Chapter 20 Infections and immunity

Introduction

The immune system is a complex of tissues, cells and molecules with specialised roles in defence against infection. There are 2 fundamentally different types of responses to invading microbes — innate (natural) immunity responses that occur to the same extent however many times the infectious agent is encountered, whereas acquired (adaptive) immune responses improve on repeated exposure to a given infection or antigen.

The mediators of the innate immune response include phagocytic cells (i.e. neutrophils, monocytes, and macrophages), cells that release inflammatory mediators (i.e. basophils, mast-cells and eosinophils), and natural killer cells. The molecular components of innate immune responses include complement, acute-phase proteins and cytokines such as the interferons.

Acquired responses involve the proliferation of antigen-specific B- and T-cells, which occurs when the surface receptors of these cells bind to antigen. Specialised cells, called antigen-presenting cells, display the antigen to lymphocytes and collaborate with them in the response to the antigen. The B-cells secrete immunoglobulins, the antigen-specific antibodies responsible for eliminating extracellular microorganisms.

T-cells help B-cells to make antibody and can also eradicate intracellular pathogens by activating macrophages and by killing virally infected cells. Innate and acquired responses usually cooperate to eliminate pathogens.

The immune system hence distinguishes entities within the body as self or non-self and acts to eliminate those that are non-self. Microorganisms are the principal non-self entities, but neoplasms, transplants, and certain foreign substances (e.g. some toxins) are also important.

A paradox shift has recently been established, between those known functions of the immune system and bacterial species. This shift has challenged the idea that all infections are adverse to health. This was the instinctive documented observations of Elie Metchnikoff from the early 20th century. There has been much interest in the beneficial effects of commensal bacteria on human health. The effect of commensal bacteria on the innate immune system of humans has changed the way we view infections with bacteria that favourably influence the health of the host by improving the indigenous microflora.

Studies of mucosal immunity and age suggest that mucosal immunity evolves with age and it is obvious that the loss of innate immunity to process, eliminate and present antigens could compromise the development of adaptive immunity.

Of significant importance is that humans represent a scaffold on which diverse microbial ecosystems are established. Immediately after birth, all mammals are initiated into a lifelong process of colonisation by foreign microorganisms that inhabit all mucosal surfaces as well as the skin. Fashioned by millennia of evolutionary inputs, some host–bacterial associations have developed into beneficial relationships, creating an environment for mutual benefit and endowing the human immune system with advantageous signalling capacities that can control pathogenic insults throughout a lifetime of interactions. This then raises the possibility that, rather than the mammalian immune system being designed to control microorganisms, it is in fact controlled by microorganisms.¹

Lifestyle factors

Lifestyle factors can significantly influence the state of the immune system. Whilst conservative approaches such as rest and fluids, and pharmaceutical treatments such as antibiotics, anti-fungal and anti-viral medication have played a very important role in the treatment of infections, it is vital to explore factors, in particular lifestyle factors, that may be contributing to lowered or altered immunity, and enhancing susceptibility to diseases of infections, chronic fatigue or even cancers.

For example, recurring infections such as recurrent ear, urinary and sinus infections are a common presentation to medical practitioners. These can be quite distressing for families to deal with, not only in its treatment but also its impact physically, psychologically and socially, such as in time away from work and school, and dependency on others such as grandparents to care for sick children.

Table 20.1 summarises the lifestyle factors that may impact adversely on the immune system. These factors will be discussed throughout the chapter. Prevention is the best method to help maintain a healthy immune system.

Table 20.1 Risk factors that impact on the immune system

Stress — chronic

• Depression

Environment

• Climate change — overheating that promotes vector-borne illnesses (e.g. malaria, gastroenteritis); poor housing and/or living conditions

• Overcrowding

• Environmental syndrome, electromagnetic radiation, Multiple Chemical Sensitivity, Sick Building Syndrome

Chemical exposure and/or pollutants

• For example, immunosuppressive, chemotherapy medications

Exposure to infection(s)

• For example, hygiene, poor water and/or food quality

• Bacterial, fungal, viral, parasites

Lack of sleep

Lack of sunshine

• Vitamin D deficiency

Exercise

• Lack of exercise

• Too much exercise (e.g. marathon runners)

Obesity

Underweight, cachectic, anorexic

Poor nutritional intake

Nutrient deficiencies

• For example, vitamin A, C, D, E, B6, B12, folate, zinc, iron, copper

Mind–body medicine

Humans as well as all other organisms have a requisite to maintain a complex dynamic equilibrium (homeostasis), which is constantly challenged by internal or external adverse stressor events. The brain’s stressor-handling system that constitutes the limbic-hypothalamic-pituitary-adrenal axis is one of the most thoroughly studied circuitry systems of the central nervous system. As a result of stressor–axis activation, different behavioural and physical changes can develop which allow the organism to adapt. These are the domains of psychoneuroimmunology (PNI) and psychoneuroendocrinology (PNE).^2,³

Psychoneuroimmunology (PNI)

The emerging specialty fields of PNI and PNE are justification enough that stress and/or adverse stressors have a profound impact upon every system within the body.^2,^{3, 4}

There is a wealth of evidence demonstrating that psychological stress can adversely affect the development and progression of almost every known disease. Both acute and chronic stressful states produce documentable changes in the innate and adaptive immune responses, which are predominantly mediated via neuroendocrine mediators from the hypothalamic-pituitary-adrenal (HPA) axis and the sympathetic-adrenal axis.⁵^–¹³

Indeed, this is an elaborate multi-directional communication system which continually and simultaneously relays multiple messages between the immune, gastrointestinal, neurological, endocrinological, dermatological and cardiovascular systems in an ongoing attempt to restore and maintain homeostasis.¹⁴^–²⁴

Neurotransmitters, hormones and neuropeptides all regulate the cells of the immune system, subsequently communicating with all other systems through the secretion of a wide variety of different cytokines.¹⁴ It is beyond the scope of this chapter to discuss such complex and intricate interactions, however, there is sufficient literature available today specifically dealing with PNI.

