Email: wullydavidson@btinternet.com
Abstract
The conclusion of this paper is that non-communicable diseases such as the psychiatric disorders, neurological diseases, autoimmune diseases and other diseases associated with immune system upregulation but not deemed to be autoimmune, such as cardiovascular disease, cancer, type 2 diabetes, porphyria and many others, all arise as a consequence of chronic, aberrant activation of an immune system response which is driven by the transcription factor, nuclear factor kappa beta (NF-kB).
One of the principal functions of the NF-kB immune response is to control intracellular pathogens which establish latency within cells. To achieve this, reactive oxygen species (ROS), such as hydroxyl radical, which are destructive to these pathogens, are generated inside cells. In addition, the cell membrane receptors which are used by these pathogens to gain entry into cells are reduced in number, desensitised, or blocked by antibodies, to prevent infection, and this causes these cells to become hypofunctional. To compensate for this, receptors on other cells may become hyperfunctional.
Aberrant activation of the NF-kB driven immune response may be caused by processes which mimic its own actions. These include chronic, excessive production of ROS inside cells, often as a consequence of metalloenzyme activity, and chronic hypostimulation or hyperstimulation of cell membrane receptors. The diseases which result from this depends on the cell type in which there is aberrant activation of NF-kB, and because the diseases arise as a result of processes which mimic the actions of NF-kB, I have called them 'Immune Mimicry Diseases' (IMDs).
The first half of the paper is a general exposition of IMD theory, while the second half deals with the specific etiologies of schizophrenia, multiple sclerosis, cardiovascular disease, porphyria, diabetes, obesity, Alzheimer's disease, cancer, autism and ADHD.
I was born in 1953. Since childhood, I have had mild to moderate symptoms of psychiatric syndromes, although I have never been professionally assessed. The symptoms have varied in character and intensity over time, with ADHD symptoms in childhood, schizoaffective symptoms predominating in adolescence and early adulthood, and Asperger syndrome symptoms becoming more pronounced in later life, as ADHD and schizoaffective symptoms weakened. Such a course may seem unusual, but may perhaps not be all that unusual (PMID: 19886976). In psychiatry, a diagnosis of one disorder tends to preclude the identification of symptoms of other syndromes (PMID: 10993392) (PMID: 18417316).
People with Asperger syndrome often have an intense interest in specialist subjects, particularly subjects of a scientific nature. This has been the case with me, and for over 20 years I have researched the etiology of schizophrenia. Since becoming connected to the Internet in 2004, the research has flourished and broadened into other areas. What became clear is that schizophrenia is not only associated with other psychiatric disorders, but also with many physical disorders, as well (PMID: 17919153) (PMID: 18370570) (PMID: 18830847).The immune system is seen to be activated in schizophrenia (PMID: 2898486) (PMID: 7862263) (PMID: 11268373). (PMID: 10553735) (PMID: 18005941) and there is a clear association with autoimmune diseases (PMID: 16513876), giving rise to speculation that it might also be an autoimmune disease as autoantibodies are seen in some patients (PMID: 8251150) (PMID: 15661036).
Schizophrenia is also associated with diseases not currently deemed to be autoimmune diseases, but which are nevertheless known to be inflammatory conditions, such as cardiovascular disease, type 2 diabetes and hypertension (PMID: 19783126) (PMID: 19570498). These associations are believed by many researchers to be due to lifestyle factors or to the neuroleptic medication used to control the positive symptoms of the disease. Many schizophrenics are heavy smokers, which would contribute to the greatly increased incidence of cardiovascular disease. Also, the medication might have a pharmacological action which could contribute to the development of other disorders. This is believed to be the cause of the Parkinsonian symptoms seen in many schizophrenic patients. The medication also causes weight gain, which would exacerbate a tendency to many other diseases. Nevertheless, my research convinced me that, although these associated conditions might be exacerbated by medication and lifestyle factors, they are also intrinsically related to the schizophrenia disease process itself, and some research supported this belief (PMID: 15056598) (PMID: 8352344) (PMID: 15820325).
NF-kB
The search for clues to the causes of schizophrenia therefore broadened into a study of many apparently interconnected disorders in order to find common factors which underlay them, and the most fundamental common factor which emerged as the driving force behind these conditions is the transcription factor, nuclear factor kappa beta (NF-kB). NF-kB was first identified in 1986 and has been intensively researched since its discovery. At the time of writing, a PubMed search for ‘NF-kB’ produces 28,852 results. Much of this research is focused on cancer and ‘NF-kB’ plus ‘cancer’ produces 7,044 results. ‘cardiovascular’ produces 2,870 results, ‘atherosclerosis’ 757, ‘diabetes’ 726, ‘Alzheimer’s’ 250, ‘multiple sclerosis’ 95 and ‘tuberculosis’ 90. ‘Schizophrenia’ produces only 12 results and in only two of the abstracts is it concluded that schizophrenia is associated with NF-kB activation (PMID: 19058794) (PMID: 11450174).
Despite this meagre amount of supporting evidence, my own review of the research convinces me that schizophrenia is being caused by aberrant NF-kB activation and, moreover, that this NF-kB activation is also the root cause of a large majority of non-communicable diseases. A list of diseases which have been demonstrated to be associated with NF-kB activation can be found at www.nf-kb.org. I believe this list represents a relatively small sample of the actual number of diseases which are being caused by chronic, pathological activation of the NF-kB driven immune response. In addition to causing non-communicable diseases, pathologically excessive activation of NF-kB may also be responsible for illnesses associated with infection by specific pathogens, such as tuberculosis, leprosy, mononucleosis, toxoplasmosis, Lyme disease etc.
Infectious Organisms
Many environmental factors appear to contribute to the activation of NF-kB and infectious organisms seem to be particularly important. Many of the diseases which are known to be associated with a chronically activated NF-kB driven immune response are also associated with an above average incidence of infection with specific pathogens. I have compiled a list of those pathogens which appear to be most important. They are herpes simplex virus-1, herpes simplex virus-2, human herpes virus-6, cytomegalovirus (herpes family), Epstein-Barr virus (herpes family), varicella zoster (herpes family), mycobacteria, Borna virus, enteroviruses, hepatitis C virus, human papilloma virus, Borrelia bacterium, Toxoplasma gondii protozoon, human endogenous retroviruses, mycoplasma pneumoniae bacterium, Chlamydia pneumoniae bacterium, Helicobacter pylori bacterium, JC virus, Candida albicans fungus and intestinal worms.
This list reveals a crucially important fact. Except for Candida and worms, all these infectious organisms are obligate intracellular parasites which are known to establish latency within cells and can persist in a dormant state for years without causing illness. However, in at least two cases, enteroviruses (PMID: 14972536) (PMID: 12925877) and H. pylori (PMID: 17382273), only a small percentage of these microbial populations actually establish latency. For example, H. pylori normally burrows deep into the mucus layer of the stomach and spends most of its life next to the stomach’s epithelial cell layer. Despite the fact that it is not normally an intracellular parasite, let alone one that establishes latency, a tiny percentage of the H. pylori population in the gut is now believed to do this (PMID: 12738380) (PMID: 17388791). H. pylori is associated with stomach ulcers, stomach cancer and gastritis, and is suspected of contributing to extragastric diseases also (PMID: 19563929) (PMID: 18396114). However, it would probably be more accurate to blame the diseases associated with H. pylori on the damage caused by the NF-kB driven immune response to the bacterium in people genetically predisposed to excessive NF-kB activation.
Normally, cells which are infected by microbes are targeted for apoptosis by the immune system. However, in certain circumstances, such as neuronal infection, apoptosis may be too drastic a response. The NF-kB driven response is essentially antiapoptic. Pathogens are suppressed within cells by the production of reactive oxygen species (ROS) at a level which does not kill the cell. This may be why the brain is subject to so many different diseases resulting from NF-kB dysregulation. Another reason why the NF-kB response may be favoured by the immune system is that the pathogens which it controls may have evolved strategies to counteract apoptic signalling. In the case of the herpes family, the viruses produce a length of RNA called HHV latency associated transcript, which suppresses apoptosis (PMID: 10688801) (PMID: 11752162). Presumably, other pathogens which establish latency do something similar. However, although the NF-kB response is essentially antiapoptic, prolonged activation will often result in the death of the cell, and this contributes to the disease pathology, particularly in the brain.
The above list of pathogens which provoke NF-kB activation and contribute to inflammatory disorders may be biased towards ‘western’ diseases. There are undoubtedly many more examples of obligate intracellular pathogens which establish latency and cause disease via chronic NF-kB activation which are to be found mainly in the tropics. An example is Chagas disease, which is endemic throughout central and South America. Chagas disease is caused by the protozoon, T. cruzi, and is spread by a family of biting insects, known as ‘assassin bugs’. Borna virus, Borrelia and T. gondii are also ‘zoonotic’ infections.
The diseases which are being caused by chronic NF-kB activation are known to be a product of both genetic, environmental and lifestyle factors. In some people, a genetic predisposition to NF-kB dysregulation is probably a factor and this predisposition is likely to be heterogeneous. NF-kB activation is boosted by many endogenous factors, such as cytokines, toll like receptor (TLR) activation by microbial molecules, perhaps including those originating from gut microbiota, receptor agonists, such as the glycoprotein fragments which bind to the receptor for advanced glycation end-products (RAGE), receptor antagonists, such as homocysteine which activates NF-kB (PMID: 19657099) and induces excitotoxicity via calcium influx after binding to the glutamate NMDA receptor (PMID: 19508427). Homocysteine appears to be used by the immune system for this purpose, but it is also produced in excessive quantities by a few people with a genetic flaw, and in people deficient in B vitamins, and is well known to be a contributory factor in several diseases.
One of the ways that the NF-kB driven immune response controls the proliferation of intracellular parasites is the production of ROS within cells. It is believed that the most destructive molecule among many that are known is the hydroxyl radical. However, these ROS are also produced inside cells by normal metabolic processes, particularly as a by-product of metalloenzyme activity. It is well known that the production of ROS within cells causes activation of NF-kB (PMID: 10391125) (PMID: 7586142) (PMID: 10678585) which will cause yet more ROS to be produced. Although infection plays a significant role in the aberrant activation of NF-kB, it may not be a prerequisite for such activation. The evidence strongly indicates that processes affecting cells which mimic the downstream effects of NF-kB activation, such as excessive ROS production or high homocysteine levels, can also induce NF-kB activation. Because of this, I refer to the diseases which are caused by such pathological activation as ‘Immune Mimicry Disease’ (IMD) in this paper.
Enzymes
Enzymes are frequently seen to be autoantigens in autoimmune diseases and are attacked by antibodies generated by B-cells. About a third of enzymes utilise a metal co-factor, very often iron, which may produce ROS, including hydroxyl radicals. However, virtually all of the enzyme autoantigens I have studied are metalloenzymes which use transition metal ions as a co-factor. The only exception I am aware of is glutamic acid decarboxylase, which utilises pyridoxal phosphate (vitamin B6) as a co-factor and is often an autoantigen in type 1 diabetes. This means that it is the metal or a product of the chemical reactivity of the metal which is attracting the attention of the immune system. The products may be ROS or alterations to the enzymes, co-factors or substrates caused by reactions with ROS.
Examples of metalloenzyme autoantigens in autoimmune diseases include thyroid peroxidase (iron in heme) in thyroiditis, tyrosinase (copper) in vitiligo, transglutaminase (manganese) in coeliac disease and cytochrome P450 (iron in heme) in Addison’s disease. The cytochrome P450 superfamily of enzymes are frequent targets of the immune system, with CYPc21 and CYPc17 both antigens in Addison’s disease, CYPc17 and CYPscc in premature menopause, CYPc17 in gonadal failure, CYP1a2 and CYP2a6 in autoimmune polyglandular syndrome type 1 and CYP1a2 in halothane hepatitis.
There is also a strong association between IMDs and a wide variety of metalloenzymes where antibodies to those enzymes are not seen. I believe that these enzymes are contributing to the pathological activation of NF-kB which gives rise to these diseases by producing excessive quantities of ROS. This activation of NF-kB is likely to result in more ROS being produced within cells. Also, excessive production of ROS by enzymes could result in degradation of the enzyme itself, or degradation of co-factor and substrate molecules, as well as depleting reserves of antioxidant defence molecules, all of which might result in yet more ROS being produced and stronger NF-kB activation. It is easy to see how this could lead to a self-perpetuating disease process which might be difficult to arrest once it had begun.
Cytochrome P450
Very often, the enzymes responsible are particular variants, or polymorphisms, and it seems plausible that, in some cases, these polymorphisms produce more ROS than other forms of the enzyme, although I have not been able to find confirmation of this. The cytochrome P450 (CYP) superfamily are ubiquitous intracellular enzymes which produce hydroxyl radicals and activate NF-kB. Diseases which have been identified to be associated with CYP enzyme polymorphisms include psoriasis (PMID: 12713578), lupus (PMID: 10599336), myocardial infarction (PMID: 17126841), schizophrenia (PMID: 17325735), psychiatric illness (PMID: 16812949), pre-eclampsia (PMID: 17167268), Behcet’s disease (PMID: 15088300), periodontitis (PMID: 15491310), chronic bronchitis and relapsing pneumonia (PMID: 15928955), porphyria (PMID: 17225875), Hodgkin’s and non-Hodgkin’s lymphoma (PMID: 12397416), leukemia (PMID: 16493615), colorectal cancer (PMID: 17695473) and gastric cancer (PMID: 15064998).
Organelles as Sites of Disease Pathogenesis
Within cells, cytochrome P450 is active in the mitochondria, the endoplasmic reticulum (ER) and at receptors on the nuclear membrane. Technically, the nuclear membrane is a continuation of the ER membrane, but I shall deal with it separately as the evidence suggests that the activity of CYP enzymes at receptors in the nuclear membrane has a particularly powerful effect on NF-kB activation. Both mitochondrial stress and ER stress result in NF-kB activation and excessive production of ROS, particularly hydroxyl radical, will cause these organelles to become stressed (PMID: 14718536) (PMID: 18272519).
Because of its role in energy production and fatty acid synthesis, a great many ROS are produced in the mitochondrion, but they are made safe by neutralising enzymes. For example, the superoxide ion is made safe by superoxide dismutase and hydrogen peroxide is neutralised by glutathione peroxidase. The half life of hydroxyl radical has been estimated at around a billionth of a second, which is too fleeting an existence to be engaged and made safe by an enzyme. So, while increased production of other ROS will result in increased production of their neutralising enzymes, this does not happen with the hydroxyl radical, which may help to explain why it seems to have greater power to activate NF-kB than other molecules.
The ER performs many functions which may result in the production of hydroxyl radicals and other ROS, including carbohydrate metabolism, protein and lipid synthesis and chemical detoxification. Excessive and prolonged production of ROS within the ER leads to ER stress, which activates NF-kB (PMID: 16581782) and contributes to disease pathogenesis.
The other intracellular region where research indicates that ROS production causes activation of NF-kB is the nuclear membrane. Receptors for chemicals such as estrogens, glucocorticoids, vitamin A, vitamin D and thyroid hormone are found on the nuclear membrane. These chemicals are metabolised at the receptors by CYP enzymes and the activation of the receptors by their ligands is also dependent on the action of the CYP enzymes. It is not clear whether the hydroxyl radicals that are produced are also required for receptor activation. The nuclear membrane is also where xenobiotic chemicals are metabolised by CYP enzymes.
Estrogen
Many IMDs, particularly those categorised as autoimmune diseases, are more common in women and estrogen is suspected of being the cause. Estrogen is synthesised from cholesterol by CYP enzymes and this synthesis produces hydroxyl radicals. In target cells, estrogen molecules are metabolised by CYP enzymes and this also causes hydroxyl radicals to be produced. There are three main forms of estrogen, all of which have four conjoined aromatic rings to which hydroxyl groups are attached. Estriol has three hydroxyl groups, estradiol has two and estrone has one. Hydroxyl groups on phenyl rings of receptor ligands are a recurring theme in IMD research. The hydroxyl group aids in binding the ligand to the receptor. The different forms of estrogen are constantly being converted to other forms, liberating hydroxyl radicals in the process.
Non-pregnant women between the ages of 15 and 45 manufacture about 500 mcg of estrogen each day, while men produce about a quarter of this amount. In women with a genetic predisposition to dysregulated NF-kB activity, the production of hydroxyl radicals due to the synthesis, conversion and metabolism of estrogen by CYP enzymes, particularly polymorphisms, could tip the balance towards disease pathogenesis, when other genetic and environmental contributory factors exist. Toxic chemicals, such as dioxins, PCBs and polycyclic aromatic hydrocarbons (PAHs) are capable of binding to, and acting as agonists at the estrogen receptor where they are metabolised by CYP enzymes. More usually, these chemicals bind to the aryl hydrocarbon receptor (AHR), which floats in the cytosol and migrates to the nuclear membrane when it traps a xenobiotic chemical. There, they are metabolised by CYP enzymes.
Foods and Chemicals
Over the years, I have noted which foods, food supplements, activities etc have an effect on my mental and physical health. I found that eggs, which I had probably eaten most days since childhood, had an adverse effect on my mood and my psychiatric symptoms improved when I excluded eggs and chicken from my diet. Vanadium supplements, as vanadyl sulphate, cause a very profound depression which lifts within a day or two of stopping them. Bone meal tablets have the same effect as vanadium. Only 8mg of zinc per day, as oxide, worsens schizophrenic symptoms in a day or two, but I can take 45mg of zinc a day as gluconate and experience only a mild adverse effect after about a week. Large amounts of vitamin B6 have an adverse effect on my mental health which is difficult to describe, but resembles descriptions of the symptoms of pre-menstrual tension. It is interesting that B6 is used in large amounts to treat that condition. Folic acid can have a similar effect. Zinc, copper, manganese, nickel and chromium have all caused pancreatitis, particularly in combination with alcohol, and magnesium as oxide or malate has caused appendicitis, which does not happen with magnesium citrate or chelate. I experimented with oils and found that a sixth of a pint of sunflower oil exacerbated schizophrenic symptoms, as did the same amount of olive oil. A third of a pint of double cream had no effect. Supplements of the amino acids, tyrosine and methionine also exacerbate schizophrenic symptoms. Tyrosine is the precursor molecule for dopamine and methionine is the precursor molecule for homocysteine.
Perhaps the most surprising chemicals which I have found to have an adverse effect on psychiatric symptoms are vitamins A and E. Vitamin A aids the functioning of the immune system and vitamin E is a free radical scavenger, so both might be expected to improve IMDs. Both vitamins are fat soluble. The RDA for vitamin E is 10mg per day. I have found that 400iu (267mg) per day worsens schizophrenic symptoms. Capsules of twice this strength are available in supermarkets. Vitamin E hypersensitivity is known from adverse skin reactions to cosmetic preparations and is not uncommon. Even more surprising, perhaps, is the fact that only 3mg per day of vitamin A also worsens schizophrenic symptoms. This amount is just four times the RDA of 750mcg. Vitamin A is actually three similar molecules, known collectively as ‘retinoids’. These are retinol, retinal and retinoic acid. An association between retinoids and schizophrenia has been suggested (PMID: 9636132) (PMID: 12081629). Vitamin A is metabolised at its receptor on the nuclear membrane by CYP enzymes. A synthetic retinoid, isotretinoin, which is used to treat severe acne, has been blamed for causing depression, psychosis and suicidal behaviour in some people (PMID: 19154613) (PMID: 16863513). A possible explanation for this could be a genetic predisposition to psychosis, combined with a CYP polymorphism. The body can manufacture vitamin A from the water soluble beta carotene. I have taken large amounts of beta carotene with no noticeable adverse effects.
Vitamin D is another fat soluble vitamin with a receptor on the nuclear membrane. The RDA for vitamin D is just 5mcg per day. It is also known to cause a hypersensitivity reaction in some people. I have taken 100mcg per day for a few months with no adverse psychiatric effects. However, I experienced sensitive teeth and ‘restless legs’ during this time.
The Aryl Hydrocarbon Receptor
As its name suggests, the aryl hydrocarbon receptor (AHR) binds hydrocarbons, in particular, polycyclic aromatic hydrocarbons, such as the carcinogenic benzopyrene. Benzene also activates it, as do PCBs and dioxins. All of these chemicals cause cancer and other IMDs and this is dependent on CYP enzyme induction (PMID: 16202979) (PMID: 12388843), leading to NF-kB activation. Some of the AHR ligands which cause the harmful health effects do so in extremely small doses. The most toxic dioxin, TCDD, has a safe intake set by the WHO of 10 picograms/kg bodyweight per day, equivalent to less than a billionth of a gram for an adult. The toxicity of PCBs and TCDD is increased by metals (PMID: 9443932) (PMID: 16093525) (PMID: 8560483) and it is a reasonable assumption that metals also potentiate the effects of other AHR ligands.
