By John Bochenek
ME/CFS has been around for decades, perhaps much longer under other names such as neurasthenia. Despite the efforts of a select number in the medical field who have dedicated themselves to helping the patient community, the current state of affairs remains difficult with no biomarker or approved medication to lead the general medical community.
This article presents a hypothesis for ME/CFS etiology. In doing so, it is meant to bring hope to patients who are suffering and at the same time gain exposure for an idea that holds promise to relieve that suffering. The concepts within it are largely based on research from the National Library of Medicine (commonly referred to as Pubmed). The style is informal, yet certain key sources will be cited.
Before presenting the hypothesis, the following list of acronyms and terms is given as a reference for the reader’s convenience:
ATP (Adenosine Triphosphate) – the primary energy currency of a cell
ATP synthase – the enzyme responsible for bonding phosphate to adenosine diphosphate to create ATP. Also known as the “proton pump” as it uses hydrogen ions (or protons) and an electrochemical gradient to turn the natural pump within the enzyme and create the energy for the bond.
NK (Natural killer cell) – a specialized type of lymphocyte capable of recognizing and killing cancer cells and virus-infected cells
NKCC (Natural killer cell cytotoxicity) – the degree to which a natural killer cell has specific destructive action against target cells
ROS (Reactive oxygen species) – chemically reactive molecules containing oxygen (often responsible for oxidative stress which damages the normal biochemical mechanisms of the cell)
Lymphocyte – a subgroup of leukocytes (white blood cells) that is capable of differentiating between the body’s self and pathogenic substances. B cells are responsible for humoral immunity (body fluids) and T cells are responsible for cell mediated immunity (tissue).
B cell – a lymphocyte involved in adaptive immunity through the secretion of antibodies and when activated by an antigen, a proliferation of the cell and clones specific for that antigen
T cell – a lymphocyte involved in adaptive immunity that is differentiated in the thymus by thymopoietin. When activated by antigens such as CD4 or CD8, T lymphocytes differentiate into subgroups (common groups are T helper and T cytotoxic).
Antigen – any substance capable of producing an immune response (toxin, particulate, bacteria, etc)
Pathogen – any disease producing agent or microorganism
Cytokine – intercellular mediators which act in the generation of an immune response
Immune System – a complex system of cellular and molecular components that distinguish self from nonself and create a defense against disease, foreign objects and organisms
Endocrine System – a system of glands and structures that secrete hormones into the circulatory system to regulate metabolism and other body processes
Mitochondrion (plural mitochondria) – the cellular component that produces ATP, the source of cellular energy. They serve other functions too, such as sending signals.
There are many feedback loops that occur in the body. One that many ME/CFS patients may have heard of in relation to ME/CFS is something called the HPA axis. The three letters stand for hypothalamus, pituitary and adrenal. It is a neuroendocrine axis where feedback from the preceding entities should shape the response of the next one. That is, the hypothalamus will determine its output based on the adrenal gland which drew input from the pituitary gland. In ME/CFS patients there is evidence of dysfunction or a negative feedback loop in the HPA axis. While some feedback loops are well documented and understood, others exist but are poorly understood or have yet to be uncovered.
One such feedback loop may exist between the functioning of the body’s immune system and the functioning of the hundreds or thousands of mitochondria that exist in each cell to produce energy for nearly all functions that happen in the body (See Fig. 1). This hypothesized loop is not a characteristic of ME/CFS, it is a naturally occurring phenomenon happening as the body deals with various pathogens. However the loop is subdued or made to function in an orderly fashion by two items.
The first would be a normally functioning innate immune system with natural killer cells that have sufficient cytotoxicity. Our body’s front line of defense in defending against an attack is the innate immune system, and a chief weapon in that system is the natural killer cell (NK). The NK cell has the ability to pick up a signal from another cell that has been corrupted by an invader such as a virus. While the virus hijacks the cell and begins replicating thousands of its own DNA strands, the cell sends out a signal, an SOS of sorts. The NK cell hears the distress call and attaches to the cell. Then it releases a toxin to kill everything inside the cell. Thousands of viral invaders are stopped before they are released to continue the attack on the body. If the NK cells are absent or inefficient in their defense duties, other immune system functions are forced to deal with an overabundance of pathogens that continue on. Principally, this means the adaptive immune system has to shift into high gear to catch up with the glut of pathogens that have escaped death at the hands of an NK cell.
The second, and perhaps most important requirement for a normally functioning loop, is an endocrine system that is sufficiently strong to subdue inflammatory cytokines produced by the adaptive immune system and the downstream reactive oxygen species (ROS) that result. This is covering a great deal of complex territory with a few sentences, but more will be said about this topic later.
If these two factors are sufficient and the loop is functioning normally, then this state will be temporary, and it can serve the useful purpose of elevating adaptive immune function during periods of acute infection. If either are insufficient, the useful purpose of this loop will be lost and the loop then becomes stuck in a feedback that is harmful. This broken loop would be characterized by elevated lymphocytes, abnormal cytokine levels, higher pathogen levels, higher oxidative stress, poor mitochondrial function and of course the two precipitating factors, low NKCC and insufficient endocrine response. This is a description of what doctors studying ME/CFS find in their patients. Another principle of this state is that as time passes, the loop deepens or intensifies. While there may be periods of reprieve in symptoms for the patient, excess pathogens will accumulate with time.
