Core abnormalities and dysfunctions in CFS

1. Immune system dysfunction  -  RnaseL abnormalities and accompanying STAT1-alpha and p53 deficiencies, increased  neutrophil  apoptosis, over-activation of the TH2 cytokines, and under-activation of TH1 cytokines, etc.

2. Chronic virus and / or mycoplasma infection co-existing with RnaseL abnormality

3. Single and Multiple virus infections  -  HHV6a virus, EBV, CMV, Coxsackie virus, stealth virus (from a subclass of retroviruses called "spumaviruses"), JHK virus, Parvovirus B-19, Enteroviruses mainly Cocksackie B virus infections of the  spinal fluid, brain, blood, nerve tissues and muscle tissues. 

4. Single and Multiple mycoplasma infections. 6 pathogenic mycoplasmas have been found in CFS :   M. fermentans, M. penumoniae, M. hominis, M. penetrans, M. pirum,  M. incognito. Co-exising with a virus infection in a  minority of cases.

5. Chronic Chlamydia pneumonia infection

6. Adrenal gland abnormalities  -  symptoms of adrenal burn-out, many of the symptoms found in Addison's disease etc.

7. Thyroid gland abnormalities  -  detected by special TRH tests

8. Pituitary gland and Hypothlamus abnormalities  -  HPA axis dysfunction

9. Chronic Ciguatera poisoning

10. Brain hypo-perfusion and lesions on the brain  -  causing brain fog, mental confusion, inability to concentrate, etc.. may be caused by viral or mycoplasma infections or toxicity in the brain.

11. Chronic insomnia caused by neurotransmitter depletion in the brain and nervous system and /or lack of neurotransmitter precursors in the diet. There is excess NMDA activity in the brain and depleted GABA activity and Serotonin and Melatonin activity, resulting in insomnia and sleep deprivation.

12. Excessive stress and anxiety over a prolonged period of time, leading to adrenal burn-out, nervous exhaustion and accompanying immune system weaknesses.

13. Genetic factors which make one susceptible to CFS  or  an interaction of genetic factors with environmental factors which make one susceptible to CFS. Gene tracking is showing up abnormal gene activity in CFS patients.

14. Mercury toxicity from mercury fillings and / or mercury in one's food and environment   -   mercury has destructive effects on the brain, nervous system, DNA, hypothalmus and pituitary glands, immune system and endocrine system

15. Undiagnosed Lyme disease

16. Excess Toxicity in the body from air pollutants, pesticides and herbicides in food and water, and exposure to chemicals in one's environment

17. Damaged mitochondria and defective ATP production throughout the body, particularly in muscle tissues  -  this accounts for the muscular pains and intolerance to exercise. It also accounts for defective immune system function.

Secondary abnormalities and dysfunctions in CFS

1. Increased oxidative stress in bones, muscles and tissues

2. Serious vascular disorders  -  inflammation in the blood vessels, failure to metabolise acetylcholine, heart beat irreglarities

3. Orthostatic Intolerance

4. Low blood volume

5. Parasitic infection of the intestines and / or overgrowth of Candida Albicans in the intestines

6. Toxicity in the intestines  -  build-up of undigested matter over many years, with toxins and poisons being re-absorbed into the blood system etc..

7. Underlying allergies and leaky gut syndrome

8. Glutathione depletion and deficiency

9. Liver abnormalities and seriously impaired detoxification  -  many CFS patients have swollen livers and fatty livers

10. Excessive use of antibiotics resulting in depletion of beneficial bacteria in the intestines. Accompanying digestive difficulties, irritable bowel syndrome. 

11. Abnormal red blood cell structure

12. Substance P is elevated in CFS / ME patients

13. High Beta 2 micro-globulin levels

14. High levels of circulating plasma RNAs

15. High levels of quinolinic acid. A serious neurotoxin.

16. High serum ACE levels

17. Raised levels of urinary toxins  -  CFSUMI, beta-alanine, Tartaric Acid and Arabinose

18. Coagulation abnormalities revealed by  Prothrombin Time (PT),  Activated Partial Thromboplastin Time (PTT) by photo-optical method,  Fibrinogen by nephelometry method. 

