by William Davidson
Since childhood, I have experienced mild to moderate symptoms of psychiatric disorders, with symptoms of Asperger syndrome (AS) predominating. It is common for people with AS to develop obsessive interests in 'specialist subjects' and these are often of a scientific nature. For over 20 years, my own specialist subject has been the study of the causation of psychiatric illness, in particular, schizophrenia and autism.
The early years were devoted mainly to schizophrenia research. What became increasingly clear was that schizophrenia was associated with an activated immune system (http://www.ncbi.nlm.nih.gov/pubmed/7862263) . There was also a higher incidence of autoimmune diseases in the families of schizophrenics (http://www.ncbi.nlm.nih.gov/pubmed/16513876) and an association with diseases not regarded as autoimmune, but which are nevertheless known to be inflammatory conditions, such as cardiovascular disease and type 2 diabetes (http://www.ncbi.nlm.nih.gov/pubmed/19570498).
My research therefore broadened into other areas to try to find a common factor which underlay these diseases, and the factor which emerged was activation of an immune system molecule called nuclear factor kappa beta (NF-kB). NF-kB has many functions, but one of its principal functions is the control of intracellular pathogens which establish latency within cells. To do this, it causes destructive molecules, known as 'reactive oxygen species' (ROS) to be produced inside infected cells. These molecules damage the cell walls of invading pathogens.
However, it is also known that if excess ROS are produced inside cells as a result of processes unrelated to immune system activity, such as enzyme activity, this can activate the NF-kB driven immune response (http://www.ncbi.nlm.nih.gov/pubmed/10391125) and it would appear that some individuals are more genetically predisposed to such aberrant activation than others.
Intracellular pathogens gain entry into cells via specific cell membrane receptors. My research revealed that many diseases associated with NF-kB activation exhibited receptor abnormalities, and these abnormalities were very often to be found in the receptors known to be used by invading pathogens. Typically, there was reduced expression of these receptors, reduced sensitivity and, in some cases, blocking of the receptors by immune system antibodies. It seemed that the NF-kB driven immune response was attempting to protect cells from infection by pathogens by closing down the receptors used by them to enter cells. In addition, cells expressing these receptors were often seen to be reduced in number, suggestive of an immune system mechanism called 'apoptosis' (programmed cell death). However, I could find no confirmation for these ideas in the medical literature. The insights appeared to be novel.
Schizophrenia is actually two closely related syndromes which can co-exist. Symptoms of the positive syndrome include delusions, auditory hallucinations and thought disorder, while the negative syndrome presents with blunted emotions, poverty of speech, lack of will, anhedonia and impaired intellect. Excessive dopamine transmission is the prevailing hypothesis for the positive syndrome, while the neurons of schizophrenics with predominantly negative symptoms have reduced numbers of dopamine D2 receptors. Bipolar disorder, formerly known as 'manic depression', also presents with both positive and negative symptoms in the form of mania and depression.
Graves' disease, also known as Basedow's disease, is a thyroid disorder which also has a bimodal character. Typically, too much thyroid hormone is produced, as a result of autoantibodies binding to, and activating, the thyroid stimulating hormone receptor (TSHr). However, blocking antibodies are also seen at the TSHr which have the opposite effect and prevent thyroid stimulating hormone (TSH), secreted by the pituitary gland, from binding to its thyroid receptor. Sometimes, the blocking antibodies outnumber the stimulating antibodies and too little thyroid hormone is produced, and sometimes the ratio of stimulating and blocking antibodies is such that a normal amount of thyroid hormone is produced.
I found this situation of 'pathological normality' intriguing and did not believe that it could be a case of two different accidents 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 they had evolved to act in concert during times of thyroid infection. The blocking antibodies would prevent pathogens from entering thyroid cells through the TSHr. To compensate for the shortfall in thyroid hormone production, stimulating antibodies would bind to other TSHrs. If the compensation mechanism had simply relied on extra production of TSH by the pituitary, this could be self-defeating as more receptors would need to be expressed, increasing the risk of infection. The stimulating antibodies are much more powerful than TSH, so fewer receptors need to be expressed to compensate for the blocking antibodies.
Translating this model to schizophrenia, the reduced expression of dopamine D2 receptors is seen as a protective mechanism to prevent infection. To compensate for the reduction in dopamine signalling, kynurenic acid is synthesized to act as as an antagonist molecule at the glutamate NMDA receptor. This increases dopamine signalling without increasing D2 receptor expression, thus protecting neurons from infection. Too much kynurenic acid would result in positive symptoms and too little in negative symptoms. In schizophrenia and Graves' disease, this hitherto unrecognised immune system functioning has become dysregulated, resulting in disease.