Dioxins are best known for their carcinogenic effects, but they also contribute to the pathogenesis of many other IMDs, including porphyria (PMID: 118163543), type 2 diabetes (PMID: 18332783), cardiovascular disease (PMID: 19057694), hypertension (PMID: 18850075), neuropsychological impairment (PMID: 16898675), thyroid malfunction (PMID: 12821272) and damage to the immune system (PMID: 12460794) and the same is probably true of the many other chemicals which bind to the AHR and cause NF-kB activation. This is probably the main cause of tobacco smoking related illness (PMID: 17189671) and it also explains the higher incidence of IMDs in the urban environment. ‘Lifestyle factors’ are often proposed to explain the higher prevalence of IMDs in cities, but it seems more likely that higher levels of chemical pollutants which bind to the AHR and are metabolised by CYP enzymes, thus activating NF-kB, are the main cause, although other factors, such as reduced vitamin D synthesis in the skin of urban inhabitants due to screening of ultraviolet light by particulate air pollution and high buildings, and possibly also an increased rate of transmissible infections due to greater population density, could also contribute. Polycyclic aromatic hydrocarbons, benzene and metal oxides are examples of AHR activating chemicals from motor vehicles which are known to cause disease by contributing to a dysregulated NF-kB driven immune response: general morbidity (PMID: 11166526) (PMID: 16960321) (PMID: 17594471), schizophrenia (PMID: 1352565) (PMID: 10858630), psychosis and depression (PMID: 15056572), cancer (PMID: 8435207) (PMID: 9617339) asthma (PMID: 18461727) (PMID: 12877240) cardiovascular disease (PMID: 2398623) (PMID: 9402447) and myopia (PMID: 18469186).
Tryptophan Metabolites
The AHR also has quite different functions which are mediated by a second messenger molecule, cAMP, in response to a variety of endogenous molecules (PMID: 15972329). However, it is also possible that some endogenous molecules may cause activation of the AHR in the same way as environmental pollutants and thus contribute to the development of IMDs. Some oxidised products of the essential amino acid, tryptophan, are known to be AHR agonists, including indigo and its isomer, indirubin (PMID: 11425848) (PMID: 15120638) (PMID: 8951347) (PMID: 10721083). Other oxidised tryptophan metabolites which are believed to activate the AHR are tryptamine and indole acetic acid (PMID: 9708986) and indole-3-pyruvate (PMID: 12920190). One pathway of tryptophan metabolism results in the production of the neurotransmitter, serotonin, which is seen to be dysregulated in psychiatric disorders. Another pathway produces kynurenine, kynurenic acid and quinolinic acid. The rate limiting enzyme in serotonin synthesis is tryptophan hydroxylase (TPH), and in the kynurenine pathway, the rate limiting enzymes are indoleamine dioxygenase (IDO) and tryptophan dioxygenase (TDO2). All use iron in heme as a co-factor, so the potential must exist for the production of aberrantly oxidised tryptophan species which could bind to the AHR and thus contribute to the development of IMDs. I have not been able to confirm that this mechanism contributes to IMD pathogenesis, but oxidised tryptophan has been found to be elevated in human lens cataracts (PMID: 17935715) and iron levels are also elevated (PMID: 11095912).
The immune system utilises the products of the kynurenine pathway in a variety of ways. The end product of the pathway, quinolinic acid, is a pro-apoptic molecule which exerts its effect at the glutamate NMDA receptor. Kynurenic acid is an antagonist molecule at the same receptor and this increases dopaminergic transmission. It will be seen later how this is also an immune system mechanism which causes the positive symptoms of schizophrenia. In IMDs, the ratio of tryptophan to kynurenine is seen to be altered, with reduced levels of tryptophan and higher levels of kynurenine. It is believed that this is a protective mechanism designed to restrict the supply of tryptophan for pathogens, thus limiting their ability to multiply. However, kynurenine activates the AHR (PMID: 20720200) and IDO expression appears to be dependent on AHR expression (PMID: 21041655). It seems likely that the conversion of tryptophan to kynurenine may also be a deliberate stratagem of the immune system to boost the NF-kB driven response by activating the AHR. There is evidence that mitochondrial stress and ER stress may also be deliberately induced for the same purpose. Many of the pathogens which appear to cause this immune system mechanism are those which establish latency and activate the NF-kB driven immune response (PMID: 17430112) . Examples of IMDs in which tryptophan is converted to kynurenine include psychosis (PMID: 18562404) , rheumatoid arthritis (PMID: 12966593) , Alzheimer’s disease (PMID: 10821443) , coeliac disease (PMID: 17362267) , Sjogren’s syndrome (PMID: 16178870) and gynecological cancer (PMID: 15896467) .
Heme Metabolites
Another group of endogenous chemicals which bind to the AHR and are metabolised by CYP and other enzymes, are the heme derived bilirubin, its precursor, biliverdin, and their oxidative metabolites, collectively known as biopyrrins (PMID: 18187559) (PMID: 9380021) . The porphyrin molecule which binds iron to form heme is made up of four pyrrole groups joined in a circle. Bilirubin and biliverdin are made up of the same four pyrrole groups which have lost their circular structure. Heme is the co-factor for CYP and other enzymes, such as the peroxidases, and it is conceivable that increased production of ROS producing CYP enzymes, particularly polymorphisms, might cause the heme to become degraded, resulting in excess bilirubin and its biopyrrin metabolites. These molecules would bind to the AHR, perhaps inducing the production of yet more NF-kB activating CYP enzymes. Bilirubin and its biopyrrin metabolites have been associated with schizophrenia (PMID: 17719094) (PMID: 17561669) .
However, bilirubin is both positively and negatively associated with disease (PMID: 15949769) and, in this respect, appears to be similar to glucocorticoids, which are also metabolised by CYP enzymes at receptors on the nuclear membrane. Synthetic glucocorticoids are prescribed to reduce inflammation in some IMDs, but are pro-inflammatory in others. The toxicity and immunostimulant properties of bilirubin in the brain appear to be related to cell type and maturation stage (PMID: 16733655) . Some research indicates that bilirubin toxicity is ROS dependent, but that this does not occur as a result of AHR activation (PMID: 16173058) , while other research appears to confirm the involvement of the AHR (PMID: 9721195) . Its apparent anti-inflammatory action in autoimmune encephalomyelitis may indicate potential therapeutic benefit in the treatment of multiple sclerosis (PMID: 18641326) .
The involvement of AHR activation in disease pathogenesis may indicate that chemicals which act as antagonist molecules at the AHR could have a role in disease prevention. Some molecules, found in plant foods, are known to have both AHR antagonist and estrogen receptor modulating properties. Examples of such chemicals are resveratrol, quercetin, kaempferol and genistein. In recent years, much research has been carried out into the ability of resveratrol to prevent disease, yielding encouraging results with implications for the prevention of cancer (PMID: 17306316), Alzheimer's disease (PMID: 19041676), arthritis (PMID: 17115116), diabetes (PMID: 16434553), cardiovascular disease (PMID: 20485301), obesity (PMID: 21439945) and multiple sclerosis (PMID: 21107122). However, my own experience of taking a daily supplement of 500 mg of resveratrol is that it worsened avolition symptoms.
Receptor Abnormalities
In addition to enzyme abnormalities, many IMDs also exhibit membrane receptor abnormalities. Typically, specific receptor types are seen to be reduced in number and also to have reduced sensitivity to their ligands. Also, genetic studies show that receptor polymorphisms are associated with IMDs. Examples of receptor polymorphisms in IMDs are: schizophrenia, serotonin 5-HT2A receptor (PMID: 17240119) (PMID: 14741324) and dopamine D2 receptor (PMID: 14593428) , autism, GABA(A) receptor (PMID: 17230033) and oxytocin receptor (PMID: 17893705) , Alzheimer’s disease, LDL receptor family (PMID: 18288927) and acetylcholine NACH receptor (PMID: 11230871) , and chronic fatigue syndrome, serotonin 5-HT2A receptor (PMID: 18079067) .
Latent Intracellular Pathogens
Many IMDs are known to be associated with infections by specific intracellular pathogens. The subject of increased rates of infection in IMDs is something of a ‘chicken and egg’ problem as an activated NF-kB driven immune response results in immune system changes which could have the effect of making a person more susceptible to infection. The most obvious alteration is a reduction in the number of natural killer (NK) cells, which are the body’s first line of defence against invading pathogens. Research which indicates maternal infection during pregnancy as a risk factor for the development of particular IMDs in the offspring later in life may simply be indicative of this. The NF-kB response is activated during pregnancy and the statistically significant excess of maternal infections may simply reflect an immune system which is genetically predisposed to aberrant NF-kB activation. Rather than the prenatal infections contributing to IMD pathogenesis in the offspring in later life, it may be the inheritance of the same genetic predisposition to dysregulated NF-kB activity which predisposes to IMDs. On the other hand, infection during pregnancy may indeed be causing changes in the unborn child which make dysregulated NF-kB activation more likely to occur later in life.
Despite this complication, there is nevertheless an unambiguous body of evidence which clearly shows that specific types of latent intracellular pathogens are risk factors for the development of specific IMDs. Examples of such associations are: Alzheimer’s disease, herpes simplex virus (PMID: 18982063) , Chlamydia (PMID: 18701222) (PMID: 18487846) , psychosis, T. gondii (PMID: 19212132) mycobacteria (PMID: 18710046) Borrelia (PMID: 11852824) , herpes family (PMID: 18801645) , metabolic syndrome, H. pylori (PMID: 19086952) , H. pylori, Chlamydia, herpes family (PMID: 17140429) , cancer, herpes family, polyomaviruses, H pylori, human papilloma virus, hepatitis B, hepatitis C (PMID: 15489139) , atherosclerosis, hepatitis C (PMID: 19477406) , type 2 diabetes, hepatitis C (PMID: 19344243) , multiple sclerosis, Epstein-Barr virus (PMID: 19664371) obesity, adenovirus (PMID: 19138827) , porphyria, hepatitis C (PMID: 11929046) .
Intracellular pathogens gain access into cells via cell membrane receptors. The study of the receptors involved and the pathogens which use them is a relatively new area of research, but from the small amount of information on the subject which I have been able to find, it is already clear that a significant number of the receptors which are seen to be abnormal in IMDs because they are underexpressed, hyposensitive or blocked by antibodies are the same receptors which are used by microbes to gain entry into cells. For example, the LDL receptor, which is abnormal in cardiovascular disease and Alzheimer’s disease, is used by the hepatitis C virus (PMID: 17156886) (PMID: 10535997) . The serotonin 5-HT2A receptor, which is involved in several IMDs, appears to be used by the JC virus (PMID: 18093678) . However, intracellular pathogens are probably not restricted to a single type of receptor and there is evidence that the JC virus can enter cells via receptors other than the 5-HT2A receptor (PMID: 17399760) . Herpes simplex virus-1 is known to use multiple receptors, perhaps the best known being the TNF-alpha receptor (PMID: 15056211) . I am not aware of any of the receptors used by HSV-1 being abnormal in IMDs but HSV-1 is one of the principal viral contributors to IMD pathogenesis and it may be found to use other receptors which are known to be abnormal in the IMDs to which it contributes. Drugs, such as amphetamine and cocaine increase dopaminergic firing and it has been found that methamphetamine enhances HIV-1 infection, but not when a dopamine D2 receptor antagonist is administered (PMID: 18958626) , suggesting that HIV-1 uses the D2 receptor to enter cells. The acetylcholine NACH receptor has reduced expression in Alzheimer’s disease (PMID: 16055943) and is attacked by blocking antibodies in myasthenia gravis (PMID: 20380581) . It is known to be used by the rabies virus (PMID: 15804965) (PMID: 11935467) and there is also evidence that one of the pathogens associated with Alzheimer’s disease, chlamydia pneumoniae, may enter cells via the NACH receptor (PMID: 12761154) .
The picture which emerges is that the reduced expression and reduced sensitivity of receptors which is evident in IMDs is a deliberate stratagem of the NF-kB driven immune response to prevent pathogens gaining entry into cells and that this mechanism is employed inappropriately, in the absence of infection, when NF-kB activation occurs as a result of factors which mimic the immune response, such as the production of ROS by metalloenzymes. Reduced sensitivity of receptors to their ligands is effected by phosphorylation of the receptor protein. Presumably, this also prevents pathogens from entering cells. This receptor hypofunction contributes to the symptoms of IMDs. Perhaps the clearest example of this is seen in type 2 diabetes in which there is reduced expression and reduced sensitivity of insulin receptors. It seems likely, therefore, that the insulin receptor will be identified as a gateway for the entry of pathogens into cells. Another example of reduced expression and sensitivity of receptors causing symptoms in IMDs is seen in early stage Alzheimer’s disease, in which hypofunction of cholinergic and noradrenergic receptors results in short term memory impairment (PMID: 18220778) .
Receptor Activation of Disease
In the same way that abnormally excessive intracellular production of ROS can activate NF-kB by mimicking its own actions, abnormal activation of receptors can also cause pathological activation of NF-kB and this represents another major mechanism in the pathogenesis of IMDs, which I call ‘receptor activation'. Until now, the focus has been on hypofunctional receptors in IMDs, but there is also evidence of hyperfunction of receptors in some IMDs and it has become evident that factors resulting in either hypofunction or hyperfunction of receptors can initiate IMDs by mimicking the NF-kB driven immune response via receptor activation. For example, type 2 diabetes is caused by chronic overconsumption of food, particularly carbohydrates, which results in chronically high levels of insulin receptor activation. This activates the NF-kB driven immune response by receptor activation which results in reduced expression and sensitivity of insulin receptors in genetically predisposed people, leading to type 2 diabetes. However, in areas where famine is endemic, usually in the tropics, ‘tropical diabetes’ is seen, which may be the result of chronic reduced stimulation of insulin receptors, which can also cause receptor activation of the NF-kB driven immune response, also resulting in type 2 diabetes. The fact that a variety of receptor polymorphisms have been shown to be associated with numerous IMDs indicates that some receptor variants are more likely to cause NF-kB activation than others via receptor activation and this constitutes part of the heterogeneity of the genetic predisposition to aberrant NF-kB activation.
Psychiatric Disease Pathogenesis
Schizophrenia is actually two different, but closely related syndromes, which can co-exist. The positive syndrome is better known, but may possibly be less common than the negative syndrome, which does not present with florid symptoms. Symptoms of the positive syndrome include delusions, auditory hallucinations and thought disorder, while the symptoms of the negative (or deficit) syndrome include blunted affect, poverty of speech, anhedonia, avolition, and impaired intellect. Although abnormal functioning of several neurotransmitter systems have been detected in schizophrenia, the ‘dopamine hypothesis’ is preferred by most researchers. The older neuroleptic medication used to treat the positive symptoms blockade the dopamine D2 receptor. Drugs which increase dopaminergic transmission in the brain, such as amphetamine, cocaine, PCP and ketamine can cause positive symptoms in heavy users who are not genetically predisposed to psychosis (PMID: 19649683) . Symptoms usually abate when the drugs are stopped, but in a minority of people, symptoms of schizophrenia persist after the drugs are discontinued, suggesting receptor activation of the disease in genetically predisposed individuals. Quite small, single doses of these drugs will worsen positive symptoms in schizophrenics.
Other psychiatric disorders also display both positive and negative symptoms, the most obvious being bipolar disorder, in which both mania, and its opposite, depression, are seen. Some people have both schizophrenic and bipolar symptoms and are categorised as ‘schizoaffective’. People with autism spectrum disorder (ASD) have predominantly negative symptoms. ASD has strong co-morbidity with attention deficit hyperactivity disorder (ADHD) (PMID: 20339663) (PMID: 19998356) (PMID: 19380514) and there is evidence for overlapping genetic influences (PMID: 18221348) . Both ASD and ADHD have a pre-school age of onset and the sex ratio of 4:1 male bias is similar in both conditions. The evidence is therefore suggestive of a bimodal psychiatric condition, like schizophrenia and bipolar disorder, and ASD is probably the deficit syndrome, since a reduction in GABA(A) receptors is seen in that condition (PMID: 11814263) (PMID: 18821008) .
Graves' Disease
The existence of positive symptoms in psychiatric disorders, presumably as a consequence of receptor hyperfunction, rather than hypofunction, seems inconsistent with IMD theory. However, there is an autoimmune disease affecting the thyroid gland, Graves’ disease, better known as Basedow’s disease throughout much of Europe, which can also present with both positive and negative symptoms. The pathophysiology of Graves’ disease is less subtle and complex than that of the psychiatric disorders, so if the presumption that the bimodal character of Graves’ disease reflects the same underlying mechanisms which give rise to the positive and negative syndromes seen in psychiatric disorders is correct, then an understanding of those processes might be more easily achieved by a study of Graves’ disease.
The thyroid gland is affected by two autoimmune diseases, Hashimoto’s thyroiditis and Graves’ disease, although the more one studies them, the more blurred the distinction between them becomes. Both diseases are much more common in women. In Hashimoto’s thyroiditis, the thyroid cells are attacked by T-cells, resulting in a reduction of thyroid hormone output. Autoantibodies to the enzyme, thyroid peroxidase, and the storage protein, thyroglobulin, are often seen and it seems possible that both iodine and iron in the heme co-factor used by thyroid peroxidase may be involved in the initiation of autoimmunity as both produce ROS.
In Graves’ disease, typically, too much thyroid hormone is produced as a result of the action of antibodies which bind to the thyroid stimulating hormone receptor (TSHr), causing persistent activation. TSH, or thyrotropin, is the natural ligand for the TSHr and is produced by the pituitary gland in the brain. TSH levels are controlled by a feedback loop involving thyroid hormone acting on receptors in the pituitary. However, another TSHr binding antibody is also present in Graves’ disease which does not stimulate thyroid cells to produce thyroid hormones. Instead, it acts as an antagonist, preventing both TSH and stimulating antibodies from binding to the receptor. In some cases, this blocking antibody is the predominant form, resulting in deficiency of thyroid hormone production, and sometimes the balance of stimulating and blocking antibodies is such that normal amounts of thyroid hormones are produced.
I found this situation of ‘pathological normality’ intriguing and did not believe it was likely that two different accidents were cancelling out each other’s ill effects. These blocking and stimulating antibodies are seen in people who have never had thyroid disease and it seemed more likely that evolution had fashioned these antibodies for a purpose, to work together in a coordinated manner, but their functioning had become dysregulated in Graves’ disease. However, it was not until I discovered that thyroid cell apoptosis in Graves’ disease was confined to those cells to which blocking antibodies were attached that a robust hypothesis began to emerge (PMID: 9409648) .
There appears to be very little information on the subject of NF-kB involvement in Graves’ disease (PMID: 11129119) (PMID: 17690684) , but the interpretation which is consistent with IMD theory is that the TSHr may be used by pathogens to gain entry into thyroid cells and the blocking antibodies are created to deny access into the thyroid cell while it is being purged of pathogens. As with other IMDs, this immune system mechanism may be aberrantly activated in the absence of infection. To compensate for the shortfall in thyroid hormone production, other antibodies are created at the same time, which act as agonists at the TSHr of other thyroid cells, causing them to make more thyroid hormone than normal. During times of infection of the thyroid gland, these opposing antibodies would act in concert to ensure normal thyroid hormone production and the reason why evolution had fashioned stimulating antibodies instead of simply relying on the pituitary to make up the thyroid hormone shortfall by secreting more TSH, is that the stimulating antibodies are much more powerful and longer lasting at the TSHr than TSH. This means that fewer TSHrs need to be expressed and this reduces the opportunity for pathogens to infect thyroid cells.
Graves’ patients are known to fluctuate from hypo to hyperthyroidism. The course of the disease can also begin as hyperthyroidism and gradually become hypothyroidism over time. This most commonly occurs after surgery or radioiodine treatment to reduce the size of the thyroid, but it can also occur in the absence of treatment. When it does, it is associated with thyroid atrophy. The course of the disease can therefore be very similar to both bipolar disorder and schizophrenia and a high prevalence of thyroid abnormalities is seen in schizophrenic patients (PMID: 7794205) . Bipolar patients often fluctuate from mania to depression and the positive symptoms of schizophrenia often come and go while negative symptoms persist. Also, it is common for the symptoms of schizophrenia to be mainly positive early in the course of the disease, with negative symptoms becoming more predominant in later life. Both bipolar disorder and schizophrenia are associated with brain atrophy and the degree of atrophy is strongly correlated with the severity and duration of the negative symptoms (PMID: 7862264).
