). Serum levels of IgG and IgM have been reported to actually increase slightly in iron deficiency in adult rats (57). The level of circulating Ig, however, is not a reflection of recent, specific antibody production. When humoral immu nity is measured as antibody titers in response to an immunization (58) or as plaque formation in response to SRBC antigens (59, 60), iron-deficient rats do not mount a normal response. Components of nonspecific immunity may be al tered by iron deficiency. Milk and salivary secretory IgA levels are protected in iron-deficient rat pups and
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dams (61). Lysozyme is another component of secre tory immunity with bactericidal activity. Increased levels of lysozyme have been found in serum and spleen of iron-deficient rat pups (62) and in kidney of iron-deficient adult rats (63). Phagocytosis by granulocytes is a cellular component of nonspecific immu nity, which is altered in iron-deficient rat pups (64). Iron deficiency has a marked effect on cell-mediated immunity. Lymphocyte blastogenesis is impaired in splenocytes of iron-deficient weanling mice (65). Irondeficient children also have lower lymphocyte blas togenesis (54, 66-68). Delayed type hypersensitivity reactions to skin test antigens may be low in irondeficient children (54, 55, 69). NK cell activity is depressed in iron-deficient rats (52, 70). The mechanism responsible for lowered NK activity is not known. Because interferon stimulates NK cytotoxicity, defective responsiveness to inter feron may explain the observed NK activity in iron deficiency. NK cytotoxicity was not fully restored by addition in vitro of either alpha/beta interferon (71) or addition of interferon containing supernatants from macrophages (52). This suggests that in iron deficiency there may be a limited capacity in NK cells to be stim ulated by interferon. Several soluble proteinous mediators of immunity are lowered by dietary iron deficiency in rodents. Interleukin 1, produced by activated macrophages, in duces the fever of infection and also intensifies the activity of T helper cells to produce interleukin 2. In iron-deficient rats, peritoneal macrophage production of interleukin 1 is impaired (72). Interleukin 2 activity is lowered in iron-deficient rats (unpublished data). Whether the role of iron in immunity is distinct from the more general biochemical functions of iron is unknown at the present time. As part of the cytochromes, hemoglobin and myoglobin, iron plays an important role in energy metabolism of all cells. Spe cific iron metalloenzymes that play roles in immunity include catalase and peroxidases. In addition, iron is part of dozens of other metalloproteins important to cellular metabolism. Iron deficiency may result in lowered protein synthesis in immunologically impor tant issues (73). Impaired protein synthesis could be a mechanism of central importance whereby iron de ficiency impairs the immune response system. Because iron deficiency is the most prevalent nu tritional disorder in the world and because it is most common in women of reproductive age and their chil dren, the implications of dysfunctional immunity re sulting from iron deficiency are vast. Although the history of nutritional immunology is recent and mechanistic information pertaining to the role of trace elements in immunity is scant, it is clear that adequate status of zinc, copper and iron is essen tial for maintaining immunocompetence. Challenges for the future include elucidation of the roles of these Downloaded from https://academic.oup.com/jn/article-abstract/122/suppl_3/604/4755216 by guest on 07 March 2018
