Arginine
The modulation of metabolism and immune functions, essential in the interaction and susceptibility to infectious diseases, is also regulated by arginine [146]. Arginine is a precursor for the synthesis of proteins, nitric oxide, urea, polyamines, proline, glutamate, creatine and agmatine. The role and relationships between the pathways of arginine synthesis and catabolism are complex, due to the compartmentalized expression of various enzymes in different organs (e.g. liver, small intestine and kidney) and subcellular compartments (cytosol and mitochondria), as well as changes in gene expression in response to diet, hormones and cytokines [147]. As reported by several studies, arginine is the precursor of macrophages and it is now clear that arginine metabolism of immune cells is particularly involved in cancer, inflammation, infections, fibrotic diseases, pregnancy and the regulation of immune system [148, 149]. Macrophage arginine metabolism influences the outcome of immune responses in which innate immune cells are involved. Arginine supplementation is reported to increase T lymphocyte response and Th cell numbers, suggesting a possible role in prolonged or repeated infection [150]. The importance of arginine metabolism as a new field of investigation includes that its depletion delays the growth of some types of tumours, while others report that its integration improves anticancer effects, probably by ameliorating immune function [150].
As discussed, vitamins E, C, D, zinc and selenium are important examples of nutrients that play a key role in supporting the immune system [65]. They can work individually or in synergy. Furthermore, other dietary components are likely to play a role in modulating immunity, but have not yet been identified. It is clear how nutritional deficiencies can compromise the immune response. In addition, inflammation related to unhealthy eating habits has reached alarming proportions, particularly concerning chronic non-communicable diseases [100] (Tables 1 and 2).
Table 1 Dietary sources and immune function roles of nutrients
Nutrient Good dietary sources Immune function roles
Vitamin A Milk and cheese, eggs, liver, oily fish, fortified cereals, dark orange or green vegetables (e.g., carrots, sweet potatoes, pumpkin, squash, kale, spinach, broccoli), orange fruits (e.g., apricots, peaches, papaya, mango, cantaloupe melon), tomato juice Normal differentiation of epithelial tissue; retinoic acid ↑ T and B cells with gut-homing specificity and array T cells and IgA + cells into intestinal tissues
Supporting the gut barrier; carotenoids; ↑immunoregulatory actions including ↓ toxic effects of ROS and regulating membrane fluidity and gap-junctional communication
Regulates number and function of NK cells,↑ to phagocytic and oxidative burst activity of macrophages
Downregulates IFN production
Helps to regulate the production of IL-2 and the pro-inflammatory TNF-γ, ↑ microbial action of macrophages; involved in phagocytic and oxidative burst activity of macrophages activated during inflammation
Development and differentiation of Th1 and Th2 cells; ↑ TGF- β-dependent conversion of naïve T cells into regulatory T cells; plays a role in acquisition of mucosal-homing properties by T and B cells
Development and differentiation of Th 1 and Th2 cells; maintains normal antibody-mediated Th2 response by suppressing IL-12, TNF-α, and IFN-γ production of Th1 cells
Normal functioning of B cells, necessary for generation of antibody responses to antigen; required for B cell-mediated IgA antibody responses to bacterial polysaccharide antigens [62, 79–82, 85, 92, 95]
Vitamin C Oranges and orange juice, red and green peppers, strawberries, blackcurrants, kiwi, broccoli, brussels sprouts, potatoes ↑ collagen synthesis and protects cell membranes from damage caused by free radicals; ↑ keratinocyte differentiation; ↑ lipid synthesis; ↑ fibroblast proliferation and migration
Proliferation, function, and movement of neutrophils, monocytes and phagocytes; ↑ NK cell activities and chemotaxis
↑ Phagocytosis and ROS generation; ↑ microbial killing
↑ Apoptosis and clearance of spent neutrophils from sites of infection by macrophages
↓ Extracellular trap (NET) formation, ↓ tissue damage
↑ Antimicrobial effects; ↑ serum levels of complement proteins
Maintains redox homeostasis within cells and protects against ROS and RNS during oxidative burst; regenerates other important antioxidants, such as glutathione and vitamin E, to their active state; modulates cytokine production and ↓ histamine levels
Roles in production, differentiation, and proliferation of T cells, particularly cytotoxic T cells; ↑ proliferation of lymphocytes, ↑ generation of antibodies [79, 85, 92, 95, 120]
Vitamin D Oily fish, liver, eggs, fortified foods (spreads and some breakfast cereals) Regulates antimicrobial proteins (cathelicidin and β-defensin), modifying intestinal microbiota to a healthier composition and supporting the gut, as well as protecting the lungs against infection; ↑ tight junction protein expression, E-cadherin and connexion 43 in the gut; maintains renal epithelial barrier function; ↑ corneal epithelial barrier function