The box on the left side of the diagram is perhaps the most important. This is the point at which the inflammation from the immune system has an impact on mitochondrial function. There are some ME/CFS researchers who have postulated a role for oxidative stress in ME/CFS, and they recognize the negative effects it has on the body’s ability to produce energy by degrading normal mitochondrial function. The term oxidation means to remove electrons from an atom or molecule. The image of a rusting piece of metal is a useful picture of the process of oxidation, as the rust is a result of oxygen removing electrons from iron. In a similar manner, the reactive oxygen species of the body will degrade the energy producing process in mitochondria known as oxidative phosphorylation. Even worse, it is a feedback loop unto itself, as mitochondria increase their output of ROS as performance degrades. An excellent article for further understanding of this important point is Oxidative stress, mitochondrial dysfunction, and aging (J Signal Transduct. 2012;2012:646354. doi: 10.1155/2012/646354. Epub 2011 Oct 2. PubMed PMID: 21977319; PubMed Central PMCID: PMC3184498).
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However there is one potential aspect of oxidative stress on mitochondria that has gone largely unnoticed. It is the recognition that impaired mitochondrial function will impact natural killer cell cytotoxicity. This concept came from researchers that inhibited the enzyme fundamental to creating ATP within mitochondria in their laboratory, then watched the effect on natural killer cells. (Abarca-Rojano E, Muñiz-Hernández S, Moreno-Altamirano MM, Mondragón-Flores R, Enriquez-Rincón F, Sánchez-Gía FJ. Re-organization of mitochondria at the NK cell immune synapse. Immunol Lett. 2009 Jan 29;122(1):18-25. doi: 10.1016/j.imlet.2008.10.008. Epub 2008 Nov 25. PubMed PMID: 19038287.)
In their research, the authors demonstrated repeatedly under several sets of conditions that by inhibiting ATP synthase in mitochondria (thereby debilitating the ATP production of the cell), that natural killer cell cytotoxicity dropped to near zero. The significance of this for ME/CFS patients is that NKCC has been seen to be persistently low in the patient population. While there may be other factors that may affect natural killer cell cytotoxicity, this avenue has been proven by this research and must be accounted for as a major contributor to the low natural killer cell cytotoxic state that exists in our patient group.
This research also suggests that the combined measure of natural killer cell cytotoxicity and ATP synthase could be used as a pair of biomarkers to diagnose ME/CFS.
Figure 2 is a repeat of Figure 1 with some color coding to indicate the malfunction in the feedback. The green box is the adaptive immune system which is an indication that it is acting as it should to clean up the pathogens in the body. The yellow box can be generalized as the inflammatory process. There is some good here in that pathogens are being eliminated, however there is some bad in that the process is less efficient than if NKCC were operating at a higher level and the innate and adaptive immune function were balanced. The red box is mitochondrial function. At this point, there is little good about what is happening. Mitochondrial function is impaired by increased ROS, which leads back to low NKCC. In addition, the mitochondrial problems inevitably lead to fatigue and pain.
The last step from mitochondrial function back over to natural killer cell cytotoxicity completes the feedback loop. It then continues on unless it is made to stop. One way for this to occur is for the endocrine system to do its job as the regulator of metabolic function and put the brakes on the inflammatory effects of the immune system. By doing so, the endocrine system defends ATP synthesis and releases energy to natural killer cell cytotoxicity. Perhaps there are other ways that natural killer cell cytotoxicity can recover, although the endocrine system appears to be the answer.
In effect this broken loop creates a gap (or is the result of a gap) between the overall inflammation output of the immune system and the endocrine response to slow down that inflammation. Figure 3 is a simplistic diagram depicting this imbalance for an ME/CFS patient. The high adaptive immune response attempting to compensate for low NKCC must be balanced by an equally robust endocrine response to bring a patient back to health. Of course the alternative is to artificially lower the immune response by depleting lymphocytes. In the end, to break the feedback loop requires the balance of immune output with endocrine response. It may require both the depletion of lymphocytes and endocrine assistance to close the gap.
With decades of experience and millions of patients worldwide, why have we come up short in finding a treatment? There are various answers to this question. First, the disease has been widely misperceived by many in the medical community. Second, with the absence of a biomarker, it is difficult to know objectively how effective a clinical trial has been. Third, there seems to be a resistance to treatments in long-term patients. In patients who have fallen ill more recently a given treatment may work, while the same treatment is not as effective in patients who have been sick for many years.
Figure 4 is an illustration why there may be problems with treating the long term ME/CFS patient. As mitochondrial function improves with treatment (medication, supplements, etc) it will release energy to the NK cells and improve cytotoxicity. This should allow for a drop in the adaptive immune function at some point in time and reduce the inflammatory process along this pathway. At the same time, NK cytokines and ROS are on the increase. If the buildup in pathogens has been minimal, the added effect of the NK ROS on the mitochondria may be tolerated. However, the patient that has a large pathogen load for the NK cells to clear will produce a significant inflammatory response from the NK cells as a backlash against mitochondrial function. Thus, even improved mitochondrial function can be self-defeating in a long term patient.
So, is there an answer for the many who have suffered from ME/CFS for five or ten years, or more? Yes there is. The answer lies in the endocrine system as it will respond to ROS whether they are a product of the adaptive immune system or NK cells. If the precepts of this hypothesis are tested by research and proven, then solutions may follow that will balance immune system output with endocrine response through the use of appropriate pharmaceuticals.
John Bochenek is a former pilot for United Airlines. He flew both domestic and international trips, serving as first officer and then as captain. His educational background includes a Bachelor of Science degree in Aeronautical and Astronautical Engineering from The Ohio State University. John became ill from the effects of ME/CFS in 2004. He now resides in Fort Myers, Florida. While he used to enjoy marathon running, he has traded in his running shoes for an acoustic guitar.