The Roles of Autoimmunity and Inflammation in Chronic Fatigue Syndrome

You still hear that chronic fatigue syndrome (ME/CFS) is a "mystery illness," but that viewpoint is becoming dated. The nature and mechanisms of the disease are beginning to take shape, thanks to the ongoing efforts of researchers. Over the years, especially recent ones, we've learned a huge amount. Some of that knowledge points to roles that inflammation and autoimmunity may play in this illness.

woman having her spine checked by doctor
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To understand the research, it helps to know a little about the processes themselves.

Inflammation: Helpful and Harmful

We all know that inflammation is involved in many illnesses and injuries, and it's rare to find a house that doesn't contain at least one anti-inflammatory drug. We ice and elevate our injuries, to keep them from getting too inflamed.

We usually view inflammation as a problem--a symptom to be treated. However, inflammation is part of a healthy response to problems in the body. When your system detects a problem—whether it be invading viruses or bacteria, or tissues damaged from injury—it triggers an inflammatory response.

What happens is that blood vessels dilate to get more blood to the area, and extra protein is pumped into that blood. White blood cells move from the blood vessels into the problem area and kill or clean up anything that shouldn’t be there. Then the tissue can begin to heal.

So when you bash your shin or twist an ankle, a little swelling is a good thing. It means the healing process is at work.

On the other hand, when inflammation becomes chronic due to ongoing damage or a misfiring immune system, then you've got a problem.

Ongoing damage can come from something like back pain from an injury that's aggravated by poor posture, or repeated damage due to disease. When that damage is due to a misfiring immune system, it can mean autoimmunity.

Autoimmunity: The System Misfires

In autoimmunity, the body is suffering from friendly fire. The immune system has gone haywire and now identifies a part of your body as a foreign invader, like a virus it needs to kill. It then triggers the inflammatory process and sends in specialized cells to destroy the target and start the healing process.

Only now, the healing process creates more of whatever body part your immune system doesn't like, so it continues to attack. And heal. And attack. And the process continues indefinitely.

Autoimmunity is a specific type of immune-system dysfunction, but it's important to note that not all immune-system dysfunction is autoimmunity.

ME/CFS: What Do We Know?

Researchers have long believed ME/CFS involved chronic inflammation. Studies reveal several biomarkers of inflammation and a sustained immune response in the blood of ME/CFS patients. Some researchers now consider ME/CFS to be a neuroimmune or neuroendocrineimmune disease.

However, we're still learning about the specific role of inflammation in the condition. Recent research paints a growing picture of autoimmunity as well. And when autoimmunity is involved, the major question is: what is its target?

Possible Causes of Inflammation

Much of the ME/CFS research community takes inflammation as a given. In the alternative name myalgic encephalitis (ME), which has been adopted by some researchers, encephalitis means inflammation of the brain and spinal cord.

Some researchers point to possible inflammatory triggers that don't involve autoimmunity.

A 2012 study published in Psychiatry Research attempted to separate chronic fatigue, chronic fatigue syndrome, and myalgic encephalitis into different categories. Researchers found that ME patients had higher levels of two specialized immune cells called cytokines, which promote inflammation. They're called interleukin-1 and tumor necrosis factor alpha. They also found elevated levels of neopterin, which is an indicator of pro-inflammatory immune activity.

More recently, studies have shown that inflammatory markers can accurately distinguish ME/CFS from depression or sickness behaviors.

A study published in Metabolic Brain Disease is just one of a growing body considering oxidative and nitrosative stress (O&NS) coupled with low antioxidant levels a possible mechanism of ME/CFS, saying these factors could point to an immuno-inflammatory pathology.

Other researchers have suggested that certain pathogens may, in predisposed people, trigger a chronic immune activation, which would create chronic inflammation and a cascade of problems. One of the main suspects in this scenario is the Epstein-Barr virus, which causes mononucleosis ("the kissing disease").

A 2013 In Vivo study investigated markers of retrovirus activity in the gut based on the theory that, through the brain-gut connection, a gut infection may lead to inflammation of the brain. Researchers did find some evidence, but this was a small, preliminary study and a lot of work remains to be done in this area.

The Case for Autoimmunity

Some researchers have found evidence suggesting ME/CFS is, at least in part, an autoimmune disease. A few different targets of a misfiring immune system have been suggested.

In a 2013 study in Molecular Neurobiology examining the possible relationship of O&NS and autoimmunity, researchers said that the presence of pro-inflammatory cytokines and several other known dysfunctions associated with ME/CFS may predispose you to autoimmunity. That means autoimmune activity may be a consequence of the condition rather than a cause of it. These researchers suspect that constant viral infections may lead to a couple of theoretical processes that may induce autoimmunity: bystander activation and molecular mimicry.

In molecular mimicry, the immune system fights an infectious agent and then begins to confuse it with a similar cell in the body and therefore begins attacking it. Essentially, because both cells look like a duck, the immune system labels them both ducks, when in fact one is a goose, and the goose belongs in that ecosystem.

In bystander activation, the body is attacked by a virus, the immune system responds by activating specialized cells, and, for some reason, that activation mistakenly triggers a different type of specialized cell—an autoimmune cell—that begins attacking the body's tissues.

In the same study, researchers also list several other methods by which ME/CFS may trigger autoimmunity, including dysfunction of mitochondria, which provide energy to your cells, and cellular damage caused by O&NS that cause your immune system to misidentify them.

A different 2013 study involving many of the same researchers puts forth the possibility of an autoimmune reaction to 5-HT, also known as serotonin. As a hormone and neurotransmitter, serotonin performs several crucial roles in both the gut and the brain. Serotonin dysregulation has long been believed to be involved in ME/CFS.

Researchers say that just over 60 percent of the participants with ME/CFS tested positive for autoimmune activity against 5-HT—more than 10 times the rate of the control group, and quadruple the rate of those with long-lasting fatigue that didn't meet the critieria for ME/CFS.

Could Several Answers Be Right?

In the end, it could be that different cases of ME/CFS have different causes of inflammation and that some cases are autoimmune while others are not. Remember that ME/CFS can be significantly different from one person to another. It may be that several different subgroups, and perhaps even different diseases, are currently lumped into one basket.

Scientists are still working to sort it all out. Meanwhile, you need to find ways to manage your condition. It's important that you work with your doctor to determine the nature of your specific case of ME/CFS and how best to treat it.

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