Further research into the causation of other diseases revealed that this immune system mechanism, characterised by NF-kB activation, reduced receptor expression and loss of cells expressing key receptors, was a common feature of a great many non-communicable diseases. Examples of this are noradrenaline receptors and acetylcholine NACH receptors in Alzheimer's disease (http://www.ncbi.nlm.nih.gov/pubmed/18220778), insulin receptors in type 2 diabetes, serotonin 5-HT2A receptors in multiple sclerosis (http://www.ncbi.nlm.nih.gov/pubmed/10681122), GABA(A) receptors in autism (http://www.ncbi.nlm.nih.gov/pubmed/11814263) and acetylcholine NACH receptor blockade by antibodies in myasthenia gravis (http://www.ncbi.nlm.nih.gov/pubmed/20380581) . However, thus far, it is only in Graves' disease and the psychiatric disorders that a dysregulated compensation mechanism is seen to cause symptoms of disease. More will probably be discovered, but it appears that the majority of diseases caused by chronic, aberrant activation of the NF-kB driven immune response are deficit syndromes, with no apparent compensation mechanism giving rise to disease. Cells malfunction due to reduced receptor activation and, when this situation becomes chronic, cell death often occurs. An example of this is Alzheimer's disease, in which the early symptom of short term memory impairment is probably a result of reduced noradrenaline and acetylcholine receptors. However, the more severe symptoms of advanced Alzheimer's disease are a result of the death of neurons in which these receptors are underexpressed.
In the same way that abnormally excessive production of ROS within cells can activate NF-kB by mimicking its own actions, abnormal activation of receptors may also cause pathological activation of NF-kB. This can occur as a result of receptor hypofunction, which mimics the reduced expression and sensitivity of receptors or the blocking of receptors by antibodies to reduce infection by pathogens, or by receptor hyperfunction, which mimics the compensation mechanism. I have called this 'receptor activation'. An example of this is type 2 diabetes, which is usually caused by chronic overconsumption of food, resulting in chronically high levels of insulin receptor activation. This activates the NF-kB driven immune response in genetically predisposed individuals, which results in reduced expression and sensitivity of insulin receptors. 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 (http://www.ncbi.nlm.nih.gov/pubmed/3927107). Insulin receptor hypofunction is also seen in type 1 diabetes (http://www.ncbi.nlm.nih.gov/pubmed/19772820), probably as a result of chronic reduced insulin secretion in that condition, and there is also an association between anorexia nervosa and later development of type 2 diabetes (http://www.ncbi.nlm.nih.gov/pubmed/3069398).
The onset of schizophrenia, usually in late adolescence or early adulthood, follows a period when there is greatly increased expression of dopamine receptors in the late stage of brain development and it is probably this surge in dopamine signalling which causes receptor activated illness in genetically predisposed people (http://www.ncbi.nlm.nih.gov/pubmed/14535941). In autism, the onset of illness in early infancy, often after a period of normal development, follows a stage in the development of the brain when there is a peak in activity of the neurotransmitter, GABA (http://www.ncbi.nlm.nih.gov/pubmed/11744314). I believe this causes receptor activation of an NF-kB driven immune response, resulting in reduced GABA(A) receptor expression.
Because these diseases are being caused by chronic, aberrant activation of the NF-kB driven immune response, which is being activated by processes which mimic its own actions, I have called them 'Immune Mimicry Diseases' (IMDs). A much more detailed explanation of IMD theory can be found on my blog at Integrative Theory of the Causation of Non-Communicable Diseases: Immune Mimicry Disease (IMD) Theory. IMDs are known to be caused by a combination of genetic and environmental/lifestyle factors. The most important genetic factors may be immune system abnormalities which predispose to aberrant NF-kB activation, enzyme variants and receptor variants. The most important enzymes involved probably belong to the cytochrome P450 superfamily.
Environmental and lifestyle factors which contribute to IMD pathogenesis include microbes which establish latency inside cells, lack of immune challenge in infancy ('hygiene hypothesis'), lack of vitamin D, chemical pollutants, environmental metals, food and chemical intolerance/sensitivity, pro-inflammatory diet, lack of physical exercise and psychological stress. Lack of immune challenge in infancy due to oversanitised living conditions and lack of vitamin D may both 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. A diet high in fats, refined carbohydrates and chemical additives is known to be pro-inflammatory and will contribute to NF-kB activation, as will a diet which is low in antioxidants.
Chemical pollutants, particularly molecules which bind to the intracellular aryl hydrocarbon receptor and are metabolised at the nuclear membrane by cytochrome P450 enzymes, liberating hydroxyl radicals in the process, are known to activate NF-kB, and this could explain much environmental illness, particularly in people with P450 enzyme polymorphisms. IMDs are more common in cities than in rural areas and this is probably due to air pollution, principally from motor vehicle exhausts. Vehicle pollution includes polycyclic aromatic hydrocarbons, benzene and metal oxides, all of which induce cytochrome P450 enzyme activity.
My research into the causation of autism convinced me that it, too, had a bimodal character, with autism symptoms being the deficit syndrome and ADHD symptoms resulting from a dysregulated compensation mechanism. There is pronounced co-morbidity between autism and ADHD (http://www.ncbi.nlm.nih.gov/pubmed/19998356) and overlapping genetic influences ("http://www.ncbi.nlm.nih.gov/pubmed/20148275). Both autism and ADHD have a pre-school age of onset and the sex ratio of three affected boys for each affected girl is the same in both conditions.
