Chapter 28 Autoimmunity
OVERVIEW
Autoimmunity is a normal event, while autoimmune diseases result from an aberration of this normal phenomenon.1 Autoimmune diseases are characterised by chronic inflammation with a loss of tolerance to ‘self’ or ‘auto’ antigens. The causes for the loss of tolerance, the shift from normal immune function to autoimmune pathology, are poorly understood but are generally agreed to be multifactorial, involving a combination of genetic, environmental, hormonal and immune factors.1,2 Probable key factors include abnormal cytokine biology and the direct activation of larger than normal quantities of auto- or self-reactive CD4 positive T-cells. Conventionally, autoimmune disorders are diagnosed and treated by physicians specialising in the particular system involved, as shown in Table 28.1. A new paradigm is emerging that groups the pathogeneses of the wide spectrum of autoimmune diseases by their common underlying mechanism: immune system dysregulation, mediated by an imbalance of pro-inflammatory and regulatory cytokines.3
| AUTOIMMUNE DISEASE | SYSTEM AFFECTED | MAIN ORGANS AFFECTED |
|---|---|---|
| Systemic lupus erythematosus (SLE) | Systemic | Skin, joints, kidneys, lungs, heart, brain and blood cells |
| Rheumatoid arthritis | Systemic; muscular skeletal | Connective tissue in joints |
| Dermatitis herpetiformis | Integumentary | Skin, particularly elbows, knees, back and back of neck |
| Multiple sclerosis | Nervous | Myelin sheath in neurons of brain and spinal chord |
| Myasthenia gravis | Nervous; neuromuscularjunction | Muscles , particularly the muscles around the eyes |
| Pernicious anaemia | Blood (haematologic); gastrointestinal | Parietal cells in stomach |
| Goodpasture’s disease | Renal; respiratory | Kidney and lungs |
| Graves’ disease (hyperthyroidism) | Endocrine | Thyroid gland |
| Hashimoto’s thyroiditis | Endocrine | Thyroid gland |
| Type I diabetes mellitus | Endocrine | Pancreatic beta cells |
| Coeliac disease | Gastrointestinal | Villi in small intestine |
| Ulcerative colitis (inflammatory bowel disease) | Gastrointestinal | Mucosa of colon, particularly large colon |
| Crohn’s disease | Gastrointestinal | Can affect entire colon wall, most commonly the lower ileum |
AETIOLOGY
Genetic factors
In the immune system, cell surface protein molecules called human leukocyte antigens (HLA) recognise self from non-self. These antigens are unique for each individual and are encoded by a group of genes on the sixth chromosome called the major histocompatibility complex (MHC).5 On exposure to a foreign antigen, MHC antigens present a component of the invading antigen to circulating T-cells. MHC class I interact with cytotoxic T (CD8+) cells, which track down and kill specific cells, and MHC class II interact with helper T (CD4+) cells which, in the presence of pro-inflammatory cytokines, activate a full immune response (discussed further below under ‘T-cells’).6
Certain MHC class II genotypes are associated with increased susceptibility to autoimmune diseases. This susceptibility may be clustered within specific populations; for instance, increased risk of rheumatoid arthritis is associated with HLA-DR1 (in Asians, Spanish and Jewish Israeli nationals) and HLA-DR4 (in Caucasians).6
Some autoimmune diseases are associated with a single mutation, such as autoimmune lymphoproliferative syndrome. Importantly, not everyone that has the mutant gene manifests the disease. Of those that do, there is a wide variation in the progression and severity of the disease. This implies that there are other factors controlling and regulating the pathogenesis of autoimmune disease.7
Most autoimmune diseases involve a combination of several genetic mutations. The net effect of a combination of mutations may manifest as a pathological phenotype (that is, the way a genotype actually manifests in an individual), depending on the presence or absence of protective factors, both genetic and non-genetic.7
Certain HLA alleles are protective against autoimmune disease. Protective genes and susceptibility genes may both be present in an individual. The net effect of protective and susceptibility genes determine an individual’s genetic susceptibility to autoimmune diseases.8
Specific gene-environment interactions are increasingly being discovered as research into the human genome progresses.9 It is estimated that there may be as many as 20 mutations associated with autoimmune diseases; these mutations are expected to be fully elucidated over the next few years as a result of work on the human genome project.10 However, it is important to note that not all individuals bearing susceptibility genes actually manifest the disease conditions. Gene–gene and gene–environment interactions that may help our understanding of the pathogenesis of autoimmune disease are gradually being discovered.
