The immune system
General overview
The immune system acts to protect the host from infectious agents, including bacteria, viruses, fungi and parasites that exist in the environment and from other noxious insults. It is a complex system involving various cells distributed in many locations throughout the body and moving between these locations in the lymph and the bloodstream.
In some locations, the cells are organised into discrete lymphoid organs, classified as primary lymphoid organs where immune cells arise and mature (bone marrow and thymus) and secondary lymphoid organs (lymph nodes, spleen and gut-associated lymphoid tissue) where mature immune cells interact and respond to antigens. The immune system has two general functional divisions: the innate (also called natural) immune system and the acquired (also termed specific or adaptive) immune system.
The immune system works by providing an exclusion barrier, by identifying and eliminating pathogens and by identifying and tolerating non-threatening sources of antigens and by maintaining a memory of immunological encounters.
The gut-associated immune system
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Why should nutrition affect immune function?
The immune system is functioning at all times, but specific immunity becomes increasingly active in the presence of pathogens. This results in a significant increase in the demand of the immune system for substrates and nutrients to provide a ready source of energy. This demand can be met from exogenous sources (i.e. from the diet) and/or from endogenous pools. Cells of the immune system are able to utilise glucose, amino acids and fatty acids as fuels for energy generation(20), which involves electron carriers and a range of coenzymes, which are usually derivatives of vitamins. The final component of the pathway for energy generation (the mitochondrial electron transfer chain) includes electron carriers that have Fe or Cu at their active site.
Activation of the immune response induces the production of proteins (including Ig, cytokines, cytokine receptors, adhesion molecules and acute-phase proteins) and lipid-derived mediators (including prostaglandins and leucotrienes). To respond optimally to an immune challenge there must be appropriate enzymic machinery in place for RNA and protein synthesis and their regulation and ample substrate available (including nucleotides for RNA synthesis, the correct mix of amino acids for protein synthesis and PUFA for eicosanoid synthesis).
An important component of the immune response is oxidative burst, during which superoxide anion radicals are produced from oxygen in a reaction linked to the oxidation of glucose. The reactive oxygen species produced can be damaging to host tissues and thus antioxidant protective mechanisms are necessary.
Cellular proliferation is a key component of the immune response, providing amplification and memory: before division there must be replication of DNA and then of all cellular components (proteins, membranes, intracellular organelles, etc.). In addition to energy, this clearly needs a supply of nucleotides (for DNA and RNA synthesis), amino acids (for protein synthesis), fatty acids, bases and phosphate (for phospholipid synthesis) and other lipids (e.g. cholesterol) and cellular components.
Some of the cellular building blocks cannot be synthesised in mammalian cells and must come from the diet (e.g. essential fatty acids, essential amino acids and minerals). Amino acids (e.g. arginine) are precursors for synthesis of polyamines, which play roles in regulation of DNA replication and cell division. Various micronutrients (e.g. Fe, folic, Zn and Mg) are also involved in nucleotide and nucleic acid synthesis.
Some nutrients, such as vitamins A and D, and their metabolites are direct regulators of gene expression in immune cells and play a key role in the maturation, differentiation and responsiveness of immune cells.
Protein–energy malnutrition and immune function
Undernutrition leading to impairment of immune function can be due to insufficient intake of energy and macronutrients and/or due to deficiencies in specific micronutrients. These may occur in combination.
Practically all forms of immunity are affected by protein–energy malnutrition but non-specific defences and cell-mediated immunity are more severely affected than humoral (antibody) responses(21–23).
Barrier function can be impaired by protein–energy malnutrition(24,25), which may permit bacterial translocation into the circulation(24,26). Protein–energy malnutrition causes atrophy of primary and secondary lymphoid organs and there is a decline in the number of circulating lymphocytes, in proportion to the extent of malnutrition(27,28). The ability of T-lymphocytes to proliferate is decreased by protein–energy malnutrition as in the synthesis of cytokines central to cell-mediated immune response including IL-2 and interferon-g(29,30), suggesting a decline in T-helper (Th)1-type responses. There is a lowered ratio of CD4+:CD8+ cells in the circulation (31) and the activity of natural killer cells is diminished(32–35).
The functional consequence of malnutrition-induced immune impairment was shown in a study in malnourished Bangladeshi children in which those with the fewest skin reactions to common bacterial antigens (i.e. the weakest cell-mediated immune response) had the greatest risk of developing diarrhoeal disease(39,40).
The influence of individual micronutrients on immune function
Vitamin A
There are a number of reviews of the role of vitamin A and its metabolites in the immune system and in host susceptibility to infection(5–7,41–45). Vitamin A deficiency impairs barrier function, alters immune responses and increases susceptibility to a range of infections(5–7,41–45).
