Dr. Martina Melzer, published: 11.05.2022


Deutsche Version


What role does the immune system play in chronic fatigue?

There are numerous studies showing that chronic fatigue is associated with an activated immune system. Thus, fatigue is a central symptom in autoimmune diseases such as multiple sclerosis and rheumatoid arthritis. Chronic fatigue also occurs in chronic inflammatory diseases such as ulcerative colitis or chronic inflammatory response syndrome (CIRS). Fatigue is one of the main symptoms in ME/CFS, but also in POTS, fibromyalgia, chronic Lyme disease, depression, long covid, and during and after cancer.

An immune system activated by whatever trigger leads to acute or chronic inflammation, which can be very mild ("silent") or very pronounced. It can occur anywhere in the body. The working immune system consumes a lot of energy in the process, which is why the small energy power plants in our cells, the mitochondria, are exhausted at some point. We lack energy. In addition, the vagus nerve and other pathways tell the brain what's going on in the periphery. This triggers the sickness behavior - we are exhausted, weak, want to sleep, eat little, are in a bad mood. Immune cells in the brain and central nervous system become active and there is an increase in pro-inflammatory immune messengers, the cytokines. This indicates inflammation in the brain. This changes the concentrations of brain messengers such as dopamine, serotonin, noradrenaline and GABA. All these changes could trigger the typical symptoms of fatigue, namely physical, mental and emotional exhaustion, brainfog, pain, low mood, etc.

That the immune system is messed up in ME/CFS is hardly doubted by anyone, I hope. For example, a study at the University of Vienna found that two-thirds of participants had a compromised immune system, and one-third had an overly active one. Carmen Scheibenbogen of Charité Berlin found autoantibodies against stress receptors of the autonomic nervous system. In other words, the sites in the body where the neurotransmitter norepinephrine binds in particular. In another part of people with ME/CFS, instead of an autoimmune reaction, the binding sites for norepinephrine may simply be exhausted and react inadequately. Researchers have also found autoantibodies in fibromyalgia and POTS, so some of these syndromes could also have an autoimmune response.

When it comes to the immune system, the gut, nervous system and psyche also play an important role. I explain this in the strategies "Gut", "Nervous System" and "Mindset" and briefly below.


Read blog post "Is Long Covid = ME/CFS?"

Triggers for inflammatory processes

So inflammation, whether subliminal or strong, very likely plays an important role in chronic fatigue. You now have to play detective - as usual - and find out what keeps these inflammations going. I'd like to name a few typical triggers here that I've come across again and again during my own research. But this list is definitely not exhaustive!

Infections as a typical trigger

If we catch a virus, a bacterium or another pathogen, our immune system notices this immediately and becomes active. If it kills the germs quickly before they multiply on our mucous membranes and in the body, we may not notice anything at all. If the pathogens have multiplied faster than the immune system can react or if they trick it, then we get a cold, a stomach flu or similar. And, of course, this is accompanied by fatigue and exhaustion.

Normally, the symptoms subside after a few days or one or two weeks and we are fit again. But if the pathogen is hiding, difficult to fight, nests permanently, or our defenses are not up to par, then the infection becomes more protracted. Anyone who struggles with persistent fatigue and other symptoms for several weeks after an infection most likely has post-viral or post-infectious fatigue syndrome. If a particular symptom complex is still present after six months and no other causes can be found, then it stands to reason that the disease is ME/CFS. For more on this, see my review article on ME/CFS.

There are pathogens that are more likely to cause post-infectious fatigue syndrome or ME/CFS. These include: Enteroviruses, Retroviruses, Coronaviruses, Herpesviruses I through VIII, which include EBV, Herpes simplex, Human Herpesvirus 6 and Cytomegalovirus, Influenza viruses, Ross River virus, Ebolavirus, Borrelia, Bartonella. The germs steal our energy fuel, ATP, for their reproduction by tapping into the mitochondria, the small energy power plants in our cells. It is clear that we then lack energy, as already described above.

