Australasian Science Magazine

Credit: alphaspirit/Adobe

By Donald Staines & Sonya Marshall-Gradisnik

Chronic fatigue has a range of debilitating symptoms that have defied a pathological explanation. Now researchers are zeroing in on receptors with a role in the immune system.

The term “chronic fatigue syndrome” is a poorly conceived diagnostic term to describe a debilitating and protracted condition. It entails profound fatigue, usually worsened by exertion, and an incapacitating type of brain fog associated with greatly impaired memory, concentration and rational and emotional thought processes. Most who experience it describe it as the worst experience of their live. Many are undiagnosed or disbelieved; a number even suicide.

Currently no confirmatory diagnostic test is available, and diagnosis depends on case definitions that have evolved over time. These definitions classify the experience of the illness in terms of fatigue, memory and concentration disorder, and a variety of other symptoms pertaining to the cardiovascular, gastrointestinal and immunological systems. Almost all bodily systems are affected by this illness.

Detective Work

Interestingly, the illness often follows infection, trauma or another incident. Consequently a psychogenic cause was once postulated, but this has largely been discredited.

While laboratory investigation has been frustratingly short of clear changes in blood or tissue samples, there are exceptions. Our laboratory, and other researchers have consistently found significantly impaired natural killer cell function. This is where our detective work began.

The immune system comprises an ancient or innate immune system as well as a more recently evolved acquired immune system. The innate immune system comprises natural killer cells, macrophages, mast cells and even nitric oxide and carbon monoxide produced by the body. The innate immune system is intended to defeat incoming threats such as infection or trauma and its consequences. This part of the immune system has no memory and relies mostly on directing its toxic effects at the threat. Clearly, poor control of this system or its protracted effects are debilitating.

The acquired immune system relies on memory and a well organised capacity to respond to a remembered threat. This is a far more adaptable and better targeted part of the immune system than the innate system.

Indeed the principle of vaccination depends on this system remembering specific antigens within B cells and plasma cells and producing antibodies to them. T cells also have a vital role to play, and this system relies on intelligent cross-activation between B cells and T cells.

The Missing Pathology

This is where the problem of chronic fatigue syndrome gets interesting. We wondered why patients could be so debilitated and yet so little apparent pathology could be identified.

Much recent work has focused on the acquired immune system. Could the illness be the result of a persistent infection, or could it be an autoimmune process? Could antibodies be identified to aid diagnosis? Could the answer lie in the fact that it was not demonstrable pathology involving changes at the histological level, but rather perturbations or changes in cellular processes critical to homeostasis?

The mystery deepens because various external threats, such as potent chemicals, toxins, tobacco smoke and even some foods, are now known to make the symptoms far worse.

Our research took a different track when we realised that these threats translated into the body in a far more sinister way than was previously recognised. In fact, there are so-called threat receptors located on and in almost every cell of the body. These ion channels are part of the ancient immune system as a first line of defence, and they hold the key to a profound miscalculation of the immune system and cellular pathways.

These ion channels permit positively charged ions to enter the cell in response to a threat. These ions then cascade a number of vital cellular pathways that maintain cell metabolism and even gene transcription.

A second receptor type we examined is the acetylcholine receptor. This is also an ancient signalling mechanism that controls the entry of ions into the cell.

The cell would usually welcome the inflow of these ions for normal and even heightened function, but in excess and in an uncontrolled way they may cause grievous harm.

The exciting part of our discovery is that we found changes in the genetic make-up of both types of receptors. These changes are known as single nucleotide polymorphisms that involve single base changes to these receptor genes. These changes may result in changes to the structure and function of the receptors.

However, the mystery was still not solved. How could relatively small changes in these single nucleotide polymorphisms lead to such a horrible illness?

Using highly complex gene informatics software we were able to identify whether single nucleotide polymorphisms in both the acetylcholine and threat receptors have an effect on pathology. We found there was a very high level of probability that these receptors did indeed lead to aberrant functioning. In other words, the homeostasis of the cell would be significantly compromised from having these changed receptors.

The Next Steps

We are now focusing on key areas in the cell where these receptors influence cell function and cell products, further explaining this illness and providing insights into other research findings. It is therefore becoming clear that chronic fatigue syndrome is not a simple illness.

Its possible association with the acetylcholine receptor might make it a distant cousin of a debilitating illness known as myasthenia gravis, an autoimmune disease affecting the acetylcholine receptor and one or two others. However, instead of the relatively straight­forward pathology of myasthenia gravis, the pathology in chronic fatigue syndrome likely involves genetic changes to the acetylcholine receptor alongside genetic changes to the threat receptors.

A Myriad of Combinations

These changes in both the acetylcholine and threat receptors suggests that this very complex association may develop different combinations of these anomalies and their effects. This is reflected in the varied symptoms reported by chronic fatigue syndrome patients.

Rather than taking a fixed view, we tend to the possibility that across different patients in different populations, and even in the same patients over time, clinical variations may occur due to the different threats that patients encounter. While this may seem contradictory, it suggests that different combinations of altered acetylcholine and threat receptors have varying effects.

Our challenge now is to describe these effects and attempt to unravel the complex pathologies that may cause them through detailed analysis of cellular function and cellular products that are being produced by cells from chronic fatigue syndrome patients and comparing them to healthy people.

If true, these relationships make for a highly complex diagnostic challenge as well as the potential for diverse treatment strategies.

Donald Staines and Sonya Marshall-Gradisnik are co-directors of the National Centre for Neuroimmunology and Emerging Diseases, Griffith University.