Acute stress has been shown to have a stimulating effect on the immune system whereas chronic stress down-regulates the immune system.^12,¹⁶ Chronic stress has been associated with increased susceptibility of the patient to infectious diseases and cancer.^6,^{7, 9} It is also linked with worse outcomes in many immune-related disorders, including cancer, inflammatory and infectious diseases, indicating that the effects of mental states on our immune system are directly and clinically relevant to disease expression.^10,^{16, 18}

Psychological interventions

There is certainly considerable variability in each individual’s immune response to stress. Encouraging particular activities that increase that person’s ability to cope with stress may therefore have a significantly beneficial effect on immune function with subsequent modification in the development and progression of many different diseases.^12,^{14, 21, 23}

It is also important to note that stress during fetal and neonatal development can alter the programming of the neuro-endocrine-immune axis, influencing stress, immune-responsiveness and even disease resistance in later life.¹⁶ Therefore identification and treatment of suboptimal moods in pregnant women is imperative.

Various behavioural strategies, psychological and psychopharmacotherapeutic interventions that enhance effective coping and reduce affective distress show beneficial effects in many disease, including cancer.^15,²⁵

A recent Australian survey of women with breast cancer indicates that 87.5% of surveyed women had used complementary therapies in order to improve their physical health (86.3%), emotional wellbeing (83.2%) and to boost their immune system (68.8%). Support groups and meditation were commonly used therapies.²⁶

Environment

Epidemiological studies have reported that the hygiene hypothesis suggests that early life exposure to a non-hygienic environment that contains endotoxin reduces the risk of developing allergic diseases. Moreover, it is increasingly recognised that microbial colonisation of the gastrointestinal tract, linked with lifestyle and/or additional geographic factors, may be important determinants of the heterogeneity in disease prevalence observed throughout the world.

Developmental immuno-toxicology (DIT) and/or Early Life Immune Insult (ELII)

Many chronic diseases of increasing incidence are now recognised to have immune dysregulation as an important underlying component of the disease process.⁴⁹ These include many childhood illnesses such as asthma, allergic disease, leukaemia, auto-immunity and certain infections.⁵⁰

The developing immune system is extremely sensitive to environmental toxins, such as infectious agents, allergens, maternal smoking, maternally administered drugs, exposure to xenobiotics, diesel exhaust and traffic-related particles, antibiotics, environmental oestrogens, heavy metals, chemicals and other prenatal/neonatal stressors.⁵¹^–⁵⁸ Dysfunctional immune responses to infections in childhood have been postulated to play a role in childhood leukaemia.^56,⁵⁷ Furthermore, many prenatal and postnatal neurological lesions are now also being recognised as being linked to prenatal immune insult and inflammatory dysregulation.⁵⁷ Evidence for an association between environmentally associated childhood immune dysfunction and autistic spectrum disorders also suggests that ELII and DIT may contribute to these conditions.^53,^{54, 56, 57}

Indeed, ELII have been proposed to be pivotal in producing chronic symptoms in later life. In particular, the period from mid-gestation until 2 years seems to be one of particular concern, with this critical maturational window displaying a heightened sensitivity to chemical disruption with the outcome of persistent immune dysfunction and/or misregulation.⁵⁷ It is also important to note that the same toxin may result in different immune maturational processes according to the dose and timing of the insult.⁵⁷ The important emerging field of epigenetics (combined environmental and genetic history) is also relevant in this situation.

T Helper lymphocytes

Available data indicates that ELII results in a shift from T-helper (Th) lymphocytes 1 towards Th2 predominance, alterations in regulatory T-cell function and problematic regulation of inflammatory cell function leading to hyper-inflammatory responses and perturbation of cytokine networks. The resulting health risks may extend far beyond infectious diseases, cancer, allergy and auto-immunity to pathologies in the neurological, cardiovascular, endocrinological, respiratory and reproductive systems.53–55, 57

Environmental syndromes

There is also strong evidence indicating that complex syndromes such as Multiple Chemical Sensitivity, Gulf War Syndrome, Sick Building Syndrome and Chronic Fatigue Syndrome, that often have no clear underlying medical explanation, may have an environmental component to their aetiology.⁵⁹

Electromagnetic radiation

There is currently much debate regarding the potential health risks from extremely low frequency electromagnetic fields (ELF) and radiofrequency/microwave radiation emissions from wireless communications (RF). In addition to immune system dysregulation, other risks may include childhood leukaemia, brain tumours, genotoxic effects, neurodegenerative diseases, allergic and inflammatory responses, breast cancer, miscarriage and some cardiovascular effects.^60,^{61, 62}

Specific reports on immunological dysfunction are scarce, however, 1 earlier study demonstrated that people who worked in close proximity to transformers and high tension cables full-time for 1–5 years experienced a significant decrease in total lymphocytes and CD2, CD3 and CD4 lymphocytes as well as an increase in NK-cells. Leukopaenia and neutropaenia were observed in 2 people who were permanently exposed to 1.2–6.6microT.⁶³

The recent Bioinitiative Report has concluded that a ‘reasonable suspicion of risk exists based on clear evidence of bioeffects at environmentally relevant levels which, with prolonged exposures, may reasonably be presumed to result in health impacts’.⁶⁴

Multiple chemical sensitivity (MCS)

Another topic of debate, MCS is characterised by various signs including neurological disorders, allergy and immune dysregulation. MCS is now becoming well recognised as a disease state affecting a number of people worldwide (see: www.nicnas.gov.au/currentissues/mcs.asp). Exposure may occur through a major event, such as a chemical spill, or from chronic exposure to chemicals at low levels. Animal studies have demonstrated immune changes and allergic reactions to different chemicals including the well-known Th2 type sensitisers TMA (trimetallic anhydride) and TDI (toluene diisocyanate) and the Th1 sensitiser DNCB (2, 4-dinitrochlorobenzene).^65,^{66, 67}

Sick Building Syndrome

This is another poorly understood syndrome whereby immunological dysfunction, neurotoxicity and allergies may arise from exposure to bioaerosols, especially moulds, in the indoor environment of water-damaged buildings.⁶⁸ Epidemiological and toxicological studies have demonstrated an increase in auto-antibodies (IgA, IgM, IgG) to neural-specific antigens with resulting neuro-physiological abnormalities, including peripheral neuropathy, in exposed individuals.⁶⁹ Mould exposure has also been shown to initiate inflammatory and allergic (IgE) processes with significant alterations in B- and T-lymphocyte counts as well as NK-cells.^51,^{52, 70, 71}

Infections and vitamin D

The spectrum of human diseases caused by infective agents can be extensive. There are 7 categories of biological agents that can cause infectious diseases. Each has its own particular characteristics. The types of agents are — metazoa, protozoa, fungi, bacteria, rickettsia, viruses and prions.

