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Iron, immunity, and infection: is there a causal link?
Clinical Research Center, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA Department of Pediatrics, Memorial University of Newfoundland, St. John's, Newfoundland, Canada
The relationship between nutritional status, immune response, and susceptibility to infection has been the focus of considerable recent investigation. It is generally accepted that moderate to severe malnutrition results in a variable impairment of several aspects of immunocompetence, most notably cell-mediated immunity, phagocyte bactericidal activity, complement system, opsonization, and mucosal immunity. Whereas these effects are well documented in protein-energy undernutrition (1), data on specific single nutrient deficiencies are less clear.
The ubiquitous iron is an essential nutrient for most tissue cells and its deficiency brings about recognizable deleterious results affecting many organs. The Iymphoid apparatus is no exception. Iron deficiency, with or without anaemia, is associated with partial atrophy of various Iymphoid organs and alterations in many molecular and cellular immune functions. This is not surprising, because a number of key tissue enzymes contain iron or are influenced by iron-containing co-factors. On the other hand, iron is also essential for microbial growth. Bacteria, with the sole exception of the lactobacilli, require iron for multiplication; availability of iron is ensured through the help of iron-chelating siderophores present on the bacterial cell surface that compete for iron with iron-binding proteins such as transferrin and lactoferrin. The balance of these apparently opposing effects of iron on the immunocompetence of the host and microbial growth determines the direction in which the eternal contest between the invader and the host will be decided (2, 3).
PREVALENCE AND CAUSES OF IRON DEFICIENCY
Nutritional anaemia is a common, world-wide deficiency syndrome. The prevalence of iron-responsive microcytic, hypochromic anaemia varies from 9 to 70 per cent in different population groups examined (4). Understandably, the incidence is higher in less developed countries and in underprivileged segments of populations in the industrialized world. Nutritional surveys using haemoglobin, red blood cell indices, transferrin saturation, free erythrocyte protoporphyrin, and serum ferritin as criteria for the diagnosis of clinical and subclinical iron deficiency have revealed prevalence figures of 2.3 to 27.g percent in Canada and the United States. The functional implications of depleted iron stores without any change in haemoglobin concentration or red blood cell morphology are not clear. It is known, however, that anaemia is a late manifestation of iron deficiency and that changes in enzyme activity and cellular function can be detected well before any change in erythropoiesis.
Many parasitic diseases, as well as dietary and cultural practices, can result in iron undernutrition. Poverty dictates a lower intake of iron-rich meats and vegetables. Moreover, the big-availability of iron in different foods varies considerably. Parasitic infestations, particularly hookworm disease, and other infections increase iron losses. Low birth-weight infants have smaller stores of iron and are more prone to develop iron deficincy. In industrialized countries, the common causes of iron deficiency include consumption of highly refined foods, use of aluminium and steel cookware rather than iron utensils, and chronic occult blood loss in the gut because of regular intake of aspirin or chronic gastro-intestinal disease.
MOLECULAR AND CELLULAR EFFECTS OF IRON DEFICIENCY
Iron deficiency, even subclinical depletion of iron stores, is causally associated with many tissue changes (5). Flattening and spooning of nails, gastric mucosal atrophy, keratinization of buccal mucous membrane, smooth tongue with flattened papillae, shorted intestinal villus height, and atrophy of Iymphoid organs have been documented in iron-deficient individuals. These morphological alterations probably underlie the symptoms of dysphagia and increased susceptibility to fungal infections of mucosae.
The molecular basis of iron-related functional changes has been extensively investigated. A variety of critically important enzymes contain iron or are modulated by iron containing cofactors. These include aconitase, catalase, cytochrome C, cytochrome C reductase, cytochrome oxidase, succinic dehydrogenase, formiminotransferase, peroxidase, xanthine oxidase, and tryptophan pyrrolase. Iron is needed for ribonucleotide reductase that reduces the sugar group of nucleotides to corresponding deoxy derivatives, the precursors of DNA. If this enzyme is decreased, DNA synthesis will be impaired with resultant effects on all cell functions. In the case of phagocytic cells, reduction in myeloperoxidase activity and oxygen generating metabolic pathways in iron deficiency may compromise bactericidal capacity. Furthermore, the microbial killing is considered to go through a free-radical process in which iron is of great importance, being the efficient catalyst in free-radical chain processes.
HOST RESISTANCE FACTORS
Many mechanical, biochemical, and cellular barriers protect us from pathogens. Skin and its fatty acid coating, mucosae with the overlying mucus layer and ciliary activity, gastric acidity, and Iysozyme are some of the important nonspecific mechanisms. Phagocytes, both polymorphonuclear leukocytes and tissue macrophages, are the next line of defence for micro-organisms that have passed through the mechanical barriers. The complement system helps in the amplification and modulation of the immune response by attracting leukocytes to the site of inflammatory response. Interferon prevents entry of viruses into healthy cells. Finally, there are two tiers of antigen-specific immunity: first, antibodies of five major classes produced by the B lymphocyte-plasma cell system-these bind to microorganisms, preventing penetration into tissues and promoting their clearance by the reticuloendothelial system; secondly, T Iymphocyte-mediated immunity, which is responsible for delayed hypersensitivity, for the production of many soluble chemical factors influencing immune response, and for cytotoxicity of target cells. It must be pointed out that, although these components of immunity have been individually listed, they often act in a synergistic fashion or occasionally as feedback influence to control the intensity of immune response.
