Thanks for info Fredd and Rich.
Rich, I have asked Klimas multiple times about methylation pathway research and there is no question that she believes that CFS patients have blocked detoxification pathways. But as you know, there are often multiple ways to skin a cat and her primary way is to improve overall cellular function and shift immune system from overdrive TH2 to more balanced response. For improved mitochondiral function, she instructed me to start taking daily 200-300 mg of CoQ10 for a month (I currently take 100 mg) and then start the Max GL. I have asked her about whether the glutathione precursor may cause detox side-effects and she didn't at all seem concerned. I am concerned about it regardless (and more so reading what Fredd has to say) so I'd be interested in what combination of supplements are needed to prevent severe detox reaction. I'll check out the post/info you referenced and if you have any other advice, would appreciate. I have made a lot of progress in recovering over past 1 1/2 years after bad relapse, have gotten to maybe 80% and am kind of stuck at this point. Haven't been stuck in bed though for a long time and would like to keep it that way!
Also, I understand the hypothesis that our NK cells are low in perforin and are basically shooting blanks at invaders. Have you found that lifting methylation block ultimately increases NK activity?
Regards,
Gregg
Hi, Gregg.
I'm glad to hear about the progress you've made. That's great!
I'm also happy to hear that you have raised the methylation issue with Dr. Klimas. She has certainly heard about it many times from me, too.
I believe that the glutathione depletion and methylation cycle block explain why the immune response is shifted to Th2 in CFS, and I explained that in my January 2007 poster paper, of which I gave a copy to Dr. Klimas. It can be found on the cfsresearch.org website. The reasons are that glutathione is particularly needed for the Th1 response, and a functioning folate system is needed to produce new DNA and RNA to support the proliferation of T cells. Both of these have problems because of the methylation cycle block. Co Q-10 is depleted because methylation is required for its synthesis. The same is true of carnitine, also found to be low in CFS. Supplementing Co Q-10 and carnitine can help the mitochondria a little, but it doesn't get at the fundamental issue. The basic cause of mito dysfunction in CFS is glutathione depletion, in my opinion. If you look at all the problems Dr. Howard at Acumen Lab finds in the mitochondria, they can all be traced back to low glutathione, initially. The methylation cycle block does lower the availability of Co-Q10 and carnitine, and those do contribute, but the main problem is low glutathione, and that won't be fixed until the partial methylation cycle block is lifted.
In my opinion, freddd's own deleterious response to building glutathione was due to his particular mutation in the intracellular B12 processing enzymes. Once glutathionylcobalamin formed, I don't think his cells were able to convert it to the coenzyme forms of B12. I don't think this problem is very common in PWCs. Many, and probably most, find that building glutathione by direct means actually helps them to feel better, though some do not tolerate it well. Nevertheless, in late 2004 I shifted my treatment recommendations from direct efforts to build glutathione to efforts to lift the partial methylation cycle block, which is what is hindering glutathione from staying at normal levels. Just boosting glutathione directly or with its precursors can help temporarily, but if one stops, the glutathione level drops back down again, because the basic problem is upstream in the sulfur metabolism at the methylation cycle.
It's true that Kevin Maher, who used to be in Dr. Klimas's group, discovered that the NK cells have low perforin levels in CFS. My hypothesis for that is that low glutathione in the NK cells lowers the production of perforin. Perforin normally has quite a few disulfide bonds in its structure, and secretory proteins that have disulfide bonds are particularly sensitive to glutathione depletion in the cells that make them. Glutathione is necessary to keep the cysteine residues in the protein chain chemically reduced until the proper partners can be joined togehter in the endoplasmic reticulum. If the molecules are not properly made, they are recycled through the proteosomes, and the output of good molecules goes down. So far, this is a hypothesis, and the measurements have not been made to see whether the perforin production goes up after the glutathione levels have been restored. I think that would be a very good thing to measure, and Dr. Klimas's group would probably be one of the best groups to do it, if they ever become interested enough and can get the necessary funding. I think they would have to bring someone in who is familiar with basic biochemistry, though, rather than immunology, to collaborate with the people who are there.
Best regards,
Rich