Natural killer cell activity is diminished by vitamin A deficiency(50). The impact of vitamin A on acquired immunity is less clear, but there is some evidence that vitamin A deficiency alters the balance of Th1 and Th2 cells, decreasing Th2 response, without affecting or, in some studies enhancing, Th1 response(41–45,51). This would suggest that vitamin A will enhance Th1-cell mediated immunity. However, in contrast to this, studies in several experimental models show that vitamin A metabolite retinoic acid decreases Th1-type responses (cytokines, cytokine receptors and the Th1-favouring transcription factor T-bet), while enhancing Th2-type responses (cytokines and the Th2-favouring transcription factor GATA-3)(52–54).
Vitamin A deficiency can impair response to vaccination, as discussed elsewhere(50). Vitamin A also appears to be important in differentiation of regulatory T-cells while suppressing Th17 differentiation (55,56), effects which have implications for control of adverse immune reactions.
Vitamin D
Individuals with low vitamin D status have been reported to have a higher risk of respiratory tract viral infections(69), while supplementation of Japanese school children with vitamin D for 4 months during winter decreased the risk of influenza by about 40%(70).
However, in contrast, there is a large body of literature showing that vitamin D and its analogues have immunosuppressive effects(71–73). It seems that under physiological conditions vitamin D probably aids immune responses, but that it may also play an active role in prevention of autoimmunity and that there may even be a therapeutic role for vitamin D in some immunemediated diseases.
Overall, the current evidence suggests that vitamin D is a regulator of immune function but that its effects will depend upon the immunological situation (e.g. health, infectious disease and autoimmune disease).
Vitamin E
Vitamin E supplementation of the diet of laboratory animals enhances antibody production, lymphocyte proliferation, Th1-type cytokine production, natural killer cell activity and macrophage phagocytosis(91–94). There is a positive association between plasma vitamin E and cell-mediated immune responses, and a negative association has been demonstrated between plasma vitamin E and the risk of infections in healthy older adults(95). Vitamin E appears to be of benefit in the elderly(96–98), with studies demonstrating enhanced Th1 cell-mediated immunity (lymphocyte proliferation and IL-2 production) and improved vaccination responses at fairly high intakes(96,97).
Zinc
Zn deficiency has a marked impact on bone marrow, decreasing the number of precursors to immune cells(106). Zn deficiency impairs many aspects of innate immunity, including phagocytosis, natural killer cell activity and respiratory burst(107–111). There are also marked effects of Zn deficiency on acquired immunity, with decreases in the circulating number and function of T-cells and an imbalance to favour Th2 cells(112,113).
Moderate or mild Zn deficiency or experimental Zn deficiency in human subjects decreases natural killer cell activity, lymphocyte proliferation, IL-2 production and cell-mediated immune responses which can all be corrected by Zn repletion(111,113).
Iron
There are a number of reviews of the role of Fe in the immune system and host susceptibility to infection(115–122). Fe deficiency induces thymus atrophy and has multiple effects on immune function in human subjects(115–118). The effects are wide ranging and include impairment of respiratory burst and bacterial killing, T-cell proliferation and production of Th1 cytokines(115–118). However, the relationship between Fe deficiency and susceptibility to infection remains uncertain(115–122).
In children in the tropics, Fe at doses above a particular threshold has been associated with increased risk of malaria and other infections, including pneumonia(123–126). Thus, Fe intervention in malaria-endemic areas is not advised, particularly high doses in the young, those with compromised immunity (e.g. HIV infection) and during the peak malaria transmission season.
There are different explanations for the detrimental effects of Fe administration on infections. First, Fe overload causes impairment of immune function(115–118). Second, excess Fe favours damaging inflammation. Third, micro-organisms require Fe and providing it may favour the growth of the pathogen. Perhaps, for the latter reasons, several mechanisms have developed for withholding Fe from a pathogen(127). Oral Fe supplementation has not been shown to increase risk of infection in non-malarious countries(118).
Selenium
There are a number of reviews of the role of Se in the immune system and host susceptibility to infection(128–132). Se deficiency in laboratory animals affects both innate and acquired immunity and increases susceptibility to infections. Lower Se concentrations in human subjects have also been linked with increased virulence(131–133), diminished natural killer cell activity(133,134) and increased mycobacterial disease(135). Se supplementation has been shown to improve various aspects of immune function in human subjects(136–138), including in the elderly(139,140). Se supplementation in Western adults with low Se status improved some aspects of their immune response to a poliovirus vaccine(141).
Probiotics, prebiotics, immunity and infection
Indigenous commensal bacteria within the gastrointestinal tract are believed to play a role in host immune defence by creating a barrier against colonisation by pathogens. Disease and the use of antibiotics can disrupt this barrier, creating an environment that favours the growth of pathogenic organisms. There is now evidence that providing exogenous, live, ‘desirable’ bacteria, termed probiotics, can contribute to maintenance of the host’s gastrointestinal barrier.
Referência :
Immun Ageing. 2009 Jun 12;6:9.