Hi, all.
I would like to do some "thinking out loud" and would appreciate thoughts from those of you who have a theoretical bent.
As many of you know, I have proposed and continue to modify the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS as I compare its predictions to real-world observations.
As many of you also know, the first step in this hypothesis involves the depletion of glutathione by stressors, and that leads to a vicious circle mechanism including functional B12 deficiency, partial methylation cycle block and depletion of folates.
As many of you also know, for about five years I encouraged people to boost glutathione, but this did not turn out to be a permanent fix to the pathophysiology. Later, based on work in autism by Jill James, I began encouraging people to treat to lift the methylation cycle block using B12 and folate. This turned out to work better for most PWMEs, and it caused glutathione to come up automatically.
Now that the Korean work has been published showing that glutathione depletion lowers the affinity of the CblC complementation group, it seems clear that this is why glutathione depletion leads to a B12 functional deficiency.
There has always been the question (and it still remains) as to why we can't just raise glutathione to overcome the B12 functional deficiency, and bring everything back to normal that way.
O.K., here's what I'm beginning to think about that: The problem is that in order for the cells to make methyl B12 to help the methionine synthase reaction, not only must the CblC complementation group be able to bind cobalamin, there must also be enough SAMe and a high enough ratio of SAMe to SAH to put methyl groups on the cobalamin to make methyl B12 fast enough. However, when the methylation cycle function is partially blocked, these conditions are not present. Also, because NADPH is low, the cells have difficulty recycling glutathione when it becomes oxidized by the oxidative stress that is present, so that just raising glutathione is not enough to overcome the vicious circle mechanism. On the other hand, when the methylation cycle is repaired using B12 and folate, the available SAMe and the ratio of SAMe to SAH are restored, and the synthesis of glutathione is also increased as the sulfur metabolism comes back toward normal operation, and this combination is able to overcome the vicious circle in most cases.
Now, what's going on in the cases that were treated with Rituximab and achieved long-term recovery? How would that fit in with the GD-MCB hypothesis?
Well, first, I want to reiterate that ME/CFS is not fundamentally an autoimmune disorder. The available evidence just doesn't support that. However, it is true that there are some reported autoimmune aspects in ME/CFS. For example, Hashimoto's thyroiditis. Another example is the elevated anticardiolipin antibodies shown by Dr. Hokama's work with the ciguatoxin test that turned out to cross-react with anticardiolipin. In addition, some PWCs have slightly elevated ANA (antinuclear antibodies). Drs. Ortega-Hernandez and Shoenfeld have reviewed the observations of antibodies in ME/CFS, and have reported that a few more have also been found.
What I suggest is that these autoimmune aspects arise as responses to damage by the oxidative stress that is a hallmark of ME/CFS, associated with the glutathione depletion. Oxidative stress damages lipids, proteins and DNA, and leads to early death of some cells. I suggest that the immune system is responding to these damaged molecules by raising antibodies, and in some cases these antibodies cross-react with normal molecules in the body, producing autoimmune reactions. These are not fundamental in the pathophysiology, but are byproducts of the oxidative stress.
As we know from observed data, there is a shift to the Th2 immune response in ME/CFS, and this is the response that favors production of antibodies. So now we have the combination of preferential production of antibodies coupled with damaged molecules that appear to be foreign to the immune system. I suggest that this favors autoimmune reactions.
These autoimmune reactions in turn promote inflammation, which in turn exacerbates the oxidative stress, and places an additional load on the antioxidant system, including glutathione. I suggest that these autoimmune reactions thus become part of problem, sustaining the vicious circle mechanism.
In addition, I suggest that the immune system is also battling actual infections, and is producing antibodies and inflammation to do that, also. Since the Th1 response is not functioning well in ME/CFS, the immune system is having to use antibodies to combat infections such as viruses, intracellular bacteria and fungi, when really, Th1 and cell-mediated immunity are needed to knock them out. So that becomes an ongoing guerrilla war.
Alright, now enter Rituximab. Rituximab knocks out the B lymphocytes, and thus lowers the levels of antibodies. Over time, this lowers inflammation. I suggest that it also thereby lowers oxidative stress, which is a component of inflammation. This would remove much of the tendency to oxidize glutathione.
In the cases in which recovery was achieved with Rituximab treatment, I suggest that the oxidative stress was lowered enough that glutathione was able to rise enough to overcome the B12 functional deficiency, even though SAMe and the SAMe/SAH ratio were still lower than normal. I suggest that this was able to overcome the vicious circle mechanism and restore the function of the Th1, so that it was able to put down the viral, intracellular bacterial and fungal infections. Then, when the B lymphocytes later regenerated, an appropriate balance was established between Th1 and Th2, and the immune system was able to re-establish its normal protective role.
I would appreciate your thoughts on whether you think this makes sense. It's sort of a trial balloon at this point.
Best regards,
Rich
I would like to do some "thinking out loud" and would appreciate thoughts from those of you who have a theoretical bent.