Vitamin D receptor found in, e.g., monocytes, macrophages, and DCs; ↑ differentiation of monocytes to macrophages; calcitriol ↑ movement and phagocytic ability of macrophages
Regulates antimicrobial protein expression (cathelicidin and defensin), which directly kill pathogens, especially bacteria; ↓ IFN-γ production
↑ The oxidative burst potential of macrophages; increases superoxide synthesis; reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages
Homing of T cells to the skin; ↓ T-cell proliferation; inhibitory effects mainly in adaptive immunity (e.g., Th1-cell activity); stimulatory effects in innate immunity; ↓ the effector functions of T helper cells and cytotoxic T cells; ↑ the production of Tregs; inhibitory effect on the differentiation and maturation of the antigen-presenting DCs, and helps program DCs for tolerance
↓ Antibody production by B cells
↑ Antigen processing; role in the down-regulation of MHC-II) [64, 71, 79–81, 85, 95, 99, 104–106, 151–153]
Vitamin E Many vegetable oils, nuts and seeds, wheat germ (e.g., in cereals) Protects cell membranes from damage caused by free radicals and ↑ the integrity of epithelial barriers
↑ NK cell cytotoxic activity; ↓ PGE2 production by macrophages (thus indirectly protecting T-cell function)
Important fat-soluble antioxidant that hinders the chain reaction induced by free radicals (chain-breaking effect) and protects cells against them; ↑ IL-2 production; ↓ production of PGE2 (indirectly protecting T-cell function)
↑ Lymphocyte proliferation and T-cell-mediated functions; ↑ Th1 response; ↓ Th2 response; helps to form effective immune synapses between Th cells; ↑ proportion of antigen-experienced memory [64, 79, 82, 95, 112, 113]
Zinc Shellfish, meat, cheese, some grains and seeds, cereals, seeded or whole grain breads Helps maintain integrity of skin and mucosal membrane (e.g., cofactor for metalloenzymesrequired for cell membrane repair)
↑ NK cell cytotoxic activity; central role in cellular growth and differentiation of immune cells that have a rapid differentiation and turnover; ↑ phagocytic capacity of monocytes
Involved in complement activity; role in IFN-γ production
Anti-inflammatory agent; helps to modulate cytokine release by dampening the development of pro-inflammatory Th17 and Th9 cells and influencing the generation of cytokines such as IL-2, IL-6, and TNF; has antioxidant effects that protect against ROS and reactive nitrogen species; influences activity of antioxidant proteins
↑ Proliferation of cytotoxic T cells; involved in Th1 cytokine production and thus supports Th1 response; essential for intracellular binding of tyrosine kinase to T cell receptors, required for T cell development, differentiation, and activation; ↑ development of Treg cells and is thus important in maintaining immune tolerance
Involved in antibody production, particularly IgG; involved in antibody response; important in maintaining immune tolerance (i.e., the ability to recognize “self” from “non-self”) [64, 82, 95, 116, 118–121]
Selenium Fish, shellfish, meat, eggs, some nuts especially brazil nuts ↑ IFN-γproduction
Selenoproteins important for antioxidant host defense system, affecting leukocyte and NK cell function
Essential for function of selenoproteins that act as redox regulators and cellular antioxidants, potentially counteracting ROS produced during oxidative stress
Roles in differentiation and proliferation of T cells
↑ Th cell counts and to maintain antibody levels [82, 85, 92, 95]
Iron Meat, liver, beans, nuts, dried fruit (e.g., apricots), wholegrains (e.g., brown rice), fortified cereals, most dark green leafy vegetables (spinach, kale) Essential for differentiation and growth of epithelial tissue
Forms highly-toxic hydroxyl radicals, thus involved in killing of bacteria by neutrophils; component of enzymes critical for functioning of immune cells (e.g., ribonucleotide reductase involved in DNA synthesis); involved in regulation of cytokine production and action; ↑ M2-like macrophage phenotype and negatively regulates M1 pro-inflammatory response
Role in IFN-γ production
Involved in regulation of cytokine production and action; required for generation of pathogen-killing ROS by neutrophils during oxidative burst
Important in differentiation and proliferation of T cells; helps to regulate ratio between T helper cells and cytotoxic T cells [85, 95, 138]
Long chain omega-3 fatty acids (EPA and DHA) Oilyfish Anti-inflammatory and antioxidant properties when enzymatically converted to specialized pro-resolving mediators (SPMs) known as resolvins, protectins, and maresins
↑ Immune system, by helping to resolve the inflammatory response [63, 66, 67]
Table 2 Nutrient’s supplementation suggested in support of respiratory infections
Nutrient Recommended supplementation suggested in support of respiratory infections
Omega 3 fatty acids 2–4 g/day [68]
Vitamin D 20,000–50,000 IU [154]
Vitamin E 135 mg/day [114]
Zinc 30–50 mg/day [98]
Selenium 25–100 μg/day [130]
Arginine and glutamine 25–35 g/day [142, 146]
Vitamin C 1–2 g/day [98]
Vitamin A 900–700 µg/day [91]
Iron 8–18 mg/day [138]