Environmental factors
Viral and bacterial infections, certain chemicals and drugs and mechanical injury have been implicated as potential triggers of autoimmune diseases in susceptible humans and animals.7,10,11 Two mechanisms that are widely accepted explanations of how an infection may cause autoimmunity are known as molecular mimicry and bystander activation
‘Molecular mimicry’ is the term given to the process of activation of autoreactive helper T (Th or CD4+) cells through cross-reactivity between foreign antigens and self antigens. The foreign antigen may so closely resemble a self antigen that the immune system, having reacted successfully to this foreign antigen, starts reacting to the self antigen as well.5 ‘Bystander activation’ refers to the spontaneous activation of local autoreactive Th cells as part of a coordinated inflammatory response, which may occur as a result of any threat to homeostasis (such as infection).12
Recent research has identified another potential mechanism whereby bacteria may elicit autoimmune pathology. A group of bacteria called superantigens, which includes streptococcal and staphylococcal exotoxins, seem to short-cut the usual immune mechanisms of presentation and directly trigger CD4 cells to launch a full inflammatory response. The result is an enormous release of pro-inflammatory cytokines from T-cells, especially tumour necrosis factor-alpha (TNF-α) and IL-2. Exposure to superantigens has been shown to drive the intense inflammatory responses that result in acute toxic shock or chronic inflammatory disease, such as rheumatic fever.5
Antigen triggers need not come from the external environment—they may be endogenous proteins. Endogenous proteins that have been implicated in the pathogenesis of rheumatoid arthritis include human cartilage glycoprotein 39, citrullinated protein and heavy-chain binding protein.13
Dietary antigens have also been implicated in the pathogenesis of autoimmune pathology, especially the gastrointestinal autoimmune diseases.14 For instance, cereal grains are known inducers of two autoimmune diseases (coeliac disease and dermatitis herpetiformis); removal of gluten from the diet ameliorates symptoms in these conditions. A process of molecular mimicry is strongly suspected in the pathophysiology of these conditions.15 An inflammatory environment in the intestine (from dietary antigens) is associated with increased permeability and increased frequency of potentially
pathogenic antigens crossing the intestinal epithelium and entering the internal environment (‘leaky gut syndrome’). This is mediated by IFN-γ and TNF-α, both altering the tight junctions between cells, while IFN-γ increases the uptake of proteins for transportation into the mucosal cells.16
Recent in vitro work has postulated a role for certain internal environmental conditions that may favour the recognition and binding of large numbers of autoantigens by antibodies. After transient exposure to protein destabilising (but not denaturing) conditions, such as low or high pH, high-salt environments and redox-reactive agents, a small percentage of autoantibodies become extremely autoreactive.17 High salt and its sequelae, widespread low-level metabolic acidity, are hallmarks of the Western diet and are suspected as having an involvement in many so-called modern lifestyle diseases.18
Whatever the environmental trigger, the process of antibody autoreactivity is mediated by cytokines, which turn on and off the signals for T-cells specific for self antigens.19 Thus, in the pathogenesis of autoimmunity, cytokine biology may provide the weakest link in the chain of events that result in pathology.11
Inflammatory mechanisms
Cytokines
Cytokines are found in tissues and in the blood and act as in autocrine, paracrine and endocrine ways. At their target cells cytokines bind to membrane receptors that use second messenger systems. The ensuing enzymatic cascade then results in stimulation or inhibition of cell functions. They can regulate the expression of membrane proteins, including cytokine receptors, and they can stimulate the expression and secretion of their own and other kinds of cytokines.20 In the immune system, cytokines are mainly secreted from activated macrophages and helper T lymphocytes (CD4+ cells). T helper (Th) cells are central to the regulation of the adaptive immune system, both the humoral and cellular arms.21 T helper cells are primarily regulated by T regulatory (Treg) cells (once known as suppressor T lymphocytes). An important role of Treg cells is the inhibition of B lymphocytes from differentiating into plasma cells, the precursors of antibodies. Altered regulatory T-cell functioning has been associated with autoimmune disease.22
T-cells
Antigen-specific cytotoxic T-cells hunt down and destroy the infected cells. Ligands that bind to MCH class II proteins alert T-cells to a threat that requires a coordinated immune system response, to be mediated by the cloning of antigen-specific helper T (CD4) cells.23
Depending on the nature of the antigen, T helper cells differentiate into distinct subsets, which tailor the adaptive immune system to suit the threat at hand. For instance, bacteria and viruses typically activate the cellular arm whereas helminths activate the humoral arm of adaptive immunity.24
CD4+ and CD8+ T-cells
MHC classes I and II antigens are recognised by two distinct subsets of T-cells. These T-cell subsets are distinguished by their respective cell surface proteins.25 Cell surface molecules have been designated as CD or ‘cluster of differentiation’, as they were identified using statistical cluster analysis to identify the specific cells that differentiated after being stimulated by certain antigens.