The greatly increased incidence of both autism and ADHD is due in large part to increased awareness of these conditions and broadening diagnostic criteria. However, there is also a belief that this is not sufficient to explain all of the increase and that some environmental factor must also be responsible. I found the temporal association between increasing folic acid supplementation and increased rates of autism/ADHD particularly intriguing. There appeared to be no direct evidence to support a causative association, but there is evidence of folate receptor blocking antibodies (http://www.ncbi.nlm.nih.gov/pubmed/18461502) and variants of enzymes involved in folic acid and folate metabolism (http://www.ncbi.nlm.nih.gov/pubmed/19440165) (http://www.ncbi.nlm.nih.gov/pubmed/17597297).
Other chemicals which have been implicated in the autism 'epidemic' include insecticides (http://www.ncbi.nlm.nih.gov/pubmed/17938740), phthalates (http://www.ncbi.nlm.nih.gov/pubmed/19822263) and mercury (http://www.ncbi.nlm.nih.gov/pubmed/19106436).
Further research revealed a crucial fact: folic acid, phthalates methyl mercury and a variety of insecticides, including organophosphates, organochlorines and pyrethroids are all antagonists of the GABA(A) receptor. There is reduced expression of GABA(A) receptors in autism, which is suggestive of an IMD deficit syndrome. Moreover, onset of autism symptoms in early infancy follows a peak in GABA signalling as GABA is involved in early brain development. This is reminiscent of the onset of schizophrenia in late adolescence and early adulthood coming after the peak of dopamine signalling in late adolescence, when the expression of dopamine receptors is greatly increased.
The hypothesis which emerged is that prenatal exposure to GABA(A) antagonists causes a reduction in GABA signalling in the developing brain of the foetus. This forces the GABA system to become more sensitive. When this sensitised GABA system reaches a peak of activity in early infancy, the combined effect of this peak of GABA activity, heightened sensitivity of the GABA system and genetic predisposition may cause receptor activation of an aberrant immune system reaction which results in GABA(A) receptors becoming underexpressed and hypofunctional. This reduced GABA signalling results in the symptoms of autism.
If ADHD is the positive syndrome, then the symptoms must result from excessive GABA signalling, but without increased expression of GABA(A) receptors. Medication which improves ADHD symptoms increases production of dopamine in the brain. Activation of the dopamine D4 receptor decreases GABA signalling (http://www.ncbi.nlm.nih.gov/pubmed/12417643") and genetic alleles of the D4 receptor are associated with ADHD symptoms (http://www.ncbi.nlm.nih.gov/pubmed/19906444). It is therefore plausible that the compensating mechanism is reduced activation of the dopamine D4 receptor and that this compensation mechanism has become excessively activated in ADHD (http://www.ncbi.nlm.nih.gov/pubmed/16209748) .
Further evidence that ADHD is the positive syndrome of autism and that both are caused by prenatal exposure to GABA(A) receptor antagonists are the association of a folate pathway enzyme variant in ADHD (http://www.ncbi.nlm.nih.gov/pubmed/18154909), an association with prenatal exposure to organochlorine pesticides in ADHD (http://www.ncbi.nlm.nih.gov/pubmed/20106937) and evidence of high urinary concentrations of organophosphates in ADHD (http://www.ncbi.nlm.nih.gov/pubmed/20478945). There is also evidence of phthalate involvement (http://www.ncbi.nlm.nih.gov/pubmed/19748073) and mercury involvement (http://www.ncbi.nlm.nih.gov/pubmed/17177150) in ADHD.
In conclusion, the modern 'epidemics' of autism and ADHD are 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 due to prenatal exposure to chemicals which act as antagonists at the GABA(A) receptor. Although there appears to be no direct evidence implicating folic acid supplementation in pregnancy as a cause of this disease process, the circumstantial evidence does suggest this. Moreover, it is very possible that the harmful effects of folic acid supplementation in pregnancy are not limited to autism/ADHD. Over the same time scale as the emerging autism/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 (http://www.ncbi.nlm.nih.gov/pubmed/19880541). The GABA(A) receptor has recently been shown to exist in airway epithelial cells and GABA(A) agonists have been successful in relieving airway constriction (http://www.ncbi.nlm.nih.gov/pubmed/19213928), suggesting that GABA(A) receptor hypofunction may be a cause of asthma, as well as autism/ADHD.
About the Author:
William Davidson is 57 and has lived with Asperger syndrome since childhood. He lives in Strathaven, Lanarkshire, Scotland, UK, where for the past 10 years he has been employed as a grounds maintenance worker in local parks. In common with many Asperger sufferers, he has a fascination with scientific specialist subjects, particularly the study of the etiology of non-communicable disease. His main area of interest for most of his adult life has been in researching psychiatric and neurological disorders. David is also interested in environmental science subjects, in particular, global warming.
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