Yet, schizophrenia is quite dissimilar to Graves’ disease. The neurons involved do not produce a hormone, nor are agonist and antagonist receptor antibodies seen. However, the neurons are involved in dopaminergic signalling and something similar to the mechanisms proposed for Graves’ disease might apply in the maintenance of dopaminergic homoeostasis. In the dysregulated immune response which gives rise to the symptoms of schizophrenia, kynurenic acid is synthesised from tryptophan to act as an antagonist at the glutamate NMDA receptor and this increases dopaminergic transmission by making the dopamine molecule persist longer at its receptor, in the same way as TSHr stimulating antibodies persist longer at the TSHr than the natural ligand, TSH.
However, dopamine D2 receptor density is modestly increased in most patients, which seems inconsistent with the need to reduce receptor expression to prevent infection. Possibly, the longer residence time of the dopamine molecule at its receptor has the effect of restricting entry to pathogens. Also, there is evidence of reduced D2 and D3 receptor binding by dopamine in some brain areas (PMID: 12740603) (PMID: 14604451) which could mean that these receptors are desensitised. In type 2 diabetes, both reduced expression and decreased sensitivity of the insulin receptors are seen. Also, dopamine D1 and D5 receptors are underexpressed in the prefrontal cortex, which may contribute to negative symptoms. In addition, there is reduced expression of the serotonin 5-HT2A receptor, which may also contribute to negative symptoms, and increased expression of the 5-HT1A receptor in schizophrenia. The serotonin and dopamine systems are highly intertwined, anatomically and functionally, with serotonin inhibiting dopaminergic transmission, and this is likely to be important in schizophrenia (PMID: 21645528) (PMID: 16613551).
The 5-HT2A receptor is known to be used by the JC virus to enter cells and research has shown that more than 50% of human brains have JC virus DNA (PMID: 1326640). Moreover, the 5-HT2A receptor appears to be more widely implicated in IMD pathogenesis than dopamine receptors, with polymorphisms contributing to schizophrenia (PMID: 17240119), rheumatoid arthritis (PMID: 18006541) and chronic fatigue syndrome (PMID: 18079067). Increased expression is seen in psoriasis (PMID: 16794822) and decreased expression in rheumatoid arthritis (PMID: 16699051) . It is conceivable that the boosting of dopaminergic signalling at the D2 receptor by kynurenic acid at the NMDA receptor also causes serotonin 5-HT2A receptor expression to be reduced and that it is this receptor, rather than the dopamine D2 receptor, which is being protected from invading pathogens.
The psychiatric disorders, Graves’ disease and, probably Hashimoto’s thyroiditis also, are the only IMDs thus far identified which have a compensating positive syndrome which may become pathologically dysregulated. Others may be uncovered, but it seems likely that only a minority of IMDs function in this way, with the majority being deficit syndromes, having no associated positive syndrome pathology. There is little information to be found on the subject of aberrant NF-kB activation in diseases which arise as a consequence of a dysregulated compensation mechanism, which may mean that NF-kB activation is only occurring in the hypofunctional cells which have reduced receptor expression and sensitivity.
Receptor for Advanced Glycation End Products
Another important IMD subgroup are those diseases in which the NF-kB driven immune response is boosted by activation of the receptor for advanced glycation end-products (RAGE). These include rheumatoid arthritis and the other collagen diseases, such as ankylosing spondylitis, Sjogren’s syndrome and lupus, the ‘metabolic syndrome’ diseases (type 2 diabetes, atherosclerosis and hypertension), as well as Alzheimer’s disease, multiple sclerosis, cancer and, possibly, autism. The RAGE can be activated by a protein called high mobility group box chromosomal protein 1 (HMGB 1) which can be released passively by necrotic cells, or actively by macrophages (PMID: 12488489) (PMID: 15162419) and is active in a variety of IMDs (PMID: 17717837) (PMID: 17895302) (PMID: 16802368) (PMID: 16487750) .
Many of the RAGE stimulated IMDs are also associated with glycoproteins and glycolipids which are processed by enzymes such as the matrix metalloproteinase (MMP) family and angiotensin converting enzyme (ACE). Collagen diseases, metabolic syndrome diseases and cancer are associated with the extracellular matrix (ECM), the pancreatic beta cells in type 2 diabetes with amyloid, Alzheimer’s disease with amyloid beta (Abeta) and multiple sclerosis with myelin. Autism may also be associated with myelin.
The activity of both MMPs and ACE is seen to be increased in RAGE stimulated IMDs, indicating that these enzymes play an active role in the inflammatory process. (MMPs), heart disease (PMID: 19626421) (PMID: 12625594) , multiple sclerosis (PMID: 15735992) (PMID: 11522577) , rheumatoid arthritis (PMID: 8625558) (PMID: 8814070) , lupus (PMID: 11876767) (PMID: 15269987) and cancer (PMID: 19738110) (PMID: 12908552) . (ACE) multiple sclerosis (PMID: 19136547) (PMID: 9267976) , Alzheimer’s disease (PMID: 17973905) (PMID: 19145983) , rheumatoid arthritis (PMID: 10666168) (PMID: 1316742) . ACE also creates the pro-inflammatory molecule, angiotensin II.
Polymorphisms in both MMPs and ACE are also evident in RAGE stimulated IMDs, again, indicative of an active role for these enzymes in the inflammatory process. (MMPs) rheumatoid arthritis (PMID: 17373931) (PMID: 19504098) , multiple sclerosis (PMID: 19631393) (PMID: 19628284) , heart disease (PMID: 15084374) (PMID: 19620856) and cancer (PMID: 16990034) (PMID: 16267613) , (ACE) Alzheimer’s disease (PMID: 17192785) (PMID: 17401152) , rheumatoid arthritis (PMID: 14719217) (PMID: 17985406) , lupus (PMID: 17937470) (PMID: 18711292) , type 2 diabetes (PMID: 19655271) and heart disease (PMID: 18504336) .
The RAGE exists in two forms, membrane bound and as a soluble receptor which is detached from the membrane (PMID: 18952609) . These soluble receptors are believed to act as a ‘decoy’, trapping glycoprotein and glycolipid molecules which have the potential to bind to membrane bound RAGE and contribute to the pathogenesis of disease. It has been found that IMDs in which membrane bound RAGE activation plays a role are also associated with low levels of soluble RAGE, presumably because this assists in RAGE activation by increasing the availability of RAGE agonists (PMID: 16133426) . These include hypertension (PMID: 16093918) , Sjogren’s syndrome (PMID: 18231794) , type 2 diabetes (PMID: 17640561) , rheumatoid arthritis (PMID: 15987496) , atherosclerosis (PMID: 15731496) , Alzheimer’s disease (PMID: 16286548) , multiple sclerosis (PMID: 18505774) and autism (PMID: 17101220) .
If all RAGE proteins and their agonist molecules were identical, the decreased level of soluble RAGE in a RAGE stimulated IMD might act to promote the pathogenesis of other RAGE stimulated IMDs due to increased levels of circulating RAGE agonists. Presumably to prevent this, a variety of RAGE isoforms, known as ‘splice variants’, have evolved (PMID: 15104125) (PMID: 15555779) (PMID: 19061941) which have major differences in different organs (PMID: 19164451) . This may prevent one RAGE stimulated IMD leading to another, although the co-occurrence of kidney disease, atherosclerosis, type 2 diabetes and hypertension in metabolic syndrome may be indicating that similar RAGE proteins and agonists are involved in these IMDs.
The weight of evidence strongly suggests that glycoproteins, and possibly glycolipids, which are seen to be aberrantly deposited, such as Abeta in Alzheimer’s disease and amyloid in the pancreas in type 2 diabetes, or aberrantly degraded, such as the extracellular matrix in cardiovascular disease, amongst others, and myelin in multiple sclerosis are being used as depots from which RAGE agonists are cleaved by MMP and ACE enzymes. The use of these substrates for this purpose is probably a normal function of the immune system which has become pathologically dysregulated in RAGE stimulated IMDs (PMID: 12370004) (PMID: 18772849) (PMID: 15975028) (PMID: 10863022) .
MMP levels are also seen to be raised in response to infections by pathogens of the type which are associated with chronic activation of NF-kB, such as Borrelia (PMID: 19205380) , mycobacteria (PMID: 19178594) , herpes simplex (PMID: 17109833) , streptococcus (PMID: 19125779) and Candida (PMID: 19171647) , further emphasising their active role in the immune response. Oddly, there appears to be relatively little information on the subject of elevated ACE levels in response to these infections.
There is a belief that dietary advanced glycation end-products can activate the RAGE. These can be created by cooking and in food processing and so can be consumed directly. It is believed that they can also be created within the body, particularly in association with a high glycemic diet, a process in which enzymes are not involved (PMID: 18051988) (PMID: 18426758) . This theory remains unproven (PMID: 18497726) , with some research in favour (PMID: 17854003) and some against (PMID: 17854004) . However, the fact that the advanced glycation end-product molecules are detected in the vicinity of substrates which I believe are cleaved by enzymes to create RAGE agonists, convinces me that it is the substrates, such as the extracellular matrix, which are the main sources of the AGEs, and not the diet (PMID: 19542215) (PMID: 16374460) , although the possibility of a contribution to IMD pathogenesis via RAGE activation by dietary AGEs cannot be ruled out.
Environmental and Lifestyle Factors
Environmental and lifestyle factors also contribute to the pathogenesis of IMDs. These include lack of immune challenge in infancy (the ‘hygiene hypothesis’), infections occurring after infancy, lack of vitamin D, diet, chronic psychological stress, lack of physical exercise, food and chemical intolerance/sensitivity, chemical pollutants, environmental metals and gut microbiota. Sensitivity to these environmental influences may be exacerbated by genetic abnormalities such as receptor and enzyme polymorphisms and immune system abnormalities.
Two of these environmental factors may exert their influence by affecting the developing immune system in a way that makes it more prone to dysfunctional NF-kB activation later in life. These are lack of immune challenge in infancy and vitamin D deficiency.
Lack of Immune Challenge in Infancy
The ‘hygiene hypothesis’ seeks to explain the high incidence of allergic and autoimmune disease in the developed world compared to developing countries as the result of oversanitised living conditions in the more affluent countries. This results in children in these countries having an unnaturally low exposure to environmental pathogens and allergens in early life which causes their immune systems to develop in an abnormal way. This abnormal development results in an immune system which is more likely to overreact to stimuli later in life, resulting in a high incidence of allergies and autoimmune disease. Experiments have confirmed that mice bred to be genetically predisposed to type 1 diabetes develop the disease more readily when reared in a sterile environment, than those raised in more ‘natural’ surroundings (PMID: 12165171) .
Worm infections may be particularly important. Until relatively recently, most people in the developed world were probably infected with worms (PMID: 12032638) and the infection rate in developing countries is often greater than 90%. It seems that intestinal worm infections in infancy, when the immune system is still developing, may help to prevent IMDs later in life (PMID: 12756068) (PMID: 18680198) (PMID: 14755074) . However, worm infections are also positively associated with the pathogenesis of IMDs. The explanation for this may be that, if the infection occurs later in life, after the immune system has developed in the absence of early immune challenge, this may cause systemic upregulation of the NF-kB driven immune response, making the development of IMDs more likely to occur. Examples of IMDs that appear to be positively associated with intestinal worm infections include schizophrenia (PMID: 18452258) , asthma (PMID: 16866053) , epilepsy (PMID: 18031545) and rheumatoid arthritis (PMID: 17124681) . An exception to this is inflammatory bowel disease, which has been successfully treated with deliberate worm infection in adults (PMID: 17313951) (PMID: 19050918) . Worms secrete chemicals known as ‘cystatins’ which downregulate local immune activity in the gut, thus helping to ensure their survival.
Vitamin D Deficiency
There is much evidence that vitamin D deficiency, particularly in childhood, is a contributory factor in the development of IMDs in later life. Most of our vitamin D comes from sunlight. Ultraviolet light converts cholesterol in the skin to pro-vitamin D. This molecule has a hydroxyl group added to it in the liver and another hydroxyl group is added in the kidney to make calcitriol, the active form of the vitamin. Most dietary and supplemental vitamin D is also in the form of pro-vitamin D and must undergo the same two stage hydroxylation process. An exception to this is the synthesis of vitamin D within immune system macrophages.
As pro-vitamin D synthesis in the skin is dependent on the intensity of sunlight, people living at higher latitudes are most at risk of deficiency, particularly if they are dark skinned. A Finnish study has found that children with rickets during the first year of life had a threefold increased risk of developing type 1 diabetes (PMID: 11705562) and analysis of blood samples from U.S. military personnel revealed that Caucasian males with the highest levels of vitamin D were 62% less likely to go on to develop multiple sclerosis than those with the lowest levels (PMID: 17179460) . The correlation was strongest for those who were under 20 years old when they entered the study and the researchers commented that this could mean that vitamin D levels prior to adulthood might be particularly important. In Iran, the incidence of MS increased 8.3 fold between 1989 and 2006, with most of the increase seen in women. This has been attributed to cultural changes following the Iranian revolution in 1979, after which women were required to wear more clothing, including a veil (PMID: 24108962) . Examples of other IMDs which have been associated with vitamin D deficiency include schizophrenia (PMID: 14984883) , cardiovascular disease (PMID: 17563024) , connective tissue diseases (PMID: 18928561) , cancer (PMID: 18550652) , type 2 diabetes (PMID: 18269634) and Parkinson’s disease (PMID: 18852350) .
The question arises as to where vitamin D exerts its protective influence. It is known to have an immune system modulating function and has been used successfully to treat a variety of inflammatory conditions (PMID: 15585793) (PMID: 16046118) (PMID: 12230797) . Cells of the immune system have vitamin D receptors, as do the various cells in which IMDs originate. It is not entirely clear where its modulating action takes place. It may even be in both types of cell. However, it is known that vitamin D inactivates NF-kB when it binds to its receptor in the cells in which IMDs originate (PMID: 16455676) (PMID: 16502254) (PMID: 17298882) . Moreover, vitamin D receptor polymorphisms are known to be associated with many IMDs, such as type 1 diabetes (PMID: 10868975) , coronary artery disease (PMID: 9761785) , Hashimoto’s thyroiditis (PMID: 18279374) , inflammatory bowel disease (PMID: 18752562) , Alzheimer’s disease (PMID: 17592215) , autoimmune liver disease/primary biliary cirrhosis (PMID: 14642064) and cancer (PMID: 10667581) (PMID: 18618252) .
The weight of evidence therefore seems to point to the action of vitamin D in the cells in which IMDs originate as being the protecting function, rather than its use by the cells of the immune system. Polymorphisms in one of the CYP enzymes responsible for the conversion of pro-vitamin D to the active form, calcitriol, have also been found (PMID: 17607662) (PMID: 15296474) and are associated with a higher incidence of IMDs, as are polymorphisms of the vitamin D binding protein (PMID: 12050214) (PMID: 11239517) .
Diet
The ‘western’ diet is pro-inflammatory. Overeating causes obesity and the mere presence of body fat causes systemic activation of NF-kB (PMID: 17702846) . This may be the reason why obesity is associated with other IMDs. The best known associations are with type 2 diabetes and cardiovascular disease, but other associations, such as asthma (PMID: 19548965) (PMID: 19439348) , cancer (PMID: 19524333) (PMID: 18280327) , and even dementia (PMID: 18331422) (PMID: 19057182) are recognised. Obese individuals also show stronger activation of NF-kB after a meal that is high in fat and carbohydrate (PMID: 17785362) .
A high fat diet is particularly pro-inflammatory and is best known as a risk factor for cardiovascular disease. However, dietary fat has also been implicated in the pathogenesis of other IMDs, including schizophrenia (PMID: 3232536) (PMID: 15682652) (PMID: 15123503) , multiple sclerosis (PMID: 7572944) (PMID: 1291885) (PMID: 1804476) , Alzheimer’s disease (PMID: 12580703) (PMID: 16710090) and macular degeneration (PMID: 11483088) . Saturated fats and the artificial trans fats are believed to be the most pro-inflammatory and the principal mechanism through which they exert their deleterious effects may be ER stress (PMID: 19302420) (PMID: 16492686) . Another possible mechanism is that environmental chemicals which activate the AHR accumulate in fats and there is a greater concentration of these chemicals in animal fat, compared to vegetable oils.
The western diet also provides an unnaturally large amount of high glycemic index food such as sugar, white flour and potatoes and this also causes activation of NF-kB (PMID: 18469238) . Much research has been done on the effects of high dietary fructose consumption, which appears to be more pro-inflammatory than other sugars (PMID: 15051594) (PMID: 19422101) (PMID: 19381015) .
A high salt diet may also be pro-inflammatory, particularly in those individuals who are ‘salt sensitive’. The best known IMD associated with high salt intake is hypertension, but the proposed mechanism of fluid retention seems dubious. Another IMD in which an association with high salt intake has been demonstrated is stomach cancer (PMID: 16984589) (PMID: 14972060) . More controversially, some research correlates high salt intake with type 2 diabetes (PMID: 15971060) (PMID: 18570670) , osteoporosis (PMID: 18410231) (PMID: 7554410) and asthma (PMID: 15353019) .
Red meat consumption is generally much higher in the developed world and is considered to be a risk factor for disease, although assessing the contribution of dietary red meat consumption to IMD pathogenesis is problematic. IMDs which have been linked to a high level of red meat consumption include cancer (PMID: 19569234) (PMID: 19457755) and type 2 diabetes (PMID: 19662376) (PMID: 15333470) . Saturated fat associated with red meat consumption is usually proposed as the cause of the adverse health effects and, while this may contribute, the main factor may be heme (PMID: 17045417) (PMID: 17192341) .
Food Intolerance and Chemical Sensitivity
Highly processed foods are pro-inflammatory for a number of reasons, including high fat, salt and sugar content. They may also contain chemical additives, such as nitrites, MSG and food dyes which can provoke an adverse reaction in some people which may be mediated by the immune system. These adverse reactions are often no more than a vague feeling of malaise, but can also be a specific symptom, such as migraine or depression. They may come on within an hour of eating, or they may take a day or more to appear. The delayed reactions are suggestive of a delayed hypersensitivity reaction, also known as type IV hypersensitivity reaction, which can occur one to three days after exposure. This can make it difficult to identify problem foods or chemicals. However, the fact that a delayed reaction may take a day or more to appear does not necessarily mean that it is a type IV hypersensitivity reaction. Similar adverse reactions can occur to the many chemicals we are exposed to in the environment. I experience a headache within a short time of opening a tin of gloss paint, but have no obvious bad reaction to emulsion.
One of the more intriguing aspects of food intolerance is that a person may have an adverse reaction to one form of a food, but not to another. Wheat and milk are both common problem foods, but people who react badly to milk may not do so to cheese. Wheat may provoke a mild adverse reaction in the form of bread, but a much stronger one as pastry and the more expensive French style breads are reputed to be worse than the cheaper breads. It is possible that protein folding plays a role in some cases, while AGEs may be the cause in others. Milk and cheese proteins have the same amino acid sequences, but are folded differently. In coeliac disease, the glycoprotein, gliadin, is attacked by antibodies and the ROS producing manganese enzyme, transglutaminase, is also attacked. Gliadin peptides bind more tightly to a genetic subtype of MHC class II antigen presenting receptor, known as HLA DQ, which activates T-cells and 95% of coeliac patients are known to have this subtype. It is possible that a similar mechanism may be operating in some cases of food intolerance.
Personal experience and anecdotal evidence suggests that the delayed reactions are the ones which are most likely to worsen existing IMD symptoms, although some foods, particularly highly processed ones, induce a mild feeling of 'malaise' within minutes, and I suspect that these also contribute. Eggs and chicken exacerbate my psychiatric symptoms, but only after a day or more has passed after eating them. The foods most likely to cause trouble are common foods which are eaten regularly, such as bread and milk. They are very often favourite foods and there seems to be an element of addiction. Chronicity and addiction are recurring themes in IMD research. There is much evidence for people being addicted to behaviours which would serve to perpetuate the pathologically activated NF-kB state. Perhaps the body becomes used to the altered biochemistry associated with perpetual NF-kB upregulation and feels the need to maintain it. The NF-kB driven immune response also seems to be activated more by chronic stimulation, rather than brief, acute stimulation. This chronic stimulation may be in the form of latent intracellular parasites, continual overeating, tobacco smoking, drug taking, adipocyte cytokines, worrying etc. Adverse reactions to foods or chemicals which are seldom encountered and which provoke novel symptoms, rather than exacerbating existing symptoms, may be due to different types of aberrant immune responses.
It is impossible to estimate the percentage of people who have an illness which is aggravated by food intolerance or chemical sensitivity. It may be a relatively small number and only a relatively small percentage of those will be aware that a food they eat almost every day, or a chemical they are exposed to frequently at work is contributing to their ill health. However, where such an association exists, stopping contact with the food or chemical is probably the single most important lifestyle change that can be made.
