Immunometabolism: nutrients for the immune system

Article by SoLongevity Research
The immune system protects us from potential threats, but if it is not functioning at its best it can give rise to exaggerated processes of inflammation and oxidation, which damage the body and promote aging and related diseases. "Feeding" it correctly is imperative

What this article is about

  • How the immune system works and why it is important to keep it in balance
  • What is immunometabolism? It’s the science that studies the metabolic-energetic mechanisms that regulate cell life as well as the mechanisms which activate the various components of the immune system
  • What are immunomodulatory micronutrients? The nutrients needed to maintain an efficient immune system

How is the immune response regulated?

Defending against external (and internal) aggression is imperative for survival. Humans have developed several lines of defense to respond to possible attacks. There are mechanisms that, if everything works properly, are effective, but can also cause harm. This happens when the inflammatory response is exaggerated and when excessive oxidative processes are generated that damage cell structure and function.

Bringing into play a disproportionate amount of force that, in an attempt to eliminate a threat, ends up harming the organism itself may be a consequence of the type of infection the immune system is dealing with(Sars-Cov-2, for example, may trigger a cytokine storm). But imbalances in the immune response (excessive inflammation and oxidation) may also be due to energetic imbalances in cells, which in turn are caused by sub-optimal intakes of specific vitamins and trace elements. These are called immunomodulatory micronutrients (MNIs). They are indispensable for the various components of the immune system to function (they are, for example, cofactors in the enzymatic processes of immune cells), and they also serve to modulate-indeed, to modulate-the defensive response and make it really efficient.

What is immuno-metabolism?

The discipline that studies the energy needs of the immune system is called immuno-metabolism. It is a new branch of science, arising from the convergence of knowledge about the metabolic-energetic mechanisms that regulate cell life and that about the mechanisms of activation of the various components of the immune system.

Immune-metabolism studies have quickly led to important discoveries about the functioning and efficiency of immune responses. For example, the discovery of the phenomenon ofmetabolic exhaustion of antigen-responsive lymphocytes (i.e., the foreign agent against which the immune system reacts), which can block the immune response altogether. This occurrence is common in the elderly, often due to adeficiency of key micronutrients. However, it can also affect younger people with insulin resistance. A striking case of functional T-lymphocyte depletion is that found in patients with Covid-19, in whom increasing markers of depletion and decreasing total T-lymphocyte, CD8+, and CD4+ counts are correlated with an increased risk of clinical deterioration, even in the absence of severe symptomatology.

Immunometabolism studies the energy needs of the immune system and the link to the body’s defense mechanisms

What are immunomodulatory micronutrients?

Research in this area has identified what the immune system needs to function at its best. Vitamins A, C, D, E, B6 and B12, as well as folic acid, copper, zinc, iron and magnesium are immunomodulatory micronutrients. Each is essential to the functioning of the physical barriers and specific components of the immune system, and each works synergistically with the others, and their optimal intake on the one hand maximizes the body’s defensive abilities, and on the other hand helps to maintain the balance between different types of immune responses to reduce collateral damage to the body.

Immunomodulatory micronutrients are usually acquired through the foods we eat. However, if we analyze one by one the various nutritional elements necessary for the immune system cells to function, we find that in the current average Italian diet many of these may be deficient. There are several reasons for this: from thedepletion of the soil from which micronutrients are derived to the industrial processing of food, to the very eating habits of Italians who prefer certain products and do not consume others that are just as important.

Immunomodulatory micronutrient deficiency impairs immune system function in both innate and adaptive response mechanisms. True deficiencies or even suboptimal levels predispose to infections. The severity of adverse health effects depends greatly on the extent and duration of immunomodulatory micronutrient deficiency. Ensuring adequate amounts of MNI, for example through supplementation, is therefore essential for the proper functioning of all our lines of defense, from physical and chemical barriers to the components of innate and adaptive immunity.

Even with a balanced diet, it is difficult to take the optimal doses of immunomodulatory micronutrients

How does the immune system work?

The first line of defense: skin and mucous membranes

The body’s first line of defense is the skin and mucous membranes. They are physical and chemical barriers that protect against potential pathogens (viruses, bacteria, parasites) and other threats in the environment (pollen, dust, toxic substances). To be efficient, these barriers must be intact both structurally and functionally, so the body needs to be well supplied with immune-modulating micronutrients. Iron and magnesium, for example, are important for skin and mucous membranes: the former supports the differentiation and growth of epithelial tissue, and the latter helps protect DNA from oxidative damage. Vitamin A and zinc maintain the structural and functional integrity of the skin and mucosa. Vitamin C, on the other hand, promotes collagen synthesis in epithelial tissue, enhances keratinocyte differentiation and fibroblast proliferation and migration. Vitamin E, along with vitamin C and endogenous antioxidants, protects cell membranes from damage caused by free radicals generated by metabolism as well as exposure to normal toxins and pollutants.

