Health rising blog post, by Cort Johnson, 23 Feb 2017: Genes, Mitochondria, Autoimmunity and Chronic Fatigue Syndrome: The Alan Light Talk

Dr. Light has said that he wants to do for fatigue what researchers have done for pain; that is uncover the molecular pathways that cause fatigue.  Some time ago Light presented one of the most spectacular graphs of ME/CFS ever done. I still remember the gasp that filtered through the IACFS/ME conference when Dr. Light showed the slide below . It showed the levels of molecular receptors associated with fatigue and pain skyrocketing after exercise in white blood cells.

The most famous graph in ME/CFS history
The healthy controls are on top and the ME/CFS patients are below. It was even worse than it seemed. In a 2011 Bateman Horne Center video, Dr. Light explained that the differences were so extreme that he had to transform the data into log scale format in order to fit the graph on the page.  The expression of some genes was 10 times greater in the ME/CFS patients as in the healthy controls.

Even 48 hours later – still well within the post-exertional malaise (PEM) period for many with ME/CFS/FM – the gene expression was still incredibly high relative to the controls.

Light has found, by the way, that many people with ME/CFS (70%) fit the criteria for FM.  When Light compared ME/CFS patients with FM vs ME/CFS without FM he found only a few differences. When he looked at FM patients without fatigue, though, they looked exactly like the healthy controls. That indicated that the Lights were really zeroing in on how fatigue is produced.

A key distinction between FM patients without fatigue and ME/CFS and FM patients with fatigue emerged when the Lights looked at the baseline findings. It turned out that ME/CFS patients looked like healthy controls at baseline but the “pure” FM patients without fatigue looked very different.  The expression of three genes were dramatically elevated – so dramatically, in fact, that Light suggested that they might not be able to get any higher during exercise.

The fact that the rest of the genes were unaffected by exercise could explain why studies suggest that exercise seems to work so much better in FM than in ME/CFS. FM patients with ME/CFS characteristics do get knocked out by exercise, but the “pure” FM patients – which make up a considerable portion of the FM population – don’t.

Light did, however, find a startlingly different subgroup hidden within the ME/CFS population. After putting them on the bike this rather large group (40% of the study) looked exactly like the healthy controls with the exception of one gene called the alpha 2A receptor (AD2A).

This ubiquitous receptor causes the blood vessels to constrict in order to keep blood from pooling in our legs when we stand. The expression of that gene plummeted in the ME/CFS subgroup. That suggested that when those ME/CFS patients most needed their blood vessels to constrict in order to pound more blood into their muscles, the gene that did that pooped out. Not surprisingly, 70% of the people with this gene expression signature have orthostatic intolerance.

(Talk about from bench to bedside or vice versa. Dr. Light found this group when Dr. Bateman told him about a young man she could not figure out at all. Looking at the gene expression data, Light found zero increase in his ADR2A gene expression. Light then went back and specifically looked at this gene and found this major group characterized by orthostatic intolerance (OI). Unfortunately most OI drugs do not work on these patients; midodrine works for a short period but has side effects.  What a nice example of a physician and researcher working together to break new ground.)

It’s important to note that the Lights were not looking at the cause of chronic fatigue syndrome (ME/CFS) – they were looking at the effects of the cause. Something, they believed – probably in the immune system – was causing the gene expression of their immune cells to go bonkers during exercise.  It could be a virus, it could be an autoimmune process, it could be toxins, it could be any number of things.

The search for the cause came next…. read more

The Gist

• in 2011 the Light’s found that the gene expression of receptors on white blood cells which responded to muscle metabolites skyrocketed during and after exercise
• Their findings suggested a large and unusual immune response occurred during and after exercise in ME/CFS/FM
• One subset of ME/CFS/FM patients with orthostatic intolerance had a very different response
• Six years later in a small study the Light’s found evidence of acquired mitochondrial mutations that could be impacting the energy levels of these immune cells
• They also found widespread evidence of mutations in some genes associated with autoimmunity
• They suggest that the low energy state in the immune cells of ME/CFS/FM patients results in the increased production autoantibodies
• They believe these autoantibodies may be targeting processes vital to producing energy and the ability to exercise
• A large NIH grant will allow them to greatly expand their study