19. Crimson crescents in the back of the mouth or throat

20. Enzyme deficiencies and accompanying poor digestion and absorption of nutrients

21. Poor quality nutrition over a prolonged period of time (junk foods and trans-fatty acids ) leading to increased damage from free radicals and to immune system weaknesses and nervous system dysfunction.

Patients will vary in the number of the above abnormalities they possess, some will have two of the Core abnormalities and dysfunctions and three of the Secondary abnormalities,  some will have five of the Core abnormalities and dysfunctions and seven of the Secondary abnormalities, others will have eight of the Core abnormalities and dysfunctions and ten of the Secondary abnormalities. This has led to a number of sub-groups within the heading "Chronic Fatigue Syndrome" . 

Examples of Sub-groups

Patients in a particular sub-group may share 6-10 abnormalities and dysfunctions but they are very different to those in other sub-groups who may have less or more abnormalities  -  yet they all have CFS. Thus the symptoms and ' Diagnostic markers ' will vary from one group of patients to another and indeed vary from one patient to another in sufficiently small groups or samples of the patient population. 

These abnormalities do not exist in isolation, as one abnormality will create, contribute to, or worsen another abnormality and so on, increasing the overall burden on the body. One example is glandular abnormalities which contribute to immune system abnormalities and vice versa, these immune system abnormalities lead on to chronic infections in various parts of the body and to further dysfunctions and abnormalities. Another example is mitochondria abnormalities which lead onto immune system abnormalities, muscular abnormalities and endocrine abnormalities, and these in turn lead onto further abnormalities, and so on. In fact the mitochondria abnormalities found in CFS affect the entire body as mitochondria are the body's "energy factories". Another is neuro-endocrine abnormalities which consist of neurological and endocrine abnormalities which in turn can lead to immune system abnormalities. The body is a series of complex interacting systems, where one or more abnormalities can create or contribute to other abnormalities.  

The long awaited Diagnostic marker has not been found by researchers and scientists because there are sub-groups even within the small groups of patients researchers have examined. Researchers will typically find a particular abnormality among 40 - 70% of their patient population, and wonder why this abnormality cannot be found in the other 30 - 50% of the patient population. These findings appear contradictory and confusing to researchers, unless one accepts the existence of sub-groups within CFS. Once one accepts this, one can progress towards more effective research methods, and more effective diagnosis and treatment. This will mean very comprehensive, thorough and sensitive tests of all CFS patients to establish the specific abnormalities and dysfunctions in each individual case, and then dividing patients into relevant sub-groups according to their diagnostic markers.

1. An abnormal immune system

1. (e) Summary of immune system abnormalities

Like AIDS, CFS has various stages. There are important  immune system differences between these various stages in CFS. Examples of stages would be those with varying levels of mild to moderate CFS, those with severe CFS and those with very severe CFS who are bed-ridden or confined to a wheelchair, then there are those people who have had CFS for 2 years or less, those who have had it 2-5 years and those who have long-term CFS. Progression to severe forms of CFS can be gradual or sudden, depending on the person's genetic and medical profile. Research shows the following: 

(i) a malfunctioning 2-5A synthetase/ribonuclease L pathway (which responsible for targeting and destroying viruses). The ratio of 37 kDa to the normal 80 kDa form of RNase-L is high in CFS patients.
- Upregulation of RNase L enzyme activity. This can be 1,500 times above normal levels in seriously ill CFS patients.
- Abnormally high levels of 2-5A (the molecule that converts RNase L from its latent to its active state) and 2-5A synthetase
- The ratio of 37 kDa to the normal 80 kDa form of RNase-L is high in CFS patients.The ratio of the 37 kDa to 80 kDa RNase-L is reported to correspond to a patient’s clinical status and can be used as an objective marker of function.
Research now shows an array of dysfunctions in the 2-5A/RNaseL/PKR pathways. The 37 kDA protein inhibits human protein synthesis and enzyme production, depletes ATP and adversely affects many body functions. 
The reason is for this abnormality is unclear, it may be triggered by a virus, bacteria, fungus or mycoplasma or stress or a build-up of environmental toxins. It has recently been found that CFS patients infected with mycoplasmas had significantly more cleavage fragments of RnaseL, this may be responsible for disrupting the 2-5A synthetase/ribonuclease L pathway.

