What is CFS?
Chronic Fatigue Syndrome (CFS) is also known as myalgic encephalomyelitis (ME), post-viral fatigue syndrome, chronic fatigue and immune dysfunction syndrome.The disease is characterized by a severe, prolonged fatigue lasting for more than six months. Patients complain of extreme exhaustion; they tire easily in the course of normal activities, and may even be unable to perform normal tasks. Fatigue is accompanied by a number of other symptoms: neurocognitive impairments (memory loss, difficulty in concentrating), muscle pain, headaches, unrefreshing sleep, sore throat, persistent low grade fever, enlarged lymph nodes.
CFS shares overlapping symptomology with several diseases. Before making a diagnosis of CFS, other specific illnesses in which fatigue is the core symptom (such as hypothyroidism, anemia, Lyme disease, lupus, diabetes, cancer…) must be excluded.
Who gets CFS?
CFS affects between 0.1 and 0.4 percent of the population. Anybody can get CFS, however women are affected more frequently than men by a ratio of 4:1. People exposed to poor working conditions, or stressful work, seem to face a higher risk for CFS; however stress alone does not cause CFS. The most common age of onset is between 20 and 40 years. CFS can also occur in children and adolescents.
What causes CFS?
There is a long history of medical interest in CFS, and in the last decade an increasing amount of studies have been done to unravel the pathogenesis of CFS. However, at this time the etiology is not known and no unique pathological abnormalities have been identified.More and more evidence points towards a combination of factors (genetic, infectious, environmental, etc.) being important in the development of chronic immune dysfunction, the cardinal finding in all CFS patients.
Over the past several years, scientists at R.E.D. Laboratories have been unraveling the biochemical and molecular mysteries surrounding CFS. The result of these efforts has been to create a number of objective clinical laboratory assays that can assist the physician in not only making the diagnosis of CFS, but can also help in staging the severity of disease and monitor the effect of a therapy.
INTERFERON SYSTEM DYSREGULATIONS IN CHRONIC FATIGUE SYNDROME
Interferons are key immune regulators that are induced following a viral infection
Interferons will promote the production of a number of anti-viral enzymes including Ribonuclease L (RNase L), 2'-5' oligodenylate synthetase (2-5OAS), and the double-stranded RNA-dependent kinase, PKR.
2’-5’ oligoadenylate synthetase recognizes double-stranded RNA of viral origin, and subsequently produces a messenger molecule, 2’-5’ oligoadenylate (2-5A). 2-5A will activate latent RNase L; activated RNase L then proceeds to cleave viral RNA.
This process ultimately results in viral destruction and programmed death of the infected cells.
Likewise, PKR is activated upon binding viral double-stranded RNA. Activated PKR will in turn initiate a number of cellular pathways, ultimately leading to programmed cell death of infected cells (through the translation factor eIF2alpha), and to the synthesis of a potent immune modulator, Nitric Oxide (a response mediated by the transcription factor NF-kappaB).
In a properly functioning immune system, these pathways are tightly regulated to contain a viral infection. In some stress situations however, the cells may produce odd RNA/DNA fragments that will lead to an improper, non-regulated activation of the 2-5A/RNase L/PKR system.
This odd RNA/DNA may result from the reactivation of endogenous retroviruses sequences; from the release of DNA/RNA fragments following cell damage; from the release of chemically modified RNA/DNA fragments due to toxic chemicals/heavy metals exposure.
Improper activation of the 2-5A/RNase L/PKR pathway is associated with various cellular and immune dysfunctions
» Cleavage of RNase L by the inflammatory protease, elastase
Upon excessive inflammatory response, inflammatory proteases such as elastase can cleave RNase L, producing a truncated form of the enzyme. This truncated enzyme is observed in a subset of CFS patients, and can be used as a marker to characterize the disease.
It was shown that activated RNase L, bound to the 2-5A messenger, is less sensitive to cleavage; but in case of 2-5OASL dysfunction the correct 2-5A molecules are not produced, and cannot exert their protective function.
RNase L cleavage in CFS therefore results from the combination of two events: production of elastase as part of an inflammatory response, and dysfunction of the 2-5OASL pathway.
» Increased, uncontrolled activity of RNase L results from the cleavage
The truncated form of RNase L still present ribonuclease activity, but this activity is uncontrolled. Excessive RNA cleavage leads to the apoptosis of immune cells, and thereby to a general dysfunction of the immune system. Opportunistic infections (herpesviruses, mycoplasma, chlamydia...) will develop more easily in CFS patients, and contribute to the severity and persistence of the disease.» RNase L fragments at the origin of channelopathies
RNase L fragments have the ability to interfere with ion channels function, resulting in channelopathy, which, in turn, results in a host of symptoms such as unexplained sweats, transient hypoglycemia, reduction in pain sensitivity threshold, depression, visual problems, and hypersensitivity to toxic chemicals.» Activation of PKR and excess production of NO
PKR dysregulation leads to an increased production of Nitric Oxide. Nitric oxide (NO) is an important cellular messenger and its dysregulation has many detrimental effects in the immune system.
When PKR and Nitric Oxide are in excess, Natural Killer and T-lymphocyte cells activities are decreased, which may favor the development of opportunistic infections.
On the other hand, excess NO will contribute to the maintenance of a chronic inflammatory condition. Excess NO also favors the production of peroxynitrite, a very potent oxidative compound that causes significant oxidative damage, which is a hallmark of CFS.» Interferon-induced proteins interfere with the thyroid hormone system
Chronic activation of the interferon system may finally interfere with thyroid hormone function. Some members of the 2-5OAS family of proteins indeed share structural homologies with the thyroid receptor, and have the ability to repress or suppress its cellular effects. This will lead to thyroid hormone resistance, with effects similar to hypothyroidism (explaining the extreme fatigue), although patients present normal levels of thyroid hormone.
Immune dysregulation is a hallmark of CFS
The involvement of elastase in the pathogenesis of the disease indicates that CFS is to a large extent an inflammatory disorder. The underlying cause of inflammation, however, remains unclear. Among the factors that could contribute to the onset or maintenance of a chronic inflammatory condition, R.E.D. Laboratories scientists are particularly interested in the consequences of intestinal dysfunctions, as well as in the role of persistent viral infections (see Intestinal Dysfunction and Viral Infections pages).