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
