Immune system dysregulation, a diagnostic biomarker, and neuroinflammation
An exact cause of ME/CFS has not been identified—likely because there is not just one cause. Different factors may contribute to the onset of the condition in different people. About 70% of cases are preceded by a virus, but it is clear that no single virus is the cause of ME/CFS. Some viruses that are known to lead to the condition are Epstein-Barr virus (EBV), cytomegalovirus (CMV), varicella-zoster virus (VZV), human herpesvirus (HHV-6, HHV-7, HHV-8), human parvovirus B19 (B19V), and enteroviruses. Bacterial infections and toxin exposure can also trigger the condition.
There have been dozens of reported outbreaks of ME/CFS, most of which followed viral outbreaks, and some of which occurred due to toxin exposure.
Since the most obvious clue to the cause of ME/CFS is that it tends to occur following viral infection, research has focused on the immune system’s role in the condition. A 2017 study found that levels of 17 cytokines (signaling proteins released by the immune system) correlated with severity of ME/CFS symptoms. These results established “a strong immune system component of the disease.” Other research has shown impaired function of natural killer (NK) cells, increased numbers of activated cytotoxic T cells, and the presence of various autoantibodies in people with ME/CFS.
In 2019, researchers at Stanford University School of Medicine developed a nanoelectrics blood-based test that, in the first phase of trials, accurately detected chronic fatigue syndrome 100% of the time. This is the first test to consistently detect a diagnostic biomarker for ME/CFS.
The test sends an electrical current through a blood sample. The immune cells and plasma of the blood interfere with the current, changing its flow, and these changes are monitored. The changes in electrical activity are directly related to the health of the blood sample. In the test, blood samples are “stressed” using salt, and then researchers compare how the blood samples respond to the stress. Immune cells and plasma of people with ME/CFS respond poorly to the stress, incapable of processing it properly, in stark contrast to the cells and plasma of healthy controls. The researchers are very hopeful that their findings will lead to more consistent diagnosis of the condition, as well as drugs being approved for the its treatment.
A 2018 article in the International Journal of Immunopathology and Pharmacology describes how ME/CFS is a complex, multi-system condition resulting from neuroinflammation. The researchers present a compelling case for the role of the hypothalamic paraventricular nucleus (PVN), a part of the brain responsible for absorbing and processing incoming stress signals.
Physiological stressors including viral infections, toxin exposure, and emotional trauma can cause dysfunction in the neural circuitry of the hypothalamic PVN. In Figure 2 below, the researchers list a wide range of stimuli—including exercise, emotional stress, sleep deprivation, viral infection, vaccinations, and toxin exposure—that all trigger the stress response, which includes inflammation. If the hypothalamic PVN was affected by neuroinflammation, it could explain the hypersensitivity of ME/CFS patients to various stressors, as well as account for their wide range of symptoms.
While it’s clear that a dysregulated immune response is present in the condition, the nervous system, endocrine system, and metabolic processes are involved as well. And recent research involving RNA sequencing shows how stress and inflammation pathways affect circadian rhythms, metabolic function, inflammation, cellular stress responses, and mitochondrial function in ME/CFS patients. With so many functions of the brain and body involved, and a range of factors that contribute to the condition, it’s no stretch to say that ME/CFS is a medical mystery.