A numeric system was designated to CD cells as they were identified.26 The T-cell subsets that express CD4 molecules (CD4+ T-cells) may belong to either the helper or regulatory T-cell subsets, where those T-cells that express CD8 molecules (CD8+ T-cells) are cytotoxic T-cells.23 The CD4 and CD8 proteins function as co-receptors in that they cooperate with the T-cell receptor (TCR) to recognise and respond to an antigen bound to MHC classes II and I, respectively.
A portion of the CD4 and CD8 receptor sits outside the cell and directly interacts with the MHC on the antigen-presenting cell. The combination of the TCR and CD4 or CD8 binding to MHC is the first signal required for T-cell activation.27
T helper 1/T helper 2 hypothesis
For 20 years the study of immunology has used the Th1:Th2 hypothesis paradigm, which depicts many disease states to be characterised by the relationship or balance of T helper type 1 (CD4+Th1 or simply Th1) cells and T helper type 2 (CD4+Th2 or Th2) cells.28
During Th1 differentiation, activated antigen-presenting cells such as macrophages and dendritic cells (DCs) produce IL-12. IL-12 signals CD4+ cells to differentiate into Th1 cells, which secrete IL-2, a pro-inflammatory mediator. Interleukin-12 in the presence of IL-18 signals natural killer (NK) cells to secrete IFN-γ,28 another potent pro-inflammatory mediator.
Th1 cells augment a predominately cellular immune response by stimulating T-cytotoxic activity and NK cells, activating macrophages and stimulating the production of other key inflammatory mediators such as nitric oxide (NO).28 Th1 differentiation mediates a potent inflammatory response and an ongoing predominance of Th1 cytokines drives chronic inflammatory activity.3
During Th2 differentiation IL-4 induces naive T helper cells to differentiate into T helper type 2 (Th2) cells. Th2 cells secrete the cytokines IL-4, IL-5, IL-6, IL-10 and IL-13. This subset of cells activates and coordinates a predominately humoral immune response by stimulating the activity of oesinophils, mast cells and B-cell differentiation into plasma cells, which secrete antibodies.28
Cytokines derived from Th1 and Th2 have been shown to regulate each other by antagonistic and mutually inhibitive activity.29 For instance, IL-10 inhibits IL-12 secretion from antigen-presenting cells, but even after IL-12 has been induced in vivo, IL-10 down-regulates its receptors, thereby limiting the effectiveness of IL-12.30 Th2 cytokines are known to suppress the activation of macrophages, the proliferation of T-cells and the production of pro-inflammatory cytokines.28 The Th2 cytokines, IL-4 and IL-10, are considered the major anti-inflammatory cytokines. Within this Th1:Th2 paradigm, most autoimmune diseases have been viewed as Th1-driven disorders.28,31 The typical cytokine profile in Th1-mediated autoimmune diseases, such as rheumatoid arthritis, multiple sclerosis, autoimmune thyroid disease, type 1 diabetes and Crohn’s disease, is an overproduction of IL-12, IFN-γ, TNF-α and under-expression of the immunoregulatory Th2 cytokine, IL-10.28
Most researchers recognise the oversimplicity and rigidity of the Th1:Th2 phenotypes paradigm, but as a simplistic model it is exceedingly useful and has rejuvenated enormous clinical interest and research in the field of helper T-cell immunology. However, the story continues to unfold as new and exciting research suggests much more plasticity and diversity in CD4+Tcell subsets in vivo, previously underestimated as it was not easily demonstrated in vitro.32
The emerging paradigm in understanding T-helper cell subsets
The recent discovery of Th-17 cells uncovers a whole new arm of adaptive immunity, specific for inflammation and autoimmunity as illustrated in Figure 28.1.24 A potent pro-inflammatory cytokine, IL-17, stimulates the production of TNF-α, IL-1β, IL-6, IL-8 and G-CSF (the colony-stimulating factor that increases neutrophils).27
Increased levels of Th17 cells have been found to be associated with both animal and human autoimmune diseases.32–36 Many cytokines, such as IL-1, IL-6, IL-21, TNF-α, IL-23 and TGF-β, are known to stimulate IL-17 production from naive CD4+ T-cells in the presence of inflammatory stimuli such as toll-like receptors.32
Toll-like receptors are pattern-recognition receptors that have evolved to recognise specific bacteria and are found on many antigen-presenting cells, such as dendritic cells, in the innate immune system. When activated, toll-like receptors induce inflammation via activation of inflammatory transcription factors such as NF-kB, which up-regulate the production of pro-inflammatory cytokines, such as IL-17 from Th17 cells and IFG-γ from Th1 cells, as shown in Figure 28.2.
