Principles of the immune system
INTRODUCTION AND OVERVIEW
The human immune system is extremely complex, with intricate multidirectional connections between our gastrointestinal, psychological, endocrinological and other systems, and communication via various neurotransmitters, cytokines and other immune system messengers. This chapter presents a simplified view of the principles of immunology, with specific focus on some of the most recently researched complementary therapies known to improve immune system health. For more comprehensive information, please refer to the resources and references listed at the end of this chapter.
Our immune system consists of two basic types of immunity: innate (or natural) immunity and adaptive (or acquired) immunity.
TYPES OF IMMUNITY
INNATE IMMUNITY
Innate immunity primarily refers to our body’s first line of defence and includes physical barriers, such as the skin and cilia, and the corresponding inflammatory markers that are produced in response to tissue injury. These may involve both cellular and humoral mediators.
The main leucocyte cells in this system are phagocytes, which include the polymorphonucleoleucocytes and macrophages.1
ADAPTIVE IMMUNITY
Adaptive immunity is antigen-specific and may take days or weeks to develop. Depending on the antigen and the route of presentation, the response can be either cellular (e.g. cytotoxic T-cells), humoral (e.g. antibodies) or both (as may be induced by viral antigens). Different protein antigens can produce different classes of specific antibodies or immunoglobulins, such as IgA, IgG and IgM.2
There are two types of lymphocytes (B-cells and T-cells) that can be activated by these antigens, with both being produced in the bone marrow. B-lymphocytes (plasma cells) mature here, whereas T-cells mature within the thymus. After initial antigen exposure, immune memory develops and can subsequently result in early recognition and stronger reactions to repeat exposures.1,2
GASTROINTESTINAL-ASSOCIATED LYMPHOID TISSUE
The state of our digestion is extremely important to the health of our immune system, as the gastrointestinal mucosa is the major contact area between the human body 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.3,4
Within the gastrointestinal-associated lymphoid tissue (GALT) is the largest number of immune cells (70–80%) in the entire body. It consists of discrete sites, known as inductive and effector sites, which can discriminate between harmful and harmless antigens while maintaining homeostasis. Inductive sites are organised into specialised aggregations of lymphoid follicles, called Peyer’s patches; effector sites are more diffusely dispersed throughout the gut tissue.5
In addition to this distinct architecture, the gastrointestinal tract has specialised immune cells that aid in promoting a tolerogenic response to orally induced antigens.5 Cytotoxic CD4+ T-cells are subdivided into Th1 and Th2 cells, and their relative presence or activation is thought to have a regulatory effect on immune behaviour.4
Th1 cells produce cytokines with pro-inflammatory activities that stimulate the proliferation of cytotoxic T-cells, with the role of providing host defence against viral, bacterial and fungal infections. They are also thought to be critically involved in some hyperinflammatory conditions, such as autoimmune (rheumatoid) arthritis, where over-activity is detrimental.
Th2 cells produce cytokines that are responsible for the activation of the humoral immune response in healthy people, primarily in response to allergens, chemicals and parasites.6 Some of the cytokines produced by Th2 cells (IL-4, IL-5, IL-10, IL-13) also have immune regulatory qualities, and hence excess Th2 activity can cause an imbalance and may lead to particular clinical conditions.
This has led to the perception that the balance between Th1 and Th2 cells is the prime denominator of tolerance, with the breakdown of this tolerance leading to disease.4 As this is a developing area of immune system science, it is possible that, in the future, the immune system may be manipulated by balancing the Th1/Th2 cell ratio—further work is required, however, to verify the specific Th1/Th2 relationships in particular medical conditions and, additionally, which therapeutic agents (pharmacological and nutriceutical/herbal) may be most effective in re-establishing normal balance in the individual patient.
IMMUNE DEFICIENCY VERSUS IMMUNE HYPER-REACTIVITY (AUTOIMMUNE DISEASE)
Both immune deficiency and autoimmune disease—two sequelae of immune dysregulation—are primarily due to an imbalance in the function of our immune system, which may occur through a variety of mechanisms. Immune deficiency can ultimately result in illnesses such as infections and cancer. In the case of autoimmunity, the body produces substances that attack our own body cells, resulting in disease. Box 32.1 provides some examples of the consequences of immune dysregulation.
BOX 32.1 The sequelae of immune dysregulation
IMMUNE DISEASES
BACKGROUND AND PREVALENCE
Unfortunately, the incidence of many atopic diseases (asthma, allergies, eczema, food intolerances) and autoimmune diseases is continuing to increase. Likewise, despite advances in medical technology and treatments, many chronic diseases (such as diabetes, metabolic syndrome, cardiovascular diseases, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD) and cancer) are also on the rise. We are also now faced with a plethora of other syndromes with likely immune system links, such as autistic spectrum disorder, chronic fatigue and multiple chemical sensitivity syndromes, all of which as yet have no specific diagnostic tests or pharmaceutical treatments. It is therefore our duty to investigate the multifactorial origins of such diseases and to aim to treat in the least harmful ways possible. Complementary therapies have a particular role in the management of these debilitating conditions.