Four types of observations have been made in studying the relationship of iron status to the incidence of infectious disease: (i) the clinical impression of doctors and other health professionals that iron-deficient individuals have a different incidence of infections than that experienced by iron-replete ones; (ii) prospective surveys of morbidity patterns of selected population groups with significant prevalence of iron deficiency-for exeample, a survey of construction and plantation workers in Indonesia revealed a higher prevalence of acute and chronic infections in the iron-deficient anaemic group compared with the non anaemic group (6); (iii) comparison of the frequency of clinical and subclinical iron under-nutrition in subjects with certain types of infections-for instance, adults with recurrent herpes labialis showed a higher incidence of iron deficiency than matched controls who did not manifest herpes infection (3); patients with chronic and subacute mucocutaneous moniliasis were reported to have moderate to severe iron deficiency anaemia (7), but the infection rapidly cleared on oral iron therapy; (iv) the effects of prophylactic or therapeutic iron supplementation on the occurrence of infectious illness. Data on this aspect are controversial (2). Some studies reported that the incidence of respiratory infections and gastroenteritis was reduced when young infants were given iron supplements. Our recent prospective observations support this contention. In a study of Colombian children, a reduction in infectious disease was noted when nutritional supplements containing iron were provided (8). Of course, higher intake of calories, protein, and other nutrients may have contributed to the beneficial effects of dietary supplements. On the other hand, some investigations yielded negative results.
A major buttress to human data is provided by controlled experiments in laboratory animals. Iron-deprived animals invariably show increased vulnerability to pathogens, particularly Gram-negative bacilli and pyogenic Grampositive cocci. In many studies using rats, morbidity and mortality following challenge with Salmonella typhimurium were significantly increased and were associated with inability to produce and deliver myeloperoxidase-containing cells. It was interesting to note that gestational and preweaning iron deprivation impaired the animal's ability to resist the stress of infection and decreased antibody response, even if a period of nutritional rehabilitation had intervened before testing (9). In other studies, a severalfold increase in susceptibility of iron-deficient rats to infection with Streptococcus pneumoniae has been seen.
These epidemiologic and animal data on iron status and susceptibility to infection have been extensively reviewed elsewhere (2, 3).
There is growing acceptance of earlier observations that selected aspects of the immune response are impaired by a lack of iron and that this is an easily reversible phenomenon. The two major effects of iron deficiency, both with and without anaemia, relate to T Iymphocyte-dependent cellular immunity and intracellular microbial killing by polymorphonuclear leukocytes.
Cellular immunity in iron-deficient subjects has been assessed by various techniques. Cutaneous delayed hypersensitivity responses to a battery of common recall antigens are diminished (10, 11), but complete energy is rare in iron deficiency. Sensitization to the powerful chemical 2,4 dinitrochlorobenzene is often achieved and the subsequent challenge with a less concentrated solution usually elicits a positive reaction. In vitro tests of the Iymphocyte function show somewhat reduced responses. The Iymphocyte transformation response to mitogens and antigens is decreased, and the production of Iymphocyte products on "Iymphokines" is less compared with cells of iron-replete controls. There is also a slight reduction in the proportion and absolute number of rosette-forming T lymphocytes (10,12). There is preliminary recent evidence that iron deficiency alters the proportion and function of various T cell subsets. Occasionally, the total Iymphocyte count in the peripheral blood is also low. All these changes are reversed after iron therapy. Occasionally, an improved immune response after iron administration may indicate the existence of an unsuspected functional iron deficiency (13).
The ability of blood neutrophils and peritoneal macrophages to kill ingested bacteria and fungi is reduced in iron-deficient individuals (11,14) and is associated with the alterations in intracellular metabolic activity. The abnormality reaches the maximum deficit with moderate iron deficiency, and no further decrease is observed in severely iron-deficient subjects; this may reflect a threshold phenomenon or the nature of the test, in that it depends upon microbial multiplication with the cell, which may itself be reduced due to decreased availability of intracellular iron.
Other aspects of immune response in iron-deficient subjects are generally normal. These include the immunoglobulin levels, the antibody titre after specific immunization, the number of B cells, the total complement haemolytic activity, concentrations of complement components, and levels of Iysozyme in mucosal secretions. There is preliminary evidence to suggest that the secretory IgA response to a viral challenge may be slightly impaired in iron deficiency (3).
It is important to emphasize that immunologic dysfunction in iron deficiency is unrelated to the presence of anaemia. Subclinical iron deficiency diagnosed on the basis of reduced serum ferritin, decreased transferrin saturation, and elevated free erythrocyte protoporphyrin, but normal haemoglobin also impairs immune responsiveness.
The consistent influence of iron deficiency on immune responses has been documented in laboratory animals. Iron-deficient rodents show a reduced Iymphocyte DNA synthesis, a decrease in the number of T cells and cytotoxic activity, and histomorphologic and ultrastructural changes (15).