Tuberculosis still kills more people than any other pathogen-associated disease, with approximately one-third of the world’s population being infected. Among these, however, only 10% will actually develop the disease. Recently identified genetic polymorphisms in the vitamin D receptor and the vitamin D-binding protein are believed to generate either susceptibility or resistance to M. Tuberculosis infection.⁷⁰

Vitamin D deficiency has also been found to be associated with bacterial vaginosis in the first trimester of pregnancy. The prevalence of vaginosis continued to reduce with treatment as the serum 25(OH)D concentration increased to 80nmol/L.

Current investigations are also focused on the role of vitamin D for the prevention of upper respiratory tract infections. In 1 study, 162 adults were randomly given 2000 IU D3 daily for 3 months. No benefits were seen in decreasing the incidence or severity of upper respiratory tract infections during winter.⁷¹ Results of trials with higher doses of vitamin D3 are currently underway.

Maternal vitamin D supplementation is also extremely important as low prenatal vitamin D levels may also increase susceptibility to the same diseases later in life.⁷²

Auto-immune diseases and vitamin D

There are a multitude of studies associating vitamin D deficiency with the development and progression of auto-immune diseases such as multiple sclerosis (MS), rheumatoid arthritis, insulin dependent diabetes mellitus (IDDM) and inflammatory bowel disease (IBD). The immune-regulatory role of vitamin D affects both the innate and the adaptive immune systems.⁷³

The discoveries that activated macrophages produce active vitamin D and immune system cells express the vitamin D receptor, both initially suggested how the vitamin D endocrine system influenced immune system function.⁷⁴ Auto-immune diseases occur because of an inappropriate immune-mediated attack against self-tissue. Without vitamin D, auto-reactive T-cells develop whereas in the presence of vitamin D, the enhanced activity of immune cells is suppressed, balance in the T-cell response is restored and the process of autoimmunity is subsequently avoided.^75,⁷⁶

Experimental animal studies have demonstrated that vitamin D deficiency accelerates the development and progression of both auto-immune diseases and cancers.⁷⁷

Recent evidence also strongly suggests that supplementation with vitamin D may be beneficial, especially for Th1-mediated auto-immune disorders. By decreasing the Th1-immune driven response, the severity of symptoms is decreased. Some reports indicate that vitamin D may even be preventative in such disorders as MS and type 1 diabetes mellitus (T1DM).^49,^78–82

Sleep

Good sleep is essential for physical and mental health.⁸³ There is strong evidence demonstrating that inadequate sleep is associated with a multitude of health problems, including cognitive impairment, mood disorders, parasitical infections, cardiovascular diseases and compromised immunity.⁸⁴^–⁸⁷ Unfortunately, frequently disrupted and restricted sleep is a common problem in today’s society with more than 50% adults over 65 years reporting at least 1 chronic complaint.^83,⁸⁵ Many younger adults also suffer chronic sleep deprivation secondary to occupational hazards such as shift work or mental disorders such as anxiety.⁸⁸

Both animal and human studies have revealed that sleep restriction/deprivation can result in mild temporary increases in the activity of the major neuroendocrine stress systems — the autonomic sympatho-adrenal system and the HPA axis. Chronic sleep deprivation may also affect the reactivity of these systems to future stresses and challenges, such as physical and mental illness.^85,⁸⁹ Chronic sleep deprivation tends to cause a gradual and persistent desensitisation of the 5-HT 1A receptor system, thus altering serotonergic neurotransmission.⁹⁰ As expected, these changes in neurotransmitter receptor systems and neuroendocrine reactivity are extremely similar to those seen with chronic stress/depression.⁸⁶

Poor sleep quality has recently been confirmed to increase susceptibility to the common cold.⁹¹ Atypical time schedules such as shift-work has also been associated with breast cancer, due to a circadian disruption and to a nocturnal suppression in melatonin production.⁸⁸

Melatonin is our natural sleep hormone and it is known to decrease with increasing age. Recent studies have shown that melatonin, itself, has an immune-modulating effect, stimulating the production of NK-cells and CD4+ cells and inhibiting CD8+ cells. It also stimulates the production of granulocytes and macrophages, as well as the release of various cytokines from NK-cells and T-helper lymphocytes. Thus, enhancement of the production of melatonin, or melatonin itself, has the potential therapeutic value to enhance immune function.⁹²

The recognition and treatment of sleep dysfunctions can therefore be an important part of management of many health-related conditions.⁸⁸

Physical activity

Exercise

There is a wealth of evidence supporting the beneficial effects of exercise upon the immune system. In particular, exercise has beneficial effects on many chronic diseases. It is known to have an anti-inflammatory effect, reducing body fat percentage and macrophage accumulation in adipose tissue as well as muscle-released IL-6 inhibition of TNF-alpha and the cholinergic anti-inflammatory pathway.^93,⁹⁴ In particular, exercise training improves macrophage innate immune function in both a beta(2) adrenergic receptor dependent and independent manner.⁹⁵

NK-cells have been found to be the most responsive immune cell to acute exercise. Their sensitivity to physiological stress combined with their important role in innate immune defences indicate that these cells are 1 link between regular physical activity and general health status.⁹⁶

Anaerobic exercise in animal studies has been shown to increase both innate and adaptive immune function, decreasing tumour growth and cancer cachexia.⁹⁷ Secretory IgA, which is the predominant immunoglobulin in mucosal secretions providing first-line of defence against pathogens and antigens presented at the mucosa, have also been shown to be increased after exercise in elderly people over 75 years.^98,⁹⁹

It is important to note, however, that exercise needs to be performed in moderation. Multiple effects of over-training resulting in impaired immune response have been documented in the literature.¹⁰⁰^–¹⁰⁴ Unlike moderate exercise, intense habitual exercise can cause chronic suppression of mucosal immune parameters, especially salivary IgA and IgM.^105,¹⁰⁶ This can result in increased susceptibility to respiratory infections.^95,¹⁰⁵

Vigorous exercise or activity may exacerbate chronic conditions such as chronic fatigue syndrome by promoting immune dysfunction, which in turn increases symptoms. It is vital that patients with chronic fatigue syndrome are provided with a well designed individualised graded exercise program to cater for individual’s physical capabilities and should take into account the fluctuating nature of symptoms. Patients should be encouraged to pace their activities and respect their physical and mental limitations with the ultimate aim of improving their everyday functioning.¹⁰⁶

A Cochrane systematic review of the literature identified 9 studies but only 5 randomised control studies were included in the review.¹⁰⁷

In general, at 12 weeks, subjects participating in an exercise therapy program were less fatigued and experienced significantly better physical functioning compared with control groups. However, there were more drop outs in the exercise groups compared with control groups. Moods of CFS sufferers improved in the exercise group and performed better than the group receiving the antidepressant fluoxetine. Furthermore, when the exercise program was combined with patient education, patients experienced less fatigue overall. The authors concluded that patients may benefit from an exercise therapy program and could not find evidence that exercise worsens outcomes.

