The Immunological Importance of Amino Acids

The functioning of the immune system is highly dependent on an adequate supply of macro- and micronutrients. Deficiencies and overeating have a negative effect on the immune system. The immune system interacts closely with the nervous system, the psyche and the endocrine system in the sense of psycho-neuro-endocrino-immunology.

Only a balanced supply of amino acids, energy sources, vitamins and minerals enables the optimal synthesis of biomolecules important for the immune system, such as immunoglobulins, enzymes, cytokines, etc.

Protein and amino acid metabolism is under endocrine control. Insulin, the main anabolic hormone, promotes the uptake of amino acids into the cell and stimulates protein synthesis. When catabolic hormones predominate as a result of massive sympathetic stimulation, this leads to increased muscle proteolysis, increased gluconeogenesis and urea synthesis. Patients who have undergone major surgery, trauma, infection, inflammation, etc., may therefore experience significant protein loss.

Diseases with catabolic muscle metabolism are characterised by an increase in glutamic acid and a decrease in plasma concentrations of glutamine and cysteine (CG deficiency syndrome). Various biochemical mechanisms lead to a massive loss of nitrogen and a weakening of the immune system.

Protein deficiency primarily affects the cellular immune response, including a reduction in the number of lymphocytes and their function. The production of cytokines is reduced, as is the cytotoxic activity of natural killer cells, macrophages, etc. The overall result is an increased susceptibility to bacterial infections. Some vitamins, minerals and trace elements have long been shown to have a positive effect on the immune system and are used therapeutically. However, the immune system is also fundamentally dependent on the availability of sufficient amino acids for peptide and protein synthesis.

A deficiency of amino acids can occur for a number of reasons: Malnutrition, all diseases associated with maldigestion and malabsorption. Changes in the neuroendocrine response (predominance of catabolic hormones) cause amino acids to be diverted to gluconeogenesis and used for energy production. In some diseases, non-essential amino acids cannot be sufficiently synthesised (e.g. renal failure). During very high levels of physical exertion, such as competitive sport, some amino acids are oxidised to produce energy.

A very important aspect that has received little attention in nutritional physiology is the quality of the nutrients available to the body. According to Ohlenschläger, all amino acids can be damaged by free radicals. Metal ions often cause changes in histidine, arginine, cysteine, lysine and methionine. Cysteine and histidine in the active centre of enzymes are the preferred targets for free radical reactions. Changes in cysteine are of particular pathobiochemical importance. SH groups are very susceptible to chelation and oxidation, which disrupts the formation of disulphide bridges. This leads to significant changes in the structure and function of proteins. Glutathione synthesis is also disrupted. Glutathione is the main intracellular antioxidant and stabilises the redox potential of the cell. Glutathione is particularly important for the cells of the immune system. The various proteins of the immunoglobulin gene superfamily have as a common function the specific recognition and differentiation of macromolecules. Cytokines are hormone-like peptides and proteins with a signalling function that control the immune system.

For proper protein synthesis, all amino acids must be sufficiently available, which of course applies in particular to the essential amino acids. In the following, some amino acids that are particularly important for the immune system will be discussed in more detail.

Glutamine

Glutamine is the amino acid with the highest concentration in plasma and muscle tissue and has the highest turnover rate of all amino acids. Glutamine plays a crucial role in lymphocyte proliferation and B-cell differentiation; macrophage phagocytosis and the expression of certain antigens are also glutamine-dependent. Catabolic disease states, such as severe infections, trauma, inflammation, cancer, etc., are almost always associated with pronounced glutamine depletion. The intestinal absorption of glutamine increases sharply during metabolic stress, reducing the glutamine pool. Endogenous synthesis cannot meet the demand, leaving the immune system with too little glutamine. This largely explains the immunosuppression in the metabolism following an attack.

Glutamine also has a major influence on the regulation of muscle protein balance; an appropriate concentration of glutamine in the muscles is required for anabolic processes. Abnormally low plasma glutamine levels are particularly common in HIV patients. Since the introduction of glutamine-containing dipeptides as part of parenteral nutrition, a significant reduction in infection and complication rates has been observed.

