My Hypothesis on Th2 to Th1 Immunomodulators in CFS

[perchance dreamer]

It's too bad that irrigation can't reach all the sinuses.

I've had what I think is a sinus infection lately, extreme congestion and a bad taste in my mouth. Since I have problems with oral antibiotics, I've used ABX in nebulized form in the past. At least the ABX is confined to the sinus cavities although a tiny amount is supposed to get into your system. This is an expensive way to go.

This time I'm trying Sunwarrior Silver Immune Shield Fulvic Complex + Gold in an oral form. I'm taking 1/2 tsp. in a little water every hour and will continue for 2 or 3 days.

The bad taste is gone, and my nasal congestion has eased somewhat. It's more the normal congestion I have. Also, it helps some with my back and neck pain for some reason.

The reason I thought of this is that someone at Whole Foods had recommended this product to ward off an upper respiratory infection. It worked great. It's an 8 oz bottle, so I had a lot left.

It's inconvenient, but worth it to me. When I'm out, I'm taking solutions that I put in little vials.

http://www.sunwarrior.com/product-info/immune-shield/

When I first saw my ENT years ago, she told me that it's very common for sinus infections to be caused by fungus. She suggested taking a stronger probiotic as well as OrthoMolecular Sinatrol to control the fungus.

http://www.iherb.com/Ortho-Molecula...&disc=0&lc=en-US&w=sinatrol&rc=1&sr=null&ic=1

It seems to have worked for the fungus. I never cultured positive for it again. I still get the bacteria sometimes, though.

 

[consuegra]

GcMAF injections and probiotic certainly work for some people for some time. As Enlander says it is the best therapy to come along in ten years. The question is why is works for some people and not others and why it works for some people and then stops (particularly MAF 314 (Bravo probiotic). At this moment there is a GcMAF conference in Dubai and perhaps more answers will come from this. Cheney, as usual, is rethinking how fo make this work better. He has a restless mind and considers many options, often all at once.

The surprising thing to me is that so many practitioners just give a drug or compound and do not think of the variables, such as are discussed in this thread. Certainly there is the possibility that some things work for some people and not for others and that is that. Conversely there very well might a variety of items that stand in the way of a particular item working. Shoemaker has a strict protocol, for instance, for implementing VIP, and he believes it will not work except when instituted in a certain order, in a series of steps. Cheney also is clearly aware of pretreatment for VIP and other items.

Chris

 

[Hip]

IHow do you think injecting GcMAF would play into the topic of this thread? It is also enormously helpful to me but I don't know how it affects the Th 1/Th 2 balance.

I don't know that much about how GcMAF (Gc protein-derived macrophage activating factor) works, but macrophages can be activated into either an M1 or M2 mode, and this study says that M1 promotes the Th1 response, and M2 promotes the Th2 response (which is why M1 and M2 were so named).

The study also says that "M1/M2 describes the two major and opposing activities of macrophages. M1 activity inhibits cell proliferation and causes tissue damage, while M2 activity promotes cell proliferation and tissue repair." In other words, M1 is the "fight and destroy" mode" of macrophages, and M2 is the "fix and repair" mode of macrophages. It is the M1 mode that has potent anti-cancer cell effects.

But how does GcMAF affect the M1 and M2 modes? Well in this article:

Overview of Macrophage Activating Factor and the Nagalase Assay – Potential for Control of Micrometastatic or Early Primary Cancer, by Mark F. McCarty

it says on page 9 that "there is currently no evidence that GcMAF can influence M1/M2 polarization in macrophages."

So it would seem that although GcMAF stimulates macrophages, it does not affect the M1/M2 balance, and therefore I presume GcMAF will not affect the Th1/Th2 balance.

 

[antares4141]

I'm wondering if your sinuses are colonized with undetectable fungi (assuming condition not diagnosable or recognized by main stream) could your lungs also be infected. If so what's the point your sinuses are going to get reinfected by the un-addressed reservoir in your lungs. I've never been a big proponent of the mycotoxin theory. But I often got a condition I called "brain burn" which was/is a burning sensation in my sinuses or forehead area. Especially after mold exposures. So I do believe there might be something to the colonization (imbalance of good to bad pathogens) of lungs, sinus and digestive tract. I was thinking if you could maybe get a snot, phlegm & fecal transplant all at the same time from a healthy individual you might be able to turn the imbalance around. Lol.
I always get a runny nose around (breathing) certain triggers and when eating certain foods. Also tend to cough up phlegm after eating certain foods.