Psychological Stress
Chronic psychological stress is another important contributory factor in the pathogenesis of IMDs (PMID: 18040814) . It activates the NF-kB driven immune response (PMID: 12578963) (PMID: 15322889) and is associated with decreased NK cell activity (PMID: 17401058) (PMID: 9088048) . The onset of many IMDs can be traced to periods of chronic stress and this is particularly true of schizophrenia.
The immune system changes are probably caused by the stress hormones, adrenaline, noradrenaline and glucocorticoids. It is therefore rather counterintuitive that the drug used to treat inflammation in many IMDs is the synthetic glucocorticoid, cortisol. However, many IMDs are also exacerbated by cortisol, including psychiatric disorders, osteoporosis, hyperthyroidism, hypothyroidism, liver cirrhosis, diabetes, hypertension and myasthenia gravis. Glucocorticoid treatment inhibits NF-kB and this probably explains its anti-inflammatory effects in some conditions. But the opposite appears to occur in others (PMID: 16597735) .
Of the three stress hormones, only glucocorticoids are allowed to pass the blood-brain barrier, although the brain increases local production of noradrenaline in response to psychological stress (PMID: 20138850) . There are more glucocorticoid receptors in hippocampal neurons than in any other part of the brain and the fact that the hippocampus is the region of the brain where there is the clearest evidence for a physical disease process in schizophrenia, characterised by hippocampal atrophy, may not be coincidence (PMID: 15050580) (PMID: 16513870) (PMID: 17616347) (PMID: 12562515) . Glucocorticoids increase dopaminergic activity and thus may contribute to a receptor activated IMD, resulting in schizophrenia, via the dopamine D2 receptor (PMID: 21081135) (PMID: 21442976).
Gut Microbiota
The human gut is a microbial ecosystem, containing about 100 trillion microorganisms, with a collective genome comprising around 100 times more genes than the entire human genome. The normal relative abundances of the gut microbial species can become abnormal ('dysbiosis'), and this has been shown to be associated with many disease states. Mechanisms which have been proposed to account for this include bacterial metabolites of dietary components, and an innate immune response to structural components of bacteria, such as lipopolysaccharides, resulting in inflammation. It is also possible that dysbiosis might result in a systemic NF-kB activation, which is independent of the egress of microbial derived molecules from the gut.
Diseases which have been linked to abnormal gut microbiota populations in humans and animal studies include obesity (PMID: 19615307) (PMID: 22064556) type 1 diabetes (PMID: 23274889) type 2 diabetes (PMID: 21681087) Crohn's disease and ulcerative colitis (PMID: 23276768) cardiovascular disease (PMID: 23372728) Hashimoto's thyroiditis (PMID: 23200063) multiple sclerosis (PMID: 22031325) (PMID: 23293933) atopic dermatitis (PMID: 18284263) (PMID: 22955359) autism (PMID: 12173102) (PMID: 23106572) and psychiatric disorders (PMID: 22968513) (PMID: 23010679) (PMID: 21832903) (PMID: 21893487).
The 'Latitude Gradient'
The geographical incidence of IMDs varies with latitude, with increasingly higher incidences the farther one is from the equator. This is particularly noticeable in the northern hemisphere. The lower incidences seen in tropical regions, particularly of those IMDs known as ‘western diseases’, are probably due to several factors, including early immune challenge, greater exposure to sunlight, low body iron levels, a more physically active lifestyle and a diet which is not pro-inflammatory. It is also possible that a higher fluid intake in warmer climates may assist in flushing water soluble toxins from the body more quickly. In addition, western diseases are less likely to be diagnosed in developing countries, and lower life expectancy means that they have less time to develop.
Outwith the tropics, the ‘latitude gradient’ is still in evidence, particularly within Europe, although many anomalies exist. Perhaps the best known anomaly is the high incidence of autoimmune diseases such as multiple sclerosis and type 1 diabetes to be found in Sardinia, where rates are comparable to northern Europe. The Sardinian anomaly can be partly explained by ethnicity (PMID: 15471889) . Other ethnic differences between northern and southern populations in Europe, such as different CYP polymorphisms, may contribute (PMID: 10460072) (PMID: 17635181) , but environmental and lifestyle factors are probably more important.
Lower levels of ultraviolet light needed for vitamin D synthesis in northern Europe will contribute to the higher incidence of IMDs there, as will a more pro-inflammatory diet. In southern Europe, less red meat and saturated fat and more fish is eaten, and the diet is richer in antioxidants from olive oil, salad vegetables, fruit and red wine. Also, more pasta is eaten, which is converted to glucose more slowly than white bread or potatoes, resulting in reduced NF-kB activation (PMID: 18469238). Another possible contributory factor in some areas may be water hardness. Soils in northern Europe tend to be more peaty and acidic and can be deficient in magnesium and calcium. Magnesium deficiency is known to be pro-inflammatory (PMID: 17402291) and adequate levels of magnesium may be protective against cardiovascular disease (PMID: 16874137) (PMID: 9888277). It is often given as a supplement by alternative health practitioners for other conditions, including schizophrenia. There is also some evidence that the efficacy of vitamin D in the treatment of IMDs may be dependent on calcium (PMID: 11726533) . In areas with calcareous soils, the drinking water contains higher levels of these two elements.
'Hygiene hypothesis' factors may also contribute to the anomalies in the latitude gradient within Europe. There is a considerable disparity in the prevalence of autoimmune diseases and allergies between children living in eastern Finland and those living in neighbouring Karelia, a region in northern Russia. Here, ethnicity does not play a part, as both regions are ethnically similar. Studies have revealed a much higher incidence of autoimmunity and allergy in the Finnish children compared to Karelian children: type 1 diabetes (PMID: 15902849) , coeliac disease (PMID: 18382888) , thyroid disease (PMID: 18073310) , atopy (PMID: 16554659) and allergy (PMID: 17302731) . The Karelian children are exposed to much higher levels of bacteria than Finnish children, particularly in drinking water (PMID: 17298346) , but also in household dust (PMID: 18707614) . Other factors, such as diet and chemical exposure may also contribute.
Many parts of northern Europe are rich in metal ores, particularly northern Sweden, which has the largest iron ore mining operation in western Europe. The rocks have also been ground down by glaciers during ice ages, forming a very fine powder, called ‘loess’, which is very susceptible to wind erosion. Downwind deposits of loess can form soils tens of metres deep. The fine grain and acidic conditions combine to leach metals from the rock and loess and these metals may exert a variety of harmful effects, some of which may be mediated by ROS production and subsequent NF-kB activation, contributing to IMD pathogenesis. (PMID: 15892631) . However, there is also evidence for the involvement of non-redox metals, such as zinc, in disease pathogenesis.
Environmental Metals
Iron is the metal most frequently associated with IMDs and excess deposition of iron is seen in several diseases, such as atherosclerosis (PMID: 18619522) , cancer (PMID: 19018762) , type 2 diabetes (PMID: 18501198) , multiple sclerosis (PMID: 18408021) , Alzheimer’s disease (PMID: 18560134) , endometriosis (PMID: 18508952) and Parkinson’s disease (PMID: 18675357) . This deposition of iron may be a deliberate stratagem of the immune system to boost the inflammatory response, similar to an adjuvant in vaccines, rather than an unfortunate accident which just happens to exacerbate the disease process.
If environmental metals contribute to the pathogenesis of IMDs, one would expect to see evidence of this in the health records of workers exposed to metals in the workplace. However, most of the research on this subject appears to focus on the effects of inhaled metals on lung function and the development of lung cancer (PMID: 19746888) , although a link with heart disease has been suggested for industrial exposure to iron and manganese (PMID: 12412847) (PMID: 18613971) . Also, occupational exposure to manganese can cause some workers to develop ‘manganism’, or ‘manganese madness’ (PMID: 10382563) and neurological symptoms have been identified in people living close to manganese mines (PMID: 16793118) .
It seems unlikely that iron in its pro-inflammatory inorganic state in drinking water has the potential to contribute significantly to IMD pathogenesis. The gut produces a binding protein to make this unsafe form of the metal less harmful and uptake is refused when it is not required. Moreover, water treatment in Europe and North America removes most of the iron and manganese from drinking water. More than 0.3 mg/l of iron is unacceptable to consumers as it stains bathtubs and laundry, so drinking water in these regions contains much less than the natural background levels in streams and wells.
The most likely way that environmental iron enters the body and contributes to IMD pathogenesis is via the lungs, as dust. There is more metal in urban dust than in rural dust due to pollution from motor vehicles and industry. A study from Australia, analyzing the metal content of household dust in the Sydney metropolitan area revealed the following figures (mcg/g) cadmium 1.9, chromium 64.3, copper 103, iron 2740, manganese 54, nickel 15.6, lead 85.2, zinc 437. It is likely that the relatively high levels of airborne metals in the urban environment, particularly of iron, contributes to the higher incidence of IMDs in cities. Similarly, higher levels of airborne iron in northern latitudes due to the grinding down of iron bearing rock by glaciers and subsequent leaching of iron in acidic conditions, probably contributes to the higher incidence of IMDs in this region.
Multiple sclerosis (MS) is an example of an IMD which is much more common at high latitudes. In Europe, the highest incidences are to be found in Scotland and Scandinavia and the lowest incidences in the Mediterranean region, with the striking exception of Sardinia, which has an incidence comparable to northern Europe. There is also a very high incidence of MS in Canada where iron rich rocks have also been ground down by glaciers and where the soil is also acidic. While researching the epidemiology of MS on the Internet, I came across the following statement:
‘Certain localities, such as the Border area of Scotland (203 per 100,000), Crowsnest Pass in Alberta, Canada (217 per 100,000), the northernmost province of Sweden (253 per 100,000) and others have been found to have extremely high incidences of the disease’.
Further research did not confirm the claim regarding the Border area of Scotland, which appears to have a MS incidence similar to other areas of Scotland. The Orkney islands off the north coast of Scotland are believed to have the highest MS incidence in the world (PMID: 22577232). There appears to be an ethnic influence on the high Scottish incidence of MS (PMID: 9647300) . Also, the county of Varmland in southern Sweden lays claim to the highest incidence of MS in Sweden (PMID: 12065879) (PMID: 19805442) . However, research into the mineralogy of Alberta revealed:
‘The average Fe2O3 content of 60 randomly selected samples from 17 localities is 29% . . . the richest deposits are located north of Burmis, in the Crowsnest Pass.'
The 'Sardinian Anomaly'
There is still the Sardinian anomaly, which is only partly explained by ethnicity. The remaining contribution must come from either environmental factors or lifestyle factors, or a combination of both. I believe the answer lies in the environment. Unlike the adjacent Mediterranean land which surrounds it, Sardinia is rich in metals and has been mined for thousands of years There is no evidence of glaciation, but mining has created metal rich spoil heaps which have poisoned the land. From the Internet:
‘Mining is the oldest industrial activity in Sardinia. The island’s ore deposits have been historically exploited for their lead, zinc, iron, silver, barium, fluorite and antimony. Mining activity continued until the 1980s. Since then, it has suffered a serious crisis, culminating in the closure of most mines. Almost all the mine sites have been abandoned, along with their spoiled heaps, flotation tailing dumps and tailing impoundment.
It is estimated that a total of 14,300,000 cubic metres of material is deposited in abandoned mine dumps throughout the island (Aru, 1993). These dumps tend to be unstable and prone to accelerated wind erosion, resulting in heavy metals contamination of soils and water bodies in neighbouring areas (Aru et al., 1995, 1998a, 1998b).
For instance, in the plain located downslope the mine of Montevecchio (southwest Sardinia) tons of wastes eroded from the mine area have covered fertile soils vertisols previously used for agriculture. Actually, the heavy metals contained in the topsoil, and sometimes in the deeper soil horizon as well, precludes their continued use for agriculture’.
Summary:
Evidence suggests that most non-communicable disease is being caused by chronic, aberrant activation of the NF-kB driven immune response. The two principal mechanisms elucidated in this paper which are deemed responsible for the aberrant activation are the production of intracellular reactive oxygen species (ROS), particularly hydroxyl radicals, and abnormal chronic positive or negative activation of cell membrane receptors (receptor activation). Both of these processes occur as a consequence of NF-kB activation. However, whenever intracellular ROS production or hypo/hyper activation of membrane receptors occurs independently of NF-kB activation, this has the potential to cause aberrant activation of the NF-kB driven immune response when it becomes persistent. Because pathological activation of NF-kB occurs as a result of processes which mimic its own actions, I have called the disease process which results from this ‘Immune Mimicry Disease’ (IMD).
One of the principal functions of NF-kB is to control the infection of cells by pathogens which establish intracellular latency. To do this, destructive ROS are produced inside cells and the receptors which these pathogens use to gain entry into cells have their numbers on the cell membrane reduced, are desensitised or are blocked by antibodies. The cells become hypofunctional and this deficit represents an early stage in the disease process. For example, the early symptom of impaired short term memory in Alzheimer’s disease is correlated with reduced numbers of both noradrenaline and acetylcholine receptors, which are involved in learning. Although the action of NF-kB is essentially antiapoptic, cell death will occur when it is chronically activated and the cerebral atrophy of long term Alzheimer’s disease is evidence of this.
In some IMDs, the immune system has evolved mechanisms to compensate for the hypofunctional cells by making other cells hyperfunctional and it is this compensation mechanism which becomes pathologically activated. Examples of this are Graves’ disease, the positive syndrome of schizophrenia, ADHD and mania.
The principal source of the intracellular ROS which causes aberrant NF-kB activation is probably metalloenzymes, in particular, the cytochrome P450 superfamily, which uses iron in heme as a co-factor. Enzyme polymorphisms are particularly implicated in IMD pathogenesis and it is assumed that this is because they produce more ROS, although evidence for this is lacking. Excessive ROS production in mitochondria, the endoplasmic reticulum and at the nuclear membrane appears to activate NF-kB most strongly.
Membrane receptor polymorphisms and polymorphisms of the transporter molecules which remove ligands from receptors are also strongly implicated in IMD pathogenesis. A plausible explanation for this is that some receptor variants are more liable to activate NF-kB by being more (or less) sensitive and some transporter variants may induce receptor activation by being less (or more) efficient.
A large and important IMD sub-group are those diseases in which the receptor for advanced glycation end-products (RAGE) plays a role in the inflammatory process. The ligands which activate the RAGE appear to be cleaved from endogenous glycoprotein, and possibly glycolipd, substrates, such as the extracellular matrix, amyloid beta, myelin and amyloid by matrix metalloproteinase enzymes (MMPs) and angiotensin converting enzyme (ACE). Polymorphisms of these enzymes are also associated with a higher incidence of RAGE stimulated IMDs.
Environmental and lifestyle factors which contribute to IMD pathogenesis include pathogens which establish intracellular latency, lack of immune challenge in infancy, lack of vitamin D, chemical pollutants, food and chemical intolerance/sensitivity, environmental metals, pro-inflammatory diet, lack of physical exercise, psychological stress and abnormal gut microbiota.
Schizophrenia
As with other IMDs, the incidence of schizophrenia increases with latitude (PMID: 16774659) (PMID: 18042349) (PMID: 19357239) and the highest incidence area in the world is believed to be in northern Sweden (PMID: 7151313) . It is more common in cities than in rural areas (PMID: 1352565) (PMID: 16150958) (PMID: 9723142) (PMID: 15056572) (PMID: 10858630) and the main reason for this is probably airborne chemical pollutants which bind to the AHR and are metabolised by CYP enzymes at the nuclear membrane, releasing hydroxyl radicals which activate NF-kB. Another reason which has been proposed for the higher incidence of the disease in cities is ‘social drift’. People with incipient schizophrenia may begin to feel stressed by social interaction in their local community. They may feel oppressed by the sense of disapproval from family and friends about their lifestyle, lack of drive, social incompetence, reclusiveness etc and may begin to perceive the anonymity of a city existence as a way to escape from this.
A small, but significant excess of births in late winter and early spring among schizophrenics has been found which is more pronounced in the northern hemisphere (PMID: 14687876) (PMID: 16594951) (PMID: 14609251) than in the southern hemisphere (PMID: 8811264) (PMID: 10093868) . There is evidence that this might be a stronger effect in cities (PMID: 9428062).
The reported incidence of IMDs in a specific area may vary over time. In the early 80s, I read an old book in the main Glasgow library, in which it was claimed that there was a high incidence of schizophrenia in Iceland. This may have been true when the book was written, but there appears to be little evidence for it today, so I have to conclude that it is no longer the case.
The west of Ireland and Croatia are other areas which have been reported in the past to have high incidences of schizophrenia and bipolar disorder, but a search of PubMed fails to confirm that this is the case today. The psychiatrist, E. Fuller Torrey, describes his visits to Croatia and western Ireland to try to find clues for the reason for these high incidences in his book ‘Surviving Schizophrenia: A Family Manual’. He co-authored a paper in 1984, confirming a high incidence of schizophrenia, schizoaffective disorder and bipolar disorder in western Ireland (PMID: 6465372 . It is interesting that it states ‘in people over 40’ in the abstract. However, there does appear to be large variations in schizophrenia prevalence in Ireland (PMID: 1996920) which could be due to a combination of factors, including continued hospitalisation after remission (PMID: 2239357) and methods of case collection (PMID: 2399478) , as well as genuine genetic and environmental factors.
In Croatia, the high incidence areas were on the coast and offshore islands, which was suggestive of some contamination originating in the sea as an environmental cause. Similarly, in Ireland, the high incidence areas were on the west coast, particularly where the people were poorest. Coeliac disease is another IMD which has been reported to be more common in western Ireland. Although a small country, the population of Ireland is not as genetically well mixed as one might expect. The western population is more ‘Celtic’ and Gaelic is still spoken in a few places as the first language. A high frequency of the HLA subtype, HLA-DR17, is seen. The same HLA subtype is also much more common in northern Spain and, significantly, in Sardinia. A further subtype of HLA-DR17 is known to be associated with coeliac disease. It seems plausible that an environmental factor formerly existed in western Ireland which, probably in conjunction with genetic predisposition, gave rise to a high incidence of psychiatric illness and coeliac disease. If it still existed, I believe it would be far more obvious than it is and research would confirm it in the same way that research confirms a high rate of autoimmunity in Sardinia and in Finland compared to neighbouring Karelia.
A possible explanation for an environmental influence which existed in the past, but has now all but disappeared, is consumption of the seaweed, carrageen, also known as ‘Irish moss’, which was also eaten in Iceland. Carrageen is considered safe to eat and is used as a thickener and stabiliser in foods such as ice cream and tinned soup. Tests on human volunteers have shown no ill effects. However, it is known to cause inflammation and ulcerative lesions in the gut of some laboratory animals (PMID: 976489) (PMID: 6468767) (PMID: 6673066) (PMID: 1356411) and in some species, this effect is only seen when the bacterium, Bacteroides vulgatus, is present in the gut (PMID: 3384476) (PMID: 6642651) . This bacterium is also much more common in the gastrointestinal tract of Crohn’s disease sufferers (PMID: 18401439) (PMID: 18289202) . Carrageen derived molecules are known to cause extraintestinal inflammation by binding to the toll-like receptor, TLR4 (PMID: 22011715) . The normal function of TLRs is to bind microbial molecules and induce immune system upregulation, including NF-kB activation, when they are detected. The endogenous RAGE ligand, HMGB-1, can also activate TLR4, which raises the question of whether dietary AGEs may do likewise.
Adverse reactions to foods, probably as a result of an aberrantly activated immune system, usually occur with foods that are eaten frequently, but can take years to develop and the initiation of intolerance often coincides with periods of infection or chronic psychological stress. Genetic predisposition is probably essential. It is therefore no surprise that brief trials in which large amounts of carrageen are fed to healthy volunteers show no adverse health effects. Carrageen was trasported inland by horse and cart, but it is reasonable to assume that consumption was highest in coastal areas and that the poorest people ate more of it than the wealthier classes. Coeliac disease is an aberrant immune reaction to gliadin in wheat and some other cereals. If NF-kB driven inflammation is activated in the gut by some other factor, such as food intolerance or bacteria, it seems likely that this would make the development of coeliac disease more likely to occur in genetically predisposed individuals. The same would be true for other intestinal IMDs and, perhaps to a lesser extent, extraintestinal IMDs.
Another environmental influence which formerly existed in western Ireland and had the potential to contribute to the development of IMDs was the burning of seaweed to produce ‘kelp’. There was also a kelp industry in Iceland. The kelp was sold to merchants who sold it in Britain, where it was used as a source of soda, potash and iodine (see Internet: ‘Kelp Burning in the Glens’ by Douglas Harper). The marine environment is chemically distinct from the terrestrial environment and this is reflected in the biochemistry of some of the species which inhabit it. An example of this is the abundance of halogens, particularly chlorine. Chlorine, bromine and iodine are much more concentrated in seaweed than in land plants. There is also much more arsenic and vanadium. Both bromine (PMID: 3822020) and vanadium (PMID: 6443582) are known to cause psychosis and arsenic is a very potent instigator of NF-kB driven disease (PMID: 11956123) (PMID: 2589305) (PMID: 10444040) . Arsenic and vanadium can both substitute for phosphorous in biomolecules.