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trace elements in immune processes, specific roles in disease states and, most importantly, prevention of deficiency states. LITERATURE CITED 1. Prasad, A. S., Miale, A., Farid, Z., Sandstead, H. H. & Schulen, A. R. (1963| Zinc metabolism in normals and patients with the syndrome of iron deficiency anemia, hepatosplenomegaly, dwarh'sm and hepogonadism. J. Lab. Clin. Med. 61: 537-549. 2. Moynahan, E. J. & Barnes, P. M. (1973) Zinc deficiency and a synthetic diet for lactose intolerance. Lancet I: 676-677. 3. Fraker, P. J., Haas, S. M. & Leucke, R. W. (1977] Effect of zinc deficiency on the immune response of the young adult A/J mouse. J. Nutr. 107: 1889-1895. 4. Luecke, R. W., Simonel, C. E. & Fraker, P. J. (1978) The effect of restricted dietary intake on the antibody mediated response of the zinc deficient A/J mouse. J. Nutr. 108: 881-887. 5. Fraker, P. J., dePasquale-Jardieu, P., Zwickl, C. M. &. Leuke, R. W. (1978) Regeneration of T-cell helper function in zinc deficient adult mice. Proc. Nati. Acad. Sci. USA 75: 5660-5664. b. Beach, R. S., Gershwin, M. E. & Hurley, L. S. (1982) Gestational zinc deprivation in mice: persistence of immunodeficiency for three generations. Science 218: 469-471. 7. Zwickl, C.M. & Fraker, P. J. (1980) Restoration of the antibody mediated response of zinc/caloric deficient neonatal mice. Immunol. Commun. 9: 611-626. 8. Bach, J. F., Dardenne, M., Pleau, J. M. & Bach, M. (1975) Isolation, biochemical characteristics and biological activity of a circulation thymic hormone in the mouse and in the human. Ann. N.Y. Acad. Sci. 249: 186-210. 9. Allen, J. I., Kay, N. E. & McClain, C. J. (1981) Severe zinc de ficiency in humans: association with a reversible T-lymphocyte dysfunction. Ann. Intern. Med. 95: 154-157. 10. Zanzonico, P., Fernandes, G. & Good, R. A. (1981) The dif ferential sensitivity of T-cell and B-cell mitogenesis to in vitro zinc deficiency. Cell. Immunol. 60: 203-211. 11. Fernandes, G., Nair, M., Onoe, K., Tanaka, T., Floyd, R. & Good, R. A. (1979) Impairment of cell-mediated functions by dietary zinc deficiency in mice. Proc. Nati. Acad. Sci. USA 76: 457461. 12. Chandra, R. K. & Au, B. (1980) Single nutrient deficiency and cell-mediated immune responses. I. Zinc. Am. J. Clin. Nutr. 33: 736-738. 13. Hambidge, K. M., Casey, C. E. & Krebs, N. F. (1986) Zinc. In: Trace Elements in Human Health and Animal Nutrition (Mertz, W., ed.), 5th éd.,pp. 1-137, Academic Press, New York, NY. 14. Moynahan, E. J. (1981) Acrodermatitis enteropathica and the immunological role of zinc. Immunodermatology 30: 437-447. 15. Lockitch, G., Singh, V. K., Puterman, M. L., Godolophin, W. L., Sheps, A. S., Tingle, A. J., Wong, F. & Quigley, G. (1987) Age-related changes in humoral and cell-mediated immunity in Down syndrome children living at home. Pediatr. Res. 22: 536540. lé.Duchateau, J., Delepesse, G., Vrijens, R. & Collet, H. (1981) Beneficial effects of oral zinc supplementation on the immune response of old people. Am. J. Med. 70: 10011004. 17. Wagner, P. A., Jernigan, J. A., Bailey, L. B., Nickens, C. & Brazzi G. A. (1983) Zinc nutriture and cell-mediated immunity in the aged. Int. J. Vitam. Nutr. Res. 53: 94-101. 18. Bogden, J. D., Oleske, J. M., Lavenhar, M. A., Munves, E. M., Kemp, P. W., Bruening, K. S., Holding, K. J., Denny, T. N., Guarino, M. A., Krieger, L. M. & Holland, B. K. (1988) Zinc and immunocompetence in elderly people: effects of zinc sup plementation for 3 months. Am. J. Clin. Nutr. 48: 655-663.