Defined disorders of the immune system are usually genetic, such as severe combined immunodeficiency or selective IgA deficiency. The International Union of Immunological Societies recognises eight classes of primary immunodeficiencies, with a total of over 120 conditions.7
The suspicion of a primary immune deficiency disease should be raised in the event of infections that are unusually persistent, recurrent or resistant to treatment, or when infections involve unexpected spread or severity, or unusual organisms.
The treatment of primary immunodeficiencies is the domain of the immunologist and is specific to the nature and severity of the deficiency. Treatment options include immunoglobulin replacement therapy, immunomodulation (e.g. interferon gamma) or stem cell transplant, reducing exposure to potential pathogens and early intervention in infections.
Immunodeficiency may be secondary to infection (HIV/AIDS), ageing, malnutrition or reaction to pharmaceuticals (disease-modifying antirheumatic drugs (DMARDs), immunosuppressive drugs or chemotherapy).
Common autoimmune diseases include Hashimoto’s thyroiditis, rheumatoid arthritis, diabetes mellitus type 1 and systemic lupus erythematosus (SLE).
AETIOLOGY
The importance of breastfeeding
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 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.8 However, the nature and species of microflora are also determined by many other factors, including external environment microflora, use of antibiotics and immunomodulatory agents, and early introduction of cow’s milk.9
Developmental immunotoxicology and early-life immune insult
Many chronic diseases of increasing incidence are now recognised as having immune dysregulation as an important underlying component.10 These include many childhood illnesses such as asthma, allergic disease, leukaemia, autoimmunity and certain infections.11
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 and other prenatal/neonatal stressors.10–16 It has been postulated that dysfunctional immune responses to infections in childhood play a role in childhood leukaemia.11,15 Evidence for an association between environmentally associated childhood immune dysfunction and autistic spectrum disorders also suggests that early-life immune insult (ELII) and developmental immunotoxicology (DIT) may contribute to these conditions.13,16
Indeed, it has been proposed that ELIIs are pivotal in producing chronic symptoms in later life. In particular, the period from mid-gestation until 2 years of age seems to be 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.10 The same toxin may result in different immune maturational processes, depending on the dose and timing of the insult.10,14
Available data indicate that ELIIs result in a shift from Th1 towards Th2 predominance, alterations in regulatory T-cell function and problematic regulation of inflammatory cell function, leading to hyperinflammatory responses and perturbation of cytokine networks. The resulting health risks may extend far beyond infectious diseases, cancer, allergy and autoimmunity to pathologies in the neurological, cardiovascular, endocrinological, respiratory and reproductive systems.12–16
Epigenetics, nutrigenomics, psychoneuroimmunology and psychoneuroendocrinology
The important emerging fields of epigenetics (combined environmental and genetic history) and nutrigenomics (combined nutritional status and genetic history) are also extremely relevant with regard to how our nutritional status and environmental influences may alter how particular genes associated with disease may be expressed in an individual. We now know that not everyone with a genetic make-up predisposing them to a particular disease will develop that disease. Lifestyle and psychological factors can explain much of this difference in terms of phenotypic expression. Therefore, avoiding potentially negative psychological, environmental and nutritional triggers of disease through optimal preventative medicine is an extremely significant factor in immune system health. Conversely, we have come to understand in more detail how unhealthy lifestyle and environment, and poor mental health, can predispose a person to a range of immunologically based illnesses. There is a wealth of evidence regarding the profound impact that psychological stress can have, not only upon our immune system but upon every system of the body. As such, the specialty fields of psychneuroimmunology (PNI) and psychoneuroendocrinology have now been created to further elucidate the significant connections that exist between mind, body and spirit.17–19 Further discussion of PNI can be found in the chapter on mind–body medicine (Chapter 8 from General Practice: The Integrative Approach by Kerryn Phelps and Craig Hassed, ISBN 9780729538046).
PATHOLOGY
The diagnosis of immune deficiency is primarily determined by comprehensive history taking and examination. Pathological investigations are more pertinent to the investigation of specific immune system disorders. In order to save critical consultation time, detailed questionnaires may be provided to the patient before the initial consultation.
DIAGNOSTIC APPROACH
History
Examination
INVESTIGATIONS
Consulting room
There are no specific investigations in the consulting room other than investigations that arise from and are related to specific history taking and examination findings.
Pathology
As always, pathological investigations are ordered with respect to particular findings at the initial consultation.
Unless the individual is suffering from a readily diagnosable clinical condition, such as hyperthyroidism, diabetes, UTI or URTIs, for example, many states of immune deficiency are not recognisable by conventional pathology testing.
Usual medical testing with respect to immunology includes a full blood count (including accurate lymphocyte and granulocyte counts) and immunoglobulin levels (the three major antibodies: IgG, IgA and IgM), CRP, ESR and fasting BSL, with more-specific tests such as serum protein EPG/IEPG (electrophoretogram and immunoelectrophoretogram), ANA (anti-nuclear antibody), ENA (extractable nuclear antigen), double-stranded DNA, rheumatoid factor, thyroid function tests (TFTs) ordered if indicated.