Most of the research into soil contamination near kelp kilns has focused on arsenic pollution, for which there is much evidence (PMID: 16620906) . However, a great variety of noxious chemicals would have been produced, possibly including dioxins, because of the high chlorine content of the seaweed. It has been noted that the kelp burners often suffered ill health, although the only specific condition I have seen mentioned is arthritis. The poor health has been attributed to the very hard work, but it seems more plausible that the cocktail of inhaled chemicals was to blame, by causing systemic upregulation of NF-kB, thus making the development of specific IMDs more likely to occur. The burning of coastal peat with a high chlorine content might also have produced dioxins.
Kelp burning seems to have peaked in the early nineteenth century and it continued until around the time of the second world war. Another industry which was common on the west coast of Ireland was the production of quicklime (calcium oxide) from the burning of chalk in limekilns. As well as being used to make cement, it was spread on the acidic peaty soil to raise the ph and make it more fertile. It would have contained metal oxides and might therefore have contributed to a pro-inflammatory environment.
Examples of infectious organisms which have been found to be associated with schizophrenia are human endogenous retroviruses (PMID: 10719148) , borrelia (PMID: 7943444) , mycobacteria (PMID: 3260975) , toxoplasma gondii (PMID: 17435677) , borna virus (PMID: 10473520) , cytomegalovirus (PMID: 16166610) , and toxocara (roundworms) (PMID: 18452258) . Except for toxocara, all of these pathogens are obligate intracellular pathogens which establish latency. An extensive collection of PubMed abstracts on the subject of autoimmunity and infection in schizophrenia can be seen at www.neurotransmitter.net. Another useful source of information on the subject on the Internet is ‘The Role of Infection in Mental Illness’ by Frank Strick.
Much of the research to be found in ‘Autoimmunity and Infection in Schizophrenia’ focuses on the correlation between prenatal exposure to influenza and the development of schizophrenia in the offspring in later life. The influenza virus is not typical of IMD stimulating infectious organisms as it is not known to be a pathogen which establishes intracellular latency. However, if a small percentage of influenza viruses were capable of establishing latency, with the potential for reactivation (perhaps by cold air, as happens with HSV-1), this could explain much that is mysterious about influenza outbreaks. The influenza research is controversial, with much of it failing to confirm an association. However, studies do reveal a clear association between prenatal exposure to the 1957 Asian flu pandemic and later development of schizophrenia (PMID: 8252293) (PMID: 3337616) (PMID: 10394481) (PMID: 1674062) (PMID: 8372158) .
There were three pandemic flu outbreaks during the 20th century, 1918 Spanish flu, 1957 Asian flu and 1968 Hong Kong flu. Spanish flu was by far the deadliest and may have been closer to an avian flu (PMID: 17526158) than the 1957 and 1968 flus, which were avian/human hybrids (PMID: 19809504) . Death from Spanish flu occurred as a result of a massive overreaction of the immune system of the same kind as that seen when humans are infected with the current H5N1 bird flu. This overreaction is driven by NF-kB and is much stronger when the infection is an avian flu than with a human flu (PMID: 19786538) (PMID: 16765340) . Many of those who succumbed to Spanish flu may have had a genetic predisposition to pathological NF-kB activation and it seems that symptoms of flu with avian characteristics can be particularly severe in those people with underlying health problems driven by aberrant NF-kB activation. The NF-kB driven immune response is also activated in pregnancy (PMID: 19282364) and in obese individuals (PMID: 19633416) and these groups have also been shown to be at greater risk in the current A(H1N1) ’swine flu’ pandemic. The connection between maternal infection with influenza during pregnancy and later development of schizophrenia in the offspring may be causal or it may be due to an inherited immune system defect which predisposes to both infection by influenza and development of schizophrenia.
Abnormalities in several neurotransmitter systems have been identified in schizophrenia, including glutamate (PMID: 18534564) , noradrenaline (PMID: 15363614) , GABA (PMID: 19073429) and acetylcholine (PMID: 18317461) . However, the strongest evidence is for abnormal functioning in the dopamine and serotonin systems and it is possible that other neurotransmitters may contribute via cross-talk with dopamine and serotonin. Receptors for most of these neurotransmitters are known to be used by intracellular pathogens which establish latency and they may all be identified as such eventually. The NF-kB driven immune response may have a ‘usual suspects’ approach and close down whatever receptors are known to be used by pathogens to gain entry into cells when it becomes activated.
The ‘dopamine hypothesis’ of schizophrenia proposes that the positive symptoms of schizophrenia are caused by excessive dopaminergic functioning. A variety of observations support this view. The binding affinity of the antipsychotic phenothiazine drugs for dopamine D2 receptors is seen to be inversely proportional to their therapeutic dose. When the dopamine precursor, levodopa, is given to patients to treat Parkinson’s disease, it can cause schizophrenia-like symptoms. Levodopa is converted to dopamine in the brain. The amino acid precursor of levodopa, tyrosine, can also worsen symptoms of schizophrenia when given as a supplement. Drugs which increase the firing rate of dopaminergic neurons by acting as antagonists at the glutamate NMDA receptor, such as amphetamine, cocaine, ketamine and PCP, can also induce schizophrenic symptoms in previously unaffected people when used heavily on a regular basis and very small amounts of these drugs will worsen symptoms in schizophrenic patients.
The IMD hypothesis of schizophrenia would suggest that NF-kB activation in the brain causes underactive dopaminergic and serotonergic firing of some neurons, while in other neurons, there is compensatory hyperactivity of dopaminergic and serotonergic firing and, when this becomes excessive, it results in the positive symptoms of the disease. The immune system in the brain has evolved the mechanism of creating an endogenous NMDA receptor antagonist, kynurenic acid, to maintain compensatory dopaminergic transmission (PMID: 16897051) (PMID: 17573079) (PMID: 19173370). Increased firing of dopamine D2 receptors is achieved by reducing the transport of dopamine from the receptor, so that the increase in D2 receptor numbers is less than it would be with normal transporter activity. This, along with the prolonged occupancy of the receptors by dopamine, helps to limit possible infection via the D2 receptor. A meta-analysis shows a ‘significant, but mild’ increase in dopamine D2 receptor density in drug naïve or drug free patients compared to healthy controls (PMID: 9796369), and evidence that the D2 receptor may be used by pathogens to enter cells is seen when the NMDA antagonist, methamphetamine, enhances the infectivity of HIV-1 via the dopamine D2 receptor (PMID: 18958626). Along with the increased firing rate of D2 receptors, there is reduced expression of D1 and D5 receptors in the prefrontal cortex and of the serotonin 5-HT2A receptor, which is known to be used as an entry point by viruses. These reductions in receptor numbers may account for the negative symptoms, including cognitive impairment.
The dopamine and serotonin systems are tightly interdependent and there is much evidence for the involvement of serotonin in schizophrenia. Supplemental tryptophan, the amino acid from which serotonin is made, can exacerbate schizophrenic symptoms and selective serotonin reuptake inhibitors (SSRIs) may cause psychosis (PMID: 11235925) . The first, and rate limiting enzyme, in the conversion of tyrosine to dopamine, is tyrosine hydroxylase and the first, and rate limiting enzyme in the conversion of tryptophan to serotonin is tryptophan hydroxylase. Both enzymes use iron and tetrahydrobiopterin as co-factors. In both pathways, the enzyme, aromatic amino acid decarboxylase, completes the conversion to dopamine and serotonin. Some studies have suggested an association of both tyrosine hydroxylase and tryptophan hydroxylase with schizophrenia, but a meta-analysis has shown only the tryptophan hydroxylase gene to be involved (PMID: 16741719) .
Both dopamine and serotonin have specific transport molecules which remove them from their receptors and transport them to storage vescicles. Dopamine can also be transported by the noradrenaline transporter. There appears to be no evidence for a genetic polymorphism of the dopamine transporter, but strong evidence (p = 0.00014) for an association between a serotonin transporter polymorphism and schizophrenia (PMID: 15940296) . With regard to receptors, genetic polymorphisms have been confirmed for both the dopamine D2 receptor (PMID: 14593428) and the serotonin 5-HT2A receptor (PMID: 14741324) (PMID: 17240119) . The older antipsychotic drugs bind to the D2 receptor, while the newer ‘atypical’ antipsychotics have only a weak affinity for the D2 receptor, but a much stronger affinity for the 5-HT2A receptor. It appears that abnormalities in the serotonin system have a major etiological influence in the pathogenesis of schizophrenia and the involvement of transporter and receptor abnormalities are suggestive of a receptor activated IMD. It is conceivable that the pathogenesis of an IMD could occur mainly through one neurotransmitter system, but the symptoms be manifested more strongly via a different system, particularly when the neurotransmitter systems are as closely intertwined as dopamine and serotonin.
Although IMDs will generally fall into one or other of the categories of receptor activation or activation by intracellular ROS production, in reality it seems likely that most IMDs are initiated by a combination of both, with one category usually playing a major role and the other a minor one. The pathogenesis of schizophrenia appears to be mainly receptor activated, but there is also a contribution from intracellular processes. For example, the association with a high fat diet may indicate some input from ER stress (but could also indicate increased AHR activation by fat soluble chemical pollutants), and the association with urban living and a polymorphism in the CYP2D6 enzyme (PMID: 17325735) suggests an input from hydroxyl radical production at the nuclear membrane. Also, the kynurenic acid which is created to maintain dopaminergic homoeostasis by acting as an antagonist at the glutamate NMDA receptor, is also capable of acting as an agonist at the AHR (PMID: 20106948).
The enzymes involved in dopamine and serotonin synthesis and catabolism utilise iron and generate ROS, and tyrosine hydroxylase, tryptophan hydroxylase and aromatic amino acid decarboxylase have all been identified as autoantigens in other diseases, such as autoimmune polyglandular syndrome (PMID: 19107747) . One of the catabolising enzymes, monoamine oxidase (MAO), localises to the mitochondria and is well known as a hydroxyl radical producer (PMID: 15082228) . MAO inhibitor drugs have an anti-inflammatory effect in rheumatoid arthritis, Crohn’s disease and tuberculosis. The other catabolising enzyme, catechol-O-methyl transferase (COMT), has a known polymorphism in which valine is substituted by methionine. This results in dopamine being catabolised four times more quickly, leading to a reduction in synaptic dopamine, an effect which is weakly associated with an increased predisposition to psychosis (PMID: 18092319) (PMID: 15866551) (PMID: 12611827) .
Although tryptophan hydroxylase uses iron and a polymorphism of the enzyme is associated with schizophrenia, it seems unlikely that ROS production by this enzyme contributes directly to NF-kB activation in the neurons which are dysregulated in schizophrenia. Serotonin synthesis takes place in the neurons of the raphe nuclei and from there it is transported to serotonergic neurons. Therefore, the contribution of a tryptophan hydroxylase polymorphism found only in the raphe nuclei to the pathogenesis of schizophrenia could be overproduction or underproduction of serotonin, which might contribute via receptor activation. Although serotonin receptor agonists have not been found to worsen the positive symptoms of schizophrenia, the hallucinogen, LSD, exerts its effects through the 5-HT2A receptor, and this can result in LSD psychosis (PMID: 8775754) (PMID: 1193515) (PMID: 6870484). There appears to be no evidence for immune mediated damage in the raphe nuclei in schizophrenia, but there is evidence for this in major depression (PMID: 19756820) (PMID: 7578661) .
The peak age of onset of schizophrenia in men is between the age of 20 and 25, while in females, it is between the age of 25 and 30. Women also tend to have milder symptoms. Surprisingly, the difference appears to be due to estrogen. Tests conducted on female patients have shown that those with the mildest symptoms also have the highest estrogen levels and exacerbations of symptoms among female patients have been correlated with the point in the menstrual cycle when estrogen levels are lowest. There is also a smaller peak of age of onset among women around 45 - 50 years of age, which corresponds to the period after the menopause when estrogen production declines (PMID: 19220172) . So, despite the fact that estrogen synthesis, conversion and catabolism may be a contributory factor in many IMDs, the hormone appears to be neuroprotective in schizophrenia. However, it is not protective in all cerebral IMDs, as women are more susceptible to multiple sclerosis, eating disorders and Alzheimer’s disease.
The reason for the age of onset of schizophrenia in young adulthood may be the greatly increased activity of the dopamine system which begins in adolescence (PMID: 18322084) (PMID: 14535941) . This increase in dopamine receptor firing simulates the compensation mechanism and will bring genetically predisposed individuals closer to the ‘tipping point’ where the schizophrenia disease process begins. Factors which could then combine to provoke pathogenesis include psychological stress, infection, smoking, drinking alcohol, drug taking etc. Even caffeine consumption could play a role as caffeine stimulates dopamine release via cross-talk, by acting as an antagonist of adenosine receptors (PMID: 20182056) (PMID: 18823369) (PMID: 20164571).
However, the main factor responsible for the activation of schizophrenia after the increase in dopaminergic functioning may be sexual arousal. Dopamine plays a key role in sexual arousal, particularly at the D2 receptor (PMID: 7770195) and it appears to work in concert with oxytocin (PMID: 18655889) and prolactin (PMID: 15889301) . In the pre-neuroleptic era, when there were many schizophrenics in asylums, patients of both sexes were seen to masturbate compulsively (PMID: 2657831) . This led to a belief that masturbation caused madness, a belief that has since been ridiculed and dismissed as an example of Victorian puritanism. However, there is not a great deal of difference between compulsive masturbation and addiction to drugs, such as those which act as NMDA receptor antagonists. Both addictions increase dopaminergic functioning and this may make an important contribution to the initiation of schizophrenia via receptor activation. Masturbation may not cause madness in normal individuals, but in those genetically predisposed to schizophrenia, it may make a significant contribution.
Oxytocin is another neurotransmitter which seems to be involved in psychiatric illness (PMID: 18336283) . There is cross-talk betwen oxytocin and dopamine which boosts dopaminergic transmission (PMID: 21050872) (PMID: 20557568). Along with GABA, it may contribute to the pathogenesis of autism (PMID: 18655901) (PMID: 17890818) (PMID: 12587149) . Oxytocin is believed to be important in maternal bonding to the newborn infant and might therefore play a role in postpartum psychosis. It is also involved in adult pair bonding and it has long been recognised that an association exists between romantic love and madness. The word, ‘lovesick’ comes to mind. Oxytocin is catabolised by the zinc dependent enzyme, neprilysin, which also acts on many other substrates, including insulin and Abeta. Neprilysin has been identified as an autoantigen in acute lymphoblastic leukemia (PMID: 19827739) and it is conceivable, though speculative, that reduced expression, or an inefficient polymorphism of the enzyme might result in an excess of oxytocin, leading to receptor activation of psychiatric illness.
There is therefore much evidence for the involvement of neurotransmitters other than dopamine in the pathogenesis of schizophrenia, and much of this may be due to receptor cross-talk in which stimulation or inhibition of other neurotransmitter systems may positively impact dopaminergic transmission. However, the evidence appears to support the theory of a dysregulated compensatory mechanism giving rise to the positive symptoms only in the case of dopamine. The density of the serotonin 5-HT2A receptors, for example, is seen to be reduced (PMID: 10867310) (PMID: 8885041) (PMID: 12641722) and this may be at least partly responsible for negative symptoms.
Schizophrenia is not only an illness caused by abnormal brain chemistry, but can probably also be considered to be a chemical addiction. For example, kynurenic acid acts as an antagonist at the NMDA receptor, as do amphetamine and cocaine, and sufferers will act in ways that satisfy this addiction to their own abnormal brain chemistry. These activities include masturbation, smoking heavily, drug taking, alcohol abuse and compulsive rumination (daydreaming). Dopamine is probably the most important chemical induced by these activities, but others, such as serotonin and oxytocin, may also contribute. Merely thinking about sex probably stimulates schizophrenia and the compulsive rumination, or morbid introspection, that schizophrenics indulge in, can probably be seen as both a symptom and a cause of the disease. Often, this rumination will dwell morbidly on painful memories which cause psychological stress, thus exacerbating schizophrenic symptoms. It would be unfortunate if this were to be interpreted as meaning that schizophrenics ‘do it to themselves’. Schizophrenia cannot be turned off by desisting from masturbation, smoking and daydreaming, but the symptoms would probably improve if these habits ceased for a prolonged period.
Multiple Sclerosis
The epidemiology of multiple sclerosis (MS) is particularly strongly influenced by ethnicity (PMID: 15648284) (PMID: 16606919) (PMID: 16374035) . It is more common in females (PMID: 19797452) and in higher latitudes (PMID: 19667017) (PMID: 8327018) and is associated with infection (PMID: 18208871) (PMID: 18566025) (PMID: 18947921) (PMID: 18208884) . Some studies also suggest that it is more common in cities (PMID: 3577681) (PMID: 3878969) (PMID: 18433841) , although in the high incidence anomaly of Sardinia, the incidence is higher in rural areas than in urban areas, perhaps because the gene pool in rural Sardinia is less influenced by recent immigration to the island (PMID: 14567554) . People living in rural Sardinia may also be more exposed to metal pollution from mining. MS has also been associated with exposure to environmental metals (PMID: 11777019) (PMID: 3658175) and chemical pollution (PMID: 17172228) (PMID: 12938645) . There is also some evidence that gut microbiota may play a role in MS disease pathogenesis (PMID: 20660719) (PMID: 22031325).
MS results from a lack of myelin, which sheaths nerve tissue in the brain and facilitates the transmission of electrical signalling. It is 80% lipid, principally galactocerebroside, and the remaining 20% is made up of protein. The principal protein constituents are myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG) and myelin associated glycoprotein (MAG). T-cells and macrophages reactive to myelin are seen in some, but not all MS patients, so the development of the disease is not dependent on a deleterious action of autoreactive immune cells. When they are present, most of the autoreactivity appears to be directed towards MOG (PMID: 9394837) .
MS is a RAGE IMD and low levels of circulating soluble RAGE are seen (PMID: 18505774) . Expression of several of the MMP enzyme family is upregulated in MS and it is believed that they facilitate entry of peripheral immune system cells into the brain by degrading the extracellular matrix of the blood-brain barrier (PMID: 15735992) (PMID: 10534241) (PMID: 17083473) . MMPs are secreted by microglia and also by cells of the immune system which enter the brain from the periphery. However, since these immune system cells are not active in all patients, the importance of ECM degradation by MMPs may have been overstated. It is likely that the principal function of the MMPs is to cleave RAGE agonists from the myelin and, although T-cells and macrophages may contribute some of the MMPs in some patients, MMP secretion from microglia may be more important. ACE levels are also higher in MS and EAE, the animal model of the disease, and this enzyme is also secreted by both microglia and cells of the immune system (PMID: 10863022) (PMID: 19136547) (PMID: 8576541) (PMID: 9267976) . However, the evidence suggests that the course of MS is more strongly influenced by MMP enzymes.
Myelin is produced by oligodendrocytes and the normal role of these enzymes is probably to contribute to the NF-kB driven immune response when oligodendrocytes are infected by pathogens which establish latency. There is abnormal serotonergic hypofunction in MS and EAE and the course of the disease may be improved by serotonergic drugs (PMID: 19014375) (PMID: 7184959) (PMID: 10681122) (PMID: 16178854) . This is consistent with the known comorbidity of MS and depression (PMID: 19722046) . It is also consistent with IMD theory as the serotonin 5-HT2A receptor is a known entry point for the JC virus, which has been shown to infect oligodendrocytes (PMID: 18579595) . This virus is also a known cause of progressive multifocal leukoencephalopathy, which is a demyelinating disease very similar to MS in which oligodendrocytes are destroyed (PMID: 15550673) . However, there appears to be little evidence that the JC virus contributes significantly to MS pathogenesis (PMID: 17548437) (PMID: 17177306) .
Although depression is the most common psychiatric manifestation in MS, other symptoms, including elation/euphoria, are also seen (PMID: 2594885) (PMID: 9482369) (PMID: 16212684) (PMID: 17531848). MS patients can fluctuate from regression to remission in the same way that bipolar patients may swing from depression to mania or Graves' patients from hypothyroidism to hyperthyroidism. This is evidence of a compensation mechanism at work in MS, but it does not appear to become dysregulated or, if it does, the excessive myelination which presumably results from this does not result in a disease state. The co-morbid states of mania and depression in MS may indicate that drugs used to treat bipolar disorder, such as lithium, could also have a role in the treatment of MS (PMID: 18566399).
