ME/CFS & Fibromyaglia are Inflammatory Conditions
What is inflammation?
Redness, heat, pain, and swelling are the stuff of acute inflammation. When acute inflammation is prolonged, a chronic inflammation ensues. The cardinal signs may be less overt, but at a cellular level a smoldering persists.
Inflammation becomes chronic when the triggering agent, perhaps a virus or pollutant, isn't entirely eliminated. It can also occur when immune cells that usually suppress the immune response don't call the whole thing off.
Inflammation is Good
Without the inflammatory process, we wouldn’t survive the outside world. One could argue that some degree of inflammation is always occurring, and is part of normal aging. It’s when the normal inflammatory processes go awry that problems arise. We know that those with higher inflammation are more at risk of diseases like diabetes, heart disease, and cancer. And those that have lower inflammatory burden are less likely to develop these condition.
Numerous conditions are characterized by chronic inflammation: allergy, autoimmunity, bowel disorders, neurodegenerative disease. It is now even believed that conditions like depression, heart disease, and cancer are associated with chronic inflammatory process. In fact, virtually every chronic condition has in common inflammation. Fibromyalgia and ME/CFS are no exception. More on these below.
Inflammation Produces Oxidative Stress
Simply put, chronic inflammation exerts damaging cellular effects primarily through excessive production of free radicals and depletion of the body’s own antioxidant defenses. With an imbalance of antioxidants and continued production of free radicals, a vicious cycle ensues that perpetuates inflammation. Essentially free radicals are fodder, and the fire itself can produce more fodder.
Free radicals alter cell function by damaging the fats and proteins that make up cell membranes. They also are known to damage DNA directly causing mutations. This damage further triggers the cell to produce inflammatory mediators—cytokines—which function in cellular communication. In this way, excess oxidative stress and inflammation go hand in hand.
The Inflammatory Cascade
All physiological pathways in the body function in cascades—a complex domino effect. A message outside the cell triggers a chain of effects within a cell. Alternately, messages within a cell can transmit a message outside the cell through a cascade of reactions. This notion becomes very important when thinking about how to reduce or enhance this communication. Essentially, if one wants to mitigate the message of inflammation, is it more effective to interact with the first or the last domino? Where is the best target?
The Main Players in Inflammation
Let’s dive into 3 of the most important upstream factors regarding inflammation.
Tumor Necrosis Factor-Alpha (TNF-α)
TNF-α is a molecule produced by macrophages and T cells. It is also released by mast cells, fat cells, neurons, and cardiac muscle cells. In the brain, it is produced by special immune cells called microglia. It is the main producer of fever when we are sick. It also inhibits viral replication and tells cells to commit cell death when they are damaged. Dysregulated TNF has been found in mast cell activation syndrome (MCAS), depression, bowel disorders, psoriasis, rheumatoid arthritis, and Alzheimer’s disease. TNF functions closely and cooperatively with inflammatory cytokines, like IL-1.
Nuclear Factor Kappa-B (NFkB)
NFkB is a protein complex that is activated by TNF. It interacts with DNA to stimulate the immune response and processes which ensure the cell survives. It is vitally important in regulating the immune response to infections. NFkB is chronically active in many inflammatory diseases, such as inflammatory bowel disease, arthritis, asthma, and heart disease.
Nuclear Factor Erythroid 2-related Factor 2 (Nrf2)
On the flip side, Nrf2 is a protein that regulates the body’s own antioxidant defenses when triggered by inflammation. It functions as a cellular sensor by interacting with DNA to communicate that the cell enhance protection against oxidative stress and liver detoxification. Another of its key targets is enzymes that recycle glutathione, the master antioxidant. Dysregulation of Nrf2 has been associated with neurodegenerative, disease, cancer, and chronic viral infections.
Many anti-inflammatory drugs target various parts of these cascades. Over-the-counter anti-inflammatories act on the downstream inflammatory processes, for instance. Pain and inflammation may reduce, but the effects are short lived. More potent drugs, such as those for autoimmune diseases, target upstream of the cascade and therefore have more potent, longer lasting effects. However, many of these drugs have such potent effects they essentially throw a wrench in the entire cascade. Drugs for autoimmunity that block upstream targets can do so, so effectively as to disrupt the entire immune system and leave one open to infection. Examples of these drugs include the popular Humira and Enbrel. Both of these are TNF inhibitors.
Is there an alternative? Yes, many other compounds have been extensively studied for their ability to reduce inflammation by targeting and modulating the main players without detriment to the entire immune system. More on this in the next post.