A sensitive way to diagnose a possibly underactive thyroid, which may be significant in immune system dysfunction, is to have the patient take three morning temperatures. If the patient is a woman who is pre/perimenopausal, this should be done during the follicular phase of her menstrual cycle (before ovulation). The patient sleeps with the thermometer next to their bed and takes their temperature before rising. Temperatures below 36 degrees may indicate an underactive thyroid, despite TFTs apparently being normal. Recently, the maximum reference range for TSH has been reduced to closer to the upper value of 2.0, which most nutritionally oriented doctors traditionally aim for. It is also important to attain a free T3 level when possible, as this is the active form of thyroid hormone.
Other tests that may be ordered include levels of specific vitamins and minerals, such as iron studies, vitamin B12 and red cell folate. The normal ranges for such nutrients are quite wide (e.g. ferritin 30–300, vitamin B12 140–1500) and it is important to note that individuals are often symptomatic when below mid-range. This is similar for other nutrients, including fasting 25-hydroxy vitamin D, urinary iodine, plasma zinc and plasma copper.
Special tests
There is a wide range of more comprehensive investigations that may assist in the diagnosis of suboptimal immune system health. Such tests are often performed by private laboratories and come with some cost to the patient. Depending upon the patient’s history and current symptoms, these may include stool tests such as a comprehensive digestive stool analysis or bioscreen, anaerobic/aerobic microbial testing, heavy metal testing through the use of hair tissue, mineral analyses or urinary porphyrins, urinary kryptopyrroles to exclude zinc and/or vitamin B6 deficiency.
INTEGRATED MANAGEMENT
Prevention and lifestyle management
Obesity
The prevalence of obesity has now reached epidemic levels in many parts of the world, and is a major public health problem.20 The accumulation of visceral fat has well-established links with chronic low-grade systemic inflammation, oxidative stress and subsequent impaired immunity, which has been associated with the development and progression of many chronic diseases.21–23 Such illnesses include metabolic syndrome, inflammatory diseases, bronchial asthma, type 2 diabetes and insulin resistance, depression, cardiovascular disease, osteoarthritis, fatty liver disease and cancer.20,22,24–26
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.27
There are also complex links between the metabolic and immune systems, with multiple neuroendocrine peptides, cytokines and chemokines interacting to integrate energy balance with immune function.28 Ghrelin and leptin are two important hormones and cytokines that regulate energy balance and influence immune function.26 Obesity reduces ghrelin, contributing to inflammation by subsequently increasing proinflammatory cytokines. In contrast, caloric restriction, which increases ghrelin and reduces leptin, can reduce oxidative stress and is a potentially immune-enhancing state that has prolonged a healthy lifespan in all species studied to date.23,28–30
Sleep
Good sleep is essential for physical and mental health.31 There is strong evidence that inadequate sleep is associated with a multitude of health problems, including cognitive impairment, mood disorders, parasitical infections, cardiovascular disease and compromised immunity.32–35 Unfortunately, frequently disrupted and restricted sleep is a common problem in today’s society, with more than 50% of adults aged over 65 years reporting at least one chronic complaint.32,34 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 hypothalamic-pituitary-adrenal (HPA) axis. Chronic sleep deprivation may also affect the reactivity of these systems to future stresses and challenges, such as physical and mental illness.33,36
Sleep restriction alters the neurotransmission of serotonin, resulting in reduced production of melatonin, our natural sleep hormone.37 Recent studies have shown that melatonin has an immune-modulating effect, stimulating the production of natural killer 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 natural killer cells and T-helper lymphocytes.
Poor sleep quality has recently been confirmed to increase susceptibility to the common cold, and atypical time schedules such as shift work have also been associated with breast cancer, due to a circadian disruption and nocturnal suppression of melatonin production.38,39 Thus, enhancement of the production of melatonin, or melatonin itself, has potential therapeutic value in enhancing immune function.40
The recognition and treatment of sleep dysfunction can therefore be an important part of management of many immune-related conditions.38
Stress management
There is a wealth of evidence 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 both our innate and our adaptive immune responses.41–48
In an elaborate multidirectional communication system, neurotransmitters, hormones and neuropeptides all regulate our immune system cells and subsequently communicate with all other systems through the secretion of a wide variety of cytokines.49
Acute stress has been shown to have a stimulating effect on the immune system, whereas chronic stress down-regulates the immune system.47,50 Chronic stress has been associated with increased susceptibility to infectious diseases and cancer.42,43,45 It is also linked with worse outcomes in many immune-related disorders, including cancer, and inflammatory and infectious diseases, indicating that the effects of our mental state on our immune system are directly and clinically relevant to disease expression.46,50,51
There is 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 their immune system, with subsequent modification in the development and progression of many different diseases.47,49,52,53
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.54 Identification and treatment of suboptimal moods in pregnant women is therefore imperative.