The evidence suggests that myelin production by oligodendrocytes is dependent on activation of the 5-HT2A receptor by serotonin, and that when NF-kB is activated within oligodendrocytes, production is reduced as a result of the reduced expression of 5-HT2A receptors. The compensation mechanism may possibly operate via reduced expression of a neurite outgrowth factor, Nogo-A, or its receptor, NgR. Expression of both Nogo-A and the NgR is increased in MS, causing suppression of myelination (PMID: 15184901) (PMID: 15751227).
Oligodendrocyte death is also seen in MS (PMID: 16996738) (PMID: 16847778) and it is likely that many more of these myelin producing cells are hypofunctional. The evidence therefore points towards myelin deficit occurring as a result of a ‘double whammy’ of reduced myelin synthesis within oligodendrocytes and degradation of existing myelin by MMP and ACE enzymes secreted by microglia and cells of the immune system to create RAGE agonists.
MS pathogenesis may be a result of intracellular ROS produced in the synthesis of myelin. Oligodendrocytes are very rich in iron as it is required as a co-factor by the enzymes which synthesise myelin (PMID: 18837051) and there is evidence for both ER stress (PMID: 18344911) (PMID: 19287390) and mitochondrial stress (PMID: 17981781) (PMID: 16635434) (PMID: 19076696) in the disease. There is evidence that when lipid metabolism is implicated in IMD pathogenesis, dietary fat intake is a risk factor. One meta-analysis describes the evidence for dietary fat as a risk factor in MS only as ‘fair’ (PMID: 14739563) . However, there is some evidence that fat intake needs to be extremely low for a protective effect to be seen (PMID: 1804476) . Japanese people have a low susceptibility to MS (PMID: 12962015) , but the prevalence of the disease among Japanese Americans is much higher, although still much lower than in Caucasian Americans, indicating that both genetic and environmental/lifestyle factors contribute to the pathogenesis of the disease (PMID: 848479) . Research also indicates that Japanese Americans are more prone to cardiovascular disease and type 2 diabetes than native Japanese subjects and that this is associated with higher blood lipid levels (PMID: 15589065) .
RAGE IMDs appear to have a particularly strong association with environmental iron, and iron deposition in tissues. MS research reveals iron dysregulation in the pathogenesis of the disease (PMID: 18408021) , increased iron turnover (PMID: 15957506) , elevated urinary excretion of iron and aluminium (PMID: 17086897) and cytokine toxicity to oligodendrocytes mediated by iron (PMID: 15968631) . Perhaps the most significant evidence implicating iron in the pathogenesis of MS is to be found in EAE studies. EAE mice given an iron chelator were seen to have significantly less disease activity (PMID: 17967839) . In another study, EAE mice were divided into three groups, one group being given a very low iron diet, another normal iron and a third, high iron. None of the very low iron group developed the EAE, while 71% of the normal group and 62% of the high group developed the disease (PMID: 12888650) .
The incidence of MS is very low in tropical countries and it is likely that many genetic, environmental and lifestyle factors contribute to this. The EAE research suggests that one possible contributory factor for the low incidence is the fact that low blood iron levels are common in many parts of the tropics due to malnutrition and the fact that many tropical disease pathogens, such as the malarial parasite and intestinal worms, utilise the iron of their hosts, causing depletion. There is also a view that people living in the tropics who are borderline anaemic may have a survival advantage due to the fact that they are poorer hosts for these parasites. If the hypothesis is correct, tropical anaemia may not only be due to malnutrition and parasitic load, but also to a genetic predisposition to low iron levels, which is passed on. However the low iron levels come about, they may be protective against autoimmune diseases in general, and MS in particular, as well as ‘western diseases’. The replication of T. gondii, which is one of the latent pathogens which activate NF-kB, has been shown to be dependent on the availability of iron (PMID: 9767436) and the same may be true for other latent pathogens.
Another metal which has been associated with MS is zinc. There are many examples of unexplained MS ‘clusters’ of cases. Some of these may be due to genetic factors, while others could be caused by infectious organisms, such as Epstein-Barr virus, which can be passed on by kissing (PMID: 19664371) (PMID: 19359987) (PMID: 16400268) . However, a common factor in some of these clusters is contamination of the soil by zinc and other metals from local zinc smelters (PMID: 11777019) (PMID: 3658175) . Comparison of high and low MS prevalence counties in Finland revealed high levels of iron, zinc, chromium and aluminium and a lower soil ph in the high MS prevalence county compared with the low prevalence county (PMID: 3823857) .
The high prevalence of MS in high latitude regions of the northern hemisphere is probably due to many factors, including ethnicity, low vitamin D levels, a high fat diet and, lack of immune challenge in infancy and an environment with high levels of ambient iron and other metals due to the grinding action of ice age glaciers on iron bearing rock and subsequent leaching of metals from loess by acidic rain water. Environmental iron is proposed to be of importance in the pathogenesis of many IMDs , but may be particularly important in MS due to the involvement of iron in the synthesis of myelin within oligodendrocytes.
Cardiovascular Disease
‘Cardiovascular disease’ (CVD) can be any disease affecting the heart and circulatory system, but the term is usually used to refer to atherosclerosis, which is the formation of plaque within arteries. The plaque causes the arteries to become narrower and to lose elasticity. It is composed of ‘foam cells’, which are dead macrophages, suggestive of immune system involvement. CVD is associated with inflammation and is caused by the same environmental and lifestyle factors which contribute to the pathogenesis of other IMDs. However, it is atypical because of the number of people it affects. Globally, 30% of people die of CVD and many more die with the disease, if not of it. In developed countries, the figures are higher still.
Obesity, fat consumption, particularly of saturated fats, lack of physical exercise and smoking are perhaps the best established risk factors for CVD. The importance of fat consumption suggests that ER stress (PMID: 19913545) (PMID: 19485711) and mitochondrial stress (PMID: 11854126) (PMID: 12147534) may be involved in the pathogenesis of the disease. Increased fat consumption would also cause increased AHR activation due to the accumulation in fats of environmental chemicals which are metabolised at the AHR.
In Europe, there is the usual north/south divide, with deaths from CVD in northern European countries roughly double the rate of southern Europe. Differences in diet are usually proposed for the disparity, but vitamin D probably plays a role too, (PMID: 17563024) (PMID: 19211206) and higher ambient iron levels in northern Europe may also contribute to the inflammatory process. Significant amounts of iron are found in arterial plaque (PMID: 18619522) and workers exposed to airborne iron have a higher incidence of CVD (PMID: 12412847) (PMID: 18613971) . Many chemical elements are capable of stimulating the inflammatory process responsible for CVD and other IMDs. The importance of iron may lie in the fact that it is so abundant and ubiquitous. Also, it is seen to be deposited in tissues in many IMDs, indicating that it is used by the immune system, so an excess of iron in the body could act as a pro-inflammatory cytokine.
In some geographical locations, an element which is usually scarce may be locally abundant and be a significant contributory factor in the activation of IMDs. An example is arsenic, which can contribute to the pathogenesis of CVD and other IMDs (PMID: 11956123) . Low levels of calcium and magnesium have also been suggested to contribute to the development of CVD (PMID: 16874137) (PMID: 9888277) (PMID: 19617602) . The redox active manganese atom can substitute for magnesium in biological processes and this is more likely to occur when magnesium intake is low and manganese intake high (PMID: 15322332) (PMID: 10511330).
As with other IMDs, CVD is more prevalent in urban populations than in rural areas. The principal environmental factor in cities is probably metal oxides and chemical air pollutants which are metabolised by CYP enzymes at the AHR (PMID: 15531779) (PMID: 18202315) (PMID: 17303673) (PMID: 16877260) and those people with CYP polymorphisms which activate the NF-kB immune response most strongly will be most susceptible to the harmful effects of these airborne chemicals (PMID: 17126841) (PMID: 17868191) .
Low levels of circulating soluble RAGE are seen in CVD, indicating that it is a RAGE stimulated IMD (PMID: 17893038) (PMID: 18926539) . There are also raised levels of the RAGE ligand, HMGB-1 (PMID: 19150066) , and increased levels of MMP enzymes (PMID: 14577520) (PMID: 17059420) (PMID: 16128859) . MMP-9 is secreted by macrophages (PMID: 16374516) and degrades the extracellular matrix, presumably to cleave RAGE agonists. This degradation of the ECM can result in the rupture of plaque and resultant thrombosis (PMID: 19330590) (PMID: 12625594) . As with other IMDs, IDO levels are raised, presumably to convert tryptophan to kynurenine (PMID: 17349013) (PMID: 18622801) .
Elevated levels of low density lipoprotein (LDL) and decreased levels of high density lipoprotein (HDL) are seen in CVD patients. Non-dietary risk factors which increase the inflammatory response in CVD, such as smoking (PMID: 1394391) (PMID: 9610530) and psychological stress (PMID: 3818030) (PMID: 6485419) also raise LDL levels, indicating that raised LDL is actually a deliberate action of the inflammatory response in CVD. As in other IMDs, CVD is associated with infection with pathogens which establish intracellular latency (PMID: 17140429) (PMID: 12884557) (PMID: 19086952) and it is known that the LDL receptor is used by pathogens to enter cells (PMID: 17156886) (PMID: 11159023) . Moreover, there is evidence that at least one virus, hepatitis C, achieves this by complexing with LDL, but not HDL (PMID: 10535997) (PMID: 16991080) . It may therefore seem strange that the raising of LDL levels is a deliberate stratagem of the immune system in CVD. Also, one might also expect to see reduced levels of LDL receptors, but evidence for this is lacking.
The answer may be that the increase in LDL serves to 'mop up' hepatitis C viruses, and possibly other pathogens. The LDL is then oxidised and absorbed by macrophages, eliminating any pathogens that may be bound to it. Macrophages also have LDL receptors and their expression increases in response to high LDL levels. The macrophages then die, and become attached to the cell walls as foam cells. A novel hypothesis to explain the attachment of foam cells to the artery wall is that it is actually a protective immune system stratagem which only becomes pathological when the NF-kB driven immune response becomes chronically activated. In normal circumstances, the foam cells are created to form a physical barrier, preventing microbes from entering endothelial cells. They might therefore be thought of as acting like ‘sandbags’ and oxidised LDL cholesterol is the ‘sand’ which fills them. When the NF-kB response is activated, this leads to elevated levels of LDL cholesterol and more vigorous oxidation of LDL to supply the sand for the sandbags. This also removes hepatitis C from the circulation and viral RNA from the pathogen is found within the plaque (PMID: 17936225) .
Porphyria
Porphyria is an IMD resulting from a disorder of heme synthesis. The manufacture of heme is disrupted due to an inherited defect in one or more of eight enzymes involved in its production. Porphyria is actually a group of disorders, with symptoms of the disease varying according to the specific enzyme deficiency, and symptoms are caused by an accumulation of molecules, called porphyrins, and their precursor molecules.
Symptoms include gastrointestinal, neurological and psychiatric manifestations, as well as photosensitivity, which results in skin symptoms. Only about 10% of the people who inherit the abnormality in one or more of the heme synthesizing enzymes, actually go on to develop symptoms of porphyria. This is the same percentage of people infected with the tuberculosis bacterium who go on to develop TB, a fact which may be more than just coincidence. It seems likely that there is a genetic predisposition to excessive NF-kB activation in both sub-groups.
Porphyria is a rare disorder and studies confirming NF-kB activation are lacking, as are epidemiological studies which indirectly support NF-kB activation as the cause of the symptoms, such as a latitude gradient or a higher incidence in cities. However, there is some evidence of an association with hepatitis C infection (PMID: 17966447) and also vitamin D deficiency (PMID: 18476956) . Moreover, porphyria is so strongly associated with both iron intake and exposure to chemicals which are metabolised by CYP enzymes, that sufferers are advised not to take iron supplements and even to avoid iron cooking pots, and the subjects of chemical injury and porphyria are often treated together (see Internet: ‘Chemical Injury and Disorders of Porphyrin Metabolism’). Porphyria is often activated in middle age by exposure to chemicals, drugs, infections and iron. NF-kB activation is associated with aging, so as we age we are taken closer to the ‘tipping point’ where IMD pathogenesis begins, and this is probably why the majority of IMDs begin in middle or old age.
It seems plausible that the chemicals produced as a result of disordered heme synthesis are metabolised by CYP enzymes at the nuclear membrane in the same way as the environmental porphyrogenic chemicals which are so closely associated with the disease. The ability of these chemicals to induce NF-kB activation is known to be boosted by iron and there is evidence of a role for a CYP polymorphism in the disease (PMID: 17225875) . The evidence therefore suggests that the pathogenesis of porphyria is at the nuclear membrane and the disease may be a rare example of an IMD which is caused by endogenous chemicals which bind to the AHR. The presence of schizophrenia-like symptoms indicates that the pathogenesis of schizophrenia in some patients may be more strongly influenced by intracellular processes, rather than by receptor activation.
Diabetes
In diabetes, there is reduced uptake of glucose by cells due to a combination of reduced insulin secretion by pancreatic beta cells and decreased expression and sensitivity of insulin receptors. This results in high levels of circulating glucose which is toxic to cells (PMID: 8198540) . Diabetes is strongly associated with obesity and a low grade systemic inflammation is evident in both conditions (PMID: 17430117) (PMID: 12829649) .
Diabetes is actually two distinct conditions, type 1 diabetes mellitus (T1DM), which is recognised as an autoimmune disease which usually begins in childhood, and type 2 diabetes mellitus (T2DM), which usually begins in adulthood, but is increasingly being diagnosed in children. Both diseases are on the increase throughout the world.
In T1DM, the insulin secreting beta cells in the pancreas are attacked and destroyed by the immune system. In T2DM, there is ‘insulin resistance’ which means that cells are less responsive to circulating insulin, usually because of a combination of reduced insulin receptor expression and reduced sensitivity of the receptors to the action of insulin. I have found no direct evidence that the insulin receptor is used by pathogens to gain entry into cells, but it seems very likely that the reduced expression and sensitivity of insulin receptors occurs as a result of NF-kB activation and is a stratagem to restrict such entry (PMID: 14704745) . Later in the course of T2DM, there is also reduced secretion of insulin from beta cells. Chronic overeating, particularly of high glycemic foods, is probably the strongest non-genetic risk factor for the development of T2DM. Both high glycemic food intake and increased insulin levels are known to activate the NF-kB driven immune response (PMID: 18469238) (PMID: 7592658) .
Type 1 diabetes mellitus (T1DM)
A child living in Finland or Sardinia is more than 350 times more likely to be diagnosed with T1DM than a child living in China or Venezuela (PMID: 11023146) . This is similar to the pattern of global incidence of multiple sclerosis and illustrates the importance of ethnicity in the predisposition to the disease. As with multiple sclerosis, Sardinia has a much higher prevalence of T1DM than nearby Mediterranean populations, which may only be partly accounted for by genetic differences (PMID: 15471889) . The contamination of the environment in Sardinia by metals from mining activity may make an important contribution to disease pathogenesis.
Early exposure to pathogens may be protective against the future development of T1DM (PMID: 15559363) (PMID: 19120494) . A sixfold gradient in the incidence of T1DM exists between children living in eastern Finland, compared to children living in neighbouring Karelia, which may be due to more hygienic living conditions in Finland, although other explanations are possible (PMID: 15902849) . Viral infections are also strongly suspected of contributing to the pathogenesis of T1DM (PMID: 12592641) (PMID: 17103489) and many of the suspected viruses are known to establish latency within cells. Vitamin D status in early life also appears to have a significant influence (PMID: 11705562) (PMID: 10027578) (PMID: 14758446) , and there may also be a correlation with a vitamin D receptor polymorphism (PMID: 10868975) .
Apoptosis of beta cells is associated with NF-kB activation (PMID: 18481950) and the principal factor initiating the NF-kB response may be ER stress, due to the heavy load caused by insulin production in that organelle (PMID: 12101393) (PMID: 18473761) (PMID: 17565413) . There is also evidence of mitochondrial stress (PMID: 18940247) . Children who are obese, or taller than average in early childhood are more likely to develop T1DM. Overconsumption of food and the deposition of fat cells creates a greater demand for insulin, as does above average growth and these conditions will serve to push the beta cells closer to the threshold of NF-kB activation if there is genetic predisposition to developing T1DM (PMID: 18540867) (PMID: 19183310) (PMID: 19409241) .
Type 2 diabetes mellitus (T2DM)
T2DM appears to be an IMD in which NF-kB activation occurs mainly by receptor activation at the insulin receptor. The most important non-genetic factor in the pathogenesis of T2DM is overeating, particularly high glycemic foods, which results in persistent activation of insulin receptors. There is evidence that the relatively recent introduction of large amounts of high fructose corn syrup into processed foods may play a role in the increasing prevalence of the disease, particularly in the US (PMID: 19342510) (PMID: 19422101) (PMID: 19381015) . The reduced expression and sensitivity of insulin receptors which results in insulin resistance suggests that the insulin receptor is used by pathogens to enter cells. Direct evidence for this is lacking, but insulin receptors are known to be implicated in the development of many cancers and there is some tantalising evidence for the involvement of viruses in this process (PMID: 19029952) (PMID: 18711691) (PMID: 19617901) .
In the initial stages of insulin resistance, the pancreatic beta cells secrete more insulin in an attempt to compensate for the resistance. However, it appears that high levels of circulating insulin and/or glucose levels may eventually lead to a shutdown of beta cells which can eventually lead to apoptosis and a reduced mass of beta cells. Thus, the initial mechanisms leading to beta cell death are fundamentally different in T1DM and T2DM. This looks very much as if the beta cells are cooperating in the NF-kB driven immune response in muscle and fat cells and are producing less insulin and that this is being effected by a separate receptor activated IMD in beta cells, in which chronic activation of beta cell insulin or glucose receptors, or both, eventually leads to the death of beta cells. However, there is evidence that NF-kB activation in beta cells may not be involved in this (PMID: 16306347) , which would appear to rule out a receptor activated IMD pathogenesis. If beta cell death in T2DM is not associated with NF-kB signaling within those cells, then this represents a perplexing anomaly. There can be little doubt that beta cell hypofunction is an integral component of the NF-kB driven immune response which originates in the cells targeted by insulin. This is highlighted by the fact that, in around 70% of cases of T2DM, beta cells secrete islet amyloid polypeptide, also called amylin, which is converted to amyloid deposits in the islets of Langerhans. This amyloid is similar to the Abeta deposits seen in Alzheimer’s disease and it is known to be toxic to beta cells just as Abeta is toxic to neurons (PMID: 11875249) (PMID: 8152488) (PMID: 17475933) .
It seems likely the amyloid is being produced to act as a depot for RAGE agonists, and beta cell hypofunction and eventual cell death is a RAGE mediated IMD which occurs in T2DM, but not in T1DM. The apparent absence of NF-kB activation in the beta cells to drive this process is an inconsistency, hinting at a seemingly improbable scenario where NF-kB activation in muscle and fat cells can drive a RAGE mediated immune response in pancreatic beta cells. It is unclear if RAGE activation plays a role in insulin resistant cells. Soluble RAGE levels are seen to be lower in T2DM (PMID: 17640561) , but this could be linked to RAGE activation in beta cells or to diabetic complications in which RAGE activation plays a role, such as atherosclerosis or nephropathy.
I have proposed that receptor activation of an IMD can occur either as a result of chronic excessive stimulation of a receptor or chronic lack of stimulation. The increased incidence of T2DM is probably mainly due to chronic excessive stimulation of insulin receptors as a result of overeating. However, if chronic lack of stimulation of insulin receptors can also result in the development of insulin resistance and T2DM, one would expect to see evidence for this in T1DM, in which there is reduced production of insulin and this has been confirmed (PMID: 19772820) (PMID: 18405504) . Also, one might expect to see an above average incidence of T2DM in people who had experienced chronic malnutrition. In areas of the world where malnutrition is common, this form of diabetes has been recognised for some time, although its existence has not been universally accepted, and it is known as ‘malnutrition related’ or ‘malnutrition modulated’ diabetes mellitus, or ‘tropical diabetes’ (PMID: 11225212) (PMID: 12021094) (PMID: 3927107) . There is also evidence for a connection between anorexia nervosa and the later development of T2DM, (PMID: 12647266) (PMID: 3069398) (PMID: 8027230) .
Specific infections which have been associated with the development of T2DM include hepatitis C (PMID: 17547292) , multi drug resistant TB (PMID: 18728934) , Candida (PMID: 19263663) and E. coli (PMID: 19180134) . Decreases in insulin receptor expression have been noted during periods of infection, evidence that the insulin receptor is used by microbes to enter cells (PMID: 6253524) (PMID: 6295750) . As with other IMDs, there may be dysregulation of more than one type of receptor in T2DM. Caffeine stimulates acetylcholine production and has been shown to be protective against Alzheimer’s disease (PMID: 19158424) (PMID: 17427282) and also T2DM (PMID: 16652136) (PMID: 16801515) .