 

[South]

IDO breaks down tryptophan, and tryptophan is needed to make serotonin

@Hip, I know this is an old thread, but wanted to ask: have you considered trying 5htp while taking the antivirals, to see if you can avoid the depression side effect while taking the antivirals? My logic is that 5htp is what tryptophan becomes on its route to becoming serotonin, and perhaps the hijacking of tryptophan you mentioned coudn't happen, since the 5htp isn't tryptophan any more.

I'm not good at explaining my thoughts, hope this makes some sense.

 

[Hip]

@Hip, I know this is an old thread, but wanted to ask: have you considered trying 5htp while taking the antivirals, to see if you can avoid the depression side effect while taking the antivirals? My logic is that 5htp is what tryptophan becomes on its route to becoming serotonin, and perhaps the hijacking of tryptophan you mentioned coudn't happen, since the 5htp isn't tryptophan any more.

I'm not good at explaining my thoughts, hope this makes some sense.

That is a truly excellent idea, @South, thank you very much for suggesting it. I will certainly try this.

What you are saying is that serotonin is made by the following steps:

Tryptophan ➤ 5-HTP ➤ serotonin

and that the IDO enzyme induced by interferon breaks down tryptophan, leading to depletion of serotonin and thus depression; but if you take 5-HTP as a supplement, this 5-HTP cannot be broken down by IDO, and so should ensure enough serotonin is made.

I just had quick Google search, and I found this paper (full article here) which hypothesises exactly what you are saying. To quote the conclusion of that paper:

Interferon-induced depression is a significant problem with considerable public health consequences.Treating this type of depression will allow more patients to complete treatment for life threatening illnesses, including hepatitis C and certain types of cancer. We have hypothesized here that IFN causes depression via a dual mechanism: by increasing serotonin reuptake and by depleting the substrate for serotonin synthesis [tryptophan].

To address these two mechanisms, we propose a combination of SSRI and 5-HTP therapy. SSRIs will block serotonin reuptake, while 5-HTP should restore CNS serotonin synthesis. Together, these interventions should act synergistically to normalize the functioning of the serotonin system and alleviate IFN-induced depression. However, the investigator is advised to exercise caution until the relevant safety issues are more fully understood.

 

[South]

@Hip

Rah! Sometimes I'm a little bit smart I guess (said in humor) Now if this little theory works in real life, that's the question.

Keep us posted!

 

[nandixon]

That is a truly excellent idea, @South, thank you very much for suggesting it. I will certainly try this.

What you are saying is that serotonin is made by the following steps:

Tryptophan ➤ 5-HTP ➤ serotonin,

and that the IDO enzyme induced by interferon breaks down tryptophan, leading to depletion of serotonin and thus depression; but if you take 5-HTP as a supplement, this 5-HTP cannot be broken down by IDO, and so should ensure enough serotonin is made.

I just had quick Google search, and I found this paper (full article here) which hypothesises exactly what you are saying. To quote the conclusion of that paper:

I've actually been working on this from the exact opposite side, and a couple things I've found might be useful. (I'm fairly sure, for my own version of ME/CFS, that the immediate cause of my fatigue and PEM is elevated serotonin; what the actual underlying cause of that is - autoimmune, infectious, genetic, etc - I'm not at all sure.)

To lower serotonin, I'm looking to inhibit tryptophan hydroxylase 2 (TPH2) and induce indoleamine 2,3-dioxygenase (IDO1), and avoid the opposite.

So, things that I need to avoid may be helpful for people trying to increase serotonin:

It was reported early last year that vitamin D up-regulates TPH2. So supplementing with that might be helpful to increase serotonin. (I give the reference in this post here.)

Fish oils, DHA and/or EPA, apparently increase serotonin production. (I'm not sure which, if either, is better in this regard.)

Caffeine increases serotonin. (I use caffeine but attempt to negate that effect by taking L-phenylalanine at the same time.)

Exercise increases serotonin. (Good luck with that for most of us.)

For the opposite effect, i.e., to actively decrease serotonin, I've been looking into several things, like TPH2 inhibitors (which probably wouldn't address the cause) and also interferon, although I was thinking about perhaps interferon gamma.

 

[Hip]

@South
I will definitely keep you posted. My plan several years ago was to take a whole raft of drugs and supplements that all shift the immune balance from Th2 to Th1, in order to create an all out attack on the viral infections.