Various behavioural strategies have demonstrated improved immune parameters, with reduced affective distress in many different diseases.43,55 These include a systematic review of the beneficial effects of mindfulness-based stress reduction in the management of cancer, particularly breast and prostate, and HIV.53–64
Hypnosis, relaxation and guided imagery have been shown to be effective in cases of breast cancer, viral illnesses, including chronic herpes simplex, and the common cold.65,66 Several studies have demonstrated the effectiveness of cognitive behaviour therapy with regards to immune parameters in HIV-positive men,67–69 while autogenic training and group psychotherapy were effective for women with breast cancer.70,71
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.72–74
Natural killer cells have been found to be the most responsive immune cell to acute exercise. Their sensitivity to physiological stress and their important role in innate immune defences indicate that these cells are one link between regular physical activity and general health status.75
In animal studies, anaerobic exercise has been shown to increase both innate and adaptive immune function.76 Secretory IgA, which is the predominant immunoglobulin in mucosal secretions providing first-line defence against pathogens and antigens presented at the mucosa, has also been shown to be increased after exercise in people aged over 75 years.77,78
Exercise needs to be performed in moderation, however. Multiple effects of over-training resulting in impaired immune responses have been documented.78–83 In the short term, this can result in increased susceptibility to respiratory infections; in the longer term, more chronic conditions such as chronic fatigue syndrome may develop.78,83
Self-help
Yoga
There have been limited studies on the efficacy of yoga practice for the immune system. Most have focused on the breathing disciplines within yoga, namely Pranayama and Sudarshan Kriya, which are both rhythmic breathing processes traditionally used to reduce stress and improve the immune system.84 Studies on both healthy individuals and those with cancer have shown increased antioxidant status and improved immune status in those practising these techniques, compared with controls.85–88
Qi gong
Qi gong 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.89–92
Although qi gong may regulate immunity, metabolic rate and apoptosis, further studies are required to validate these findings.90
Massage
There are mixed results as to the benefits of massage for immune enhancement. Two earlier studies noted increases in dopamine, serotonin, natural killer cells and lymphocytes in women with breast cancer after thrice weekly massage for 5 weeks.93,94 However, a more recent RCT showed that effleurage massage had no significant effect on immune and neuroendocrine parameters.95
Nutrition/dietary modulation
Many natural foods are thought to balance the immune system and prevent excessive immune activity. These foods include fish, fruit and vegetables, and culinary herbs such as ginger, garlic and turmeric. In contrast, there is strong evidence regarding the pro-inflammatory effects of ‘fast foods’ that contain large amounts of saturated fatty and trans-fatty acids, refined carbohydrates with a high glycaemic index, and artificial colours, flavours and preservatives.
Box 32.2 lists the main foods thought to have an immune-modulating effect by altering the inflammatory reactivity of the human environment.
However, any food 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. 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 greatly 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 GALT, which is profoundly affected by changes in commensal flora.96
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 reintroduction of individual foods. Some of the most common dietary intolerances are to wheat, dairy and soy. However, seemingly innocuous foods such as apples and tomatoes may be associated with immune reactivity.97
Alcohol in light–moderate amounts (10 g for women, 20 g for men) has been shown to be particularly beneficial for the immune system when compared with both non-drinkers and heavy drinkers.98 Resveratrol, a polyphenol from red wine, is able to stimulate both innate and adaptive immune responses such it that may be important for host protection in different immune-related disorders.99–101
Epigallocatechin-3-gallate (EPG), present in green tea, is well known for its ability to reduce the risk of a variety of immunodeficiency disorders.102 Green tea possesses antioxidant, anti-inflammatory, anti-carcinogenic and immune-enhancing properties.103
Environment
As stated previously, many chronic diseases of increasing incidence, such as atopic illnesses, autoimmune diseases, certain infections and cancers are now recognised to have immune dysregulation as an important underlying component.10,11
The developing immune system is extremely sensitive to a wide range of environmental toxins, such that DIT and ELII are now important recognised aetiologies for many illnesses.10–16
There is also strong evidence that complex syndromes, such as multiple chemical sensitivity, Gulf War syndrome, sick building syndrome and chronic fatigue syndrome, which often have no clear underlying medical explanation, may have an environmental component to their aetiology.104
Such syndromes may be associated with exposure to electromagnetic radiation,105–109 novel environmental chemicals,110–112 moulds and other bio-aerosols113–117 and/or heavy metals.118–120
Paramedical
Acupuncture
Acupuncture has been used for centuries to prevent and treat various conditions, and simply to maintain good health.121 In addition to its known effects on the nervous system, emerging evidence suggests that it may also effectively modulate the innate immune system, which plays important roles in inflammation, pain, metabolism, cell proliferation and apoptosis.122,123
There is now experimental evidence that the electrical stimulation of the vagus nerve inhibits macrophage activation and the production of pro-inflammatory cytokines, including TNF, IL-1 beta, IL-6 and IL-18, indicating a possible underlying neuro-immune basis to acupuncture.124 Such observations suggest that acupuncture may regulate the immune system by promoting both humoral and cellular immunity as well as natural killer cell activity.125,126
Acupuncture may therefore be used as an adjunct to conventional medical treatment for a number of chronic inflammatory and autoimmune diseases. More studies, however, are required.124
Pharmacological/surgical
There are no pharmaceutical medications that have been designed to generally enhance or balance the immune system, other than for conditions associated with specific immune deficiency (e.g. IgG deficiency). In a similar manner, certain surgical procedures such as thyroidectomy, tonsillectomy and tooth extractions may be necessary when indicated. In such cases, specialist referral is strongly recommended.
