Gene Expression Study Gets Results

Cort

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1: BMC Med Genomics. 2009 Jun 25;2:38. Links
A gene signature for post-infectious chronic fatigue syndrome.


What genes did this study find that were either overactive or under active in ME/CFS? It's encouraging that the study highlighted some areas researchers are interested in:

Oxidative Stress genes were acting abnormally. They suggested that an inflammatory process is occurring.

with a large change in the genes for prostaglandin-endoperoxide synthase 1 and 2 (also known as COX-1 and -2). These enzymes are responsible for the regulation of synthesis of the pro-inflammatory mediators, prostaglandins. The inducible form of COX-2 catalyses the conversion of arachidonic acid to prostaglandins, the release of prostanoids, which sensitise peripheral nociceptor terminals and produce localised pain hypersensitivity.
We're probably going to hear more about NF-kB in the future. De DeMeileir was interested in it and Dr. Maes is focused on it.

a recent study by Maes et al. [8] showed that TNFα-stimulated lymphocytes cultured from CFS patients resulted in over-expression of NFkappaB (NFκB). COX-2 is responsible for multiple inflammatory actions, whilst NFκB is the major upstream mechanism which regulates inflammatory and oxidative stress mediators, such as pro-inflammatory cytokines, and COX-2 and inducible NOS (iNOS) production.

Increased Rates of Cell Suicide -
Why are more cells than usual possibly killing themselves? No one knows but it could have connections to oxidative stress - since themselves get to a certain damage point they essentially commit suicide. The increased macrophage activation fits with high rates cell suicide since they clean up the pieces.

They can then be efficiently phagocytosed by macrophages or neighbouring cells. From the gene array there is also evidence of macrophage activation, with the up-regulation of Toll-like receptor (TLR)-4 and TLR-8, and monocyte-to-macrophage differentiation genes. As to exactly which cells are undergoing apoptosis, theories abound.
Immune problems - there are several interesting things here. Note the emphasis on the innate immune system. - or the early warning system. This system is often overlooked but Dr. Peterson and Dr. Klimas think it is a key system in ME/CFS. Note though that these authors believe that ME/CFS patients at most have 'subtle' immune dysfunction. This is not a cut and dried subject. It's not like these huge immune deficiencies are staring researchers in the face. It was good to see natural killer cells show up and the Th1 to Th2 shift mentioned.

In addition to the MHC, within the top up-regulated genes there are several genes encoding immune proteins which belong to the innate immune system. Patients with CFS have been suspected to have subtle immune dysfunction. Altered NK cell function in CFS patients has been reported previously by Morrison et al. [33], and is verified by the significant down-regulation of NK KIR receptors in our gene array (Table 2). This data helps to confirm that immunomodulatory gene expression is significantly different in CFS patients, as compared to healthy individuals. Immune dysfunction appears to be present in patients with CFS in the absence of any particular pathogen. The classical Th1 to Th2 switch allows intracellular pathogens to evade detection. As mentioned above, DAF is a regulator of the complement system and is an immune regulator. DAF appears to inhibit NK cells [34] and is known to be one of the most potent activators of tumourigenesis/viral dissemination.
Interestingly immune profile is very similar to one found in Post-Lyme disease.

The immune modulation in post-Lyme disease fatigue is remarkably similar to the gene signature presented here for patients with CFS [38].
Their conclusions: a significant yet subtle perturbation of function regards to the immune issues. (Significant yet subtle....?). They found three genes in common with Dr. Kerr's study which is encouraging actually as few gene expression studies have found many genes in common - a real problem.

The overall picture emerging from these results point to a significant, albeit phenotypically subtle, perturbation of function in relation to microbial defence, viral immuno-surveillance and cell growth amongst patients with post-infectious chronic fatigue.
 
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"The overall picture emerging from these results point to a significant, albeit phenotypically subtle, perturbation of function in relation to microbial defence, viral immuno-surveillance and cell growth amongst patients with post-infectious chronic fatigue."

That's actually beautifully put--absolutely the most succinct description of CFIDS/ME/Lyme I've ever seen.

And phenotypically subtle it is, which is the whole damn problem. You can feel totally sick and look normal. And microbial defense, viral immuno-surveillance and cell growth (or perhaps cell death?)--that's it in a nutshell.

What to do about it? Who knows.