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19. Ballester, O. F. & Prasad, A. S. (1983) Anergy, zinc deficiency, and decreased nucleoside phosphorylase activity in patients with sickle cell anemia. Ann. Intern. Med. 98: 180-182. 20. Ades, E. W., Hirson, A. & Morgan, S. K. (1980| Immunological studies in sickle cell disease. I. Analyses of circulating T-lymphocyte subpopulations. Clin. Immunol. Immunopathol. 14: 459-462. 21. Classman, A. B., Deas, D. V., Berlinsky, F. S. & Benne«, C.E. (1980) Lymphocyte blast transformation and peripheral lymphocytes percentages in patients with sickle cell disease. Ann. Clin. Lab. Sci. 10:9-12. 22. Hernandez, P., Cruz, C., Santos, M. N. &.Ballester, J. M. (1980) Immunologie dysfunction in sickle cell anemia. Acta Haematol. (Basel) 63: 156-161. 23. Tapazoglou, E., Prasad, A. S., Hill, G., Brewer, G. J. &. Kaplan, J. (1985) Decreased natural killer cell activity in patients with zinc deficiency and sickle cell disease. J. Lab. Clin. Med. 105: 19-22. 24. Chandra, R. K. (1984) Excessive intake of zinc impairs immune responses. J. Am. Med. Assoc. 252: 1443-1446. 25. Mulhern, S. A., Vessey, A. R., Taylor, G. L. & Magruder, L. E. (1985) Suppression of antibody response by excess dietary zinc exposure during certain stages of ontogeny. Proc. Soc. Exp. Biol. Med. 180: 453-461. 26. Prohaska, J. R. & Lukasewycz, O. A. (1990) Effects of copper deficiency on the immune system. Adv. Exp. Med. Biol. 262: 123-143. 27. Prohaska, J. R. & Lukasewycz, O. A. (1981) Copper deficiency suppresses the immune response of mice. Science 213: 559561. 28. Prohaska, J. R. & Lukasewycz, O. A. (1989) Biochemical and immunological changes in mice following postweaning copper deficiency. Biol. Trace Elem. Res. 22: 101-112. 29. Blakly, B. R. & Hamilton, D. L. (1987) The effect of copper deficiency on the immune response in mice. Drug-Nutr. Interact. 5: 103-111. 30. Vyas, D. & Chandra, R. K. (1983) Thymic factor activity, lym phocyte stimulation response and antibody producing cells in copper deficiency Nutr. Res. 3: 343-349. 31. Failla, M. L., Babu, U. a Seidel, K. E. (1988) Use of immunoresponsiveness to demonstrate that the dietary requirement for copper in young rats is greater with dietary fructose than dietary starch. J. Nutr. 118: 487-496. 32. Koller, L. D., Mulhern, S. A., Frankel, N. C., Steven, M. G. & Williams J. R. (1987) Immune dysfunction in rats fed a diet deficient in copper. Am. J. Clin. Nutr. 45: 997-1006. 33. Jones, D. G. (1984) Effects of dietary copper depletion on acute and delayed inflammatory responses in mice. Res. Vet. Sci. 37: 205-210. 34. Kishore, V., Latman, N., Roberts, D. W., Barnett, J. B. & Sorenson, J. R. (1984) Effect of nutritional copper deficiency on ad juvant arthritis and immunocompetence in the rat. Agents Ac tions 14: 274-282. 35. Lukasewycz, O. A. & Prohaska, J. R. (1982) Immunization against transplantable leukemia impaired in copper deficient mice. J. Nati. Cancer Inst. 69: 489-493. 36. Lukasewycz, O. A. & Prohaska, J. R. (1983) Lymphocytes from copper-deficient mice exhibit decreased mitogen reactivity. Nutr. Res. 3:335-341. 37. Lukasewycz, O. A., Prohaska, J. R., Meyer, S. G., Schmidtke, J. R., Hatfield, S. M. & Marder, P. (1985) Alterations in lym phocyte subpopulations in copper-deficient mice. Infect. Immun. 48: 644-647. 38. Davis, M. A., Johnson, W. T., Briske-Anderson, M. &. Kramer, T. R. (1987) Lymphoid cell functions during copper deficiency. Nutr. Res. 7:211-222. 39. Carelton, W. W. &. Price, P. S. (1983) Dietary copper and the induction of neoplasms in the rat by acetylaminofluorene and dimethylnitrosamine. Food Cosmet. Toxicol. 11: 827-840.