Cytokines as the third signal
Recently, a ‘third signal’, provided by pro-inflammatory cytokines, has been postulated as a necessary requirement for full T-cell activation.37 For instance, a soluble antigen injected into mice resulted in an increase in antigen-specific CD4+T-cells in lymph nodes and follicles. However, CD4+ cells activated in this way simply died off and did not react when re-exposed to the antigen. Although the CD4+ cells differentiated into antigen-specific T-cells in the first instance, when they received no further signal within a week after exposure to the antigen, they became hypo-responsive to the antigen on re-exposure.37,38
An important observation was made during these studies. It was noted that the effect of the bacteria was mediated by the secretion of the cytokine, IFN-γ, from T-cells.39 More importantly, the enhanced effect on T-cell activation by the bacteria was replicated when the bacteria were altogether replaced by the pro-inflammatory cytokines, tumour necrosis factors and IL-1. In addition, the bacterial-induced IFN-γ was replicated by IL-12. Thus, successful activation of T-cells in vivo after exposure to an antigen requires the presence of certain pro-inflammatory cytokines even in the absence of bacteria or other infecting agent.39
This ‘three-signal model’ has been further developed to specify IL-1 as the actual third signal for the antigen-induced activation of naive CD4+ T-cells, and IL-12 as that for CD8+ T-cells.37 It has been proposed that the first two signals are adequate for a transient, localised response but that a long-term, sustained response depends on the presence of certain pro-inflammatory cytokines. IL-1 and TNF-α appear to have significant roles in the cytokine-driven longevity of antigen-specific memory T-cell populations.38
Autoreactive CD4+ T-cells
Low levels of auto-reactive (or self-reactive) CD4+ T-cells naturally circulate in the blood of healthy people and are regulated by regulatory CD4+ T (Treg) cells.40 Naturally occurring regulatory T-cells such as CD4+CD25+ suppress the proliferation of autoreactive T-cells and are therefore critical in the maintenance of peripheral tolerance.41
The regulatory cytokines IL-4, IL-10 and TFB-β are believed to be involved in the suppression of activated autoreactive T helper cells by regulatory T-cells.42 Activation of autoreactive T helper cells and their subsequent differentiation into autoantigen-specific pro-inflammatory Th1 subsets is a pivotal step in the pathogenesis and progression of autoimmune diseases, such as multiple sclerosis.12
Cytokines are the signalling molecules that activate and deactivate autoreactive T-cells.19 However, pro-inflammatory cytokines such as TNF-α, which have been heavily implicated in the pathogenesis of autoimmune diseases, have also been shown to have immunoregulatory activity. It may be that in the short term TNF-α is pro-inflammatory, but chronic exposure leads to down-regulation of the immune response.43
One known mechanism is via pituitary-stimulated secretion of glucocorticoids (see Section 5 on the endocrine system for discussion of the HPA axis), which may constitute a homeostatic role for TNF-α in inflammation. It may also be that other cytokines more specific to autoimmune pathology, such as IL-17, are more critical to the long-term sustained activation of the immune system as observed in autoimmune diseases.44
Pro-inflammatory cytokines activate local autoreactive T-cells as a normal part of the coordinated response to a threat to homeostasis, such as infection or cell damage. In some cases, however, autoreactive T-cells may induce IL-12 secretion from antigen-presenting cells in the absence of infection or other threats to homeostasis, launching an unnecessary inflammatory response and enhancing susceptibility to autoimmune disease.30 This appears to be mediated by abnormal cytokine biology.