As many of you know, I have proposed and continue to modify the GD-MCB hypothesis for the pathogenesis and pathophysiology of ME/CFS as I compare its predictions to real-world observations.
As many of you also know, the first step in this hypothesis involves the depletion of glutathione by stressors, and that leads to a vicious circle mechanism including functional B12 deficiency, partial methylation cycle block and depletion of folates.
As many of you also know, for about five years I encouraged people to boost glutathione, but this did not turn out to be a permanent fix to the pathophysiology. Later, based on work in autism by Jill James, I began encouraging people to treat to lift the methylation cycle block using B12 and folate. This turned out to work better for most PWMEs, and it caused glutathione to come up automatically.
Now that the Korean work has been published showing that glutathione depletion lowers the affinity of the CblC complementation group, it seems clear that this is why glutathione depletion leads to a B12 functional deficiency.
There has always been the question (and it still remains) as to why we can't just raise glutathione to overcome the B12 functional deficiency, and bring everything back to normal that way.
O.K., here's what I'm beginning to think about that: The problem is that in order for the cells to make methyl B12 to help the methionine synthase reaction, not only must the CblC complementation group be able to bind cobalamin, there must also be enough SAMe and a high enough ratio of SAMe to SAH to put methyl groups on the cobalamin to make methyl B12 fast enough. However, when the methylation cycle function is partially blocked, these conditions are not present. Also, because NADPH is low, the cells have difficulty recycling glutathione when it becomes oxidized by the oxidative stress that is present, so that just raising glutathione is not enough to overcome the vicious circle mechanism. On the other hand, when the methylation cycle is repaired using B12 and folate, the available SAMe and the ratio of SAMe to SAH are restored, and the synthesis of glutathione is also increased as the sulfur metabolism comes back toward normal operation, and this combination is able to overcome the vicious circle in most cases.
Now, what's going on in the cases that were treated with Rituximab and achieved long-term recovery? How would that fit in with the GD-MCB hypothesis?
Well, first, I want to reiterate that ME/CFS is not fundamentally an autoimmune disorder. The available evidence just doesn't support that. However, it is true that there are some reported autoimmune aspects in ME/CFS. For example, Hashimoto's thyroiditis. Another example is the elevated anticardiolipin antibodies shown by Dr. Hokama's work with the ciguatoxin test that turned out to cross-react with anticardiolipin. In addition, some PWCs have slightly elevated ANA (antinuclear antibodies). Drs. Ortega-Hernandez and Shoenfeld have reviewed the observations of antibodies in ME/CFS, and have reported that a few more have also been found.
What I suggest is that these autoimmune aspects arise as responses to damage by the oxidative stress that is a hallmark of ME/CFS, associated with the glutathione depletion. Oxidative stress damages lipids, proteins and DNA, and leads to early death of some cells. I suggest that the immune system is responding to these damaged molecules by raising antibodies, and in some cases these antibodies cross-react with normal molecules in the body, producing autoimmune reactions. These are not fundamental in the pathophysiology, but are byproducts of the oxidative stress.
As we know from observed data, there is a shift to the Th2 immune response in ME/CFS, and this is the response that favors production of antibodies. So now we have the combination of preferential production of antibodies coupled with damaged molecules that appear to be foreign to the immune system. I suggest that this favors autoimmune reactions.
These autoimmune reactions in turn promote inflammation, which in turn exacerbates the oxidative stress, and places an additional load on the antioxidant system, including glutathione. I suggest that these autoimmune reactions thus become part of problem, sustaining the vicious circle mechanism.
In addition, I suggest that the immune system is also battling actual infections, and is producing antibodies and inflammation to do that, also. Since the Th1 response is not functioning well in ME/CFS, the immune system is having to use antibodies to combat infections such as viruses, intracellular bacteria and fungi, when really, Th1 and cell-mediated immunity are needed to knock them out. So that becomes an ongoing guerrilla war.
Alright, now enter Rituximab. Rituximab knocks out the B lymphocytes, and thus lowers the levels of antibodies. Over time, this lowers inflammation. I suggest that it also thereby lowers oxidative stress, which is a component of inflammation. This would remove much of the tendency to oxidize glutathione.
In the cases in which recovery was achieved with Rituximab treatment, I suggest that the oxidative stress was lowered enough that glutathione was able to rise enough to overcome the B12 functional deficiency, even though SAMe and the SAMe/SAH ratio were still lower than normal. I suggest that this was able to overcome the vicious circle mechanism and restore the function of the Th1, so that it was able to put down the viral, intracellular bacterial and fungal infections. Then, when the B lymphocytes later regenerated, an appropriate balance was established between Th1 and Th2, and the immune system was able to re-establish its normal protective role.
I would appreciate your thoughts on whether you think this makes sense. It's sort of a trial balloon at this point.
Best regards,
Rich
. And btw, I get IV glutathione every two weeks for years. Definitely could use even more than I get. However I just tried the cream from Lee Silsby that Dreambirdie likes and it's not doing nuthin' for me.