Complementary therapies
In light of the above, the use of an integrative approach that can specifically enhance our immune health is therefore of even greater relevance and importance. Indeed, to ignore the wealth of evidence regarding the efficacy of complementary therapies is to remove a vital tool from the doctor’s armament and may prematurely lead to the use of pharmaceutical medications and the risk of unnecessary side effects.
Nutritional supplementation
Nutrition is a critical determinant of immunity, with malnutrition being the most common cause of immunodeficiency worldwide.127 Nutrients either enhance or depress immune function, depending on the nutrient and level of its intake.128 Indeed, both insufficient and excess nutrient intakes can have negative consequences for immune status and susceptibility to a variety of pathogens.129 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 lead to increased susceptibility to infections, which can then lead to further nutrient deficiency, and so on.130
Available data indicate that vitamins A, B6, B12, C, D, E, folic acid and the trace elements iron (Fe), zinc (Zn), copper (Cu) and selenium (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.127,130 Antioxidant vitamins and trace elements (vitamins C, E, Se, Cu, Zn) counteract damage to tissues secondary to reactive oxygen species, while simultaneously modulating immune cell function by affecting the production of cytokines and prostaglandins.
Adequate intake of vitamins 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, avoiding a shift to an anti-inflammatory Th2 immune state and an increased risk of extracellular infections. Supplementation with these nutrients can reverse the Th2-cell-mediated immune response to Th1, thereby enhancing innate immunity.131
Presented below is a summary of evidence for the most recently studied nutrients and herbs with regards to immune system enhancement.
Probiotics
Probiotics are recognised for their role in nutrient absorption, mucosal barrier function, angiogenesis, morphogenesis and postnatal maturation of intestinal cell lineages, intestinal motility and, most importantly, maturation of the GALT, which contains 70–80% of immune cells in the body.132
An important adjustment of the immune system to bacterial colonisation of the gut is the production of secretory IgA by B-cells in the GALT.133–135 Probiotics stimulate both production and secretion of polymeric IgA, the antibody that coats and protects mucosal surfaces against harmful bacterial invasion.8 Secretory IgA also promotes an anti-inflammatory environment by neutralising immune stimulatory antigens.136 Thus, sIgA plays a significant role in the regulation of bacterial communities and maintenance of immune homeostasis.134
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.
Thus, pre- and probiotics are 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 gastrointestinal 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.137 The change in gut microflora may reduce intestinal permeability, consequently influencing both intestinal and systemic body functions.138 Further, gut microflora are able to modify the structure of potentially harmful food antigens and thereby alter their immunogenicity.139
Both inulin and oligofructose stimulate the colonic production of short-chain fatty acids and favour the growth of lactobacilli and/or bifidobacteria, which have all been associated with reduced mucosal inflammation.140
Zinc
Zinc is an essential trace element that is critical for cellular function and structural integrity.141 Normal zinc homeostasis is required for a functional immune system (both innate and adaptive), metabolic homeostasis (energy utilisation and hormone turnover), antioxidant activity, glucose homeostasis and wound healing.142,143 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.144,145
Zinc is also 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.144,146,147 Zinc also affects entire functional networks of genes that are related to pro-inflammatory cytokines and cellular survival.141 An individual’s zinc status therefore has a significant impact on their immune system, with zinc deficiency having the potential to profoundly modulate immune function, and zinc supplementation the potential to prevent and treat many acute and chronic diseases.148–152
Even a mild zinc deficiency in humans can result in immune dysfunction by shifting from a Th1 to a Th2 cell response.146,153 This in turn can enhance susceptibility to malignancies and infections with viruses and bacteria.146 Ageing is associated with the same Th1/Th2 imbalance, and moderate zinc supplementation has been shown to alter these proportions.154–156
Zinc also directly influences GALT, contributing to host defence by maintaining the integrity of the gut mucosal barrier and thereby controlling inflammatory cell infiltration.157 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.158 Zinc supplementation has been shown to decrease the gene expression and production of both pro-inflammatory cytokines and oxidative stress markers.143,146,153 As such, zinc may be a useful chemopreventative agent for a range of chronic diseases, including neurodegenerative disorders such as Parkinson’s disease and multiple sclerosis, autoimmune diseases such as rheumatoid arthritis and inflammatory bowel disease, as well as macular degeneration, and cancer.146
Many studies have also 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.146,159–163 Current evidence also shows that zinc (and selenium) improves humoral immunity in elderly subjects after an influenza vaccination.143