(ii) low Natural Killer cell counts & abnormal Natural Killer cell function. Reseachers found an increased proportion of CD56+CD3+ T cells, which may account for the decreased natural killer (NK) cell cytotoxic activity seen in several studies of CFS patients. Researchers also also found a decreased percentage of CD56+Fcgamma receptor+ NK cells, which suggests a reduced capacity for antibody-dependent cellular toxicity

(iii) abnormal CD8 cytotoxic lymphocyte activity

(iv) CFS has a number of stages, in one stage patients have abnormally high T cells which makes them very ill and can produce cognitive and memory problems. Greater numbers of activated T cells were associated with a greater frequency of tender lymph nodes and cognitive difficulties and sleep problems. In another stage they have abnormally low levels of T cells which leaves them susceptible to opportunistic infections. Among CFS patients the degree of cellular immune activation and cytokine levels is associated with the severity of CFS-related physical symptoms, cognitive complaints, and perceived illness burden.

(v) reduced CD8 cell counts

(vi) an abnormally high CD4 to CD8 cell ratio. In CFS, high levels of TH2-type CD4’s in the blood are not protecting people from constant outbreaks of thrush and candidiasis. In CFS patients, CD4 / CD8 ratios often run from 3.0 to as high as 6, which is way above the norm of 1.8 . The higher the CD4 / CD8 ratio, the worse the symptoms (fatigue, food allergies, chemical sensitivities, insomnia and neurological problems).

(vii) abnormally low levels of friendly bacteria in the intestines, particularly those strains which support the immune system.

(viii) poor lymphocyte response to mitogens and frequent immunoglobulin deficiencies, most often IgG1 and IgG3

(ix) abnormal antigen presentation and inefficent humoral system function. There is a strong possibility that B-cells and T-cells have lost their memory for targeting and destroying certain pathogens, thus these pathogens are free to cause internal injuries. Yet certain parts of the immune system (cytokines) remain over-activated in response to such pathogens.

Too many TH2 cytokines and too few TH1 cytokines, suggesting one part of the immune system (TH2) is over-active and ineffective at combatting pathogens while the other (TH1) is underactive or unactive. TH2 cytokines are pro-inflammatory, capable of producing pains, aches, inflammation throughout the body. They can also affect the functioning of the brain and central nervous system. Since TH2 cytokines and humoral immunity depend on antigen presentation, it is obvious that deficits in antigen processing, transport and presentation would have an adverse effect on humoral immunity (and TH2 cytokines) keeping them in a constant state of activation but ineffective in their ability to target and destroy pathogens

(x) Inadeqate production of ATP (Adenosine Triphosphate) which is necessary for transporting antigen to the cell surface (for an effective immune response). ATP is produced in the mitochondria of each living cell. But normal ATP production is impossible when the mitochondria are being attacked and destroyed by a virus (CAV virus). This leads to a defect in antigen presentation and processing. (See below)

(xii) weak cell mediated immunity

(xiii) impaired ability of lymphocytes from CFS patients to produce IFN-gamma in response to mitogenic stimuli. The inability of lymphocytes from CFS patients to produce IFN-gamma might represent a cellular exhaustion as a consequence of persistent viral stimulus. Elevated levels of leukocyte 2'5'-oligoadenylate synthetase, an IFN-inducible enzyme, has been found in lymphocytes of CFS patients.

(xiv) High levels of IFN-alpha. This is implacated in fatigue and a slowing down of mental information processing speeds, verbal memory, and executive functions.

(xv) patients with CFS have significantly higher levels of bioactive TGF-beta levels compared to healthy controls and to patients with various diseases known to be associated with immunologic abnormalities.

(xvi) CFS patients have higher levels of sTNF-RI or sCD120a and sTNF-RII or sCD120b. Levels of sTNF-Rs are negatively correlated with NK cell cytotoxic and lymphoproliferative activities in CFS.

(xvii) elevated levels of neopterin in CFS patients

(xviii) elevated levels of Beta-2 microglobulin. Beta-2 microglobulin is a marker of immune activation, high levels suggest a serious viral or mycoplasma infection

(xviv) an abnormal Hypothalamic-Pituitay-Adrenal (HPA) axis which has an impact on immune system functioning. Hormone and neurotransmitter levels can have a direct effect on the functioning of immune system cells.