An interesting recent study has shown that heavy exercise in early post-partum months may be associated with elevated pro-inflammatory cytokines in breast milk. More studies are required to confirm these findings.¹⁰³

Yoga

There have been limited studies on the efficacy of yoga practice on the immune system. Most have been focused on the breathing disciplines within yoga, namely Pranayama and Sudarshan Kriya, that are both rhythmic breathing processes traditionally used to reduce stress and improve the immune system.¹⁰⁸

Studies on healthy individuals practicing the above techniques have shown a better anti-oxidant status (increased glutathione peroxidise, SOD; reduced lactic acid) at the enzyme and RNA level accompanied by improved immune status secondary to the prolonged lifespan of lymphocytes by up-regulation of anti-apoptotic genes and pro-survival genes in the subjects.^109,¹¹⁰

Cancer patients who were either undergoing or had completed their conventional therapy also showed a significant increase in NK-cells at 12 and 24 weeks after practicing the above yogic breathing techniques compared with controls.^111,¹¹²

Qigong

Qigong is an ancient Chinese psychosomatic exercise that integrates movement, meditation and breathing into a single exercise. All studies have been on healthy people and most demonstrate that after 1 month, there are significant changes in immune parameters.¹¹³ Neutrophil phagocytosis and lifespan was significantly increased whilst the inflammatory neutrophils displayed accelerated apoptosis. The changes in gene expression compared with controls were characterised by enhanced immunity, down-regulation of cellular metabolism and alteration of apoptotic genes in favour of rapid inflammation resolution.¹¹⁴ There is also evidence in some, but not all, studies of reduced cortisol and changes in the number of cytokine-secreting cells (increased IFN-gamma and reduced IL-10).^115,¹¹⁶

It is possible that qigong may regulate immunity, metabolic rate and apoptosis, perhaps at the transcriptional level.¹¹⁴ Further studies are required to validate these findings.

Obesity

The prevalence of obesity has reached epidemic levels in many parts of the world and therefore represents a major public health problem.¹¹⁷ The accumulation of visceral fat has well-established links with chronic low-grade systemic inflammation (metaflammation), cellular metabolic imbalances and impaired immunity.¹¹⁸^–¹²²

Through different biochemical cascades leading to immune cell senescence, obesity can promote a multitude of chronic diseases.¹²³^–¹²⁵ Amongst many others, these include metabolic syndrome, inflammatory diseases, bronchial asthma, Type II diabetes and insulin resistance, depression, cardiovascular disease (CVD), osteoarthritis, fatty liver disease and cancer.^2,^{9, 126, 127} Leptin is increased in states of obesity and can influence mediators of innate immunity, such as IL-6. Leptin-resistance can therefore injure numerous tissues, including the liver, pancreas, platelets, vasculature and myocardium.

Major endogenous endocrine and steroid hormones can combine with lifestyle factors (low exercise, excess weight, poor diet etc) to heighten the risk of many diseases, including cancer. Indeed, obesity has been associated with increased mortality from all cancers combined and there is an accumulating body of research regarding all mechanisms by which obesity can contribute to the carcinogenesis process.

White adipose tissue actively participates in many physiological and pathological processes, including immunity and inflammation, playing a major role in the development of leptin, adrenaline and insulin resistance.There are, indeed, complex links between the metabolic and immune systems, with multiple neuroendocrine peptides, cytokines and chemokines interacting in order to integrate energy balance with immune function. Such interactions are heightened in obesity and lessened with caloric restriction (CR).¹²⁶

Ghrelin and leptin are 2 important hormones and cytokines that both regulate energy balance and influence immune function.¹³ Ghrelin regulates immune function by reducing pro-inflammatory cytokines and promoting thymopoiesis during ageing and is found to be reduced in states of obesity. Thus, this provides 1 mechanism by which obesity can be associated with a state of immunodeficiency and chronic inflammation which can contribute to an increased risk of premature death.

In stark contrast, CR, which increases ghrelin and reduces leptin, can reduce oxidative stress and is a potentially immune-enhancing state which has prolonged a healthy lifespan in all species studied to date.^10,^{16, 127, 128}

Nutrition

Dietary modulation

Pro-inflammatory foods

There is strong evidence regarding the pro-inflammatory effects of fast–foods that contain high amounts of saturated fatty and trans-fatty acids, refined carbohydrates with a high glycaemic index.^122,^{123, 129–142}

The presence of these substances, in particular trans-fatty acids, fructose, glucose (sugars) in the diet negatively impacts on immunity and induces inflammation, creating a pro-inflammatory state, which contributes to many diseases.¹⁴³^–¹⁵⁸

Protective foods

Likewise, there is a wealth of evidence concerning the anti-inflammatory and immune-enhancing properties of foods such as fish, fruits, vegetables, nuts, seeds, cocoa / dark chocolate, low GI foods, white button, maitake, oyster and shiitake mushrooms, high fibre intake, dairy calcium, green tea, and lean game meats.¹⁵⁸^–¹⁷⁷

Spices, herbs, garlic and ginger

Spices, garlic, ginger and herbs have traditionally been highly regarded in cooking for many centuries by many cultures who believe they play an important role in health enhancement and protecting the immune system.¹⁷⁸^–¹⁸³

For instance, curcumin and capsaicin are known to protect the immune system and re-regulate the systemic inflammatory responses.^179,^{184, 187}

Grape polyphenols

Polyphenols have diverse biological effects.¹⁸⁸ Polyphenolic compounds found in red wine are a complex mixture of flavonoids (predominantly anthocyanins and flavan-3-ols) and non-flavonoids such as resveratrol and gallic acid. Flavan-3-ols are the most abundant, with oligomeric and polymeric procyanidins often representing 25–50% of the total phenolic constituents.¹⁸⁹ Inflammation is the process by which the immune system deals with infections or injury due to pathogenic bacteria, viruses and other pathogens. Recently it has been reported that the daily moderate consumption of alcohol and of red wine for 2 weeks at doses which inversely correlate with CVD risk had no adverse effects on human immune cell functions.¹⁹⁰ Polyphenol-rich beverages such as red grape juice and de-alcoholised red wine did not suppress immune responses in healthy men.