Several recent animal studies have also demonstrated a link between zinc deficiency and several autoimmune diseases, including systemic lupus erythematosus and type 1 diabetes.164,165
Vitamin A
Vitamin A has received particular attention in recent years. It is now known to modulate 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.166,167
Retinoic acid is produced naturally from intestinal dendritic cells.168 The presence of high levels of retinoic acid in the intestine and GALT can boost the production of IgA in the intestinal mucosa.135 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—that is, in the development of ‘oral tolerance’.169 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, diphtheria/pertussis/tetanus (DPT) and measles. This is because vitamin A appears to promote the vaccine antibody response.170
Current recommendations for vitamin A intake are based simply on the maintenance of normal vision. However, it has been realised that higher levels may be necessary in order to optimise innate immune function.171 Vitamin A supplementation above dietary requirements has been shown to enhance inflammatory responses, with decreased Th1 and increased mucosal responses in animals.172
Selenium
Selenium is a potent nutritional antioxidant that significantly influences both inflammatory and immune responses.173,174 Selenium is known to be essential for the proper functioning of neutrophils, macrophages, natural killer cells and T-lymphocytes. However, there are many other proposed mechanisms for its protective effects.174–178
Evidence is accumulating that selenium levels lower than previously thought can cause adverse health effects, such that the recommended daily allowance (RDA) levels have recently been increased to 150 μg/day. It has also been demonstrated that higher levels of selenium may give additional protection from many diseases by significantly enhancing immune responses.179
Selenium is a key nutrient in protection from certain viral infections, including Coxsackie virus, influenza virus and HIV progression to AIDS.175,179–183
Just as an inadequate status of selenium is linked to an increased risk of cancer, there is also growing evidence that elevated selenium intake may be associated with a reduced risk of cancer.175,179–181,184 Interventions with selenium (at least 200 μg/day) have shown benefit in reducing both the incidence of cancer and the mortality in all cancers combined. This has been shown to be particularly relevant in liver, prostate, colorectal, lung, oesophageal and stomach cancers, the effect of which is most pronounced in those who are most deficient in selenium. There is also some new evidence that selenium may also affect the risk of cancer progression and metastasis.185,186
Vitamin C
The human body is unable to synthesise vitamin C, and hence we are entirely dependent upon dietary sources and/or nutritional supplementation to maintain adequate levels of this important water-soluble antioxidant.187,188 It has long been known that vitamin C concentrations in the plasma and leucocytes decline rapidly during infections and stress, resulting in reduced resistance to pathogens.160,189 For this reason, vitamin C has traditionally been used as a ‘cure for the common cold’.
Supplementation of vitamin C has, indeed, been found to improve components of the immune system, such as antimicrobial and natural killer cell activities, lymphocyte proliferation, chemotaxis and delayed-type hypersensitivity. It also contributes to the maintenance of the redox activity of cells, thereby protecting them from reactive oxygen species generated during the inflammatory response.160
A large number of RCTs have indicated that vitamin C supplementation (up to 1 g/day) with zinc (up to 30 mg/day) can ameliorate the symptoms and shorten the duration of respiratory infections when used prophylactically. A recent Cochrane review has concluded that supplementation of vitamin C is only effective in preventing the common cold in cases of excessive physical activity or in cold environments.189,190
While the efficacy of vitamin C supplementation is still controversial, it is argued by some authors that to achieve an optimal daily allowance of vitamin C, we require 1 g daily supplementation accompanied by a diet high in fruits and vegetables.187
Vitamin D
Vitamin D has been rediscovered in recent years and there have now been many studies of the serious health consequences of vitamin D deficiency. Very few foods naturally contain vitamin D, so sun exposure is the primary source.191
Indeed, vitamin D deficiency is a recognised global pandemic, in both developing and developed countries, including Australia.191–193 As such, a growing number of diseases are now known to be associated with vitamin D deficiency.194 Originally, vitamin D deficiency was only considered important for bone health; it is now understood that this ‘vitamin’ is actually a complex hormone that is intricately involved in the integrity of the innate immune system.195
The immune-regulatory role of vitamin D affects both the innate and the adaptive immune systems.196 The discoveries that activated macrophages produce active vitamin D, and that immune system cells express the vitamin D receptor, first suggested how the vitamin D endocrine system influenced immune system function.197 Autoimmune 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 avoided.198,199
Vitamin D deficiency is strongly associated with an increased risk of 17 common cancers, autoimmune diseases (such as multiple sclerosis, type 1 diabetes, irritable bowel disease (IBD), rheumatoid arthritis), infectious diseases (tuberculosis), mental health disorders, cardiovascular disease (hypertension), skin disorders (psoriasis) and bone disorders (osteoporosis, osteomalacia and rickets).193–195,192,200–203
