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Histamine and the Glutathione Depletion--Methylation Cycle Block Hypothesis

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Hi, all.

I want to bounce something off of you.

As you may be aware, there have been several studies that have

found that IgE-type allergies are not more common in PWCs than in

the general public. However, PWCs report having big problems with

allergies, and they also report worsening of allergies they had

before developing CFS.

I think I now have something new to add to this topic. I am in the

process of writing a poster paper for the IACFS meeting coming up

next month. This one is about the Glutathione Depletion-

-Methylation Cycle Block Hypothesis for the Pathogenesis of CFS.

It's based on my past work on glutathione depletion in CFS, and also

on what's going on in autism research, where Jill and

coworkers have found that glutathione depletion there is linked to a

block in the methylation cycle. As I've mentioned before, it looks

to me as though the same thing is going on in at least a major

subset of PWCs.

So what I've been doing today is to try to figure out what the

effects of a blocked methylation cycle are, and to see if these are

things that show up in CFS. One of the several things I've come

upon is the fact that the deactivation of histamine requires

methylation reactions. Thus, if a person has a blocked methylation

cycle and thus decreased capacity for methylation (because the ratio

of S-adenosylmethionine to S-adenosylhomocysteine drops, and this

blocks the methyltransferase enzymes), then I think we should expect

that if they have an allergic reaction to something, the histamine

will rise higher and stay up longer than it would in a person with

normal methylation capacity. Therefore, the allergic reaction would

be expected to be more severe.

This would explain why, even though the prevalence of IgE allergies

in PWCs is not significantly different from that in the general

population, the PWCs would experience more severe reactions when

they did get them. It would also explain why allergies they had

prior to developing CFS were observed to get worse after their CFS


So what do you think about this?

My experience with this overall hypothesis continues to be that the

pieces keep falling into place. I've never had an experience like

this before, in about 40 years of working in science.

Another thing that is really a mind-blower is this: research in

secretory protein synthesis is showing that glutathione is necessary

in the process of putting disulfide bonds (into those secretory

proteins that are supposed to have them) correctly to establish

their tertiary structure (folding) before they are secreted from the


I've pondered what would happen if the cells that secrete them do not

have enough glutathione. They end up not being able to secrete the

proteins properly, and there will likely be misfolding. (Recall

that Jim Baraniuk et al. reported widespread misfolding of proteins

in the spinal fluid in CFS.) O.K., here's the mind-blower: this

cuts right across the symptoms of CFS. It can explain the low

perforin production and thus the low cytotoxic activity of natural

killer (NK) cells, one of the cardinal immunological features of

CFS. It can also explain low production of ACTH, leading to the

well-known observed blunting of the HPA axis. It can also explain

why both oxytocin and antidiuretic hormone are low, the latter

producing the diabetes insipidus, with its excessive urination,

constant thirst, and low blood volume. The story just goes on and

on. This is really a sweeping hypothesis, and I don't know if the

community will believe it or not. In my view, too many things keep

coming out right for there not to be some truth in this thing.

Take care, and I wish you all the best in this season, however you

celebrate it.


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