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40. Suttle, N. F. &. Jones, D. G. (1986) Copper and disease resis tance in sheep: a rare natural confirmation of interaction between a specific nutrient and infection. Proc. Nutr. Soc. 45: 317-325. 41. Castollo-Duran, C., Fisberg, A., Vanlenzuela, J. I., Egana, J. I. & Uauay, R. (1983) Controlled trial copper supplementation during the recovery from marasmus. Am. J. Clin. Nutr. 37: 898920. 42. Mackay, H. M. M. (1928) Anaemia in infancy: Its prevalence and prevention. Arch. Dis. Child. 3: 117-147. 43. Andelman, M. B. & Sered, B. R. (1966) Utilization of dietary iron by term infants. Am. J. Dis. Child. 3: 45-55. 44. Masawe, A. E., Muindi, J. M. a Swai, G. B. (1974) Infections in iron deficiency and other types of anaemia in the tropics. Lancet II: 314-317. 45. Murray, M. J., Murray, A. B., Murray, N. J. & Murray, M. B. (1975) Refeeding-malaria and hyperferraemia. Lancet I: 653654. 46. Murray, M. J., Murray, A. B., Murray, M. B. & Murray, C. J. (1978) The adverse effect of iron repletion on the course of certain infections. Br. Med. J. 2: 1113-1115. 47. Barry, D. M. J. & Reeve, A. W. (1977) Increased incidence of gram-negative neonatal sepsis with intramuscular iron admin istration. Pediatrics 60: 908-912. 48. Sherman, A. R. (1984) Iron, infection, and immunity. In: Mal nutrition, Disease Resistance, and Immune Function (Watson, R. R., ed.), Marcel Dekker, New York, NY. 49. Rothenbacher, H. & Sherman, A. R. (1980) Target organ pa thology in iron-deficient suckling rats. J. Nutr. 110: 1648-1654. 50. Kochanowski, B. A. &.Sherman, A. R. (1982) Cellular growth in iron-deficient rat pups. Growth 46: 126-134. 51. Kochanowski, B. A. & Sherman, A. R. (1985) Cellular growth in iron-deficient rats: effect of pre- and postweaning iron reple tion. J. Nutr. 115: 279-287. 52. Hallquist, N. A. Si Sherman, A. R. (1989) Effect of iron defi ciency on the stimulation of natural killer cells by macrophageproduced interferon. Nutr. Res. 9: 282-292. 53. Skikantia, S. G., Bhaskaram, C., Prasad, J. S. &.Krishnamachari, K. A. V. R. (1976) Anaemia and immune response. Lancet II: 1307-1309. 54. Macdougall, L. G., Anderson, R., McNab, G. M. & Katz, J. (1975) The immune response in iron-deficient children: Im paired cellular defense mechanisms with altered humoral com ponents. J. Pediatr. 86: 833-843. 55. Chandra, R. K. (1975) Impaired immunocompetence associated with iron deficiency. J. Pediatr. 86: 899-902. 56. Bagchi, K., Mohanram, M. & Reddy, V. (1980) Humoral im mune response in children with iron-deficiency anaemia. Br. Med. J. 280: 1249-1251. 57. Sherman, A. R. (1984) Immunoglobulins and lysozyme in irondeficient and iron-overloaded rats. Nutr. Rep. Int. 29: 859-868. 58. Nalder, B. N., Wahoney, A. W., Ramakrishnan, R. &.Hendricks, D. G. (1972) Sensitivity of the immunological response to the nutritional status of rats. J. Nutr. 102: 535-542. 59. Kochanowski, B. A. & Sherman, A. R. (1985) Decreased an tibody formation in iron-deficient rat pups—effect of iron re pletion. Am. J. Clin. Nutr. 41: 278-284. 60. Sherman, A. R. (1990) Influence of iron on immunity and dis ease resistance. Ann. N.Y. Acad. Sci. 587: 140-146. 61. Kochanowski, B. A. &. Sherman, A. R. (1982) Serum and se cretory proteins in iron-deficient rat pups and dams. Nutr. Res. 2: 689-698. 62. Sherman, A. R. &.Wolinsky, I. (1978) Lysozyme levels in tis sues of iron-deficient rats. Experientia 34: 367-368. 63. Wolinsky, I. & Sherman, A. R. (1979) Maternal and neo-natal tissue lysozyme levels: Effects of iron nutriture in rats. Proc. Soc. Exp. Biol. Med. 162: 369-373.
SYMPOSIUM: HISTORY OF NUTRITIONAL 64. Kochanowski, B. A. & Sherman, A. R. (1984) Phagocytosis and lysozyme activity in granulocytes from iron-deficient rat dams and pups. Nutr. Res. 4: 511-520. 65. Kuvibidila, S., Nauss, K. M., Baliga, B. S. & Suskind, R. M. j 1983| Impairment of blastogenic response of splenic lympho cytes from iron-deficient mice: In vivo repletion. Am. J. Clin. Nutr. 37: 15-25. 66. Buckley, R. H. (1975) Iron deficiency anemia: Its relationship to infection susceptibility and host defense. J. Pediatr. 86: 993995. 67. Chandra, R. K. (1976) Immune response in iron-deficient chil dren. J. Pediatr. 88: 698-699. 68. Chandra, R. K. (1976) Iron-deficiency anaemia and immunological responses. Lancet II: 1200-1201.
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69. Krantman,
70.
71.
72.
73.
IMMUNOLOGY H. J., Young, S. R., Ank, B. J., O'Donnell,
609 C. M.,
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