It has recently been estimated that there is a 30–50% reduction in the risk of developing breast, colorectal and prostate cancer by increasing one’s vitamin D intake to at least 1000 IU/day. Women who are vitamin D deficient are estimated to have a 253% increased risk for developing colorectal cancer. Women who consume 1500 mg/day of calcium and 1100 IU/day of vitamin D3 for 4 years reduce their risk of developing cancer by more than 60%.204
There are a multitude of studies associating vitamin D deficiency with the development and progression of autoimmune diseases such as multiple sclerosis, rheumatoid arthritis, insulin-dependent diabetes mellitus and IBD. Recent evidence also strongly suggests that supplementation with vitamin D may be beneficial, especially for Th1-mediated autoimmune 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 multiple sclerosis and type 1 diabetes mellitus.196,205–209
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.210
Iodine
There is emerging evidence regarding iodine deficiency and the state of our immune health, in particular with regards to thyroid and breast health. Iodine deficiency is very common in Australia, such that it has been determined that salt iodisation is now not considered an effective strategy to correct iodine deficiencies in this country.211
It has been specifically proposed that the reduction in risk of breast disease associated with increased levels of thyroid hormones, or iodine, may derive from the pro-oxidant properties of its compounds. Conversely, the increased risk from hypothyroidism may derive from its ability to inhibit this stress-mediated apoptotic process.212
The protective effects of iodine against breast cancer have been increasingly demonstrated through epidemiological evidence and animal models.213 Iodine-deficient breast tissues are more susceptible to carcinogen action, and promote lesions earlier and in greater profusion.214 Treatment with iodine can reverse this dysplasia.215,216 Furthermore, molecular iodine has clear antiproliferative and apoptotic effects in the human breast cancer cell line, MCF-7.217
Reports have documented the antiproliferative properties of molecular iodine and the arachidonic acid derivative, 6-iodolactone (6-IL) in both thyroid and mammary glands. Recent data has shown that both molecular iodine and 6-IL trigger the same intracellular pathways and suggest that the antineoplastic effect of iodine in breast cancer involves the intracellular formation of 6-IL. Mammary cancer cells are known to contain high concentrations of arachidonic acid, which may explain why iodine exerts apoptotic effects at lower concentrations only in tumour cells.218 Iodine may therefore be useful as an adjuvant therapy in the pharmacological manipulation of the oestrogen pathway in women with breast cancer.213
Herbal medicine
Astragalus
Astragalus membranaceus is a common traditional Chinese medicinal plant that has for centuries been widely used to enhance the body’s natural defence mechanisms.219
There have been numerous studies demonstrating the immunomodulating and immunorestorative effects, both in vitro and in vivo, of the roots of A. membranaceus.219–221 It appears that the immunopotentiating effect of Astragalus is primarily due to the polysaccharide fraction (APS), as it increases both cellular and humoral immune responses.221
Astragalus has been shown to be efficacious in infective, atopic and autoimmune health conditions by its ability to reverse the Th2-dominant status of many common illnesses.222,223 Many studies have shown that Astragalus has the potential to reverse the Th2-predominant status in patients with asthma.224–226
Th2 cytokines are also predominant in cancer patients and have been found to be associated with tumour progression.222 Astragalus has been shown to be capable of restoring the impaired T-cell functions in cancer patients. It exhibits anti-tumour effects, both in vitro and in vivo, which appear to be achieved through activating the host’s anti-tumour immune mechanisms.227 Therefore patients may use Astragalus to help inhibit tumour growth or to boost resistance to infections.228,229
A 2005 Cochrane review concluded that Astragalus can stimulate immunocompetent T-cells and significantly reduce side effects such as nausea and vomiting in patients treated with chemotherapy. There was no evidence of harm arising from the use of Astragalus.230
Other herbs
Many other herbs, European, Chinese and Ayurvedic, have a long history of traditional use for immune system enhancement. Recently, there have been more randomised, placebo-controlled quality studies regarding the immune-boosting effects of many of these herbs. Of particular note are studies involving echinacea, cranberry, manuka honey, garlic and ginger.
Many studies have demonstrated the protective effects of proanthocyanidins in cranberry (Vaccinium macrocarpon) in reducing susceptibility to urinary tract infections by preventing bacteria from attaching to uroepithelial cells.231,232 This decrease in bacterial adherence has been noted to occur in a dose-dependent relationship in which Escherichia coli loses its adherence the higher the dosage of cranberry given to a subject (36 mg vs 108 mg of cranberry capsule).233 A 2008 Cochrane review of the clinical efficacy of the use of cranberry juice for urinary tract infections concluded that use of cranberry over a 12-month period may reduce the incidence of recurrent infections among women.234 It should be noted that many commercial cranberry juices contain high levels of sugar, a concern that can be avoided by using cranberry extract capsules.
