Review and feature article
Mechanisms of nutrient modulation of the immune response

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Lack of adequate macronutrients or selected micronutrients, especially zinc, selenium, iron, and the antioxidant vitamins, can lead to clinically significant immune deficiency and infections in children. Undernutrition in critical periods of gestation and neonatal maturation and during weaning impairs the development and differentiation of a normal immune system. Infections are both more frequent and more often become chronic in the malnourished child. Recent identification of genetic mechanisms is revealing critical pathways in the gastrointestinal immune response. New studies show that the development of tolerance, control of inflammation, and response to normal mucosal flora are interrelated and linked to specific immune mechanisms. Nutrients act as antioxidants and as cofactors at the level of cytokine regulation. Protein calorie malnutrition and zinc deficiency activate the hypothalamic-pituitary-adrenal axis. Increased circulating levels of glucocorticoids cause thymic atrophy and affect hematopoiesis. Chronic undernutrition and micronutrient deficiency compromise cytokine response and affect immune cell trafficking. The combination of chronic undernutrition and infection further weakens the immune response, leading to altered immune cell populations and a generalized increase in inflammatory mediators. Obesity caused by excess nutrition or excess storage of fats relative to energy expenditure is a form of malnutrition that is increasingly seen in children. Leptin is emerging as a cytokine-like immune regulator that has complex effects in both overnutrition and in the inflammatory response in malnutrition. Because the immune system is immature at birth, malnutrition in childhood might have long-term effects on health.

Section snippets

Primary malnutrition

PCM is a major common cause of secondary immune deficiency in the world. Deficiencies are usually complex, frequently involving both protein calorie and varying degrees of micronutrient deficiency of vitamin A, vitamin E, vitamin B6, folate, zinc, iron, copper, and selenium.2, 27, 28 On the basis of severity and features at presentation, PCM is defined as marasmus, a chronic wasting condition, or kwashiorkor, which is distinguished by edema and anemia. Marasmus occurs when there is

Micronutrient deficiencies

Micronutrient deficiencies are a major complication of PCM and promote infectious processes. Oxidative stress is worsened in infection if micronutrients are deficient. Vitamin A, β-carotene, folic acid, vitamin B12, vitamin C, riboflavin, iron, zinc, and selenium have immunomodulating functions and influence both the susceptibility of the host to infectious diseases and the course and outcome of these diseases.54 Many apparently healthy looking children have subclinical deficiencies of vitamin

Secondary malnutrition

When malnutrition presents in association with an underlying genetic disorder, chronic infection, or other illness that affect the metabolism, such as congenital heart disease, cystic fibrosis, or renal insufficiency, resolution cannot be obtained by nutritional means unless the underlying cause is treated. A more extensive discussion of secondary malnutrition is provided elsewhere.3 Parenteral nutrition might be required in some conditions, and this has been associated with nutrient deficiency

Chronic infection

Proinflammatory cytokines initiated during the acute-phase response to infection act to elicit cellular responses throughout the body, and nutrients are lost during any generalized febrile infections. This response is affected by malnutrition.127, 128, 129 Energy expenditure increases at the same time that the infected host experiences a decrease in intake, and diarrhea might result in decreased intestinal absorption of nutrients.4

Summary

PCM is the major common cause of secondary immune deficiency in the world. In most cases PCM involves both protein calorie and micronutrient deficiency of vitamin A, vitamin E, vitamin B6, folate, zinc, iron, copper, and selenium. PCM is defined as marasmus, a chronic wasting condition, or kwashiorkor, which is distinguished by edema and anemia. Marasmus occurs with caloric insufficiency, whereas kwashiorkor develops from protein deficiency. PCM leads to atrophy of lymphoid organs, profound

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    Series editors: William T. Shearer, MD, PhD, Lanny J. Rosenwasser, MD, and Bruce S. Bochner, MD

    Disclosure of potential conflict of interest: S. Cunningham-Rundles has received grants–research support from Probi and Lund and is on the Board of Scientific Advisors for Probi. A. Moon has received grants–research support from Probi and Lund. There are no other potential conflicts of interest to disclose.

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