of infected subjects with diets, improved and altered environmental conditions and every other conceivably helpful measure. After the discovery of effective drugs, this aspect of TB therapy quickly became secondary and largely uncontroversial. (With the more recent emergence of multi-drug resistant and extensively drug-resistant TB strains especially, these older measures may again have to be looked at as potentially valuable supportive measures in our total arsenal).
Because HIV infection cannot be cured but only controlled, with drugs being applied at particular, serious stages of progressive disease (according to current guidelines, at least) the emphasis in the management of infected people during the phases prior to drug administration is still on general, non-pharmacological support, especially as for many reasons it is highly desirable to postpone the introduction of specific antiretroviral therapy for as long as possible.
This study has examined the role nutritional support can play, in individuals and populations, at this time and in this place, against these two pandemic microbial enemies of Homo sapiens, in the light of the above macro-considerations.
The complexity of the immune system has been notoriously difficult to convey to students of human physiology and pathophysiology, and teachers have made frequent use of military analogies to help to explain some of the basic principles. Thus, pathogenic organisms are depicted as foreign invaders, with the cells and molecules of the immune cells cast in the role of “home-army soldiers” and their “weapons”, respectively. In terms of these analogies, and with special relevance to the intersection of the science of immunology with the science of nutrition, the destruction of foreign invaders, such as the M. tuberculosis organism, is critically dependent on effective deployment of one of the most effective weapons in the immunological arsenal – the “flamethrower”. This analogy is representative of the respiratory burst, whose central role in the intracellular killing of pathogenic organisms is well established. Moreover, it has emerged that strains of M. tuberculosis that have effectively evolved strategies to evade oxidant damage (effectively dousing the “fire”) are associated with particular virulence in causing severe disease in the human host3. The “flamethrower” is thus the weapon that burns (oxidises) foreign organisms to death. It is self-evident that such a weapon is rendered ineffective if not kept supplied with adequate energy, explaining the nutritional need for energy fuels such as carbohydrates and fats. The complete burning, or oxidation within cells of these fuels to generate the energy needed to power “flamethrowers” is accomplished as they are metabolised through the Krebs cycle. Vitamins B1 (thiamine), B2 (riboflavin) and B3 (niacin), are essential precursors of components of the electron transport chain, and are critical requirements for this process.
Not surprisingly, such dangerous weapons as “flamethrowers”, when deployed to fight foreign microorganisms, are prone to cause significant collateral damage to friendly forces and structures. Accordingly, a critical nutritional component in the functioning of the immune system concerns the generation of chemical energy in a form that can be safely directed at foreign organisms. The risk of damage to host structures, cells and tissues is minimised by antioxidants, whose functions are thus analogous to “fire extinguishers”. Many of the micronutrients function in this antioxidant capacity. While B-group vitamins have a number of critical roles in cellular metabolism, including rate- limiting functions in cell growth and regeneration (a vital process in the production of sufficient white cells to combat infectious microorganisms), indirectly contributing towards intracellular antioxidant activity is one such role. Similarly, many of the trace elements are metals, each of whose available electron orbitals is precisely tailored to absorbing or releasing a specific energy quantum; the full complement of trace metals such as iron, zinc, magnesium and copper thus provides a range of quanta to cover the equivalent range of biological energy transfer oxidation-reduction reactions. Sulphur and selenium are, like oxygen, chalcogens (Group VIa elements). They are thus similar chemically to each other and to oxygen, but with subtly different electron affinities and
electronegativities. Sulphur is a component of the amino acids methionine and cysteine, the latter being the central active component of the archetypal intracellular antioxidant
“fire extinguisher”, the tripeptide, glutathione. Its other constituents are the amino acids glycine and glutamic acid, the latter derived from dietary glutamine, another amino acid.
Selenium is a component of the 21st amino acid, selenocysteine. The role of selenocysteine containing proteins, such as glutathione peroxidase, is to regulate a number of critical oxidation-reduction reactions.
