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.

gene polymorphisms me-cfs

This was the first study to fully assess gene polymorphisms in innate immune and inflammatory genes.

Given the interest in the immune system you might think that this basic question – do ME/CFS patients have a genetic predisposition to an altered immune response – would have been answered long ago, but it hasn’t. Thus far studies have looked at the genetic makeup of only a few immune genes.

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.

Was your immune system tweaked from the beginning? Let’s see what they found.

The Study

Pathway-focused genetic evaluation of immune and inflammation related genes with chronic fatigue syndrome. Rajeevan MS, Dimulescu I, Murray J, Falkenberg VR, Unger ERHum Immunol. 2015 Jun 24

Please note that because the study used the empirical definition and population sampling to gather its participants it may have corralled  an “ME/CFS-lite” group. This  group may be different from the kinds of patients that show up in Dr. Lapp’s, Dr. Peterson’s and Dr. Klimas’s offices. 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 the 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.

Digging Deeper into the Complement Genes


The complement portion of the immune system involved in killing pathogens was signaled out.

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.

The takeaway: people with chronic fatigue syndrome tend to have higher levels of “unusual” forms of genes regulating the complement system than do healthy controls.

It’s not often that one section of the immune system pops out so consistently. It’s time to take a deeper look at the complement system.  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.

Increased C4a levels have been associated with Lyme disease. Richie Shoemaker also asserts that C4a levels increase after exposure to mold. One website stated that C4a elevations are found in acute pancreatitis, systemic lupus erythematosus and rheumatoid arthritis, Lyme disease, HIV/AIDS and immune complex diseases such as serum sickness.

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.

exercise exhaustion ME/CFS

Two exercise studies suggest complement system may be involved in producing post-exertional malaise

Eleven of those genes were activating normally in ME/CFS patients but almost half – ten – were hardly being activated at all. (Eight of those genes were associated with metabolism.). The study suggested that many of the genes that rev up during exercise in healthy people, more or less flatline in people with ME/CFS. The authors (one of which was Suzanne Vernon) had this to say about the significant differences in gene expression seen between the healthy controls and the ME/CFS patients.

“Because this difference in gene expression is so dramatic, it implicates a fundamental perturbation in the biochemical activity of lymphocyte and monocyte peripheral blood fractions from CFS subjects, compared with control subjects”.

The authors noted that this decline in immune expression would probably not show up classical markers of immune dysfunction – which are generally normal in ME/CFS.

The results of a “GO” biological pathways analysis nailed ion transport and voltage gated ion channel genes in ME/CFS patients. It suggested that differences in the activity of these genes exist prior to exercise, in people with ME/CFS,  and are exacerbated by exercise.  Recent studies have implicated ion channel problems in chronic  fatigue syndrome and in chronic pain disorders.

Note the prevalence of autoimmune or suspected autoimmune disorders, in a list of other fatiguing disorders the authors reported are associated with ion channel problems: multiple sclerosis, myasthenic syndromes, neuromyotonia and polyneuropathies. All of these disorders are suspected of having an autoimmune component. All affect the nerves and  all cause symptoms often found in ME/CFS and FM. Polyneuropathies, for instance, typically cause weakness, numbness, pins-and-needles, and burning pain and may affect the autonomic nervous system.

The GO analysis also implicated genes in the complement system.

The next steps, the authors declared were to examine the gene expression of larger numbers of individuals, during and after exercise. That work is going on right now in the big ME/CFS experts multi-center study.

Turning the Complement System On

Clearly impressed by having the complement system pop up in both a blood and a gene expression study the CDC next did a more detailed analysis of the complement system after exercise.  A 2008 study examining the “transcriptional control of complement activation” after exercise, looked at which genes might be turning on the complement system 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. It appears that MASP2 shoots up in both healthy controls and ME/CFS patients during exercise, but then is immediately downregulated in healthy controls, but not ME/CFS patients. The authors suggested that the inability to tamp down the expression of the MASP2 gene could set the stage for “localized and uncontrollable inflammation-mediated tissue damage”.

What might be increasing MASP2  levels (and thus the complement system) in ME/CFS? 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.

A Case Study

Next we turn to a case study. After developing infectious mononucleosis in 1989 a 39 year old female became bedridden and unable to work.  Her symptoms included severe fatigue, muscle and joint pain, cognitive problems and shortness of breath during exercise. In 1991 she was referred to the NIH where she underwent additional testing and got an ME/CFS diagnosis.


One case study linked complement down regulation with a return to health

A long series of tests were either normal or negative. (They included pathogens: Lyme disease, toxoplasmosis, cytomegalovirus, hepatitis C, brucellosis, histoplasmosis, blastomycosis, coccidioidomycosis and Mycoplasma pneumoniae, C-reactive protein, lupus panels, antimicrosomal and antithyroglobulin antibodies, cosyntropin stimulation, CA antigen 125, HIV antibodies, immunoglobulins IgG, IgM, IgA and IgE, and IgG sub-classes, total C4 and C3, tumour necrosis factor, interferon α, interferon γ, interleukin (IL)1β, IL2, IL3, IL4, cutaneous immunoflourescence antibodies, lymphocyte enumeration, total lymphocytes, natural killer cells, natural killer cell activity and immune Raji cell activity).

Further tests, however, indicate consistently increased levels of C4A and other complement products were present. The case study didn’t say how her complement levels returned to normal but a year later they did. Within two months of that occurring she had a complete resolution of all her symptoms  and returned to health. She’s been healthy ever since.

The Complement System

 “The complement system has the potential to be extremely damaging to host tissues, meaning its activation must be tightly regulated.” Wikipedia

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. Most are produced by the liver but a good number are also produced by monocyctes and macrophages and epithelial cells, of the genitourinal tract and gastrointestinal tracts.

During times of pathogen invasion or inflammation these proteins get cleaved  by enzymes to release cytokines and quickly upregulate the immune response.  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.

The Future

One small exercise study is not enough to validate the CDC’s complement findings.  We’ll hopefully get a much better idea of how important the complement system is in “true” ME/CFS patients soon.  The exercise portion of the CDC’s ME/CFS experts studies includes a gene expression analysis. Given the CDC’s findings thus far, it’s hard to imagine them not doing a full-bore analysis of the impact of exercise on complement gene expression and complement blood levels. The results of a huge gene expression study at  Stanford should be released shortly as well.

If the complement system pops up in the ME/CFS experts study that would be a very big deal. Alterations in all three legs of the triad: the gene level (gene polymorphisms), gene expression and blood levels would be validated.  I don’t know that that’s been done for any other substance.  The basis for an immune cause of PEM would be laid.



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