Trace Minerals: Keys to Immunity

by Larry L. Berger, Ph.D.
Professor, Animal Sciences
University of Illinois

Immunology is not a new science. In 1718, an English physician Edward Jener documented the fact that milkmaids who contracted cowpox were then immune to smallpox. German scientists in 1890 were the first to illustrate the mechanisms of immunity by showing that blood serum taken from animals immunized against diphtheria could be used to transfer this immunity to unimmunized animals. In the 1930s the term "antibody" was coined to described the antitoxins in serum that caused the neutralization and precipitation of toxins and lysis of bacteria. In the past few years there has been a great deal of research published showing the key role of trace minerals in maximizing immunological function. The purpose of this review is to update the nutrition professional to our current level of understanding concerning the role of copper, iron, selenium, chromium, cobalt and zinc in the immune system.

Immune Function

To understand how trace minerals affect immune competency, a brief review of immune system function is in order. The purpose of the immune system is to render harmless a foreign agent which may be a bacterium, protozoan, virus or noninfectious entity such as a chemical or toxin. The immune system uses several methods to detoxify these foreign agents or antigens. For example, phagocytosis is a nonspecific immune response in which a particle is engulfed by a phagocyte and subsequently digested. Phyagocytes are present in the spleen, liver, and lung, and circulate in the blood.

In contrast to the phagocytic system, which lacks specificity and memory to an antigen, the lymphoid organ dependent immune system develops different antibodies for each antigen. The major cell type involved is the lymphocyte, which can be found free in tissues or blood, or concentrated in distinct organs like spleen, lymph nodes, and thymus gland. Depending on the organ of origin, the lymphocytes will differentiate to become B-cells or T-cells. Upon antigenic stimulation, these cells will produce specific antibodies that destroy the antigen.

Trace mineral requirements are determined largely by animal growth or reproductive response, and not by the ability of the immune system to respond to a challenge. Usually, efforts are made to minimize exposure to antigens during the feeding studies used to determine trace mineral requirements. There is increasing evidence that the concentrations of trace minerals required for healthy animals are often below what is required for animals experiencing an immunological challenge. Consequently, this review will focus primarily on experiments where the trace mineral concentrations are above what would be present in the basal diet.

Copper

Copper level in the diet has been shown to affect the resistance of sheep to bacterial infections (Woolliams et al., 1986). The Scottish Blackface hill breed, which is naturally susceptible to copper deficiency, is highly vulnerable to microbial infections. Copper supplementation has increased their resistance and survival rate. In one study with 65 lambs, death losses varied from 2 to 10% in lambs with less than 3.0 micromoles of copper per liter of blood, while there were no losses in lambs with greater than 4.0 micromoles of copper per liter of blood. In these studies, copper deficiency did not decrease the prevalence of microbial infection, but it did decrease mortality. Infections, found mainly in the gastro-intestinal tract and lungs, apparently were more damaging because of enhanced inflammatory reactions when the lambs were copper deficient.

Resistance to internal parasites is also compromised with copper deficiency. For example, Hucker and Yong (1986) found that copper deficient lambs inoculated with t. axei and t. colubriformis had maximum fecal egg counts 2 weeks sooner and became more hypoalbuminemia than lambs receiving supplemental copper. The infection also reduced plasma copper levels in the deficient lambs, but not in the copper supplemented lambs. In lambs grazing areas with a parasite load, having adequate copper in the diet is a key to controlling the worm burden.

It is widely recognized that feeder cattle from copper deficient areas are less responsive to vaccinations for diseases associated with shipping fever compared to cattle that have had adequate copper. Diets that are high in molybdenum and sulfur can compromise the copper status of cattle by forming insoluble complexes in the rumen. Ward et al. (1993) reported that prolonged exposure to molybdenum (10 ppm) and sulfur (0.2% sulfur) decreased in vivo cell-mediated immune function in feeder cattle. The lower (P <.10) in vitro viability of lymphocytes collected from steers receiving the molybdenum and sulfur suggests that these cells are more fragile. These researchers interpreted their data to suggest that cell-mediated immunity is more susceptible to molybdenum and sulfur supplementation (decreased copper availability) than is humoral immunity.