RISK FACTORS
As work on the human genome continues, so does our knowledge of how multiple susceptibility and protective genes combine to contribute towards an autoimmune-prone phenotype.45 However, the presence of a genetic susceptibility does not necessarily mean it will manifest as an autoimmune disease. Environmental factors may interact with genetic susceptibility to alter immunity to result in the production of autoantibodies.
Once genetically susceptible individuals have been identified, disease may be prevented, delayed or mitigated by avoiding or minimising exposure to known triggers.46 In a large Danish cohort study involving 37,338 twins, genetic factors were found to be less important than environmental factors.47 Environmental factors include exposure to infections and environmental chemicals but also include the internal environment, such as sex and stress hormones, and immune dysfunction.
Altered immune function
Ageing of the immune system has been associated with a decline of its ability to recognise self from non-self, thereby increasing the risk of the development of autoimmune diseases.48 People with autoimmune diseases have immune systems that resemble those in the elderly, such as involution of the thymus, and premature ageing has been postulated as a risk factor for autoimmune disease.49 On the other hand, young age is a risk factor for multiple sclerosis, with 70% of people with multiple sclerosis aged between 20 and 40 years.50
Viruses have been shown in animal models to be potent triggers of autoimmunity through molecular mimicry and promoters of pathogenic responses through bystander activation. Humans with rheumatoid arthritis and SLE have an altered virus-specific response to the Epstein-Barr virus, for example. Of particular note, the virus-specific T-cells that drive autoimmune pathology appear to be directed by cytokines rather than by the virus itself.51 In genetically susceptible individuals, a combination of a latent Epstein-Barr viral load and altered immune regulation, for instance a functional deficit of Epstein-Barr virus-specific T-cells, may trigger rheumatoid arthritis and SLE.52 The occurrence of chronic recurrent infections is a known risk factor for rheumatoid arthritis.53 A partial or complete deficiency in the complement proteins is a risk factor for SLE.54,55 Immunodeficiency, for any reason (congenital or iatrogenic), increases the risk of non-Hodgkin lymphoma. Inflammatory diseases also increase the risk of non-Hodgkin lymphoma, with more severe inflammation increasing risk further.56 Interestingly, a prospective cohort of 27,290 postmenopausal women found that NSAID use was associated with an increased risk of non-Hodgkin lymphoma.57 It is likely that the NSAID use indicates an unresolved underlying inflammation, which is the actual risk factor for non-Hodgkin lymphoma.
Exposure to chemicals
There is conclusive evidence that smoking is a risk factor for rheumatoid arthritis.58 There is also evidence that mercury from dental amalgam may increase the production of autoantibodies in mercury-sensitive patients with autoimmune thyroiditis.59 Occupational and environmental exposure to asbestos and silica, respectively, increases the risk of developing an autoimmune disease.60,61 Occupational exposure to mineral oil increased the risk of autoimmunity by 30%.58 Epidemiological studies that have looked at vaccinations and exposure to environmental toxins have failed to show them as strong risk factors for autoimmunity, but because there is evidence for an association in animal and case-controlled studies there has been a call for more research in this area.62,63
Diet and lifestyle
Many dietary and lifestyle factors may exacerbate autoimmune diseases. Early exposure to cow’s milk has been associated with increased risk of autoimmune diseases, especially type I diabetes.64 Antigens from milk, grains and legumes have also been found to contain peptides that mimic those found in the joints of people with rheumatoid arthritis.15 Vitamin D deficiency is a risk factor for SLE and multiple sclerosis.65 Dietary fatty acids is a possible risk factor in multiple sclerosis.66 Sleep deprivation was shown to be a risk factor for disease in mice with a genetic susceptibility to develop SLE.67 Ultraviolet radiation and geographic location are known risk factors for multiple sclerosis.66
Hormones
Sex is a risk factor for autoimmune diseases. The prevalence of many autoimmune diseases, such as multiple sclerosis, rheumatoid arthritis and SLE, are higher in women than men. For instance, 90% of SLE cases occur in women.68 On average, women experience their first symptoms of rheumatoid arthritis during menopause, around the time of the decline of ovarian oestrogens.69 In a randomised controlled trial of hormone replacement therapy (HRT) in rheumatoid arthritis of 200 women, those that responded well to the HRT (they had significantly increased serum oestrogen levels) demonstrated improvements in disease symptoms and progression compared with controls.70
Oestrogen appears to have a dual role in immune function, suppressing inflammation while stimulating antibody production.71 Oestrogen receptors have been found on cells from many different systems, including immune cells. In a mouse model of rheumatoid arthritis, when oestrogen receptors were blocked there was an earlier onset of the disease.72
Phytoestrogens are very interesting compounds from plants and can produce mild oestrogenic activity in humans. One such example is quercetin from soybeans. It was demonstrated that quercetin could block antigen-specific Th 1 differentiation in neurons and ameliorate clinical severity and duration of disease in a mouse model of multiple sclerosis by binding to oestrogen receptors.73 This suggests a potentially promising role for phytoestrogens in autoimmune disease.
