Though this article relates to CFS/ME, it shows the incredibly complicated interaction between exercise with the function of our immune system, a link that may have relevance for other conditions as well.
Thousands of small alterations in our genes exist. This propensity for genetic experimentation has helped the human race adapt and thrive. Many never have an impact. Others may be helpful in some situations and problematic in other situations, and some, often in combination with other gene variations can significantly impact how our bodies function.
The question the CDC was asking in their most recent study was whether chronic fatigue syndrome patients as a whole tend to have more variations – more unusual forms– of the genes that produce inflammation than normal. These variants or polymorphisms are often not rare. They can exist in say 10% or 30% or whatever percent of the population. The point is that they are not the common form of the gene found.
In this study The CDC used a chip (Affymetrix Human Immune and Inflammation Chip) that was designed to systematically assess the genetic component of the genes involved in inflammation and immune pathways. How many gene variants are we talking about? 11,000 very small alterations or SNP’s (single nucleotide polymorphisms) in 1000 genes representing 38 immune sub-pathways.
The most significant finding would probably come from finding increased rates of gene polymorphisms not in genes scattered around the immune system but clustered in one section of the immune system. That would suggest enough changes were present in that system to affect how it was functioning.
Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Rajeevan MS, Dimulescu I, Murray J, Falkenberg VR, Unger ER. Hum Immunol. 2015 Jun 24
The study consisted of 50 CFS and 121 non-fatigued (NF) controls.
Out of the ten thousand polymorphisms in 1,000 genes a couple of polymorphisms stood out. The CDC categorized polymorphisms according to their type. Check out branch of the innate immune system that stood out again and again; it wasn’t natural killer cells
- Non – synonymous changes – First they looked for gene changes that actually changed the form of the protein the gene produced (non-synonymous changes). They found three genes in this category: two of those genes played a role in the complement immune pathway.
- Synonymous gene changes – Then it was onto synonymous gene polymorphisms – ones that don’t change the protein produced by the gene. Four gene variants of this type were unusually common or rare in the ME/CFS group – two of them in the complement pathway.
- Genes in the Untranslated Regions – Then they looked at gene polymorphisms found in the “untranslated regions” (UTR) that often affect gene expression. Again the complement cascade popped up with two genes highlighted.
- Intronic Genes – Finally they looked at gene polymorphisms found in the intronic regions which also affect gene expression. This was the only group that did not feature genes.
The CDC took notice and took a deeper look at six more gene variants in the complement pathway. They found aberrations in their prevalence (either unusually high or unusually low) in the ME/CFS group in all of them.
We rarely hear much about the complement system but it turns out that it has quite a history in ME/CFS research.
The Complement System and Chronic Fatigue Syndrome: A History
Exercise Induces Complement Activation #1
Activation of the complement pathway is one of the rare measures of immune dysfunction that’s approaching being validated following exercise in ME/CFS. A 2003 CDC study examining levels of complement split products, cell-associated cytokines, and eosinophilic cationic protein found before and after exercise started it off. It found increased C4a levels 6 hours (but not 24 hours) after exercise.
C4a induces the contraction of the smooth muscles lining the blood vessels and increases vascular permeability. It may cause histamine release from mast cells and basophilic leukocytes.
Dr. Nathan has stated that Procrit can lower C4a levels.
Exercise Induces Complement Activation #2
The findings of a 2005 CDC gene expression exercise study provided more validation. The results were so unusual that they bear repeating. Out of 3800 genes analyzed it found that in healthy controls the expression of 21 genes changed during and after exercise.
Eleven of those genes were activating normally in ME/CFS patients but almost half – ten – were hardly being activated at all.
differences in the activity of these genes exist prior to exercise in people with ME/CFS and are exacerbated by exercise.
Note the prevalence of autoimmune or suspected autoimmune disorders in a list of other fatiguing disorders the authors reporated are associated with ion channel problems: multiple sclerosis, myasthenic syndromes, neuromyotonia and polyneuropathies. All of these disorders are suspected of having an autoimmune component.
The GO analysis also implicated genes in the complement system.
Turning the Complement System On
A 2008 study examining the “transcriptional control of complement activation” after exercise looked at which genes might be turning on the complement system on in ME/CFS during exercise.
The study found increased expression of the mannan-binding lectin serine protease 2 (MASP2) gene one hour post-exercise in ME/CFS patients.
Leaky gut syndrome, infection, injury, vaccination and a variety of autoimmune diseases could all increase MASP2 levels. Because exercise induces cortisol production – which inhibits MASP2 activation – the low cortisol levels seen ME/CFS could result in increased MASP2 activation as well. Cortisol is also being measured in the CDC ME/CFS experts study.
The Complement System
The complement system is part of the innate immune response that “complements” antibodies and phagocytic cells such as macrophages in their efforts to remove pathogens. It consists of 30 or so inactive proteins floating through the blood
The complement system may play a role in many immune mediated diseases and is increasingly being thought to play a role in central nervous system diseases as well
Polymorphisms in several complement genes have been linked with several disorders including macular degeneration.