Because many factors affect the responsiveness of the immune system, there are trials where copper deficiency has not had much effect (Stabel et al. 1993). However these same researchers indicated, that "viral and bacterial challenge of cattle can cause a rapid transient increase in serum ceruloplasmin and plasma copper in copper-replete animals, suggesting a major protective role for copper in infectious diseases." These researchers also showed that copper concentrations in organs critical to the immune system such as the liver, spleen, thymus, and lung were substantially reduced by copper deficiency. These data help explain why copper deficient cattle are at greater risk for infection than are the copper supplemented cattle.

Iron

Iron is an interesting trace element in that either a deficiency or an excess can compromise the immune system. It has been well documented that serum iron falls early in response to bacterial and viral infections and rebounds quickly with recovery. This hypoferremia is believed to be an important protective component of the acute phase response to infection. With Pasteurella haemolytica, a major respiratory pathogen of cattle and sheep, the iron-regulated cell wall proteins have been identified as important vaccine components because of their antigenicity. If iron is in great excess, then the key proteins required to initiate recognition and antibody production may be masked.

This does not mean that iron deficiency resulting in anemia will enhance immunity. To the contrary, anemic animals are much more susceptible to infections than those with adequate iron. Once the infection is established, iron supplementation has been shown to increase the bactericidal activity of liver and splenic marcrophages. For example, chicks inoculated with S. Gallinarum had increased (P <.01) survival when iron (100 ppm of diet or more ) was added to a basal diet containing 200 ppm of iron. Anemia was found in the diseased chicks three days post-infection and continued through day nine as measured by decreased hemoglobin and hematocrits. However birds receiving additional iron, up through 600 ppm, had less severe anemia and increased antibody titres. These and other data in broilers show that once the infection has occurred, increased supplemental iron enhances the immune system in destroying the invading organism.

Selenium

Selenium is recognized as an immonostimulant in swine, poultry and ruminants. Often selenium and vitamin E are supplemented together because they play similar physiological roles. However, recent research has shown that their effects are additive when measured as immune response in pigs. Peplowski et al. (1980) measured humoral antibody production to sheep red blood cells in weanling pigs receiving selenium and/or vitamin E. Pigs were fed a basal diet to which 0 or 0.5 ppm of selenium and 0 or 220 IU of vitamin E / kg were added. The basal diet contained 0.02 ppm selenium and 7 mg of alpha-tocopherol/kg. Humoral antibody titres were increased (P <.01) when either selenium or vitamin E were added alone, and were further increased (P <.01) when both nutrients were added.

Colnago et al. (1984) challenged male broiler chicks with E. tenella oocysts from 22 to 32 days of age in six experiments to determine if selenium would affect the ability of the bird to cope with coccidiosis. Graded selenium levels from 0.1 to 1.0 ppm or 100 ppm of vitamin E/kg were added to the diet from day one of age. Dietary supplementation of at least 0.25 ppm selenium or vitamin E reduced mortality (P <.05) and increased weight gains (P <.05). These authors showed that feeding 0.25 ppm selenium or more, increased leucocyte numbers in the blood after infection with coccidia and may explain the immune enhancement.

Boyne and Arthur (1981) reported that neutrophils from selenium-deficient calves had a decreased ability to kill ingested Candida albicans compared to neutrophils from selenium supplemented calves. The authors linked the decreased effectiveness of the neutrophils to reduced glutathione peroxidase activity resulting from selenium deficiency. When glutathione peroxidase activity is reduced, peroxide and lipid hydroperoxide tend to accumulate to toxic levels in the neutrophils. In these trials the calves were fed diets containing 0.01 mg selenium/kg for six months before glutathione peroxidase activity was reduced. Rate of clinical mastitis was negatively correlated to plasma selenium concentration in nine well-managed dairy herds in Ohio (Weiss et al. 1990). Plasma selenium was positively correlated to selenium intake by cows up to 5 mg selenium per day, and was independent at higher intakes. The role of vitamin E is also important in that high intakes of selenium without adequate vitamin E did not reduce mastitis. The exact mechanism by which these two nutrients interact to reduce mastitis is quite complicated and requires additional research.