Soil depletion, food processing, and even unbalanced eating habits are responsible for sub-optimal levels of micronutrients and, consequently, immune system defaults

The second line of defense: innate immunity

If potential threats succeed in overcoming physical and chemical barriers, the organism’s second line of defense intervenes:innate immunity, that is, the set of mechanisms activated by the presence of foreign antigens. Innate immunity includes both antimicrobial molecules in the blood, such as interferons and complement proteins, and cells such as phagocytes and Natural Killer (NK) cells. It is a very rapid, powerful, but unspecific type of immune response that does not track the encounter with pathogens.

Micronutrients are also critical for components of innate immunity. For example, acting as cofactors and coenzymes in the metabolic reactions of immune cells, selenium, vitamin C, zinc, and iron participate in the production of interferon gamma, a molecule that hinders the growth of microbes. Vitamin C increases serum levels of complement proteins, which serve to mark pathogens and help cells such as phagocytes to localize and eliminate them. Complement proteins also attract other cells of the immune system, destroy the cell membranes of bacteria, and fight viruses by destroying their envelopes, or directly virus-infected cells. Vitamin A helps regulate the number and function of Natural Killer cells, which serve to destroy pathogen-infected cells. Vitamins B6, B12, C and E, folate and zinc maintain and enhance the cytotoxic activity of Natural Killer cells, while calcitriol (the active form of vitamin D) regulates the production of potent antimicrobial and signaling peptides called defensins and cathelicidins. Both vitamin A and calcitriol also regulate the activity of macrophages, which are another cellular component of innate immunity. And both micronutrients stimulate the production of the pro-inflammatory molecule TNF-alpha, which fuels the antimicrobial action of the macrophages themselves.

Calcitriol, however, also intervenes in reducing the expression of other pro-inflammatory cytokines while increasing that of anti-inflammatory cytokines. This action of modulating the inflammatory response is also carried out by several other micronutrients, such as zinc and vitamin B2, also called riboflavin. Their role is therefore essential in maintaining the balance between the need to eliminate potential threats and the need not to harm the organism.

Innate immunity is the body’s second line of defense: from its molecular to cellular components, every mechanism requires micronutrients to function properly

The third line of defense: adaptive immunity

The organism’s third line of defense are the mechanisms ofadaptive immunity. These intervene later than innate immunity, but their response is specific and allows the creation of an “immune memory” that will allow them to react to a possible new future attack by the same pathogen faster and more effectively. Adaptive immunity can be expressed in two different modes, called Th1 and Th2.

The Th1 immune response is that sustained by a particular type of CD4 lymphocytes called, precisely, Th1. These coordinate the activity of CD8 lymphocytes and other cells that collectively contribute to cellular immune responses. This mode of defense consists of a very powerful initial inflammatory response, but this can easily degenerate into chronic inflammation and damage the body.

The Th2 immune response, supported by CD4 Th2 lymphocytes and antibody-producing cells, on the other hand, is considered anti-inflammatory. This modality is also involved in allergic reactions.

Because micronutrients modulate the immune response, there are studies evaluating the possibility of using them to increase the efficacy of vaccines

A question of balance

Th1 and Th2 modes must be in balance, and immunomodulatory micronutrients help to maintain this. For example, vitamin A, vitamin D3, and riboflavin are molecules that support the Th2 response. In fact, they ensure the good function of cellular and molecular components by supporting enzyme activity that modulates the inflammatory response of T lymphocytes, anti-inflammatory cytokines, and the regeneration of reduced glutathione. In particular, vitamin A helps regulate the production of interleukin-2 and pro-inflammatory TNF-alpha, while vitamin D reduces the expression of pro-inflammatory cytokines and increases the expression of anti-inflammatory cytokines by macrophages. Riboflavin has antioxidant and anti-inflammatory actions: in the form of FAD (flavin adenine dinucleotide), it is a coenzyme of glutathione reductase and thus contributes to the regeneration of reduced glutathione (GSH), which is the cells’ main defense against free radicals. Vitamins E, C, B6, B12,folic acid, and trace elements such as zinc, iron, and copper support the Th1 response, intervening in the proliferation, differentiation, and activation of T lymphocytes and the synthesis of pro-inflammatory cytokines.

Immunomodulatory micronutrients help maintain the balance between different modes of immune response, limiting collateral damage to the body

How does immune memory work?

Immune memory consists of T and B lymphocytes that have learned to recognize a specific antigen specifically and that, after the first encounter, remain circulating in the body for years. Thus, should a new encounter with the same pathogen occur, these memory cells are quickly activated: the T lymphocytes act immediately against the threat, while the B lymphocytes begin to produce antibodies, that is, proteins “designed” specifically to be complementary to that particular pathogen antigen, to bind to it and facilitate its recognition and elimination.

And so, immune-modulating micronutrients are also critical in supporting antibody synthesis. As with the production of all proteins, in fact, vitamins B6, B12 and folate are needed. Vitamin B12 also supports cell replication, and a deficiency of it is associated with decreased levels of lymphocytes. Vitamin A, on the other hand, influences the proper functioning of B lymphocytes and is necessary for IgA antibody responses to bacterial antigens, while zinc is involved in IgG antibody production. Vitamin C increases serum levels of antibodies, and both copper and selenium have roles in their production. Finally, magnesium acts as a cofactor for their synthesis.

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