Clinical evaluation of echinacea and its influence on the immune system are, unfortunately, problematic due to the disparate use of different preparations across studies. A 2006 Cochrane review suggested that use of the aerial component of Echinacea purpurea may be beneficial in the early treatment of the common cold in adults.235
Manuka honey has been found to have therapeutic effects on wound and ulcer healing when applied with dressings.236,237 Due to its antibacterial quality, clinical evidence as reported by a 2008 Cochrane review indicates that honey may reduce wound healing times compared with conventional dressings in partial thickness burns238; however, it does not appear to provide additional benefit to compression bandages for leg ulcers when measured over a 12-week period.239 Manuka honey also appears to have benefit in reducing MRSA infections in patients with sloughy venous leg ulcers, although the results of this RCT were derived from a small population. It must be noted that honey used in medical practice should be of ‘medical grade’—that is, sterilised by gamma irradiation and having standardised antibacterial activity.240
ONGOING REVIEW AND MONITORING
As with any other illness, it is imperative to review the patient as often as is necessary. In general, nutritional/herbal therapies may take up to 3 months to reach maximum effect. Unless the condition requires urgent follow-up, it is advisable to review the patient at 1 month to discuss any investigation results and review any change in their symptoms. Usually, the patient will notice some improvement in their symptoms at 4 weeks, more at 8 weeks and the greatest difference at 12 weeks. If there are no obvious improvements at 8 weeks, the nutritional/herbal regimen is generally changed.
Just as nutritional/herbal supplementation is a valuable initial tool in the healthcare provider’s armament, most supplements may be weaned or discontinued, generally after 3–6 months, without the patient’s health suffering. It is at this time that the patient now has enough knowledge and wisdom to recognise whether their own body’s specific signs of deficiency return. In this case, the patient will notice a return of their symptoms and can take more active control of the management of their condition.
It is also significant to note that, as the integrity of the gut strengthens, reactions to specific foods may change. It is therefore advisable to repeat a food elimination regimen at an appropriate time (at least 6 months) to be certain that the patient is not avoiding foods that they were originally intolerant of, thereby unnecessarily reducing their nutritional status and quality of life.
IMPORTANT PITFALLS
It is most important to remember to always treat the patient, and not the number on the investigation report before you. Unless there is an obvious abnormality that requires treatment, if the patient is feeling well, it does not necessarily always matter that all their levels are not within the ideal reference range.
It is also extremely important to know and accept your own limitations. This is relevant with respect to both complex medical history/investigations, where referral to specialists may be required, and to appropriately qualified complementary therapists who may be more experienced and qualified than yourself in determining specific complementary medicine regimens.
PATIENT EDUCATION: CLINICAL TIPS
Physical activity
Diet
Sunshine
Stress reduction
Environment
Supplementation
Broad-based multivitamin with high antioxidant value
Because of the synergistic manner in which vitamins and minerals support the immune system, it is recommended that a broad-based high-strength multivitamin be used.
Vitamin A
Indications
Reducing infection severity (measles and infectious diarrhoea), very low birth weight infants, chemoprevention, night blindness, retinitis pigmentosa, xerophthalmia, glaucoma and cataract prevention, acne, psoriasis, ichthyoses, skin cancers, improving dental health, Crohn’s disease, asthma, sinusitis, rhinitis.
Dosage
See Table 32.1 for recommended daily intakes.
TABLE 32.1 Recommended daily intake of vitamin A*
| Age (years) | RDI (μg/day)** |
|---|---|
| 1–3 | 300 |
| 4–8 | 400 |
| 9–13 | 600 |
| 14+ (females) | 700 |
| 14+ (males) | 900 |
| Pregnancy < 18 | 700 |
| Pregnancy > 18 | 800 |
| Lactation | 1100 |
Treatment doses
Contraindications
Caution with concurrent use of isotretinoin, minocycline, oral contraceptive pills, or with liver or renal disease. Toxicity may occur at doses > 10,000 IU vitamin A/day or > 2000 IU/day when pregnant. Early signs: dry rough skin, cracked lips, coarse or sparse hair, alopecia of eyebrows, diplopia, dryness of mucous membranes, peeling of skin, bone and joint pain, fatigue, nausea and vomiting.
Vitamin C
Indications
Upper respiratory tract infections, sinusitis, atopy, asthma (exercise-induced), to enhance the efficacy of some medications (cisplatin, cyclophosphamide, doxorubicin, etoposide, fluorouracil, L-dopa, tamoxifen, vincristine), to improve connective tissue integrity, wound healing, sunburn prevention, antihistamine, cancer prevention and treatment, prevention of cardiovascular disease, diabetes complications.
Dosage
For acute infections, short-term use (3–6 g) or until bowel tolerance, then reduce dose. For cancer, 10–30 g vitamin C IV 2–3 times weekly.
Vitamin D
Dosage
In the absence of adequate sun exposure, at least 800–1000 IU vitamin D3 per day may be needed for adequate vitamin D levels in children and adults. Treatment doses vary considerably depending on condition: generally, 2000–6000 IU per day vitamin D3. Up to 50,000 IU vitamin D2 twice weekly for 5 weeks has been shown to be safe. Loading doses of 600,000 IU IM can be used for deficiency states.
Zinc
Astragalus
Dosage
Liquid extract or solid dose equivalent (1:2) 4.5–8.5 mL/day.
Decoction: 8–12 g divided into two doses daily on empty stomach.
Echinacea
Dosage
E. angustifolia or E. purpurea, 1–3 g/day.
E. purpurea dried aerial part, 2.5–6 g/day.
DrWeil.com. http://www.drweil.com.
Integrative Medicine. http://www.integrative-medicine.com.au.
Mercola.com. http://www.mercola.com.
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