Two Newcastle research studies – one of them part-funded by The ME Association – have concluded, having investigated immune responses and muscle dysfunction in people with M.E.
IMMUNE RESPONSES OF PEOPLE WITH M.E.
Prof Stephen Todryk, Professor of Immunology, Department of Applied Sciences, Northumbria University, investigated the immune responses of people with M.E. in a £19,500 study joint-funded by Action for M.E. and The ME Association.
He found that those who were more severely affected had fewer natural killer cells and fewer bacteria-fighting antibodies, but more inflammatory interferon.
“The study of larger numbers of patients over a period of time will help to prove these associations, making these measurements useful for working out new and effective ways of diagnosing and treating CFS/M.E.,” says Prof Todryk in his lay summary which appears below.
UNDERSTANDING MUSCLE DYSFUNCTION IN M.E.
In May 2012, Action for M.E. awarded £25,000 to Dr Phil Manning and Prof Julia Newton at Newcastle University for their study into muscle dysfunction.
The funding provided by Action for M.E. was matched by Newcastle University’s Faculty of Medical Sciences to establish the Action for M.E. PhD Studentship, awarded to top science graduate, Gina Rutherford.
“In this project, muscle samples were obtained from CFS/M.E. patients in an attempt to investigate muscle function in more detail,” explains Gina in her lay summary.
“This research project did not find any evidence of biochemical or metabolic dysfunction in muscle cell samples obtained from CFS/M.E. patients. This contrasts previous work that has reported muscle dysfunction in CFS/M.E. patients following exercise. Further investigations are required to determine the biological basis of fatigue in CFS/M.E. patients.”
PROFESSOR TODRYK'S LAY SUMMARY
There are likely to be many causes of CFS/ME, but various laboratories report that immune function in people with CFS is different to otherwise healthy people. CFS often follows after an infection, and the immune response that usually fights the infection may become out of control in CFS. So the measurement of immune responses may tell us about the cause and severity of a sufferer’s disease and suggest how it can be treated.
Our research in Newcastle has involved the clinical network at the local Hospitals and the immunology lab at Northumbria University.
We recruited 50 CFS sufferers whose illness was measured for severity, and we made many measurements of their immune systems (white blood cells and antibodies).
We found that people with worse disease had fewer cells called NK cells, known to fight viruses. They also had less antibody against bacteria called Mycoplasma, but more inflammatory interferon. This is interesting, and the study of larger numbers of patients over a period of time will help to prove these associations, making these measurements useful for working out new and effective ways of diagnosis and treatment of CFS.
Summary of findings
NK cells are reduced with increased fatigue severity
CD57+ NK cells are reduced with increased fatigue severity
Antibodies against Mycoplasma are reduced with increased fatigue severity
Non-specific IFN-gamma production is increased with increased fatigue severity
CMV IgM is increased with increased fatigue severity
GINA RUTHERFORD'S LAY SUMMARY
Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/M.E.) is a debilitating disorder of unknown aetiology and is characterised by severe disabling fatigue in the absence of an alternative diagnosis. Historically, there has been a tendency to draw psychological explanations for the origin of fatigue. However, this model is at odds with patient descriptions of their fatigue, with many citing difficulty in maintaining muscle activity due to perceived lack of energy and discomfort.
Studies have demonstrated that when CFS/M.E. patients complete relatively low-level repeat exercise, they experience profound muscle dysfunction which is accompanied by acidity in the muscle. This has been speculated to be due to abnormalities within the muscle. (1,2)
These abnormalities may lead to patients using anaerobic energy-producing pathways, rather than aerobic energy pathways that enable the muscle to function for longer without excessive fatigue. Studies that have reported abnormality have used magnetic resonance spectroscopy (MRS) to measure internal pH of the lower limb musculature in patients.
In this project, muscle samples were obtained from CFS/M.E. patients in an attempt to investigate muscle function in more detail. This involved using novel approaches to measure pH at rest and following electrical impulse stimulation which functioned to experimentally mimic muscular contraction and simulate exercise. Furthermore, other approaches were used to investigate specific energy producing pathways such as glycolysis (anaerobic respiration) and mitochondrial oxidative phosphorylation (aerobic respiration).
During each experiment, the cells were treated with key drug compounds to test the capacity of new drugs to modulate cellular energy production and to investigate the capacity of these drugs to treat peripheral muscle fatigue in CFS/M.E.
Fluorescent dye was used to measure the pH inside the muscle. Interestingly, there was no difference in pH when CFS/M.E. muscle samples were compared to healthy control sample, which contrasts previous work conducted when CFS/M.E. patients performed an exercise intervention .
When specifically measuring glycolytic (anaerobic) activity there was no significant difference in lactate which is produced at a rate comparable to glycolysis or any of the glycolytic parameters measured.
Mitochondrial (aerobic) function was also assessed using a technique called extracellular flux analysis, which measures the rate of cellular oxygen consumption. Data revealed there to be no differences in the mitochondrial function of CFS/M.E. muscle cells compared to healthy control samples. Thus, it can be determined that mitochondrial dysfunction is not the cause of muscle fatigue symptomology experienced by CFS/M.E. patients.
Free radical generation in CFS/M.E. muscle samples was also investigated in this project. Briefly, free radicals are atoms that contain an unpaired electron in their outermost ring, this results in a highly reactive configuration which will readily interact with other molecules to become stabilised, which is potentially damaging to key components of the cell and could lead to cellular dysfunction.
However, the results demonstrated there to be no evidence of elevated free radical generation when compared to control samples. This would suggest that the muscle fatigue phenotype exhibited in CFS/M.E. patients is not related to elevated oxidative stress at the isolated muscle cell level.
This research project did not find any evidence of biochemical or metabolic dysfunction in muscle cell samples obtained from CFS/M.E. patients. This contrasts previous work that has reported muscle dysfunction in CFS/M.E. patients following exercise. Further investigations are required to determine the biological basis of fatigue in CFS/M.E. patients.
1) Jones DJ, Hollingsworth KG, Jakovijevic DG, Fattahova G, Pairman J, Blamire AM, Trennel MI and Newton JL (2012) Loss of capacity to recover from acidosis on repeat exercise in CFS/M.E. patients-a case control study. European Journal of Clinical Investigation. 42(92):186-194
2) Jones DJ, Hollingsworth KG, Taylor R, Blamire AM and Newton JL (2010) Abnormalities in pH handling by peripheral muscle and potential regulation of the autonomic nervous system in chronic fatigue syndrome. Journal of Internal Medicine. 267(4):394-401