Once the immune system is compromised this leaves the body wide open to viral / fungal / bacteria / mycoplasma attack. This applies in particular to the malfunctioning 2-5A synthetase/ribonuclease L pathway which is responsible for targeting and destroying viruses. Several pathogens do attack the body as it continues to weaken over time. Recent research shows that the vast majority of CFS patients are infected with one or more of the following pathological organisms: HHV6a virus, stealth viruses, JHK virus, HTLV virus, CMV virus, EBV virus, the CAV virus, Enteroviruses (in muscle and tissue) and mycoplasma parasites while healthy controls have no such infections.
Research by Dr. John Martin shows a strong relationship between stealth virus infection and chronic fatigue syndrome. Stealth viruses are a new discovery and were given their name because they apparently lack crucial antigenic determinants that would act as effective targets for cell mediated anti-viral immunity. The viruses can be grown in a wide range of cells of both human and animal origins, inducing a foamy, vacuolating cytopathic effect (CPE). A similar CPE can be seen in brain biopsies obtained from severely ill stealth virus infected humans and from experimentally inoculated animals. To summarise, stealth viruses can live undetected and unrecognised in the human body, and the immune system is powerless against them. All of the above viruses and mycoplasmas are recent discoveries in the world of medicine / science, and are shedding new light on old and new diseases. The above pathogens may be causative, a co-factor or opportunistic in the illness. They may be exploiting weaknesses in the immune system OR they may actually trigger the illness. The HHV6a virus, CAV virus and mycoplasma parasites are capable of attacking immune system cells, and the CAV virus can infect the mitochondria of cells. HTLV virus, a close relative of HIV, has also been found in CFS patients. HTLV virus infects macrophages, B-cells and T-cells, thus undermining immune system function. Pathogens which attack and destroy the human immune system are rare.

Opportunistic or secondary infections in ME / CFS patients include one or more of the following: Coxsackie virus, Herpes 1 / 2 / 3 viruses, Candida Albicans, Candida Tropicalis, Pneumocystis carinii (PCP), streptococcus and staphylococcus bacteria. Since individual patients have different genetic structures and different levels of immunity to begin with and different exposure levels to viruses and other pathogens, it is obvious that the viral / bacteria / mycoplasma / fungal disease will vary from victim to victim. Though the abnormal immune system is the one feature which is present in all cases. These pathogens are capable of infecting important organs and glands, disrupting hormone output and giving rise to a wide variety of health problems and symptoms. Once such pathogen is Human Herpes Virus 6a or HHV-6a virus.

HHV-6a virus deserves special attention as it has been found in a high percentage of ME / CFS patients in several studies, this virus attacks the CD4 cells and Natural Killer cells of the immune system, thus compromising vitally important parts of the immune system. It can also attack the brain and central nervous system, the bone marrow, the glands and the lymph system - the virus has been found in these body parts. HHV-6a also plays an important part in AIDS, having a close working relationship with the HIV virus. HHV-6a is present at the very early stages in HIV infection, when T-cell counts are normal. This is very unusual, as it normally takes from 2-7 years for opportunistic infections to occur after initial HIV infection. HHV-6a is far more destructive than the actual HIV virus. For some reason, HHV6a virus becomes extremely virulent and destructive when it is combined with the HIV virus, it has been found that both produce bio-chemicals which assist the other, speeding up the onset of full blown AIDS. HHV6a virus is also implicated in Multiple Sclerosis (MS) where it attacks the brain and central nervous system and this virus has also been found in Fibromyalgia patients and some Cancer patients. Since HHV6a virus can be found in Multiple Sclerosis, in Fibromyalgia, in ME / CFS and in AIDS, it is not surprising that these diseases share many characteristics. HHV6a is contagious as it is airborne, it can be picked up in the air, in water and food supplies, from physical contact, on objects and in the transmission of body fluids, just like a flu virus. The virus thrives in conditions of weakened immunity. This virus has only been recently identified in humans, due to improvements in PCR testing. Considering the destructive effects of HHV-6a virus it is amazing that many developed countries do not have testing equipment for identifying HHV-6a virus infection in human blood and tissue. Similarly there is a lack of equipment for identifying infections by mycoplasma parasites, HTLV virus, JHK virus, CAV virus and stealth viruses, all of which are destructive to the human body.