Chromium

Recent Canadian research has shown that chromium is most beneficial in high-stress periods. Shipping stress, for example, will often impair the immune system and make animals more susceptible to invading pathogens. Chang and Mowat (1992) evaluated the effects of supplemental chromium, from high-chromium yeast, on the performance and health of stressed calves with or without long-acting oxytetracycline. During the first 28 days after shipping, feeding 0.4 ppm chromium increased averaged daily gains (1.34 vs. 1.74 lb/day) and gains per unit of dry matter intake (0.123 vs. 0.156) in calves not receiving oxytetracycline. However, chromium supplementation had no effect on performance of calves receiving the antibiotic. Calves in this trial were stressed in that they were transported by truck for 18 hours, rested and offered hay and water for 10 hours, and then transported an additional 26 hours before arrival. It is likely that this level of stress increased urinary chromium excretion and depleted body chromium stores. Stress often causes increased glucose mobilization which increases mobilization of chromium from body stores.

In a second study, Monnsie-Shageer and Mowat (1993) fed 0, 0.2, 0.5, and 1 ppm supplemental chromium from high-chromium yeast, to 84 Charolais-crossed feeders stressed due to shipment. Chromium supplementation decreased morbidity (P <.05) and rectal temperature at day 2 and 5 after arrival. Peak antibody titers to human red blood cells and immunoglobulin G1 concentrations were increased (P <.07) due to chromium supplementation. The basal corn silage diet contained 0.16 ppm chromium. In a third experiment, the effects of supplemental chromium on immune responses of dairy cows subjected to physical and metabolic stresses associated with late pregnancy, calving, and peak milk yield were determined. Chelated chromium (0.5 ppm) was fed beginning six weeks prepartum and continued through 16 weeks postpartum. To measure humoral immune responses, all cows were immunized with ovalbumin and human red blood cells approximately two weeks before and two weeks after calving. Chromium caused increased anti-ovalbumin response (P <.01) but did not affect the immune response to the red blood cells. These data suggest that chromium supplementation may enhance resistance to mastitis in dairy cows. The exact mechanism by which chromium enhances the immune system is not known. However, one of the consistent results of the studies was that chromium reduced serum cortisol levels. Glucocorticods, which include cortisol, are known to suppress the immune system.

Whether the organic forms of chromium are required to stimulated the immune response is unknown. It is known that organic forms are absorbed 5 to 10 times more effectively than chromium chloride, which is absorbed at 3% or less. However, because small concentrations are required, chromium chloride may be an economical source in many diets. Additional research is also needed to determine if the same stimulatory effects on the immune system can be obtained in swine and poultry.

Cobalt

Fisher and MacPherson (1986) reported that cobalt deficiency rendered sheep more susceptible to bacterial infections. Of eight lambs in the severely deficient groups (B12 100 pg/ml or less), seven succumbed to microbial infections. In contrast, none of the eight on the adequate cobalt treatment died. Reductions in candidacidal activity of ovine neutrophils have been reported as a result of cobalt deficiency. These authors noted that the changes in the health of the neutrophils became evident before vitamin B12 status decreased.

Zinc

Substantial evidence has been reported that adding zinc above the supposed requirement enhances disease resistance in chickens. Southern and Baker (1983) reported that adding 50 ppm zinc to broiler diets containing 40 ppm zinc increased (P <.05) gain and feed efficiency when infected with E. acervulina. Coccidiosis caused a decrease in liver zinc concentrations.

Stahl et al. (1984) reported that the immunocompetence of progeny chicks from hens was affected by dietary zinc. White Leghorn breeding hens were fed a corn-soy diet supplemented with 0, 10, 20, 40 or 150 ppm zinc. Progeny from unsupplemented hens had reduce titers to sheep red blood cells compared to those receiving the 10 and 20 ppm zinc treatments. However, excessive zinc (150 ppm) also depressed the immunocompetence of the progeny.

Salt as a trace mineral carrier

To maximize immune functions these trace minerals must be provided on a regular basis. Because many of the trace mineral compounds are unpalatable in the pure from, providing a delivery method that ensures the proper intake on a regular basis is essential. A well-fortified trace mineralized salt has proven to be the safest, most effective delivery method.

In summary, the immune system is one of the most complex and intricate cellular and molecular interactions known in all of biology. Trace minerals act as keys which unlock the ability of the immune system to ward off invaders. Proper trace mineral supplementation will not eliminate disease, but it will allow the animal's immune system to respond with peak efficiency to minimize the risk of significant economic losses.

Literature Cited

Boyne, R, and J.R. Arthur. 1981. Effects of copper and selenium deficiency on neutrophil function in cattle. J. Comp. Path. 91:271.

Burton, J.L., B.A. Mallard, and D.N. Mowat. 1993. Effects of supplemental chromium on immune response of periparturient and early lactation dairy cows. J. Anim. Sci. 71:1532.