People often take just one Th1 shifting immunomodulator, such as inosine or oxymatrine, but my idea was to take a dozen or so such immunomodulators at the same time. There are many Th1 boosters available, including:

Immunomodulators That Shift The Immune Response To Th1:

Imunovir (isoprinosine) or inosine1
(Inosine sometimes a Th2 booster?: in diabetic mice, inosine switches from Th1 to Th2 1)
Oxymatrine 1
Astragalus 1
Glutamine 1 2
Colostrum 1
Neem (Azadirachta indica) 1
Silica 1
Grape seed extract 1
Heparin (anticoagulant) 1 (mentioned at bottom of cited paper)
Chondroitin sulphate 1
Ashwagandha (Withania somnifera) 1
Cetirizine (antihistamine) 1 (Histamine promotes Th2 1)
Noni (Morinda citrifolia) 1
Garlic enhances Th1 at low doses, and Th2 at high doses 1
Azithromycin 1
(But macrolides azithromycin and clarithromycin have also been shown to inhibit Th1 1)
Camel milk 1
Glycyrrhizin (from licorice) 1
Beta glucans 1
(But beta glucans has also been shown to inhibit Th1 and boost Th2 1)
Gynostemma pentaphyllum 1
Pro-glutathione molecules like N-acetyl-cysteine shift to Th1 1
Coconut oil promotes Th1 1

My plan was to take all of the above together, but the significant depression side effects I got from these Th1 boosters thwarted my plan.

 

[South]

@Hip

I would think a combination of many ingredients with a common purpose could be better than simply one ingredient, even if that one ingredient had been taken at a large dose. Just seems better to do a blend, to me.

I'm trying to figure out my own th1/th2. Bearing in mind that I don't have ME, I don't fit neatly into any common th1/th2 theory.

For example, I've had for years what may be candida (yeast) problem in my digestion, and a blood test showed high antibodies toward yeast (can't remember name of the test). So I'm fairly sure my gut problems are from yeast, not from overgrowth of a bad bacteria.

But until this winter, I have been completely immune to all viruses/colds/flu that go around our town, for the past 10 years.

If people who over-react to allergens or bacteria, and under-react to yeast and viruses are Th2 dominant, I don't fit the theory. I under-react to yeast (have symptoms of yeast overgrowth despite low sugar diet), yet until recently reacted just fine to viruses (never get colds or flu). And I've over reacted to allergies for decades.

So what caused me to suddenly catch a cold this winter? well, I experimented with many new supplements this fall, and some of them may have shifted my th1/th2. I'm still picking through my notes to figure out which may have done it.

Is my yeast less of a problem now? Not that I can tell; I still can't eat a single dessert without major gut problems, so I still for the most part avoid sugar, and most fruit.

Which brings me to trying to boost my probiotics. Maybe my body could fight the yeast, but if my gut is low in probiotics, any dose of sugar would result in yeast simply because there isn't enough of the good probiotics to handle the job.

Which brings me to the following thread, in which Lotus97 posts that probiotics gave her depression, and theorized a th1/th2 reason: http://forums.phoenixrising.me/inde...thogen-candida-th1-th2-immune-response.22499/

Nothing I took this fall gave me any kind of depression (I've felt low serotonin in the more distant past and know what it feels like). But if I'm going to venture into probiotics, maybe I should be watchful of this possible result. Maybe keep some 5htp handy, in case.

 

[South]

@nandixon Although it may be too weak to address your goal, there's some evidence that the herb feverfew reduces serotonin.

I stumbled on this study when I was researching migraines (which can be serotonin related, I think)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210009/

In it, if you scroll down to the section called "effect on platelets", it states:

"Feverfew extracts are not only potent inhibitors of serotonin release from platelets but also of polymorphonuclear leukocyte granules, providing a possible connection between the claimed benefit of feverfew in migraines..."

 

[Hip]

@South
A good hypothesis by Rich Van Konynenburg of why many ME/CFS patients rarely catch colds is give here. Basically, the idea is that the first line in antiviral defence, the type I interferon responses, is chronically ramped up in ME/CFS patients (to compensate for other parts of the immune system that are weak), so that any cold virus landing in your throat is instantly killed by this ramped up first line of immune attack.

For example, I have had for years what appears to be a candida (yeast) problem in my digestion, and have had a blood test show a high level of an antibody toward yeast (can't remember name of the test). So I'm fairly sure my gut problems are from yeast overgrowth, not from overgrowth of a bad bacteria.

This anti-Candida strategy, using Candida hyphal form inhibitors, may be of interest.

 

[South]

@Hip

Thank you for the links.

I wish I knew if specific immune-affecting supplements would help people with gut problems. I know several people like myself, with very strange digestive problems yet who never get colds or the flu (we don't have ME).

As for the candida hypha inhibitors, I have a little list of those supplements. Many of them are also backed by studies to prevent biofilm formation. Certain enzymes can also break down existing biofilms.

So, I'm taking baby steps with trying enzymes, while continuing to take small amounts of a few hypha-inhibitors.