Chronic infections or reactivations

Especially pathogens that remain in us for life or at least remain in the body for a long time can cause chronic infections or reactivations. Herpes viruses in particular are known to reactivate when the immune system is weakened - see cold sores on a beach vacation. Bhupesh Prushdy of the University of Würzburg has found that herpes virus 6 always breaks down mitochondria into their component parts when it reactivates. He suspects this plays a central role in ME/CFS. Amy Proal and Michael vanElzakker from the U.S. are also doing research in this direction. Coronaviruses, or at least parts of them, could also remain in the body longer after infection and be involved in long covid symptoms. Germs carried by ticks, such as Borrelia, Rickettsia and Bartonella, also seem to last longer in the body.

If you feel you have a constant cold or infection, please see a health care professional who is knowledgeable about infections and the immune system. Proper tests can detect persistent infections.

Environmental toxins

In tracking down the causes of my own ME/CFS, I have repeatedly come across molds as triggers. We are not talking about the typical mold allergy, but an inflammatory reaction to mold toxins. I have not yet found out whether this could play a role in my case. However, my apartment does not look like mold. The problem is that few doctors seem to be familiar with the subject, and tests that detect mold toxins and an immune system overreaction to them are hard to come by. Most likely in the United States.

Some people also react to pesticides, chemicals from cleaning products or personal care products, to gasoline or tobacco smoke with inflammation. You'd have to Google "multiple chemical sensitivity."

Autoimmune reactions

Fatigue is one of the most common symptoms of autoimmune diseases such as multiple sclerosis or rheumatoid arthritis. These diseases are usually well recognized by physicians, especially those in appropriate specialties, and there are also established diagnostic procedures. ME/CFS can occur in parallel with an autoimmune disease, for example, together with systemic lupus erythematosus. And there is evidence, as mentioned at the beginning of the text, for autoimmune reactions in ME/CFS, fibromyalgia, and POTS.


In the "Gut" and "Diet" strategies, I describe that numerous foods can lead to intolerances and immune system activation. The best known are gluten and milk.


Allergies also activate the immune system, triggering inflammation and thus fatigue.


During my research, I have heard from time to time of individual cases in which the occurrence of ME/CFS was associated with vaccination. In fact, individual cases of a so-called post-vaccine syndrome have been described. This is probably due to an excessive activation of the immune system to the vaccine or components of the vaccine. Nevertheless, in my view, vaccinations are important and useful in the vast majority of cases.

Stress, trauma, dysregulated nervous system

From everything I have heard, read and seen over the last years, a dysregulated autonomic nervous system is the central trigger for ME/CFS and other syndromes like POTS, fibromyalgia, irritable bowel syndrome. But it probably also plays an important role in other diseases such as cancer, depression, anxiety and many chronic conditions. Namely, if the activating part of the nervous system, the sympathetic nerve, and the calming part, the parasympathetic or vagus nerve, are out of balance, it affects all systems and organs in the body.

Our autonomic nervous system is inextricably linked to the immune system, the hormonal system and the psyche or emotions. This is summarized under the hardly pronounceable technical term "psychoneuroendocrinoimmunology". A wide variety of stress factors upset this interplay. These can be of a physical nature, such as infections, accidents, obesity, a great deal of sport, and of an emotional nature, such as psychological trauma, a heavy workload, caring for relatives, character traits. Environmental toxins such as mold, incompatible foods and chemicals are also stressors. If enough factors come together, the autonomic nervous system goes into overdrive and you get disease A or B, depending on your predisposition.