Chang, X., and D.N. Mowat. 1992. Supplemental chromium for stressed and growing feeder calves. J. Anim. Sci. 70:559.

Colnago, G.L., L.S. Jensen, and P.L. Long. 1984. Effect of selenium and vitamin E on the development of immunity to coccidiosis in chickens. J. Poultry Sci. 63:1136.

Fisher, G., and A. MacPherson. 1986. Cobalt deficiency in the pregnant ewe and lamb viability. In: Proceedings of the 6th International Conference on Production and Disease in Farm Animals, pp. 158. Veterinary Research Laboratory, Stormont, Belfast, N. Ireland.

Hucker, D.A., and W.K. Yong. 1986. Effects of concurrent copper deficiency and gastrointestinal nematodiasis on circulating copper and protein levels, liver copper and bodyweight in sheep. Vet. Parasitol. 19:67.

Monnsie-Shageer, S., and D.N. Mowat. 1993. Effect of level of supplemental chromium on performance, serum constituents, and immune status of stressed feeder calves. J. Anim. Sci. 71:232.

Peplowski, M.A., D.C. Mahan, F.A. Murray, A.L. Moxon, A.H. Cantor, and K.E. Ekstrom. 1980. Effect of dietary and injectable vitamin E and selenium in weanling swine antigenically challenged with sheep red blood cells. J. Anim. Sci. 51:344.

Stabel, J.R., J.W. Spears, and T.T. Brown, Jr. 1993. Effect of copper deficiency on tissue, blood characteristics, and immune function of calves challenged with infectious bovine rhinotracheitis virus and Pasteurella hemolytica. J. Anim. Sci: 71:1247.

Stahl, J.L., and M.E. Cook, and M.L. Sunde. 1984. Enhanced humoral immunity in progeny chicks from hens fed diets supplemented with zinc. Poultry Sci. 63:(Suppl. 1),187.

Southern, L.L., and D.H. Baker. 1983. Eimeria acervulina infection and zinc-copper interrelationships in the chick. Poultry Sci. 62:401.

Ward, J.D., J.W. Spears and E.B. Kegley. 1003. Effect of copper level and source (copper lysine vs copper sulfate) on copper status, performance, and immune response in growing steers fed diets with or without supplemental molybdenum and sulfur J. Anim. Sci. 71:2748..

Weiss, W.P., J. S. Hogan, K.L. Smith, and K.H. Hoblet. 1990. Relationship among selenium, vitamin E, and mammary gland health in commercial dairy herds. J. Dairy Sci. 73:381.

Woolliams, C., N.F. Suttle, J.A. Woolliams, D.G. Jones, and G. Wiener. 1986. Studies on lambs genetically selected for low and high copper status. I. Differences in mortality. Anim. Prod. 43:293.

Questions & Answers

Q. Which minerals should I be concerned with to prevent grass tetany in my lactating beef cows?

A. The best way to prevent grass tetany is to feed free-choice a mixture of equal parts magnesium oxide: trace mineral salt and grain (corn, barley, etc) beginning two weeks before the cows are turned out to pasture. The disease is caused by excess potassium in the forage which prevents magnesium absorption. Magnesium oxide will provide the magnesium and the salt will increase the sodium:potassium ratio in the rumen which improves magnesium absorption.

Q. Can I use a trace mineralized salt designed for beef cattle to feed my 4-H lambs?

A. It depends on the copper level in the trace mineral salt and the diet you are feeding. To be safe, the total diet for sheep should be under 10 ppm copper. Sheep are more susceptible to copper toxicity at levels which may just meet the needs of cattle.

Q. Do horses exhibit "nutritional wisdom"? When given a choice will they select the appropriate amounts of each mineral, if I offer a variety of mineral sources cafeteria style?

A. Generally, animals do not have the ability to consume only the amount required to meet their need for given minerals. Also, many of the pure mineral forms are not very palatable, and will not be consumed readily unless mixed with the other feedstuffs. It is more likely your horse will get the balanced nutrition you desire if you feed a balanced mineral supplement mixed with the rest of the diet.

Q. Does particle size affect salt's ability to act as an intake regulator for free-choice supplements being fed to cattle while grazing?

A. Yes. Usually a finer grind of salt work best. This is especially true if the supplements are in the meal form. If the supplement is pelleted, salt particle size may not make much difference.

© Salt Institute, 1996

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