Slowly though; because if I take something that too quickly busts up biofilm and/or causes die-off, I often get a severe migraine and worsening digestion. Not fun.

Tiny baby steps with probiotics are on my plan too.

Hip have you seen the theory that probiotics can cause a Th2 immune response if a person is Th2 dominant? I've seen the theory, but no studies backing it. I did see a study giving probiotics to mice, who got stronger th1 (not th2) immunity as a result, but those were healthy mice, not humans with pre-existing immune imbalances or other crud going on.

 

[nandixon]

@nandixon Although it may be too weak to address your goal, there's some evidence that the herb feverfew reduces serotonin.

I stumbled on this study when I was researching migraines (which can be serotonin related, I think)
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3210009/

In it, if you scroll down to the section called "effect on platelets", it states:

"Feverfew extracts are not only potent inhibitors of serotonin release from platelets but also of polymorphonuclear leukocyte granules, providing a possible connection between the claimed benefit of feverfew in migraines..."

@South
Thanks very much! I have tried feverfew before, a year or two ago. I can't remember now exactly why I tried it, except I do remember thinking the headache preventative aspect might be helpful. I don't think I tried it for the antiserotonergic effect. (5-Hydroxytryptamine-inhibiting property of Feverfew: role of parthenolide content)

It did seem very helpful (=less fatigue) the first few days I took it, but then seemed to stop working. It didn't at any point make me feel worse, so that's a positive.

I still have a portion of the bottle left so I think I'll give it another trial, perhaps in a higher amount. Thanks again!

 

[Hip]

Hip have you seen the theory that probiotics can cause a Th2 immune response if a person is Th2 dominant?

I have not seen such a theory. Do you have a weblink?

In general Gram positive bacteria in the gut will induce Th1, whereas Gram negative bacteria will induce the Th2 response. 1 For ME/CFS patients, Th1 is desired, and too much Th2 undesired.

So depending on the bacterial species you have in your gut (you can get a digestive stool analysis to find out), my thoughts are that these species may play a role in determining the overall Th1/Th2 balance in your intestines. Since the intestines are a major home for the ME/CFS-associated enterovirus infections, shifting the gut Th1/T2 balance towards the antiviral Th1 response may help fight these enteroviruses in the gut.

Gram positive gut bacteria include: Streptococcus, Staphylococcus, Bacillus, Clostridium, and most probiotic bacteria.

Gram negative gut bacteria include: Escherichia coli, Shigella, Pseudomonas, Moraxella, Helicobacter, Proteus, Klebsiella.

I was looking for an antibiotic that I could safely take long term, which would selectively target the Gram negative bacteria in the gut, so as to kill these, and leave the Gram positive bacteria untouched. I think such an antibiotic should boost the Th1 response in the gut. However, there are not that many selective Gram negative antibiotics available. Here are the anti-Gram negative agents I found:

• Aminoglycoside antibiotics do selectively target the Gram negative bacteria, 1 but these antibiotics are quite toxic and can have serious side effects.

• Hydrogen peroxide mixed with ascorbic acid has been shown effective against Gram negative bacteria, 1 but there are unknown health risks involved in taking hydrogen peroxide internally.

• Cinnamon, clove, geranium, lemon, lime, orange and rosemary essential oil have significant inhibitory effects against Gram negative bacteria, 1 and these are fairly safe to take. So these essential oils may be the safest option for long term suppression of the undesired Th2-inducing Gram negative bacteria in the gut.


Here is some info on the Th1-inducing effects of various probiotics:

Probiotics that increase the Th1 immune response:
Saccharomyces boulardii? 1
Lactobacillus sporogenes 1
Lactobacillus acidophilus 1
Lactobacillus casei 1
Lactobacillus rhamnosus GG 1
Lactobacillus paracasei 1
Lactobacillus salivarius 1
Bifidobacterium longum 1
Bifidobacterium bifidum 1
Lactobacillus brevis 1
Lactobacillus fermentum 1
Streptococcus thermophilus 1 (more potent inducer of Th1 than Lactobacillus strains)

Probiotics that decrease Th2 immune response:
Lactobacillus reuteri 1
Lactobacillus plantarum 1
Lactobacillus salivarius 1
Lactococcus lactis 1

Source: How To Rebalance An Elevated Th2 Immune System

 

[South]

@Hip (argh, I can't figure out how to use 'multiquote')

I've not seen any proof of the theory that "probiotics can cause a Th2 immune response if a person is Th2 dominant", I've only seen the rumor, or statements in a few books unsupported by any study. I'm deeply hoping it's wrong, as I'm about to experiment with probiotics after avoiding them for 5 years. Every time I tried them from about 2002 to 2010, I'd get worse gut problems the day after I started them. During those years, I always gave up within a few days.