Cocoa and/or dark chocolate

Cacao liquor polyphenols have been reported to affect human immune system cells in vitro. The results demonstrated that at least in vitro, treatment of normal peripheral blood lymphocytes inhibited mitogen-induced proliferation of T-cells and polyclonal Ig production by B-cells in a dose-dependent manner. Also the treatment inhibited both IL-2 mRNA expression of and IL-2 secretion by T-cells. These results suggest that cacao derived polyphenolic compounds have immuno-regulatory effects.¹⁹¹ The effects of polyphenolic compounds from chocolate may be due to the modulation of cellular metabolic functions (re-regulation of inflammatory responses) that are synergistic with immunological functions.¹⁹² A number of phenolic compounds can be found in a variety of food sources (see Table 20.2).

Table 20.2 Flavonoid types, representative flavonoids in food and beverages sources

Class	Representative flavonoids	Food and beverage sources
Flavonols	• Quercetin • Kaempferol • Myricetin	• Tea • Apples • Onions
• Catechins • Procyanidins	• Tea • Red wine • Red grapes • Grape seeds • Cocoa	Flavones
• Apigenin • Luteolin	• Herbs • Vegetables	Flavanones
• Hesperidin • Naringenin	• Citrus fruits (i.e. oranges and lemons)	Anthocyanins
• Cyanidin	• Berries	Isoflavones
• Genistein • Daidzein	• Soy protein-containing foods

Dairy calcium

A recent study provides significant in vivo evidence that dietary calcium and dairy may regulate metabolic processes associated with inflammatory responses in a mouse model of diet-induced obesity and redox metabolism aberration as well as in obese adult humans. Dietary calcium-induced suppression of circulating 1alpha, 25-dihydroxycholecalciferol may be responsible for calcium-induced suppression of inflammatory responses, although further effects of dairy foods on oxidative stress appear to be mediated by additional mechanisms.¹⁹³

Lactoferrin from milk

Lactoferrin is an iron-binding glycoprotein of the transferrin family with a molecular mass of about 80 kilodalton (kDa). It is a component of milk, saliva, tears, airway mucus and secondary granules of neutrophils.^194,¹⁹⁵ It is also a major component of mammals’ innate immune system. Lactoferrin has a range of protective effects from direct antimicrobial activities — in relation to bacteria, viruses, fungi, and parasites — and anti-inflammatory and anti-cancer activities.¹⁹⁶ In addition, lactoferrin has demonstrated activities that are immuno-modulatory/anti-inflammatory (down-regulating cytokines)¹⁹⁷ and that regulate cell proliferation¹⁹⁸ and intestinal iron absorption.¹⁹⁹

Similar to human lactoferrin, bovine lactoferrin has been shown to induce proliferation and differentiation of human enterocytes and to modulate their cytokine production.²⁰⁰ The beneficial effects of orally administered bovine lactoferrin on infections and iron status have also been recently demonstrated in clinical trials in human adults and infants.²⁰¹^–²⁰⁶ The protective effect of lactoferrin towards microbial and viral infections has been widely demonstrated in a large number of in vitro studies, although the number of clinical trials so far completed is not extensive. Nevertheless, lactoferrin can be considered not only a primary defence factor against mucosal infections but also a polyvalent regulator, which interacts with several microbial, viral and host components involved in infectious processes. The capability of lactoferrin to exert antiviral activity through its binding to host-cells and/or viral particles strengthens the hypothesis that this glycoprotein constitutes a significant barrier in the mucosal wall of the GI tract, which has been demonstrated to be effective against both microbial and viral insults.

Essential fatty acids; omega-3 fish oils

Inflammation is part of the body’s immediate response to infection or injury. It is typified by redness, swelling, heat and pain. These occur as a result of increased blood flow, increased permeability across blood capillaries, which allows large molecules (e.g. complement, antibodies, pro-inflammatory cytokines) to leave the bloodstream and cross the endothelial wall, and increased movement of leukocytes from the bloodstream into the surrounding tissue. Inflammation functions to begin the immunological process of elimination of pathogenic and toxin insults and to repair damaged tissue. The key link between fatty acids and inflammation is that the eicosanoid family of inflammatory mediators is generated from 20 carbon polyunsaturated fatty acids (PUFAs) liberated from cell membrane phospholipids. The membrane phospholipids of inflammatory cells taken from humans consuming typical Western diets usually contain approximately 20% of fatty acids as the n-6 PUFA arachidonic acid.^207,²⁰⁸ The proportions of other 20 carbon PUFAs such as the n-6 PUFA linolenic acid and the n-3 PUFA eicosapentaenoic acid are typically about 2% and approximately 1% of fatty acids, respectively. Therefore arachidonic acid is usually the dominant substrate for eicosanoid synthesis promoting and sustaining the inflammatory response. Addition of n-3 PUFAs to the diet adds potentially useful anti-inflammatory agents that can regulate the inflammatory response by directly replacing arachidonic acid as an eicosanoid substrate, by inhibiting arachidonic acid metabolism, and by giving rise to anti-inflammatory resolvins, and indirectly, by altering the expression of inflammatory genes through effects on transcription factor activation.^209,²¹⁰

Mediterranean diet, portfolio diet, healthy diet

Different dietary regimes have been reported to be useful in influencing immune function.^180,^211–217

Recently it was demonstrated that adherence to a Mediterranean type diet with addition of virgin olive oil resulted in down-regulation of cellular and circulating inflammatory biomarkers.²¹⁸ Additional dietary strategies that focus on healthy food consumptions, such as the portfolio diet, reduced low-density lipoprotein cholesterol by approximately 30% and produced clinically significant reductions in CHD risk.²¹⁹ Consequently it would be expected that pro-inflammatory mediators would be reduced and re-regulated to normal levels.