Dioxin exposure has been shown to be a risk factor for the development of T2DM (PMID: 10911003) (PMID: 17107852) . It is therefore likely that exposure to other chemicals which bind to the AHR and are metabolised at the nuclear membrane by CYP enzymes will also contribute to pathogenesis, particularly in people with CYP polymorphisms which have been shown to be associated with IMDs. Urban living is also a risk factor, probably for the same reason (PMID: 15975110) (PMID: 3403139) . Other risk factors are dietary heme from red meat (PMID: 16732023) (PMID: 14684399) (PMID: 17909092) and possibly a high salt intake (PMID: 15971060) (PMID: 18570670) .
Obesity
Obesity is caused by excessive accumulation of adipose tissue due to overeating, so it may be surprising to see it included as an IMD. However, there is increasing evidence that morbid accumulation of body fat is associated with dysregulated immune system functioning, including NF-kB activation (PMID: 19337955) (PMID: 16613757) , activation of toll-like receptor signaling, (PMID: 19625959) (PMID: 11278967) , conversion of tryptophan to kynurenine (PMID: 17430117) and that the weight gain might also occur as a consequence of receptor activation via the insulin receptor (PMID: 17924864) (PMID: 17102158) . Clearly, there is much more to obesity than simply overeating and not taking enough exercise, and some people appear to be more at risk of putting on weight than others. Fat deposition appears to be mediated by the immune system and seems to occur more readily in those predisposed to aberrant NF-kB activation. At the same time, the deposited fat cells appear to aggravate this situation by secreting pro-inflammatory cytokines (PMID: 17845592) (PMID: 16613757) .
The same environmental factors which are associated with other IMDs are also associated with obesity. Lack of vitamin D appears to be a predisposing factor (PMID: 18191047) (PMID: 19549738) (PMID: 17923796), and, as with other IMDs, obesity is associated with specific infections by intracellular pathogens which establish latency. These include adenoviruses (PMID: 17908526) (PMID: 19138827) , H. pylori and Chlamydia (PMID: 17943636) (PMID: 11006888) . This has led to the suggestion that obese individuals may be more susceptible to infection and, while this may be true, it is also true that infection by these pathogens will result in some degree of systemic activation of NF-kB which may exacerbate a predisposition to morbid deposition of body fat.
Exposure to chemicals which bind to the AHR and are metabolised by CYP enzymes, activating NF-kB in the process, such as benzopyrene (PMID: 16689925) and PCBs (PMID: 18560532) is also a risk factor. Such chemicals are found at higher concentrations in urban air and people living in cities are more likely to become obese (PMID: 18331534) (PMID: 18987267) , although some anomalies also appear to exist (PMID: 18608637).
However, PCBs and PAHs, such as benzopyrene, also activate another nuclear receptor which is particularly implicated in obesity and other 'metabolic syndrome' illnesses. The Peroxisome Proliferator-Activated Receptor (PPAR) functions as a transcription factor, regulating the expression of genes. There are three sub-types, alpha, beta and gamma, and endogenous ligands include free fatty acids and immune system molecules called 'eicosanoids'.
Some hereditary disorders of PPARs are known in which there is loss of function resulting in obesity and insulin resistance. Some populations with a high incidence of a PPAR polymorphism have a greater incidence of obesity. PPAR agonist drugs are used to treat diabetes, insulin resistance and cardiovascular disease (PMID: 19318113) (PMID: 18288280) and it would appear that ligands for this receptor may also have a broader antiinflammatory action in the CNS (PMID: 18670616).
As with the AHR, a wide range of chemicals are capable of binding to the PPAR (PMID: 12740826). These chemicals may promote adipogenesis and have been called 'obesogens'. There is a belief that these obesogenic chemicals may play a significant role in the modern obesity epidemic, with some individuals being more affected by them than others due to genetic factors (PMID: 18769210) (PMID: 18031666) and there is evidence that exposure during the perinatal period may predispose to obesity in later years (PMID: 17321108) (PMID: 19433248).
Many of these obesogenic chemicals are common household pollutants, such as phthalates, which are easily released from plastics, such as PVC (PMID: 17468099) (PMID: 12805656) (PMID: 15310864) and bisphenol A, which is also used in the manufacture of plastics and can be found in baby bottles, plastic drinks bottles and as a coating on the inside of food and beverage cans (PMID: 19890158) (PMID: 20019905).
Perfluorooctanoic acid (PFOA) and perfluorooctanesulfonic acid (PFOS) are similar chemicals which have a wide variety of uses, including as water and oil repellants in fabrics and leather. They are also used in polishes, varnishes, floor waxes, general cleaning products, waxed papers, fire fighting foam, electronic products and PTFE cookware. They are resistant to degradation and are persistent pollutants which bioaccumulate and which have increased in the environment over time (PMID: 14587845) (PMID: 15667078). Both chemicals activate PPARalpha (PMID: 18802816), but also appear to have PPAR independent effects which might be due to AHR binding. They are associated with a higher incidence of cancer and elevated blood lipid levels (PMID: 16609670) (PMID: 19846564), and early exposure has been found to increase the body weight of mice in mid-life (PMID: 19433254).
Many prescription drugs are known to cause weight gain as a side effect. These include the various types of antidepressant, antipsychotics, ADHD medication, progesterone, corticosteroids, diazepam and breast cancer drugs. Some of these drugs act on cell membrane receptors and some act on nuclear membrane receptors. The various antidepressants increase the availability of serotonin by different mechanisms.
It is conceivable that some environmental chemicals may be exacerbating the modern obesity epidemic by acting on the same receptors as prescription drugs. Pre-natal exposure to chemicals which act as antagonists at specific receptors could result in increased sensitivity and/or expression of these receptors, while pre-natal exposure to receptor agonists could have the opposite effect (PMID: 20074626) (PMID: 19060027).
GABA receptors appear to be particularly important. Baclofen, a GABA(B) receptor agonist, has been shown to have a weight reducing effect (PMID: 20930428), and an increase in GABA appears to cause weight loss by both inhibition of appetite and increased metabolic rate (PMID: 3417101). There is little doubt that GABA plays a key role in control of body weight, but its importance appears to have been underestimated (PMID: 19401161). Some of the drugs which induce weight gain bind to receptors which cross talk with GABA receptors (PMID: 17034954) (PMID: 11161597), and this indirect activation of GABA receptors may be responsible for the weight gain (PMID: 19100273).
Environmental chemicals which act as GABA(A) receptor antagonists include pesticides, phthalates, folic acid and methyl mercury. It is possible that early exposure to such chemicals could result in increased sensitivity and/or expression of GABA(A) receptors, resulting in obesity (PMID: 18166376). Research into the obesogenic effects of environmental chemicals is still at an early stage, but it seems certain that many more obesogenic chemicals remain to be discovered.
Alzheimer's Disease
Alzheimer’s disease (AD) is a disease of aging neurons characterised by extracellular deposits of proteinaceous plaques, axonal degradation, neuronal death and brain atrophy. The main component of the plaques is amyloid-beta (Abeta), which derives from amyloid precursor protein (APP). APP has both an intracellular and an extracellular domain and the extracellular Abeta is derived from fragments of extracellular APP which have been enzymatically cleaved. Many experiments have demonstrated the toxic effect which Abeta has on neurons, although the principal mechanism by which it exerts its toxicity has remained obscure. Abeta is also present inside cells and some evidence suggests that it may induce CYP enzymes, which would contribute to NF-kB activation (PMID: 11432979) , which is upregulated in AD (PMID: 19387114) (PMID: 19241975) . Other abnormal protein deposits are seen in AD, in particular, intracellular neurofibrillary tangles, which are comprised of hyperphosphorylated tau protein. Some research suggests that tau proteins are essential for Abeta toxicity (PMID: 11959919) . Also, intracellular APP may enhance the sensitivity of neurons to pro-apoptic signaling, which is seen in IMDs when the essentially anti-apoptic NF-kB driven immune response has become chronically activated (PMID: 18722509) (PMID: 18764939) .
Abeta toxicity is generally believed to be the principal cause of the neurodegeneration seen in AD and the mechanism of action which is most consistent with IMD theory is that fragments are cleaved from Abeta by enzymes to act as agonists at the RAGE. However, Abeta is capable of binding to a bewildering array of membrane receptors, including the RAGE (PMID: 15160835), so it is possible that it is also exerting an immune boosting effect at receptors other than the RAGE (PMID: 18400893). Another possible explanation for the binding of Abeta fragments to many different receptor types could be that they are being used to block those receptors to prevent them being used by pathogens to gain entry into cells, and this would also serve to boost NF-kB activation.
In all IMDs in which RAGE activation plays a part, the clearest evidence for the participation of RAGE in the inflammatory process is low levels of circulating soluble RAGE. In AD, the evidence for low levels of circulating soluble RAGE is not as great as it is in other RAGE mediated IMDs (PMID: 18431028) (PMID: 16286548) (PMID: 16842191) (PMID: 18506386) . However, there is little doubt of the involvement of RAGE and this involvement appears to be mediated by Abeta (PMID: 16842100) (PMID: 15053925) (PMID: 15975028) (PMID: 19273137) .
The prevailing view of Abeta seems to be that it is a kind of accidental toxic byproduct of some pathological process taking place inside aging neurons. However, smaller amounts of extracellular Abeta are present in healthy brains and it seems likely that they are created deliberately by the immune system to act as depots for RAGE agonists during times of infection. In AD, this normal activity of the immune system has become inappropriately and chronically activated, resulting in excessive deposition of Abeta and excessive activation of the RAGE.
Excessive accumulation of extracellular Abeta could be caused by either increased production, or decreased degradation by enzymes, or a combination of both. At the same time, one could expect to see an increase in the enzyme or enzymes responsible for the cleaving of RAGE agonists from Abeta. Enzymes involved in Abeta degradation include neprilysin, insulin degrading enzyme (IDE), MMPs, ACE, endothelin-converting enzyme and plasmin. There is evidence that polymorphisms of neprilysin (PMID: 15548496) (PMID: 14739539) (PMID: 17928142) and IDE (PMID: 16876916) (PMID: 17496198) (PMID: 15277615) can increase the risk of AD, but many studies have also failed to confirm these findings. There appears to be little evidence for increased Abeta production in AD (PMID: 14511676) . Instead, the evidence seems to support a general reduction in Abeta degrading enzymes, but an increase in ACE (PMID: 18363935) .
ACE therefore becomes the prime suspect for the enzyme responsible for the production of RAGE agonists from Abeta and the greater the load of Abeta, the more ACE is expressed (PMID: 17973905) . ACE inhibitor drugs are prescribed for the prevention of cardiovascular disease, hypertension and nephropathy associated with diabetes. This reduces production of the pro-inflammatory angiotensin II, a molecule which is known to cause NF-kB activation (PMID: 10864918) . However, all of these conditions are also RAGE mediated and it is significant that an increase in soluble RAGE is seen when ACE inhibitors are used (PMID: 15930093) . The fact that ACE inhibitors have been shown to be effective in slowing the progress of AD (PMID: 18679002) is further evidence for the proposed role for ACE in the disease process and could indicate that drugs which inhibit ACE may have broader therapeutic potential than is currently realised.
AD is caused by a combination of genetic, environmental and lifestyle factors, but the evidence for the importance of environmental and lifestyle factors appears to be less robust than for most other IMDs. The strongest evidence for an environmental risk factor appears to be for infections, particularly herpes simplex virus-1 (HSV-1) (PMID: 18973185) (PMID: 18982063) . The latent intracellular bacterium, Chlamydia pneumoniae, is also implicated (PMID: 18701222) (PMID: 18487846) as are other bacteria (PMID: 18487847) . Experiments in which mice and cell cultures were exposed to HSV-1 and Chlamydia pneumoniae caused amyloid deposition, indicating that production of Abeta is a response to infection (PMID: 15013562) (PMID: 17980964) . Other environmental and lifestyle factors which have been associated with AD are head injury (PMID: 18289429) (PMID: 17367583) , a high saturated fat and cholesterol diet (PMID: 9392577) (PMID: 12214118) , exposure to aluminium (PMID: 15666086) (PMID: 19064650) (PMID: 12520766) (PMID: 19818510) (PMID: 15961160) , exposure to general anaesthetics (PMID: 19116131) (PMID: 18326038) , exposure to pesticides (PMID: 17525096) and psychological stress (PMID: 19330182) (PMID: 17499446) . Psychological stress has also been shown to promote extracellular Abeta deposition in mouse models (PMID: 18571864) (PMID: 19012747) .
The most important known genetic factor which contributes to the pathogenesis of late onset AD is an isoform of apolipoprotein E, APOE4. People with one copy of the E4 allele have a risk of developing AD which is three times the average, while those with two copies have an increased risk which is greater than ten times the average. Between 40 and 65% of AD patients have at least one copy of the APOE4 allele, which means that at least a third of people with AD are APOE4 negative. Therefore, APOE4 is neither necessary nor sufficient by itself to cause AD.
APOE is a major component of very low density lipoprotein (VLDL) and one of its functions is to transport lipoproteins and cholesterol around the body. So, it functions similarly to LDL, and one of the receptors through which it enters cells is the LDL receptor. Like LDL, it appears to facilitate hepatitis C infectivity (PMID: 17913825) . However, the APOE4 isoform appears to facilitate infection of cells by pathogens more readily than APOE2 or APOE3. The pathogens include HSV-1 (PMID: 18572164) (PMID: 16699018) , HSV-2 (PMID: 18708484) and Chlamydia pneumoniae (PMID: 17997273) . Since HSV-1 and Chlamydia pneumoniae are the pathogens with the strongest association with AD, this may explain why APOE4 is so strongly associated with the disease. Carriers of the APOE4 allele are more susceptible to brain infection, so their immune systems in the brain are on a heightened state of alert, and thus more likely to become inappropriately activated, resulting in the development of AD.
Enzyme polymorphisms which have been identified in AD are aromatase (CYP) (PMID: 15079018) , CYP 46 (PMID: 12533085) , cholesterol 25-hydroxylase (PMID: 16909003) and lipoprotein lipase (LPL) (PMID: 16965549) . The first two use iron in heme as a co-factor, while C25H uses a non-heme di-iron co-factor. I have not found evidence that LPL uses a metal co-factor. All four enzymes localise to the ER, which suggests that the main initiating factor in AD is probably ER stress (PMID: 15363492) (PMID: 16691116) (PMID: 19264902) . The fact that ER stress is believed to increase with advancing age is supportive of this (PMID: 14661099) . There is also evidence of mitochondrial stress in AD (PMID: 19393033) (PMID: 18855587) (PMID: 18295378) , although much of the research proposes that mitochondrial dysfunction is being caused by intracellular Abeta toxicity. It is quite possible that, when chronic activation of the normally antiapoptic NF-kB driven response makes it become pro-apoptic, mechanisms designed to induce mitochondrial and ER stress in order to boost the NF-kB driven immune response could come into play. Oxidative stress in both organelles probably contributes to AD pathogenesis by activating NF-kB, but the association with polymorphisms in four enzymes, all of which localise to the ER, strongly suggests that most of the pathogenesis occurs in the ER.
In IMD theory, the activation of the NF-kB driven immune response results in reduced expression and sensitivity of membrane receptors which are capable of being used by intracellular pathogens to gain entry into cells. The most common early symptom in AD is impairment of short term memory and one would expect this to be a consequence of receptor hypofunction of the neurotransmitter system or systems involved in learning. In AD, the evidence points strongly towards hypofunction in two receptors, the acetylcholine NACH receptor and the noradrenaline receptor. Both of these receptors are involved in learning and the acquisition of new memories (PMID: 18220778) . There is evidence of NACH receptor subunit deficits (PMID: 10617125) (PMID: 11230871) and loss of cholinergic neurons (PMID: 19375072) which are not seen in the brains of healthy aged subjects (PMID: 19484724) . Within the brain, noradrenaline is synthesized in the locus coeruleus and transported from there to noradrenergic neurons. There is some evidence for noradrenergic neuronal deficit in brain areas other than the locus coeruleus (PMID: 1646966) (PMID: 17324522) , but a larger body of evidence to suggest that hyponoradrenergic functioning is due to a reduced supply of noradrenaline because of degeneration of the locus coeruleus (PMID: 16452658) (PMID: 18537547) .
This situation appears similar to that seen in type 2 diabetes, in which the insulin receptors of muscle and fat cells are underexpressed and desensitised. This is accompanied by reduced secretion of insulin from pancreatic beta cells and the eventual death of these cells, indicating the participation of the beta cells in the NF-kB driven immune response. In AD, the cells of the locus coeruleus appear to become involved in the aberrant immune response in the same way as the beta cells in type 2 diabetes. Output of noradrenaline is reduced, possibly as a result of another NF-kB response which inactivates cells in the locus coeruleus via unknown receptor hypofunction. When this situation becomes chronic, cells in the locus coeruleus die and this region of the brain atrophies.
Thus, the involvement of the locus coeruleus can be seen as a downstream consequence of NF-kB activation in those neurons which it supplies with noradrenaline. However, insulin resistance can occur as a consequence of type 1 diabetes, presumably as a result of receptor activation of NF-kB in muscle and fat cells brought about by a reduced supply of insulin, and it is conceivable that a similar situation could occur in a minority of AD patients. The synthesis of noradrenaline from tyrosine via dopamine involves metalloenzymes which produce ROS and which have been identified as autoantigens in other medical conditions, so it is conceivable that an NF-kB driven immune response could originate in the locus coeruleus as a result of excessive ROS production, which would result in reduced output of noradrenaline, leading to receptor activated AD pathogenesis in noradrenergic neurons. If such a situation does occur, the development of AD in this minority of patients would probably be preceded by psychiatric symptoms, particularly depression.
Aging is associated with a reduction in our ability to learn, and this is probably accompanied by receptor hypofunction, particularly of the acetylcholine NACH and noradrenaline receptors. This hypofunction mimics the receptor hypofunction induced by the NF-kB driven immune response, when it attempts to prevent pathogens from entering neurons, and is probably the principal factor causing aberrant NF-kB activation, leading to disease pathogenesis, in concert with genetic predisposition.
Cancer
NF-kB is activated in cancer (PMID: 10713699) (PMID: 12452071) (PMID: 9918209) (PMID: 14689584) and low levels of soluble RAGE are seen, indicating it is a RAGE mediated IMD (PMID: 19895173) (PMID: 18058469) . As with other IMDs, it is more common in cities than in a rural environment (PMID: 8435207) (PMID: 10121550) (PMID: 7721511) , probably due to chemical pollutants. Activation of many IMDs appears to be particularly sensitive to specific risk factors and this can often provide a clue to the main site of disease pathogenesis. Examples of this are emotional states in schizophrenia, fat consumption in cardiovascular disease, excessive high glycemic food consumption and type 2 diabetes, iron in multiple sclerosis and iron and chemical pollutants in porphyria. Chemical pollutants appear to be particularly important in carcinogenesis, and this suggests that the production of ROS, particularly hydroxyl radicals, at the nuclear membrane as a result of CYP enzyme activation, may be the principal cause. Polymorphisms of cytochrome P450 enzymes are associated with an increased risk of cancer, presumably due to increased ROS production (PMID: 16493615) (PMID: 15308589) (PMID: 17695473) (PMID: 15064998) and some CYP enzymes involved in the metabolism of exogenous chemicals are seen to be overexpressed (PMID: 17683511) (PMID: 12869499) (PMID: 17549345) , which would probably also result in increased ROS production.
Some research indicates that vitamin D deficiency may contribute to carcinogenesis (PMID: 17578830) (PMID: 17302200) (PMID: 17207891) , although other evidence for a latitude gradient appears to be lacking. Skin cancer rates are higher in lower latitudes due to stronger UV radiation, which may be an obscuring factor.
There is a growing body of evidence for the involvement of pathogens in carcinogenesis and most of these are known to establish latency (PMID: 18338378) (PMID: 10539899) (PMID: 11693428) (PMID: 17208515) . Tryptophan metabolism on the kynurenine pathway as a stratagem to deprive pathogens of tryptophan, and to boost NF-kB activation via CYP production at the AHR is also seen (PMID: 15896467) (PMID: 17191041) .
It is known that oral contraceptives protect against ovarian cancer (PMID: 18294997) (PMID: 18368558) and endometrial cancer (PMID: 7895220) (PMID: 16434833) , while increasing the risk of breast cancer (PMID: 7791232) (PMID: 2653859) and cervical cancer (PMID: 15543923) (PMID: 17993361) . There are two forms of oral contraceptive, one which contains both estrogen and progestin, a synthetic form of progesterone, and another which contains only progestin. Estrogen and progesterone are very similar molecules and each affects the functioning of the other. Both are produced in the ovaries and estrogen is also produced in the endometrium. CYP enzymes are involved in their synthesis from cholesterol and this will produce ROS, leading to NF-kB activation. In target cells, both molecules are metabolised by CYP enzymes at receptors on the nuclear membrane, and this activity will also produce ROS, activating NF-kB. The breast and cervix are target organs for estrogen and progesterone, so taking these chemicals supplementally on a daily basis will probably intensify the pro-inflammatory effects of their metabolism in these organs, leading to an increase in cancer cases. The converse of this is also true. Daily oral intake will reduce the need for synthesis of these hormones in the ovaries and endometrium, and this will cause a decrease in CYP ROS production, resulting in fewer cases of cancer in these organs.