Chronic stress or trauma initially activate the release of the stress hormone cortisol, which in high concentrations suppresses the immune system and has an anti-inflammatory effect. If the stress continues, the brain eventually sends a signal to produce less cortisol or to make its target areas less sensitive to it. This throws the immune system out of whack and promotes chronic inflammation, not just fatigue. Prolonged stress also permanently stimulates the sympathetic nervous system, which also promotes inflammation. The antagonist, the vagus, is suppressed or goes into its survival mode, sending a message to the body to shut down all systems to the bare minimum. Normally, the vagus has an anti-inflammatory effect, bringing the immune system back into balance. But that is now failing.

You can find more about the nervous system in the strategy "Nervous system", more about cortisol in the "Hormones" and more about the influence of the psyche or emotions under "Mindset".

What is good for the immune system?

  • Rest
  • Sleep (more tips in the strategy "Sleep")
  • Healthy diet (more under "Diet")
  • Healthy intestines (more under "Gut")
  • Sauna
  • In case of deficiencies, possibly high-quality nutritional supplements
  • Moderate but regular exercise (more under "Movement")
  • Being in nature

What harms it?

  • Stress
  • Traumas
  • Lack of sleep
  • Processed food, sugar
  • Cigarettes
  • Plastics
  • Chemicals
  • Obesity

PS: Of course, I research and check everything I write here as well as possible. Nevertheless, I am only human and make mistakes. In addition, I may draw completely different conclusions as someone else would. Simply because they fit my story. But every story is different.

Important: The content on this page is for informational purposes only and is not a substitute for talking to your doctor or other therapist. The content reflects my personal experiences, research and findings that have helped me and that I therefore want to share. However, in your personal case, completely different things may play a role and other things may help. Please talk to your doctor or therapist before making any decisions that affect your physical or mental health. Also important: I don't want to convince anyone of anything here. Rather, I want to point out possible ways that hopefully can help some people to improve or overcome their Fatigue or ME/CFS.



Fatigue Super Conference 2021

Dr. Kasia Kines: The EBV-Solution

Dan Neuffer: CFS Unravelled

Dr. Rosamund Vallings: CFS/ME – Symptoms, Diagnosis, Management

Christian Schubert: Was uns krank macht, was uns heilt

Christian Schubert: Psychoneuroimmunologie und Psychotherapie

J Couzin-Frankel, G Vogel: In rare cases, coronavirus vaccines may cause Long-Covid like symptoms. Science 2022

Hennig T, Prusty AB, Kaufer BB, Whisnant AW, Lodha M, Enders A, Thomas J, Kasimir F, Grothey A, Klein T, Herb S, Jürges C, Sauer M, Fischer U, Rudel T, Meister G, Erhard F, Dölken L, Prusty BK. Selective inhibition of miRNA processing by a herpesvirus-encoded miRNA. Nature. 2022

Aucott JN, Yang T, Yoon I, Powell D, Geller SA, Rebman AW. Risk of post-treatment Lyme disease in patients with ideally-treated early Lyme disease: A prospective cohort study. Int J Infect Dis. 2022

Proal AD and VanElzakker MB (2021) Long COVID or Post-acute Sequelae of COVID-19 (PASC): An Overview of Biological Factors That May Contribute to Persistent Symptoms. Front. Microbiol 2021

Lee C-H and Giuliani F (2019) The Role of Inflammation in Depression and Fatigue. Front. Immunol.

Dantzer R, Heijnen CJ, Kavelaars A, Laye S, Capuron L. The neuroimmune basis of fatigue. Trends Neurosci. 2014

Lutz, L.; Rohrhofer, J.; Zehetmayer, S.; Stingl, M.; Untersmayr, E. Evaluation of Immune Dysregulation in an Austrian Patient Cohort Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomolecules 2021

Wirth, K.J., Scheibenbogen, C. & Paul, F. An attempt to explain the neurological symptoms of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. J Transl Med 19, 471 (2021)

Ryabkova VA, Churilov LP, Shoenfeld Y. Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination? International Journal of Molecular Sciences. 2019

M vanElzakker: Chronic fatigue syndrome from vagus nerve infection: A psychoneuroimmunological hypothesis. Medical Hypothesis 2013