Nuts

The consumption of nuts (i.e. almonds, brazil nuts, cashews, chestnuts, hazelnuts, macadamias, pecans, pine nuts, pistachios, walnuts) in the diet can significantly down regulate inflammatory responses of the immune system.²²⁰^–²²² Nuts are an excellent source of phytochemicals (phyotsterols, phenolic acids, flavonoids, stilbenes, and carotenoids). The total phenolic constituents probably contribute to the overall metabolic regulation of immune function anti-inflammatory responses.²²⁰

Soy protein

The intestines are an important organ responsible for nutrient absorption, metabolism and recognition of food signals.²²³ Soy proteins have been reported to modulate immune function pro-inflammatory activity.^224,²²⁵ Recently it was demonstrated that soy milk and supplemental isoflavones modulated B-cell populations and appeared to be protective against DNA damage in post-menopausal women.²²⁶

Teas

Green tea

EPG (Epigallocatechin-3-gallate), present in green tea, is well-known for its ability to reduce the risk of a variety of immunodeficiency disorders.²²⁷ Green tea possesses anti-oxidant, anti-inflammatory, anti-carcinogenic and immune enhancing properties. They have also been found to be photo-protective in nature, having the potential to be used for the prevention of photo-ageing, melanoma and non-melanoma skin cancers.²²⁸ In a recent randomised, double-blind, placebo-controlled trial, healthy adults were given green tea capsules or placebo twice daily for 3 months. Those taking the active formulation had enhanced gammadelta T-cell function with 32% fewer subjects experiencing symptoms of cold and flu. Those who did become unwell experienced a significantly shorter duration of symptoms.²²⁹^–²³²

Black tea

Habitual consumption of tea has been associated with improved immune system function.²³³^–²³⁵

A recent review has concluded that the current scientific evidence supports the concept that dietary intervention with tea or L-theanine leads to T-cell priming. Such priming is beneficial because it is associated with an enhancement of the magnitude and the breadth of early responses to microbial and neoplastic disease. Small clinical trials in normal volunteers have demonstrated that increased intake of tea or a supplement containing the bioactive tea components L-theanine and epigalenocatechins affect T-cell activity and the latter was associated with a decrease in cold and flu symptoms.²³⁶

Food intolerance

It is important to realise that any food, however, may be pro-inflammatory for an individual who is intolerant to that food. Adverse reactions to foods can have a significant impact on the immune system and general wellbeing of an individual’s life. Immune-mediated adverse reactions may be roughly divided into IgE-mediated and non IgE-mediated. Non IgE-mediated food reactions are not well understood and their negative effects on wellbeing and immune efficiency may be highly underestimated. In the first few years of life, humans gradually develop an intricate balance between tolerance and immune reactivity in the gut mucosa along with a tremendous expansion of the gut-associated lymphoid tissue (GALT), which is profoundly affected by changes in commensal flora.²³⁷

The simplest test to determine which foods contribute to gastrointestinal or other symptoms is to perform a food elimination diet (FED), with initial avoidance then separate re-introduction of individual foods (see: www.integrative-medicine.com.au for details). Some of the most common dietary intolerances are due to wheat, dairy and soy. In such cases, immune reactivity may be associated with apparent dietary protein intolerance (gliadin, cow’s milk protein, soy) and gastrointestinal inflammation that may be partly associated with an aberrant innate immune response against endotoxin, a product of specific gut bacteria.²³⁸

Alcohol

Alcohol in light-moderate amounts (1 glass for women, 2 glasses for men, every second day) has been shown to be particularly beneficial for the immune system when compared with both non-drinkers and heavy drinkers.²³⁹ Resveratrol, a polyphenol from red wine, is able to stimulate both innate and adaptive immune responses; in particular, the release of cytokines such as IL-12, IL-10 and IFN-gamma and immunoglobulins that may be important for host protection in different immune-related disorders.^240,²⁴¹ Its effects may be also related to cytokine production by both CD4+ and CD8+ T-cells.²⁴²

Nutritional supplementation

Nutrition is a critical determinant of immunity and malnutrition is the most common cause of immunodeficiency worldwide.²⁴³ Nutrients either enhance or depress immune function depending on the nutrient and level of its intake.²⁴⁴ Indeed, both insufficient and excess nutrient intakes can have negative consequences on immune status and susceptibility to a variety of pathogens.²⁴⁵ Deficiency of nutrients may suppress immunity by affecting innate, T-cell mediated and adaptive antibody responses, leading to dysregulation of the host response. This can subsequently lead to increased susceptibility to infections which can then lead to further nutrient deficiency and so on.²⁴⁶

Available data indicates that vitamins A, B6, B12, C, D, E, folic acid and the trace elements Fe, Zn, Cu and Se all work synergistically to support the protective activities of the immune cells. With the exception of iron and vitamin C, they are all also intricately involved in antibody production.^245,²⁴⁶ Anti-oxidant vitamins and trace elements (vitamins C, E, Se, Cu, Zn) counteract damage to tissues secondary to reactive oxygen species whilst simultaneously modulating immune cell function by affecting the production of cytokines and prostaglandins. Adequate intakes of vitamin B6, B12, C, E, folic acid and trace elements Se, Zn, Cu and Fe all support a Th1 cytokine-mediated immune response with sufficient production of pro-inflammatory cytokines. This maintains an effective immune response,²⁴⁶ avoiding a shift to an anti-inflammatory Th2 immune state and an increased risk of extracellular infections. Supplementation with these nutrients reverses the Th2 cell-mediated immune response to Th1, thereby enhancing innate immunity.²⁴⁷^–²⁴⁹

Presented below is a summary of evidence for the most recently studied nutrients, supplements and herbs with regard to immune system enhancement.

