Possible Causes

People with ME/CFS often have their illness begin in a way that reminds them of getting the flu. This has made researchers suspect an infection may trigger ME/CFS. In addition, about one in ten people who become infected with Epstein-Barr virus, Ross River virus, or Coxiella burnetti will develop a set of symptoms that meet the criteria for ME/CFS. People with these infections who had severe symptoms are more likely than those with mild symptoms to later develop ME/CFS symptoms. But not all people with ME/CFS have had these infections.

Other infections that have been studied in connection with ME/CFS are human herpesvirus 6, enterovirus, rubella, Candida albicans, bornaviruses, mycoplasma, and human immunodeficiency virus (HIV). However, these infections have not been found to cause ME/CFS.

It is possible that ME/CFS is caused by a change in the person’s immune system and the way it responds to infection or stress. ME/CFS shares some features of autoimmune illnesses (diseases in which the immune system attacks healthy tissues in own body, like in rheumatoid arthritis). For example, both ME/CFS and most autoimmune diseases are more common in women and both are characterized by increased inflammation. However, other signs of autoimmune disease, like tissue damage, are not found in patients with ME/CFS.

Scientists think that the immune system might be contributing to ME/CFS in other ways, including:

• Chronic production of cytokines (cytokines are proteins that are produced by the immune system and regulate behavior of other cells). Higher levels of cytokines for a prolonged period can lead to changes in the body’s ability to respond to stress and might lead to the development of health conditions, including ME/CFS.
• Low-functioning natural killer (NK) cells. NK cells are cells of the immune system that help the body fight infections. Many patients with ME/CFS have NK cells with lower functional ability to fight infections. Studies have found that the poorer the function of NK cells in ME/CFS patients, the worse the severity of the illness. NK cell function tests are hard to do and their results are not reliable outside of research studies. Because of this problem, NK cell function testing is not yet useful for healthcare providers. Also, low NK cell function can occur in other illnesses and thus cannot be used to diagnose ME/CFS.
• Differences in markers of T-cell activation. T-cells are cells of the immune system that help activate and suppress immune responses to infections. If they become too active or not active enough, the immune response does not work as it should. However, not all patients with ME/CFS appear to have these differences in markers of T-cell activation.

Physical or emotional stress affects the hypothalamic-pituitary-adrenal axis (HPA axis). The HPA axis is a complex network that controls our body’s reaction to stress and regulates a lot of body processes such as the immune response, digestion, energy usage, and mood. This occurs through connections between two glands of the nervous system (hypothalamus and pituitary) and adrenal glands (small organs that reside on top of the kidneys). The glands release various hormones, like corticotrophin-releasing hormone (CRH), cortisol, and others. When these hormones get out of balance, many body systems and functions, like the immune response, can be negatively affected. Cortisol, also called “the stress hormone,” helps to lower inflammation and calm down the immune system. Low levels of cortisol thus may lead to an increase in inflammation and chronic activation of the immune system.

Patients with ME/CFS commonly report physical or emotional stress before they become ill. Some patients with ME/CFS have lower levels of cortisol than healthy people, but their cortisol levels are still within the normal range. Therefore, doctors cannot use cortisol levels to diagnose or treat ME/CFS.

Scientists found differences between people with ME/CFS and healthy people in the way cells in their bodies get their energy. However, more studies are needed to figure out how these findings may be contributing to the illness.

Members of the same family sometimes have ME/CFS. Studies done in twins and families suggest that both genes and environment might play a role in ME/CFS. Scientists have not yet found the exact genes or other factors from the environment that may be responsible. More research is needed.