Cysteine

Cysteine plays an important role in the immune system. Infections and/or immune deficiencies often result in cysteine deficiency. By forming disulphide bridges, cysteine is important for the composition, conformation, structure and function of almost all peptides, proteins and enzymes. This is particularly true for immune cells with their various receptor forms.

Defined disulphide bridges ensure the physiological three-dimensional spatial unfolding. The cysteine content is particularly important for the biological function of the tripeptide glutathione. The glutathione system ensures the basic redox regulation of all cells and is the most important intracellular antioxidant. The SH groups of cysteine also protect DNA and RNA from various types of radiation damage. However, the sulphur-containing amino acids methionine and cysteine are particularly sensitive to oxidative stress. According to Ohlenschläger, foods containing heavy metals and proteins often contain cysteine in chelated form. The biological availability of unaltered cysteine molecules is therefore increasingly being questioned.

In serious diseases such as HIV infection, tumour diseases and inflammatory bowel diseases, a low cysteine level is almost always found in the blood in addition to a glutamine deficiency, and glutamic acid is often elevated. This is known as the low-CG syndrome (CG deficiency syndrome). This leads to massive nitrogen losses in the body. There is increased glycolytic activity with lactate formation in the muscles, and increased cysteine breakdown in the liver. The ammonia produced during protein breakdown is converted to urea and excreted.

In principle, the ammonia produced during protein breakdown could also be used to produce glutamine and thus for anabolic metabolic processes. In this particular situation, this pathway is very limited. N-acetyl-Cysteine (NAC) is a derivative of cysteine that, unlike cysteine, is chemically stable and therefore suitable for substitution therapy. NAC also stimulates glutathione synthesis. Initial studies suggest that NAC may also counteract the loss of skeletal muscle that is typical of CG deficiency syndrome.

Taurine

Taurine is found in high concentrations in leucocytes and increases the activity of NK cells and the release of interleukin 1. Taurine depletion from the tissue pool increases the inflammatory response. Taurine protects cells from increased calcium influx as a result of lipid peroxidation by free radicals.

Arginine

Arginine is the precursor of nitric oxide (NO), a signalling molecule also released by macrophages and now recognised as an important immunomodulator. NO also has a direct antimicrobial effect through various biochemical mechanisms. There are now numerous experimental results on the immunological effects of arginine, such as an increase in thymus weight, the number of lymphocytes, lymphocyte proliferation, the cytolytic capacity of macrophages and much more. The clinical studies available to date show an immune stimulation in the gram range with arginine.

Threonine

Threonine is an essential amino acid that is poorly absorbed in the small intestine. It plays an important role in the immune system because it is the only essential amino acid that acts as a link between the protein and carbohydrate parts of glycoproteins. The various immune cell receptors and most immunoglobulins are glycoproteins. We often observe low serum threonine levels in the various forms of malabsorption and intestinal dysbiosis.

Carnitine

Made up of the amino acids methionine and lysine, carnitine is the carrier molecule that transports fatty acids from the cytoplasm to the mitochondria. Carnitine can also influence various cells of the immune system, e.g. it increases the phagocytic capacity of human granulocytes and stimulates macrophages. HIV patients often suffer from carnitine deficiency. The example above shows the amino acid profile of an HIV patient (Figure).

Low levels of glutamine and cysteine are characteristic of severe infectious diseases (CG deficiency syndrome). Glutamic acid is typically elevated, and elevated extracellular glutamate concentrations prevent cysteine uptake into macrophages and interfere with glutathione synthesis.

The serum methionine concentration in this patient is also very low, suggesting inadequate endogenous cysteine formation and camitine synthesis.

Low normal taurine levels are detrimental in HIV infection due to the antioxidant and anti-inflammatory properties of this amino acid.

Threonine deficiency is often seen in malabsorption, as this amino acid is the least well absorbed. Threonine is an important constituent of immunoglobulins.

Author:
Dr med. Hans-Günter Kugler, M.D.
Diagnostic Centre for Mineral Analysis and Spectroscopy
Löwensteinstraße 7 – 9
97828 Marktheidenfeld

Phone 09394/ 9703-0
Fax 09394/ 9703-33

www.diagnostisches-centrum.de

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