Probiotics

The gastrointestinal mucosa is the major contact area between the host and the external world of microflora. Over 400 square metres in size, it is colonised by an immense number of bacteria that are in constant communication with our immune cells.²⁵⁰ In fact, it is the GALT itself that houses the largest number of immune cells in the body.²⁵¹

Although the intestinal immune system is fully developed after birth, the actual protective function of the gut requires the microbial stimulation of bacterial colonisation. Breast milk naturally contains prebiotic oligosaccharides, designed to feed and proliferate specific resident bacteria with important protective functions (probiotics), primarily Lactobacillus and Bifidobacterium, in the infant’s gut.²⁵¹ However, the nature and species of microflora is also determined by many other factors, including external environment microflora, use of antibiotics and immuno-modulatory agents and early introduction of cow’s milk.²⁵²

Until recently, the gut bacteria were regarded as residents without any specific functions.²⁵¹ However, it now appears that altered mucosal microflora in early childhood alters signalling reactions which determine T-helper cell differentiation and/or the induction of tolerance.²⁵³^–²⁵⁴ Thus, the nature of mucosal microflora acquired in early infancy determines the outcome of mucosal inflammation and the subsequent development of mucosal disease, autoimmunity and allergic diseases later in life.²⁵⁴

Probiotics are recognised for their roles in nutrient absorption, mucosal barrier function, angiogenesis, morphogenesis and postnatal maturation of intestinal cell lineages, intestinal motility and, most importantly, the maturation of the GALT.²⁵⁶

An important adjustment of the immune system to bacterial colonisation of the gut is the production of secretory immunoglobulin A (sIgA) by B-cells in the GALT.^248,^{255, 256} Probiotics stimulate both the production and secretion of polymeric IgA, the antibody that coats and protects mucosal surfaces against harmful bacterial invasion.²⁵³ Secretory IgA also promotes an anti-inflammatory environment by neutralising immune stimulatory antigens.²⁵⁰ Thus, sIgA plays a significant role in the regulation of bacterial communities and maintenance of immune homeostasis.²⁵⁵

In addition, appropriate colonisation with probiotics helps to produce a balanced T-helper cell response and prevent an imbalance which can contribute in part to clinical disease. For example, Th2 imbalance may contribute to atopic disease and Th1 imbalance may contribute to Crohn’s disease and Helicobacter pylori-induced gastritis.²⁵³ Th1>Th2 cytokine expression in the respiratory tract associated with increased allergic disease has been correlated with reduced exposure to microbial agents associated with Th1 responses. In contrast, reduced exposure to helminths in the gut associated with reduced Th2 expression appears to correlate well with dominant Th1 cytokine expression and IBD.^249, ^254,²⁵⁵

Pre and probiotics are certainly attractive options for maintaining the steady nutritional state of the host with defective gut barrier functions. Prebiotics (inulin from chicory root, fructooligosaccharides, arabinogalactans) resist enzymatic digestion in the upper GI tract and therefore reach the colon virtually intact where they undergo bacterial fermentation. The consumption of prebiotics favours the growth of probiotics and impedes growth of pathogenic organisms, thereby modulating immune parameters in the GALT, secondary lymphoid tissues and peripheral circulation.²⁵⁷ The change in gut microflora may decrease intestinal permeability, consequently influencing both intestinal and systemic body functions.²⁵⁸

Adverse reactions to foods can have a significant impact on an individual’s life. In the first few years of life, humans gradually develop an intricate balance between tolerance and immune reactivity in the gut mucosa along with a tremendous expansion of the GALT, which is profoundly affected by changes in commensal flora.²³⁷

Probiotics modify the structure of potentially harmful food antigens and thereby alter their immunogenicity.²⁵⁸ Both IgE and non IgE-mediated food allergy are frequently seen in the early years of life, with cow’s milk and soy proteins being the most common causative dietary proteins for non IgE-mediated food allergy.²³⁷ Certain probiotics have recently been found to release low-molecular-weight peptides into milk products using bacterial-derived proteases that degrade milk casein, and thereby generate peptides, triggering immune responses. Thus the intestinal microbial communities contribute to the processing of food antigens in the gut.²⁵⁹

Abnormalities in Th1 function may not only play a role in some patients with non IgE-mediated food allergy in whom decreased Th1 function is seen, but also in patients with coeliac disease in whom an increased Th1 is seen. Lymphonodular hyperplasia may also be a hallmark histologic lesion in patients with non IgE-mediated food allergy.²⁶⁰ In such patients, a localised IgE-mediated response rather than a systemic food-specific IgE response may be responsible for these gastrointestinal symptoms.²⁶¹

The pathogenesis of IBD involves an interaction between genetically determined host susceptibility, dysregulated immune response and the enteric microbiota.^262,²⁶³ Inappropriate secretion of quorum sensing molecules by certain gut bacteria may alter the GALT and thereby deregulate the immune tolerance normally present.^264,²⁶⁵ Thus manipulation of the luminal contents with antibiotics, prebiotics or probiotics represents a potentially effective therapeutic option.²⁶⁶ Both inulin and oligofructose stimulate the colonic production of short chain fatty acids and favour the growth of lactobacilli and/or bifidobacteria, which are associated with reduced mucosal inflammation, particularly in relapsing pouchitis.²⁶⁷ Clinical trials using specific probiotics to treat IBDs have demonstrated that the multi-agent mixture VSL3# is particularly beneficial for ulcerative colitis and pouchitis whereas Escherichia coli Nissle 1917 is effective in the prevention of recurrence of ulcerative colitis.^268,²⁶⁹ Thus far, probiotics seem to be less effective in patients with Crohn’s disease.²⁷⁰ Lactobacillus rhamnosus GG is another strain that has been effectively used for the prevention and treatment of rotavirus and antibiotic-associated diarrhoea, the prevention of cow’s milk-induced food allergy and pouchitis.²⁷¹^–²⁷⁵

Some gluten peptides are able to induce an innate immune response in intestinal mucosa and gluten intake is linked to the production of pro-inflammatory cytokines IL-15, IL-18 and IL-21. The failure to control this inflammatory response may also be one of the factors underlying gluten intolerance in individuals with coeliac disease.²⁷⁴

Zinc

Zinc is an essential trace element that is critical for cellular function and structural integrity.²⁷⁶ Normal zinc homeostasis is required for a functional immune system (both innate and adaptive), metabolic homeostasis (energy utilisation and hormone turnover), anti-oxidant activity, glucose homeostasis and wound healing.^276,²⁷⁷ Zinc is known to regulate the immune system systemically as well as having direct T-cellular effects resulting in the regulation of gene expression, bioenergetics, metabolic pathways, signal transduction and cell invasion, proliferation and apoptosis.²⁷⁸