Now I'm starting to think those problems may have been die off, or even some effect of the acid from the probiotics loosening up some evil biofilm...or something. Hopefully not some unwanted effect on my th1/th2 balance.

Cinnamon, clove, geranium, lemon, lime, orange and rosemary kill gram negative bacteria as per that study, but also killed some gram postive bacteria in the study. Your existing probiotics in your gut are either positive or negative gram (they have to be one or the other), and might also be killed to some degree by the strong cinnamon, clove, etc plant extracts.

Many people preach taking probiotics if you take a lot of these strong plant extracts (and at a different time of day from them), to try to keep the number of probiotics in the gut from depleting during the program.

And luckily, you already have a handy list of probiotics to take, that as a bonus help your th1 goal!

So is this your plan:
Take substances that shift your immunity away from th2 and toward th1
Some of these substances may also be antiviral to kill off any viruses
Take substances that kill certain bad bacteria, particulary since shifting your th could aid those bad bacteria
At the same time take specific probiotics to avoid a loss of total gut probiotics...
And the same probiotics also help shift your th in the correct direction.

Did I get that right? May the force be with you!

 

[Hip]

Yes, that's the general idea, @South.

If you look at the change in the cytokine profile of ME/CFS patients who successfully responded to Dr Chia's oxymatrine immunomodulator protocol, you see that these patients all shifted from Th2 towards Th1, and at the same time that their ME/CFS symptoms got better.

But those who did not improve on oxymatrine showed no shift towards Th1. You can see a graph showing the cytokine profiles of responders and non-reponders to oxymatrine in this post here.


So I am questioning why some patients were successfully able to shift towards Th1 while taking oxymatrine and get improvement in symptoms, and why others were not able to achieve this shift.

My idea is that in the non-responders, there may be some factors present that block the shift towards Th1. Any factors in the body that are Th2 shifters would tend to block the desired Th1 shift. There are quite a few factors that can shift to Th2:

Some Undesired Th2 Shifters:

• LPS from Gram negative bacteria induces Th2. 1 Though can also induce Th1. 1

• Some mold toxins shift to Th2. 1

• Lack of intracellular glutathione promotes Th2. 1

• The viruses EBV, CMV and HHV-6 make a fake (homolog) version of the Th2 cytokine IL-10, in order to shift your immune response to Th2 (and away from the antiviral Th1 response). So if these viruses are in a state of active infection in your body, they will tend to thwart the desired antiviral Th1 response by shifting to Th2.

• The cytokine IL-6, which is produced in massive amounts by the muscles during exercise, is known to IL-6 inhibit Th1 and promote Th2. 1 So IL-6 inhibitors may be useful.

• Histamine shifts towards Th2, so antihistamines may be useful in a Th1 boosting protocol. 1

• Magnesium deficiency promotes Th2, whereas zinc deficiency promotes Th1 (in malaria, but this may not apply to other infections). 1

• Dietary lectins shift to Th2. 1


Thus my idea is that if you address and eliminate all the Th2 shifting factors in you body, then you may be more successful when you take the Th1 boosting immunomodulators like oxymatrine, etc.


There may be other Th2 shifters not in my list that might also be thwarting the desired Th1 shift. Some Th2 shifters are listed here.

 

[South]

no shift towards Th2

@Hip I think that part of the sentence might have a typo, did you mean "no shift towards Th1"?

The program you've designed for yourself covers many bases and seems well thought out. Is this thread a place where you might keep us updated, or maybe a different place in Phx Rising? Whatever your reactions will be to the various parts of your plan, I'm sure many will be interested in reading (and supporting you no matter what the results for you are)

 

[Hip]

@South Yes it was a typo, thanks, I have corrected it.

For me to be able to do this Th1 boosting protocol depends on whether the 5-HTP you suggested earlier works or not to prevent the depression side effect that I seem to get from many Th1 boosters.

I will start testing this soon, and we'll see if the force is with me or not!

At the moment, I have several other protocols I that I am currently testing / will be testing. I always have so many medications I want to try out, and only one of me to do the testing on!

 

[South]

and only one of me to do the testing on!

Yes, like many here, I too wish I had clones of myself to test things on. It would save years of time.

I plan on doing a search, once a month or so, for the words th1 and th2 (and "migraine" and a few other terms that may relate to my own situation) within Phx Rising, to look for other experiences that may relate to my own as they happen. I'm sure I'll bump into you again on that topic Hip. (no idea what this little icon is really supposed to be, but it's the closest on the list for one that looks like an "explorer").