Stress
Stress is a risk factor for many autoimmune diseases.53,74,75 Stress is also known to worsen symptoms in many autoimmune diseases, particularly rheumatoid arthritis and multiple sclerosis.76,77 Animal and human studies have linked defective neuroendocrine function with enhanced susceptibility of autoimmune diseases, such as rheumatoid arthritis, SLE, type 1 diabetes and Sjögren’s syndrome.78–81 In animal models of autoimmune disease, the onset of the disease is associated with a lack of HPA axis responsiveness (see Section 5 on the endocrine system for discussion) to IL-1, where resistance to autoimmune pathology was maintained by normal HPA axis–immune system responsiveness.82
CONVENTIONAL TREATMENTS
Conventional treatments focus on suppressing and managing the symptoms. Treatment will depend on the type and severity of the autoimmune disease. The conventional treatments for three major autoimmune diseases are given in Table 28.2.
Table 28.2 Conventional treatment for common autoimmune diseases81,82,84,87
| AUTOIMMUNE CONDITION | THERAPEUTIC AGENTS | METHOD OF ACTION |
|---|---|---|
| Rheumatoid arthritis |
Simple analgesics such as paracetamol and aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) are given in the first instance for symptomatic relief.
|
Research into new drugs for autoimmune diseases are primarily focused on biological agents in inflammatory pathways.83 In order to suppress inflammation and prevent damage, the inhibition of pro-inflammatory cytokines, especially TNF-α and IL-1, would appear to be the most useful approach.84 However, these are new and expensive drugs, and need to be monitored for potential adverse effects.85
In a review of the literature comparing clinical trial outcomes to clinical practice86 anti-TNF-α therapies were shown to produce remarkable improvements in clinical trials, reducing clinical symptoms and slowing disease progression; however, in clinical practice these improvements were found to be much more modest. It should be noted that while anti-TNF-α therapy has enjoyed spectacular success in clinical trials and modest success in clinical practice, it has also been associated with some serious side effects such as the induction of a reversible syndrome very similar to lupus (SLE is associated with the under-expression of TNF-α).7
KEY TREATMENT PROTOCOLS
It is essential that the imbalances of the background diet be fully understood and corrected as a priority in dealing with chronic inflammation. Correcting dietary imbalances has been shown to augment medical interventions, and may reduce reliance upon them.89,90 Dietary modifications that favour balanced immune function should, for the most part, be sustained throughout life.
Lifestyle factors must also be explored thoroughly for potential pro-inflammatory and protective influences. Pro-inflammatory influences need to be identified and minimised. Psychological stress induces an inflammatory state in the immune system by generating the production of pro-inflammatory cytokines.91 Chronic stress results in a chronically imbalanced and under-functioning immune system (see Section 5 on the endocrine system).
The perception of stress is the net result of the perceptions of the actual stressor minus available coping resources. Potential stressors need to be identified and reduced, and available coping resources need to be increased. This may require referral for psychological counselling, meditation or relaxation training, relationship counselling, or other integrative health-care stress and mood management interventions.
NATUROPATHIC TREATMENT AIMS
Protective lifestyle factors need to be instigated and sustained throughout life in all individuals interested in balancing immune function, and especially those with chronic inflammation. For instance, physical exercise has a protective influence on the immune system through several known mechanisms. Interestingly, moderate physical activity actually provides an essential nutrient, glutamine, for immune cells that is stored in skeletal muscles and released through muscle contractions. Glutamine is the precursor for an essential intracellular antioxidant, glutathione, which protects the cell from damage and subsequent inflammation. Exercise also has a favourable effect on cytokine biology, inducing anti-inflammatory factors.