Cancer is the disease best known for its association with aberrant NF-kB activation. However, it also appears to be an anomalous IMD, as there does not appear to be hypofunctional membrane receptor types and, instead of abnormal cell death being seen, the opposite appears to happen, with cancer cells becoming 'immortal' and multiplying out of control.
Aging is associated with an increase in oxidative stress, inflammation and activation of NF-kB (PMID: 12424787) (PMID: 18055696). But aging is a normal process, which cannot be considered to be an IMD, although the systemic increase in NF-kB activity with which it is associated contributes to the activation of IMDs in specific cell types where genetic predisposition exists. Cancer is also associated with aging, although a few types are more common in children, but it looks oddly like a dysregulated compensation mechanism disease, albeit one without a discernible association with hypofunctional membrane receptor types.
Although it is caused by the same genetic, environmental and lifestyle factors as other IMDs, cancer's apparently anomalous character makes it difficult to classify it as an IMD and it may have to be assigned to a category of its own. NF-kB not only activates genes involved in the immune response, but also activates genes involved in cell division, and it seems that it is this role of NF-kB which is being chronically and aberrantly activated in cancer.
Autism Spectrum Disorder (ASD) and Attention Deficit Hyperactivity Disorder (ADHD)
ASD
Autism was first described by Dr Leo Kanner in 1943. A year later, a milder form of the disease was described by Dr Hans Asperger, now known as Asperger syndrome. These conditions, along with Rett syndrome, Childhood Disintegrative Disorder and Pervasive Developmental Disorder Not Otherwise Specified, make up the Autism Spectrum Disorders (ASD). All of these disorders are characterised by varying degrees of impairment in communication abilities, interpersonal relations and repetetive, stereotyped patterns of behaviour.
Over the past 40 years, there has been a huge rise in the incidence of ASD which appears to show no signs of plateauing (PMID: 15858952) (PMID: 15148861) (PMID: 19234401). This increase has been described as an 'epidemic' and, although much of the increase is almost certainly due to greater awareness of the condition, broadening diagnostic criteria and sociological factors, there is also a belief that there may be an environmental contribution.
However, the very early age of onset of ASD, with some cases being diagnosed in the first year of life, suggests that the environmental factors which normally contribute to IMD pathogenesis are less important, although there is some evidence for prenatal exposure to viruses as a risk factor (PMID: 15804954).
Evidence of NF-kB activation in ASD has only recently emerged (PMID: 21573053) (PMID: 21629840). There is also evidence of oxidative stress (PMID: 16766163), evidence of immune system abnormalities (PMID: 20160651) (PMID: 19840888) (PMID: 19640207) (PMID: 19157572) and evidence of an increased incidence of familial autoimmune diseases (PMID: 10385847) (PMID: 17518928) (PMID: 19581261). There is also evidence for vitamin D deficiency in autistic children (PMID: 20569030), for maternal vitamin D deficiency (PMID: 20592795) and for a genetic polymorphism of a CYP enzyme essential for vitamin D metabolism (PMID: 19774457). Abnormal gut microbiota populations are also repeatedly observed in ASD (PMID: 22114588).
If there is an environmental factor which is partly responsible for the huge rise in the incidence of ASD, it seems that it must be specific for ASD, rather than being broadly pro-inflammatory, and it is difficult to imagine how it could be anything other than environmental chemicals that are responsible.
The temporal association between the increasing incidence of ASD and increasing intake of folic acid by pregnant women is particularly intriguing (PMID: 18514430) (PMID: 21388746) , but there appears to be only a little preliminary evidence which suggests a link (PMID: 21454018). Nevertheless, there is much evidence to support a link between folate and ASD, with some research indicating an association with reduced CNS folate (PMID: 18027081), a high incidence of folate receptor blocking antibodies (PMID: 18461502) and polymorphisms of the enzymes involved in folic acid and folate metabolism (PMID: 19440165) (PMID: 17597297).
There is also a belief that children with ASD are more likely to be found in higher socioeconomic status (SES) families (PMID: 6746221) (PMID: 479098) (PMID: 7129258) (PMID: 16951989), although other research has failed to find such a bias. Women of higher SES are more likely to take supplemental folic acid than women of lower SES (PMID: 18810617) (PMID: 17380058). Much of the research confirming a higher incidence of ASD in higher SES families is from the 70s and 80s, when there was there was less awareness of the benefits of taking supplemental folic acid in early pregnancy to prevent neural tube defects. Today, with greater awareness and much more food fortification with folic acid, there is probably less disparity of intake between higher and lower SES groups. An alternative explanation is simply that people in higher SES groups are more likely to be aware of autism and be more 'pushy' in their efforts to get a diagnosis in order to access support services.
Other environmental chemicals which have been implicated as causative factors include insecticides (PMID: 17938740) (PMID: 16027737), phthalates (PMID: 19822263), mercury (PMID: 16914205) (PMID: 19106436), lead (PMID: 21763301) bisphenol A (PMID: 18245062) and anticonvulsant medication, particularly valproic acid (PMID: 16108456) (PMID: 19490988). The question arises as to how this apparently disparate group of chemicals could all be contributing to the pathogenesis of ASD. The answer may be that folic acid (PMID: 1327745) , phthalates (PMID: 17646496) , methyl mercury (PMID: 20060493) , bisphenol A (PMID: 21277317) , valproic acid and a variety of insecticides, including pyrethroids (PMID: 2562766) , organophosphates (PMID: 10591520) and organochlorines (PMID: 21278053) , are all either GABA(A) receptor antagonists, or otherwise inhibit the receptor's functioning, except for valproic acid, which is a GABA(A) receptor agonist and bisphenol A, which also appears to augment GABAergic currents (PMID: 17574659) , although it is not clear if it does so as an agonist or by some other means.
Information appears to be lacking about the effects of lead on GABA(A) transmission, but many metals, including mercury, copper, zinc and lanthanum are GABA(A) modulators (PMID: 7641224), which raises the possibilty of a contribution from food fortification with zinc. Breakfast cereals, in particular, have large amounts of zinc added to them. Aluminium also modulates GABA(A) receptor transmission (PMID: 9705466), and the action of the GABA transporter (PMID: 14507469). It is used in baking and is added to drinking water to clarify it. Other chemicals which may modulate GABA(A) transmission include perfumes, such as those in air fresheners, and some food additives (PMID: 9438986).
Folic acid is a synthetic form of folate, which is the active form of the vitamin found in food. Both forms are epileptogenic in high doses and this is caused by their antagonistic action at the GABA(A) receptor (PMID: 1327745). Folic acid is a more powerful GABA(A) antagonist than folate (PMID: 2166659). The conversion of folic acid to folate is carried out by dihydrofolate reductase in the liver and the efficiency of this conversion process is highly variable between individuals, with a fivefold difference between the most and least efficient converters (PMID: 19706381). Therefore, people who supplement with folic acid and convert it slowly to folate will have more circulating folic acid and experience stronger GABA(A) receptor antagonism.
Phthalates are chemicals which are used in a wide variety of products, such as shampoo and makeup, but their main use is as 'plasticisers' to increase flexibility of plastic products. They are easily released into the environment because there is no covalent bond between the phthalates and the plastic. They suppress GABA(A) receptor currents (PMID: 17646496).
Children are exposed to insecticides in their diet and from household use (PMID: 18766203). The various types of insecticide currently in use are GABA(A) antagonists (PMID: 19572480) (PMID: 2562766) (PMID: 18023957) (PMID: 8597060) and organophosphates are also used as flame retardants in household fabrics (PMID: 2446940). Both the bioavailability and activity of the enzyme which metabolises organophosphates, paraoxonase 1, is seen to be deficient in autistic children, compared to controls. This enzyme also degrades bisphenol A (PMID: 16027737) (PMID: 18624774) (PMID: 20488557). Pyrethroid insecticides, often found in household sprays, are used in conjunction with chemicals which inhibit their metabolism (PMID: 16180929).
Research to establish a role for mercury pollution in the ASD epidemic has produced conflicting results (PMID: 20077234). Part of the reason for this may be that different mercury compounds have opposite effects at the GABA(A) receptor. Methyl mercury suppresses GABA(A) receptor activity, while mercuric chloride augments it (PMID: 7641224) (PMID: 20060493) and could conceivably even act to counter the effects of methyl mercury.
Valproic acid is an anticonvulsant medication used to treat epilepsy. Unlike most of the other chemicals mentioned, it is a GABA(A) receptor agonist. Children with ASD are prone to epileptic seizures and it is plausible that women with dysfunctional GABAergic transmission, resulting in epilepsy, may have children who inherit this genetic trait, making them more likely to develop ASD. The association between maternal exposure to valproic acid in pregnancy and ASD in their children may therefore not be a causal one. Alternatively, the association may indeed be causal and valproic acid may be inducing ASD by causing GABA(A) receptor hyperfunction. Valproic acid has recently been shown to activate NF-kB (PMID: 21722408). Thalidomide also acts as a GABA(A) receptor agonist and has also been associated with increased risk of autism (PMID: 21388746).
Bisphenol A has many uses, including as a coating on the inside of food and drink cans and in plastics, including baby bottles. In 2010, the US FDA expressed concerns regarding the exposure of fetuses and infants to bisphenol A. It is considered a neurotoxin and has been linked to autism (PMID: 18245062).
The question arises as to how it comes about that prenatal exposure to GABA(A) receptor antagonists in the unborn child results in ASD in infancy, often after an initial period of normal development. ASD is an atypical IMD because of the early age of onset. Schizophrenia has a later age of onset than ASD, but is also atypical as it, too, has a relatively early age of onset in late adolescence and young adulthood. I have proposed that the reason why schizophrenia begins at this time is because this period follows a stage in the development of the brain in which there is a large increase in dopamine receptor density, and the consequent surge in dopaminergic signalling may cause receptor activation of the NF-kB driven immune response in people with a genetic predisposition to developing schizophrenia.
It seems possible that something similar may be happening in ASD. I propose that prenatal, and possibly early postnatal exposure to chemicals which suppress GABA(A) receptor transmission in the developing brain forces the brain to compensate for the reduced GABAergic transmission, with the result that the GABAergic system becomes hyperfunctional. This could result in an increase in GABA(A) receptors, increased sensitivity of those receptors, increased production of GABA, decreased catabolism of GABA, or any combination of these.
The peak expression of the GABA transporter is seen in early infancy, and that of the GABA synthesising enzyme in the perinatal period (PMID: 11744314), indicating that early infancy is a time of heightened GABAergic activity. This, in combination with a hyperactive GABAergic system and genetic predisposition, could result in aberrant receptor activation of NF-kB in GABAergic neurons and consequent reduced expression of GABA(A) receptors. This reduction in the number of GABA(A) receptors has been confirmed (PMID: 18821008) (PMID: 11814263). Reduced levels of GABA(B) receptor subunits have also been detected (PMID: 19002745). There is also evidence of polymorphisms of GABA(B) subunits, which represents a part of the genetic predisposition to ASD (PMID: 17230033) (PMID: 18271397). In addition, there is reduced expression of the GABA synthesising enzyme, GAD, which could either be genetic or a consequence of the aberrantly activated NF-kB driven immune response (PMID: 12372652). It is conceivable that exposure to GABA(A) agonists in early infancy could also contribute to the pathogenesis of ASD by boosting GABAergic signalling further during this critical period.
The reduced number of GABA(A) receptors is an aberrantly activated immune system stratagem to restrict the entry of pathogens into cells. In a few cases of ASD, there is an association with prenatal infection with viruses such as HSV-1 and HSV-2 (PMID: 19961054), polyomaviruses, including the JC virus (PMID: 20345322), cytomegalovirus (PMID: 12959425) and rubella virus (PMID: 20171592), but evidence that any of these use the GABA(A) receptor to enter cells appears to be lacking. It is conceivable that prenatal exposure to pathogens which gain entry into cells via receptors other than GABA receptors might cause those receptors to be underexpressed and that this could impact GABA receptor expression via cross-talk.
Further evidence for the involvement of GABA in the pathology of ASD is the consistent finding of losses of the GABAergic Purkinje cells (PMID: 18514431) (PMID: 8463065), with decreased GAD (PMID: 17235515) and also NACHr subunit losses (PMID: 12076999). There is also evidence of increased levels of advanced glycation end-products in the brains of ASD sufferers and reduced levels of soluble RAGE (PMID: 17101220) which may contribute to Purkinje cell losses (PMID: 9593803), and also high levels of amyloid precursor protein (APP) (PMID: 16948926). The loss of NACHr subunits, increased AGEs, low levels of soluble RAGE and increased APP could indicate that people with ASD are at increased risk of developing Alzheimer's disease.
ASD often presents with early brain overgrowth, followed by brain atrophy later in life. The GABAergic system has a key role in early brain development (PMID: 9527049) (PMID: 10444657), a function which is intimately linked with the expression of brain-derived neurotrophic factor (BDNF) (PMID: 12196581). There is evidence of increased levels of BDNF in early ASD (PMID: 15893122) and it is plausible that this contributes to receptor activated pathogenesis. This idea is supported by evidence of an association between BDNF gene polymorphisms and ASD (PMID: 19582215) (PMID: 17349978). There is also evidence of reduced BDNF levels in adult males with ASD (PMID: 16876305).
Neurotransmitters do not function in isolation. There is cross-talk between the various types of neurotransmitters and GABAergic transmission is influenced by activity in other systems. Activation of the dopamine D4 receptor causes inhibition of GABAergic currents (PMID: 12417643) (PMID: 14684868) (PMID: 15363981) and activation of the serotonin 5-HT3 receptor increases GABAergic transmission (PMID: 19369358). Oxytocin boosts GABA release and induces a switch in the action of GABA from excitatory to inhibitory (PMID: 19589347) (PMID: 18655887). Caffeine acts as an antagonist at the adenosine A(2A) receptor, which causes reduced GABAergic activity (PMID: 15224155) (PMID: 15246859). High caffeine consumption in pregnancy may therefore be an additional risk factor. There is therefore the potential for other neurotransmitter systems to contribute to the pathogenesis of ASD (PMID: 19949574) (PMID: 16002261) (PMID: 18655901). Genetic studies have revealed associations between ASD and polymorphisms of the oxytocin receptor (PMID: 17893705), the serotonin transporter (PMID: 19369912) and tetrahydrobiopterin, the co-factor used by dopamine and serotonin synthesising enzymes (PMID: 19674121). These abnormalities represent part of the heterogeneity of genetic predisposition to the development of ASD and probably exert their influence through cross-talk with the GABA(A) receptor.
ADHD
The increasing incidence of ASD has occurred at the same time as increasing rates of ADHD, which has also been described as an 'epidemic'. The incidence of ADHD today is estimated at around 3-9% of the childhood population, which is roughly four to ten times the estimates for ASD incidence. Boys are about four times more likely to be diagnosed with ADHD than girls, which is about the same gender disparity seen in ASD, and both conditions have a pre-school age of onset (PMID: 19393378).
There is a pronounced co-morbidity between ASD and ADHD (PMID: 19908138) (PMID: 19998356) and overlapping genetic influences (PMID: 20148275) (PMID: 18221348) which is highly suggestive of the co-morbidity of mania and depression in bipolar disorder, hyperthyroidism and hypothyroidism in Graves' disease and the positive and negative syndromes of schizophrenia. It seems likely that, like these other conditions, ADHD and ASD are two sides of the same coin, with ASD being the deficit syndrome and ADHD resulting from a dysregulated compensation mechanism.
The normal role of compensation mechanisms is to maintain homoeostasis in the functioning of specific cell types when those cells have become hypofunctional due to reduced receptor expression, reduced receptor sensitivity or receptor blockade by antibodies as a defence against infection. The compensation must be effected without significantly increased receptor expression as this would increase the risk of infection.
If ASD is a consequence of reduced GABAergic activity, then it is probable that ADHD is a consequence of increased GABAergic activity, but perhaps with little or no increased GABA(A) receptor expression. Medications used to treat the symptoms of ADHD increase dopamine levels and it is believed that it is the increase in dopaminergic activity which is exerting a positive influence. Therefore, if ADHD is caused by excess GABAergic activity, but is improved by an increase in dopaminergic activity, then the compensation mechanism may involve cross-talk between dopamine and GABA. It has been found that activation of the dopamine D4 receptor decreases GABAergic activity (PMID: 12417643) (PMID: 14684868) (PMID: 15363981) (PMID: 19715708) and genetic alleles of the D4 receptor are associated with ADHD symptoms (PMID: 19906444) (PMID: 20305304) (PMID: 20468072). It is therefore plausible that the compensating mechanism is reduced activation of the dopamine D4 receptor, leading to increased GABAergic activity and that this compensating mechanism has become inappropriately and excessively activated in ADHD (PMID: 16209748).
Although there are overlapping genetic influences in ASD and ADHD, there are also differences, and it is possible that these differences will determine whether a child develops ASD or ADHD (PMID: 16135997) (PMID: 11462757) (PMID: 19506906) (PMID: 19757024). As would be expected, increased levels of BDNF are seen in ADHD (PMID: 18760321), as well as BDNF genetic variations (PMID: 19603419) (PMID: 17216343) (PMID: 17044097). There is also evidence of a polymorphism in a folate pathway enzyme (PMID: 18154909). However, there is a puzzling anomaly with regard to the socio-economic status of families with ADHD affected children. While ASD familes tend to be of high SES, the evidence for ADHD families apears to indicate low SES (PMID: 17514469) (PMID: 10821627).
Most studies which have attempted to find associations between ADHD and exposure to environmental chemicals have focused on urinary concentrations in affected children, rather than prenatal exposure. However, an association with prenatal exposure to organochlorine pesticides has been established (PMID: 20106937) (PMID: 17116700) (PMID: 17431497) and there is evidence of high urinary concentrations of organophosphates (PMID: 20478945). Very few studies have looked at phthalates, but there is some evidence of phthalate involvement (PMID: 19748073). High urinary levels of lead are perhaps the most common finding in studies investigating an association with exposure to heavy metals (PMID: 20434143) (PMID: 19100765) (PMID: 18941585), with some evidence for high mercury levels, also (PMID: 17177150). There is a widespread belief that ADHD symptoms can be provoked by chemicals which are added to food, such as food dyes and the preservative, sodium benzoate. The evidence for this appears to be conflicting, although there is evidence for both activation and inhibition of GABA receptors by food additives (PMID: 9438986) and sodium benzoate appears to boost GABA production in mouse neurons (PMID: 20120762).
In conclusion, the modern 'epidemics' of ASD and ADHD appear to be the negative (deficit) and positive (compensation) dimensions of the same disease process. The huge rise in the incidence of this disease process in recent times is probably partly due to pre-natal exposure to environmental chemicals which act to modulate GABA(A) receptor functioning, usually by being antagonists of the receptor, or by inhibiting its functioning by some other means, although there is also evidence for involvement of GABA(A) receptor agonists.
Although there appears to be only a little preliminary evidence implicating folic acid supplementation in pregnancy as a causative agent in the pathogenesis of this disease process, the circumstantial evidence suggests that it may be contributing. Moreover, it is very possible that the putative harmful effects of folic acid supplementation in pregnancy are not limited to ASD and ADHD. Over the same time scale as the emerging ASD/ADHD epidemic, there has also been a growing asthma epidemic affecting children more than adults, and there is evidence for maternal folic acid supplementation as a cause (PMID: 19880541) (PMID: 19052032). The GABA(A) receptor has recently been shown to exist in airway epithelial cells and GABA(A) agonists have proved effective in relieving airway constriction (PMID: 19213928) (PMID: 18408071), suggesting that GABA(A) receptor hypofunction may be a cause of asthma, as well as ASD. Folic acid supplementation may also be a contributory cause of the recent increasing incidences of type 1 diabetes and childhood obesity. Antibodies to the GABA synthesising enzyme, glutamic acid decarboxylase(GAD), are seen in type 1 diabetes (PMID: 21749442) and GABA has been shown to exert protective and regenerative effects on islet beta cells, reversing type 1 diabetes in severely diabetic mice (PMID: 21709230). GABA(A) receptor activation causes insulin secretion in pancreatic beta cells, suggesting that the proposed mechanism for the pathogenesis of ASD may also be causing type 1 diabetes (PMID: 20413510) .