ME/CFS is Characterized by Inflammation
Numerous studies point to dysregulation of normal inflammatory processes in ME/CFS. There is also a body of evidence showing excessive oxidative stress in the condition. A clear indication of excess inflammation in the condition is the intolerance to exercise. Exercise, especially cardiovascular exercise, is a known stimulator of oxidative stress. Elevated oxidative stress is evidenced by studies that have measured free radicals directly: super oxide, nitric oxide, peroxynitrite, and 8-hydroxy-deoxyguanosine.
Studies have also found deficiencies in crucial antioxidants and antioxidant enzymes including CoQ10, zinc, vitamin A, glutathione, DHEA, and super oxide dismutase (SOD). Countless studies of cytokines in ME/CFS have implicated a shift to inflammatory cytokines, like IL-6. There is also evidence of TNF over production. In immune cells stimulated to produce NFkB, levels were significantly higher in ME/CFS patients than in controls. Lastly, ME/CFS patients seem to have low Th1 immunity and a dominant Th2 immunity. Inflammatory pathways shift immune responses to Th2 which perpetuate TNF activation.
Neuroinflammation refers to inflammatory responses at the brain and spinal cord. Activated glial cells, a type of immune cell, produce pro-inflammatory cytokines that provoke neuroinflammation. This phenomenon increases the central processing of pain—enhancing otherwise non-painful stimuli. This is known as allodynia and hyperalgesia. It is also believed to create the “sickness experience,” commonly referred to as malaise.
Research in ME/CFS has detected neuroinflammation and this may underpin the cardinal symptoms of the condition: brain fog, fatigue, exercise intolerance. Here are a few examples:
Nakatomi, Y et al. (2014) Neuroinflammation in Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: An 11C-(R)-PK11195 PET Study. J Nucl Med Vol. 55 no. 6 945-950
Shungu, DC, et al (2012) Increased ventricular lactate in chronic fatigue syndrome. III. Relationships to cortical glutathione and clinical symptoms implicate oxidative stress in disorder pathophysiology. NMR Biomed. 25(9):1073-87.
VanElzakker MB et al (2019) Neuroinflammation and Cytokines in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): A Critical Review of Research Methods. Front Neurol. 9:1033.
Fibromyalgia is Characterized by Inflammation
The inflammatory cytokine IL-8 is elevated in cerebrospinal fluid of fibromyalgia patients. Other inflammatory cytokines have been found in several studies: IL-6, IL-17, and TNF. The anti-inflammatory cytokine IL10 is greatly increased in fibromyalgia patients. This suggests an over compensation from inflammatory burden. Immune cells of fibromyalgia patients have reduced Q10, indicative of low antioxidant capability, and they contain high levels of reactive oxygen species, free radicals.
Neuroinflammation has also been studied in fibromyalgia. Here are several examples:
Natelson BH et al. (2015) Effect of Milnacipran Treatment on Ventricular Lactate in Fibromyalgia: A Randomized, Double-Blind, Placebo-Controlled Trial. J Pain. 16(11):1211-9.
Bäckryd E et al. (2017) Evidence of both systemic inflammation and neuroinflammation in fibromyalgia patients, as assessed by a multiplex protein panel applied to the cerebrospinal fluid and to plasma. J Pain Res. 10:515-525.
Natelson BH, et al. (2017) Elevations of Ventricular Lactate Levels Occur in Both Chronic Fatigue Syndrome and Fibromyalgia. Fatigue. 5(1):15-20.
Next up, learn effective ways to combat chronic inflammation by targeting TNF, NFkB, and Nrf2.
Maes, M & Twisk, F (2009) Why myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) may kill you: disorders in the inflammatory and oxidative and nitrosative stress (IO&NS) pathways may explain cardiovascular disorders in ME/CFS. Neuro Endocrinol Lett. 30(6):677-93.
Maes M, Mihaylova I, & Bosmans E. (2007) Not in the mind of neurasthenic lazybones but in the cell nucleus: patients with chronic fatigue syndrome have increased production of nuclear factor kappa beta. Neuro Endocrinol Lett. 28(4):456-62.
Coskun Benlidayi, I. (2019). Role of inflammation in the pathogenesis and treatment of fibromyalgia. Rheumatology International.
Bocci, V & Valacchi, G. (2015) Nrf2 activation as target to implement therapeutic treatments. Front Chem. 3: 4.