Furthermore, zinc is an essential cofactor for the structure and function of a wide range of cellular proteins including enzymes, structural proteins, transcription and replication factors. It is now known that nearly 2000 of these transcription factors require zinc for their structural integrity.²⁷⁹^–²⁸² Zinc also affects entire functional networks of genes that are related to pro-inflammatory cytokines and cellular survival.^282,²⁸³ Thus an individual’s zinc status has a significant impact on their immune system, with zinc deficiency having the ability to profoundly modulate immune function and zinc supplementation, the ability to prevent and treat many acute and chronic diseases.²⁸⁴^–²⁸⁸

Even a mild deficiency of zinc in humans results in immune dysfunction by decreasing serum thymulin activity, which is required for the maturation of T-helper cells. In particular, Th1 cytokines are decreased whilst Th2 cytokines remain relatively unaffected.^287,²⁸⁸ This shift of Th1 to Th2 function results in cell-mediated immune dysfunction. Decreased Th1 results in decreased IL-2 production, which leads to decreased activities of NK-cells and T-cytolytic cells, in turn enhancing susceptibility to malignancies and infections with viruses and bacteria.²⁸⁹ Ageing is associated with the same Th1/Th2 imbalance and moderate zinc supplementation has been shown to alter these proportions.²⁹⁰^–²⁹²

Recent research has shown that zinc can either activate or inhibit several signalling pathways that interact with the signal transduction of pathogen-sensing receptors, the so-called toll-like receptors (TLR), which, upon activation, lead to secretion of pro-inflammatory cytokines. Thus zinc can play a major regulatory role in the immune system.²⁹³

Zinc also directly influences GALT, contributing to host defence by maintaining the integrity of the gut mucosal barrier and thereby controlling inflammatory cell infiltration.²⁹⁴

Oxidative stress is known to be an important contributing factor in many chronic diseases and zinc deficiency is constantly observed in states of chronic inflammation.²⁹⁵ Zinc supplementation has been shown to decrease the gene expression and production of both pro-inflammatory cytokines and oxidative stress markers.²⁹⁶ Metallothionein increase in ageing and chronic inflammation allows a continuous sequestration of intracellular zinc with subsequent low zinc ion availability against stressor agents and inflammation. This phenomenon influences NF-kappaB and the inhibitory protein A20, leading to an impaired inflammatory/immune response.²⁹⁵ Zinc deficiency also induces vascular pro-inflammatory parameters associated with NF-kappaB and PPAR signalling, markedly modulating mechanisms of the pathology of inflammatory diseases such as atherosclerosis.²⁹⁷ As such, zinc may prove to be a useful chemo-preventative agent for many chronic diseases, including neurodegenerative disorders, rheumatoid arthritis, macular degeneration, IBD and cancer.²⁹⁸

Many studies have demonstrated the beneficial effects of zinc supplementation in the management of the common cold, cold-sores, influenza, acute and chronic diarrhoea and acute respiratory infections. Average daily doses were 15–30mg elemental zinc for adults, 7.5–20mg for children and 10mg for infants < 6 months.²⁹⁷^–³⁰¹ Zinc gluconate lozenges, in particular, have been shown to significantly decrease common cold duration and number of antibiotics required whereas prophylactic use significantly decreased cold frequency.³⁰²^–³⁰⁶ The formulation of the lozenge also appears to be important because the addition of citric or tartaric acid may reduce the efficacy due to chelation of the zinc ions.^307,³⁰⁸ Current evidence also shows that zinc (and selenium) improve humoral immunity in elderly subjects after an influenza vaccination.

Serum levels of zinc are significantly lower in HIV+ individuals and an imbalance between Th1 and Th2 responses in these patients has been implicated in the immune dysregulation. Researchers have proposed that resistance to infection and/or progression to AIDS is dependent on a Th1>Th2 dominance.^309,³¹⁰

Several recent animal studies have also demonstrated a link between zinc deficiency and several auto-immune diseases, including systemic lupus erythematosus (SLE) and type 1 diabetes. Egr-2 is a zinc-finger transcription factor which controls the self-tolerance of T-cells preventing the development of auto-immunity.³¹¹ Another zinc-finger transcription factor, Gfi1, is also emerging as a novel master regulator restricting B-cell mediated autoimmunity.³¹² The zinc transporter ZnT8 is targeted by 60–80% new-onset type 1 diabetics compared with <2% controls and <3% Type 2 diabetics. It is also targeted in up to 30% patients with other auto-immune diseases associated with T1DM.³¹³^–³¹⁶

Vitamin A

Vitamin A has received particular attention in recent years. It is now recognised that it modulates a wide range of immune functions, such as lymphocyte activation and proliferation, T-helper cell differentiation, tissue-specific lymphocyte homing, the production of specific antibody isotypes and regulation of the immune response.³¹⁷

Retinoic acid is produced naturally from intestinal dendritic cells.³¹⁸ The presence of high levels of retinoic acid in the intestine and GALT can promote B-cell class switching to IgA, hence boosting the production of IgA in the intestinal mucosa.³¹⁸ When B- and T-cells are activated in the GALT, gut-homing receptors are induced on these cells via the actions of retinoic acid. These gut-homing B- and T-cells play essential roles in protecting the digestive tract from pathogens i.e. the development of ‘oral tolerance’. Furthermore, retinoic acid is also³¹⁸ required for the maturation of phagocytes in the bone marrow.^318,³¹⁹

Superfluous activation of natural immune system cascades is now thought to be one of the underlying mechanisms in psoriasis. vitamin A derivatives are currently being investigated in the treatment of psoriasis.³²⁰

Vitamin A deficiency is also a risk factor for low antibody production. In countries where vitamin A deficiency is endemic, many children are receiving retinol as an adjunct in their vaccinations, especially polio, DPT and measles. This is because vitamin A appears to promote the vaccine antibody response. In particular, the oral polio seroconversion rate is increased by vitamin A in those children who are deficient in this nutrient.³²¹

Current evidence does not support vitamin A supplementation to pregnant HIV+ women to reduce transmission to their child, however, there is an indication that supplementation improves birth weight.³²² Periodic vitamin A supplementation of HIV-infected infants and children is recommended as it has been shown to be beneficial in reducing all-cause mortality and morbidity.^323,³²⁴

Current recommendations for vitamin A intake are based simply on the maintenance of normal vision. However, it has been realised that higher levels may in fact be necessary in order to optimise innate immune function.³²⁵ Vitamin A supplementation above dietary requirements has been shown to enhance inflammatory responses with decreased Th1 and increased mucosal responses in animals.³²⁶

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