As regards mycoplasmas, it has recently been found that CFS patients infected with mycoplasmas had significantly more cleavage fragments of RnaseL, this may be responsible for disrupting the 2-5A synthetase/ribonuclease L pathway (which responsible for targeting and destroying viruses). It has been recently acknowledged by scientists / researchers that serious exposure to toxic chemicals and pollutants can initate an infection by mycoplasmas.

In ME / CFS the immune response to opportunistic infections is defective, the TH2 arm of the immune system (humoral immunity) becomes overactive, while the TH1 arm (cell mediated immunity) remains underactive or unactive. The overactive TH2 arm leads to the production of large quantities of antibodies, TH2 cytokines, IL-1, TNF and Substance P but these are unable to effectively target and destroy the germ(s), due to a deficit in antigen presentation / processing, this leads to an excess build-up of cytokines producing inflammation, pain and aches throughout the body. In the condition, CD4 cells begin to outnumber CD8 cells, raising the the CD4 / CD8 ratio. The higher the CD4 / CD8 ratio, the worse the symptoms (fatigue, food allergies, chemical sensitivities, insomnia and neurological problems).

This makes it appear that the overactive immune system is fighting a non existant or "ghost pathogen", when in reality the problem is due to a malfunctioning immune system. As this condition worsens, the excessive levels of TH2 cytokines disrupts hormone output, the glands, the HPA axis, the brain, the CNS and important biological feedback loops, leading to deficiencies of important bio-chemicals, hormones, chemical messengers and more health problems and symptoms. Excessive TH2 cytokines over long periods of time can damage these key systems and down-regulate other parts of the immune system (NK cells, CD8 cytotoxic lymphocytes, cell mediated immunity, CD4 cells). The overactive arm (TH2) of the immune system may over a prolonged period of time lead to increased immune cell stress / exhaustion  ;  evidence is emerging of high immune cell apoptosis rates. There are additional complicating factors, stealth viruses are capable of infecting the body and since they lack crucial antigenic determinants the immune system cannot recognise them and destroy them, but they set off a TH2 cytokine response which is ineffective at combatting the virus, the excessive levels of TH2 cytokines build up over time leading to serious health problems. HHV-6a which directly attack the immune system worsen this situation, destroying NK cells and T cells, adding new factors to a deteriorating problem. CD cell numbers, NK cell numbers will vary according to what stage of the illness the patient is at. This combination of factors leads onto a "domino effect" where one set of abnormalities creates new abnormalities and new problems and symptoms and so on, thus explaining the complex, wide ranging symptoms found in CFS patients, and the different states in CFS.

Why is the immune system not working properly ? Why are there so many people suffering from immune system abnormalities and new diseases ? Why have the CDC in the USA found a rising incidence of disease worldwide ? What modern day factors could account for this - very high levels of stress, decreasing levels of sleep time, changes in the diet from organic nutrient rich foods to fatty, sugar-laden foods with no nutrients, electro-magnetic pollution, new virus and bacteria mutations, greater foreign travel, too many chemicals and dangerous toxins in the air, water and food supplies ? In 1945, the annual production of chemicals in the United States was eight million tons. By 1985, it had risen to 110 million tons — 950 pounds of chemicals for every US citizen, every year. People in western and eastern Europe have had similar exposure. In addition to chemicals, we’re now being exposed to unprecedented numbers of foreign pathogens for various reasons, including the ease of international travel. On top of the exposures that are occurring as a result of societal change, the medical literature has documented that approximately 100 million Americans were injected with more than two dozen monkey viruses that contaminated the early polio vaccines.

Every day we are breathing in thousands of toxic chemicals from cars, trucks, cigarette smoke, factories, incinerators, odour sprays, disinfectants, cleaning chemicals etc. ; eating foods with additives, trans fatty acids, toxins and chemicals ; drinking water and sodas with chemicals, toxins and additives. This level of environmental contamination is unprecedented in human history. These chemicals and toxins are poisonous to the human immune system. After much research and medical practise, Dr. Sarah Myhill (of the British Society for Allergy, Environmental and Nutritional Medicine) believes that CFS is caused by environmental pollutants, especially organophosphate poisoning and household chemicals eg. timber preservatives, damp course treatment, cleaning chemicals, pesticides, herbicides, carbon monoxide. Professor Peter Behan, Consultant Neurologist in Glasgow, found that the mechanism in organophosphate poisoning is the same as that in CFS. Evidence is mounting that environmental pollution may lie at the root of weakened immune systems and the appearance of new diseases and illnesses. Microbes which were once harmless are becoming deadly as human immune systems continue to weaken.