Research into the newly established field of psychoneuroimmunology has greatly advanced the understanding of the psychological and emotional factors that influence immune function. It is known that negative and stressful emotions directly stimulate the production of pro-inflammatory cytokines that mediate and intensify disease.92 The idea that emotions affect health outcomes is not new and can be dated as far back as Hippocrates. What is new is that, through psychoneuroimmunology, science is providing evidence to support the ‘mind–body’ link.93 Laughter,94 meditation,95,96 spiritual beliefs,97 positive thinking98 and even choir singing and listening99 have all been shown to beneficially influence immune parameters. For more detail on this exceedingly interesting field of research, see the discussion in Chapter 6 on respiratory infections and immune insufficiency.
Dietary modulation to reduce inflammation
In human evolution, there have been two major changes that have resulted in an increased consumption of grain (the agricultural and industrial revolutions) and have dramatically increased the availability of omega-6 rich vegetable oils.100 Further, the domestication of livestock and poultry, with its associated decrease in omega-3-rich grass feeding and increase in omega-6 rich grain-supplemented feeding, resulted in a shift in the polyunsaturated compartment of animal products to higher levels of omega-6 fatty acids and lower levels of omega-3 fatty acids.101 During the 1960s the epidemic in coronary heart disease was attributed to the increased consumption of saturated fatty acids from animal products. High cholesterol was identified as a risk factor and every attempt was made to reduce cholesterol.102 There was a public health campaign that declared a ‘war on fat’. All Australians were urged to reduce fat consumption or at least to replace saturated fats with omega-6 rich polyunsaturated fatty acids, such as that from readily available vegetable oils.
The focus on reducing cholesterol by reducing dietary fat intake led to a new market range of ‘low-fat’ products. Natural products such as yoghurt were stripped of their fat content, which was replaced by a whole new range of synthetic additives, usually carbohydrate based. But this new Western diet, the combination of low fat and high carbohydrate intakes, over time has fed an epidemic of obesity and diabetes and the incidence of autoimmune diseases, especially type 1 diabetes, is rapidly rising.103
Carbohydrate intake in the Western diet is much higher than that of most traditional diets and there is a compelling argument that the modern high-carbohydrate diet is associated with negative health outcomes, including increased risk of various autoimmune diseases.15 Grains may contain antinutrients, such as lectins, which not only reduce the absorption of micronutrients from the small intestine but have been shown to induce intestinal secretion of IFN-γ and up-regulate MHC class II expression in enterocytes, thereby exacerbating inflammation in coeliac disease.104 The wheat protein gliadin was shown to inappropriately up-regulate MHC class II presentation in the presence of IFN-γ in inflammatory bowel disease.105 Several gliadins are suspected of
DIETARY CONSIDERATIONS TO REDUCE PRO-INFLAMMATORY CYTOKINES
molecular mimicry. Certain self-proteins, such as alpha-gliadin and the autoantigen BM 180, which has been isolated from the basement membrane of affected exocrine glands in Sjögren’s syndrome, share an almost identical amino acid sequence.15
Low levels of omega-3 intake, together with a high level of omega-6 intakes, creates an imbalance between n-6 and n-3 fatty acids that has been related to many modern-day diseases, from mental health problems to chronic inflammation and autoimmune disease. For instance, in habitually violent and impulsive male offenders with antisocial personality, plasma phospholipid DHA levels were significantly lower than controls, while the arachidonic acid metabolites PGE2 and TXB2 levels were elevated.106 The raised level of arachidonic acid metabolites are evidence that the inflammatory pathways related to NF-κB and COX-2 have been activated, the former stimulating the up-regulation of the expression and activity of genes that code for the pro-inflammatory cytokines. According to one study,107 the Palaeolithic diet consisted of an equal ratio of omega-6 and omega-3 fatty acids. This ratio is currently estimated at 10–15:1 in Australia, and 20–30:1 in the USA. The correction of the imbalance between the essential fatty acids has major clinical implications. For instance, the author of this study states that inflammation was reduced in patients with rheumatoid arthritis by reducing the ratio of n-6 to n-3 fatty acids to 2–3:1.
Early work in nutritional immunology showed that protein- and calorie-restricted diets were associated with dramatic and significant alterations in immune function, readily demonstrated in several animal models of autoimmune diseases.108 In animal studies low-protein diets have delayed the onset of autoimmunity and blunted the clinical progression of autoimmune disease, and caloric restriction has more than doubled life span.109