There is some evidence to suggest that hyperferremia states, such as haemolytic anaemia, may also be associated with a higher frequency of infectious illness, but such an association is not invariable as, for instance, observed in haemochromatosis. The presence of haeme-iron compounds such as blood in local situations, e.g., the peritoneum, enhances bacterial growth. In laboratory animals, the in vivo administration of iron decreases the dose of the inoculum of E. coli, P. aerogunisa, P. pestis, C. perfringes, and other micro-organisms required to produce disease and death. The data on physiologic or moderate iron administration to healthy individuals suggest that such a cautious intake does not compromise the immune system or increase the occurrence of infectious illness. The expression of disease may, however, be more visible, leading to the superficial impression that iron deficiency protects against infection (16).
FUTURE RESEARCH NEEDS
There are a number of questions that await much-needed answers. First, the divergence of epidemologic data prompts prospective, carefully controlled studies in which the iron status and morbidity information of a population group is assessed at periodic intervals. Other confounding variables will require rigid control. Since there are many contributing factors that can increase the incidence of infection, a systems-analysis approach should be adopted in which all such influences are recorded and taken into account. Secondly, careful prospective studies are also required to assess the morbidity effects of prophylactic iron administration on apparently healthy infants, children, and adults in order to prevent the development of anaemia. Thirdly, the pathogenetic contribution of iron deficiency to the presence and chronicity of selected infectious diseases should be evaluated. Fourthly, more immunologic data on individuals deficient in iron alone are required. Such studies should meticulously exclude the coexistence of deficiences of proteins, calories, vitamins, and trace minerals. Lastly, the molecular basis of iron-related immunologic changes needs to be further dissected out.
Obviously, the most relevant data of clinical significance must be obtained from work in human populations. However, selected aspects of the above questions may warrant appropriate studies in laboratory animals, at the same time keeping in mind that distortion from the natural situation should be kept to the minimum. Finally, intervention programmes to prevent and eradicate the scourge of iron deficiency anaemia must not await answers to the questions posed above.
1. R.K, Chandra and P.M. Newberne, Nutrition, Immunity and Infection: Mechanism of Interactions (Plenum, New York, 1977).
2. R.K. Chandra, "Iron and Immunocompetence," Nutr. Rev., 34:129-132 (1976).
3. R.K. Chandra, "Iron Status, Immune Response and Susceptibility to Infection," in Iron Metabolism, Ciba Foundation Symposium 51 (Elsevier, Amsterdam, 1977), pp. 249-262,
4. World Health Organization, Control of Nutritional Anaemia with Special Reference to Iron Deficiency, WHO Tech. Rep. Ser. 580 (Geneva, 1975).
5. A. Jacobs, 'Tissue Changes in Iron Deficiency," Brit. J. Haematol., 16:1-4 (1969).
6. S. Basta. Soekirman, D. Karyadi, and N.S. Scrimshaw, "Iron Deficiency Anemia and the Productivity of Adult Males in Indonesia," Am. J. Clin. Nutr., 32:916-925 (1979).
7. J.M. Higgs and R.S. Wells, "Chronic Mucocutaneous Candidiasis: Associated Abnormalities of Iron Metabolism," Brit. J. Dermatol. 86 (supplement 8): 88-94 (1973).
8. A. Arbeter, L. Echevarri, D. Fraco, D. Munson, H. Velex, and J.J. Vitale, "Nutrition and Infection," Fed. Proc., 30:1421-1428 (1971).
9. R.B, Baggs and S.A. Miller, "Nutritional Iron Deficiency as a Determinant of Host Resistance in the Rat," J. Nutr., 103: 1554-1560 (1973).
10. R.K. Chandra, "impaired Immunocompetence Associated with Iron Deficiency," J Pediat., 86:899-902 (1975).
11. L.G. MacDougall, R. Anderson, G.M. McNab, and J. Katz, "Immune Response in Iron-deficient Children: Impaired Cellular Defense Mechanisms with Altered Humoral Components," J. Pediat, 86: 833-843 (1975).
12. K. Bagchi, M. Mohanram, and V. Reddy, "Humoral Immune Response in Children with Iron-Deficiency Anaemia," Brit Mod, J., 2:1251-1253 (1980).
13. R.L. Gross, J.V.U. Reid, P.M. Newberne, B. Burgess, R. Marston, and W. Hift, "Depressed Cell-mediated Immunity in Megaloblastic Anemia due to Folic Acid Deficiency," Am. J. Dis. Child, 28: 225-232 (1975).
14. R.K. Chandra, "Reduced Bactericidal Capacity of Polymorphs in iron Deficiency," Arch. Dis. Child, 48: 863-866 (1973).
15. S.R. Kuvibidila, "Effect of Iron Deficiency Anemia on the Immune Function," (Ph, D. thesis, Massachusetts Institute of Technology, Mass., USA, 1980).
16. M.J. Murray, A.B. Murray, M.B. Murray, and C.J. Murray, "The Adverse Effect of Iron Repletion on the Course of Certain Infections," Brit. Med J., 4: 1113- 1115 (1978).
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