Some patients in the USA have reported rapid progress and eventual recovery from taking a supplement known as "Transfer Factor" which is antigen specific, this apparently teaches the immune system to effectively target specific germs and destroy them. Several studies show that Transfer Factor improves antigen presentation, T-cell function and Natural Killer cell function and numbers. Scientific trials are still being conducted with this product in the USA and Canada (in the year 2002). Other studies show that an experimental drug called Ampligen is very effective and in some cases it has led to a complete recovery for patients. Ampligen restores the 2-5A synthetase/ribonuclease L pathway to normal, thus helping the immune system to effectively target and destroy viruses. Trials with Ampligen are still under way in the USA (in the year 2002). Doctors in Canada (where Ampligen is available on prescription since 2001) claim that Ampligen has led to significant improvements in their patients.

2. Damaged mitochondria: Research shows significant viral infection of the mitochondria in CFS patients, and significant destruction of the mitochondria. Since the mitochondria are involved in cell function, cell energy creation and cell energy expenditure and are found all over the body, this destruction of mitochondria leads onto a very wide range of problems and symptoms. It is no surprise that patients have a low exercise tolerance level, and weak muscles, pains and cognitive problems after exercise. In short it is devastating to the body, damaged mitochondria would explain much of the chronic fatigue, exhaustion, brain problems, muscle pains, etc.. found in the condition.

Here again there is immune system involvement - experts in immunology have stated that the single event that triggers a strong CD8 Killer T cell response against virus infected cells is when a cell presents viral antigen on the cell surface. In order for a cell to do this it must be healthy and produce enough ATP (Adenosine Triphosphate) to transport antigen to the cell surface. ATP is produced in the mitochondria of each living cell. But normal ATP production is impossible when the mitochondria are being attacked and destroyed by a virus. Inadequate ATP leads to a defect in antigen presentation and processing and this can lead to immune system dysfunction. Is there a virus / mycoplasma / toxin (Ciguatera) / rogue enzyme (37 kDa) disrupting or destroying the mitochondria and using up valuable ATP,  thus making the patient very tired and exhausted and generating immune system dysfunction ??.

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Studies show abnormal levels of cortisol, HGH, melatonin and serotonin, shrunken adrenal glands and an abnormal HPA axis (Hypothalmus Pituary Adrenal axis), high levels of ciguatoxin, a potent neurotoxin, and significant lesions in the brain and damage to brain cells. This may point to (a) excessive levels of cytokines and disruptions to neuro-endocrine function (b) deficencies in mitochondria function (c) damage caused by ciguatera, which is a potent neurotoxin (d) disruptions caused by toxic chemicals / pollutants (and a compromising of the blood brain barrier) (e) infection by a pathogen (virus / mycoplasma), HHV-6a virus produces quinolinic acid which is a severe neurotoxin.

The abnormal immune system may be the starting point for deficiencies in important biological feedback loops, it is known that excessive levels of TH2 cytokines and an over-active (TH2 / humoral) immune system over a prolonged period of time can produce inflammation, sleep disturbances, aches, pains and mental confusion. Excessive cytokines can disrupt hormone output, the glands, the brain, the neurons and CNS and important biological feedback loops, leading to deficencies of important bio-chemicals, hormones, chemical messengers and more health problems and symptoms. There is a domino effect here where disruptions to one biological feedback loop interferes with another biological feedback loop and so on, affecting the functioning of several areas, adding to the complexity of the illness and the suffering of the patient.

Viral infection of the mitochondria can worsen this scenario as mitochondria are involved in energy production at the cellular level throughout the entire body, including various neuro-endocrine and immunological functions. A weakening condition leaves one susceptible to opportunistic viruses and mycoplasmas. Viruses such as HHV-6a can attack the nervous system, the brain, the glands, immune system, the lymph, the organs and worsen this situation, HHV-6a virus also produces quinolinic acid which is a severe neurotoxin ; all of this adds new factors to the whole scenario which make diagnosis and treatment very difficult.

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