Cell membranes are composed largely of fats, and in the metaphoric sense being used here, highly “inflammable”. Vitamin E (tocopherol) is one of the fat-soluble vitamins whose prime function is to act as a fire extinguisher for deployment in cell membranes. Collateral oxidation damage resulting from the deployment of intracellular
“flamethrowers” is not necessarily contained within cells, because cells may die and release oxidising chemicals. The role of vitamin C (ascorbic acid) is to mop up potentially dangerous extracellular oxidants, and its prime function is therefore also largely that of a “fire extinguisher”.
To summarise the role of nutrition in immune function, a key strategy is the use of chemical energy to “burn” or oxidise foreign microorganisms. Much of the nutritional demand of the immune system concerns the safe provision of chemical energy for this purpose. The macronutrients, carbohydrates and fats, are the raw fuels for this energy, and the prime function of many of the micronutrients, including most of the B-group vitamins, vitamin C, vitamin E, many of the trace elements and some of the amino acids, is to provide the machinery for this energy to be extracted and deployed safely, minimising the risk of collateral damage to host cells and tissues. The dietary vitamin A precursors, the carotenoids are also antioxidants, while vitamin A itself has other immunologically relevant functions, including gene regulation and the preservation of mucous membrane integrity.
With regard to the second generic need for nutrition, the growth, replacement and repair of cells and tissues, virtually all the other nutrients not covered above in this brief conceptual overview of immunonutrition, are largely devoted to this purpose in immune cells. The B-group vitamins, folic acid and vitamin B12 are primarily concerned with the process of DNA synthesis, which is needed especially for the replacement of immune cells undergoing rapid turnover during infectious episodes. (Soldiers have a high attrition rate in wartime).
Vitamins A and D are critical requirements in the process of regulating the production of many of the immunologically important proteins such as antibodies, cytokines, etc (more weapons in the military arsenal, other than the “flamethrowers”). The amino acids needed to construct these weapons are derived from the macronutrient, dietary protein.
The assessment of subclinical nutritional deficiency is notoriously difficult. This factor confounds the identification of early phases of nutrient depletion, which may well impact on immune function. Simple measurements of blood or tissue fluid levels of
specific nutrients frequently fail to reveal even quite advanced depletion states. Nutritional depletion states, leading in time to overt deficiencies, represent a spectrum of accumulated negative balance between whole-body intake and loss. With the typical elegance that is characteristic of biological systems, there are mechanisms to protect vital functions, and decreasing urinary excretion, or curtailing it completely, is one of the first of the strategies the body deploys to preserve its vital nutritional resources. This is accompanied by the scaling up of intestinal absorption efficiency, but eventually these devices may fail and only in very advanced deficiency states do blood concentrations of many micronutrients begin to fall. Functional impairment to cell or tissue systems follows, with the inevitable development of the clinical symptoms and signs of a deficiency state.
Different cells and tissues vary in their position within the hierarchy of claimants to available resources, reflecting variations in the affinities and turnover rates of tissue specific vitamin-derived coenzymes. Where the immune system lies within this hierarchy is currently poorly understood, partly because the correlates of immune deficiency and its restitution are generally ill defined, and in any event these correlates are probably themselves highly variable between immune responses to differing microbial pathogenic organisms. Nevertheless, certain markers to measure putative dietary immunomodulation are recommended in a general immunological setting4. These include vaccine-specific serum antibody synthesis, total and vaccine antigen- specific salivary IgA, delayed hypersensitivity reactions, responses to attenuated pathogens, natural killer cell cytoxicity, lymphocyte transformation assays, cytokine production by activated immune cells, and phagocyte respiratory burst activity. Which of these assays are of value in the setting of widespread HIV and TB prevalence is not yet clear, and few reported studies have applied these markers. Despite this, the word
“immunomodulation” is widely used to describe activities of foods, often in the complete absence of evidence to support such claims.