My Hypothesis on Th2 to Th1 Immunomodulators in CFS

[lansbergen]

So just to clarify.

If we have an increases immune response due to an infection we can't get rid of and then we try to divert the immune system away from fighting it with immune modulators.

This is not counter productive?

Is this true if we are taking something to kill the infection or not?

Or should we only try to divert the immune response when it is an auto immune response that we can't find a reason for? Thanks

I take the immune modulator to fight the infection.

 

[Hip]

@Ema @mermaid
I really wish I did not get the depression side effect, as I would really like to take a Th1 boosting cocktail like you have.


Bacteria and the Th1 / Th2 Balance

Going back to the original hypothesis at the beginning of this thread — the hypothesis that the bacterial co-infections you may have will pull your immune system away from the desired Th1 response, and into the undesired Th2 response: what I would like to do is take antibiotics and/or probiotics with this Th1 boosting cocktail, in order to control my bacteria infections, to try to ensure that the immune response remains in the Th1 mode.

This study showed that the LPS toxins released by many bacteria reduce the Th1 response. So bacterial LPS is one mechanism by which bacterial infections in your gut, etc may be holding your immune system in the undesired Th2 mode, and preventing viral clearance. Antibiotics and/or probiotics may reduce bacteria and bacterial LPS, so that your immune system can swing back to the Th1 mode.


High Cortisol Inhibits the Th1 Response

Glucocorticoids are another possible player in the Th1 / Th2 balance. Glucocorticoids such as cortisol are thought to reduce the Th1 response, and ramp up the Th2 response (ref: here). This means that any ME/CFS patient who has high cortisol levels may suffer an impeded Th1 immune response. Phosphatidylserine and the anti-fungal drug ketoconazole are quite potent inhibitors of cortisol, if you do have high cortisol levels.


The Daily Cortisol Cycle and the Th1 / Th2 Balance

The daily cortisol cycle is present in everyone, and this natural daily cycle significantly ramps up your cortisol levels in the morning, and then significantly lowers your cortisol levels in the afternoon and evening. Because of this daily cortisol cycle, your Th2 response will likely be stronger in the morning, and your Th1 response will likely be stronger in the afternoon and evening.

The possible upshot of this is that if you are taking Th1 boosting immunomodulators (such as those included in the Th1 boosting cocktail), you may be best off taking these immunomodulators in the afternoon, when your body is naturally moving into the Th1 mode, rather than in the morning, when you body is more in the Th2 mode. If you take Th1 boosters in the morning, you may be "swimming against the tide."

In fact, it may be that you are doing harm if you take Th1 boosting immunomodulators in the morning, as in the morning, your immune system is shifted towards the Th2 mode, and therefore will be busy fighting the Th2 pathogens in your body (like the bad bacteria you have in your gut). If you take Th1 boosting immunomodulators in the morning, you may thwart the normal morning Th2 antibacterial response, and thwart the good work that this Th2 response performs against bacterial infections.

And if you want to employ both Th1 boosting immunomodulators and antibiotics/probiotics together, possibly you may be better off taking the antibiotics first thing in the morning, when you body is naturally in Th2 mode and fighting extracellular bacteria, and take the Th1 boosters in the afternoon, when you body is naturally in Th1 mode and fighting viruses (and any intracellular bacteria you may have).


Other Factors that Reduce the Th1 Response

There are also a number of other factors that can reduce the desired Th1 response, and shift to the Th2 response; these factors include:

• Prostaglandin E2 inhibits the Th1 response and IFN-alpha secretion. Fortunately, alpha acids from hops (available as Perluxan) is a very potent prostaglandin E2 inhibitor supplement (ref here). And this study states resveratrol potently reduces prostaglandin E2 in the brain.

• Dr Cheney points out that Epstein-Barr, cytomegalovirus and HHV-6 make a fake version of the cytokine IL-10 in order to shift to the immune system aways from the antiviral Th1 mode, and into the Th2 mode. So if you have any of these viruses reactivating in your body, you may want to take antivirals to target these herpes family viruses.

There is list of various other Th2 increasing factors HERE.

I think it may be possible that one or more of the above Th1 inhibiting and Th2 increasing factors may be present in ME/CFS patients, and impeding their ability to properly fight viruses.

 

[Hip]

@knackers323
There are two major modes of operation of the immune system: the Th1 mode and the Th2 mode (there is also the Th17 mode, but we won't go into that here).

The immune system switches into Th1 mode when it wants to fight pathogens that live inside our cells; such pathogens include viruses, and certain species of intracellular bacteria like Chlamydia pneumoniae which lives inside human cells.

The immune system switches into Th2 mode when it wants to fight pathogens that live outside our cells; such extracellular pathogens include most bacteria.

So depending on the infection you have, your immune system needs to be in the right Th1 or Th2 mode.

Unfortunately, I believe the immune system is not very good at working in both Th1 and Th2 at the same time. So if the immune system is working hard in Th2, then is will only be working quite weakly in Th1, and vice versa.

This leads to the concept of the Th1 / Th2 balance of your immune system: that is, you immune system is a bit like a pendulum that can swing between Th1 and Th2. When your immune system is working hard in Th1 mode, then Th2 will be weak, and when your immune system is working hard in Th2 mode, then Th1 will be weak.

In general, it has been shown that ME/CFS patients are permanently swung too far into the Th2 mode, which means we have difficulty in fighting of viruses, intracellular bacteria like Chlamydia pneumoniae.

That is why doctors try to use Th1 boosting immunomodulators to bring us back towards the Th1 side of the pendulum, so that we can fight off the viruses thought to be driving ME/CFS.

 

[Ema]

I've taken everything on this list at one time or another and am currently still taking most of it. I'm no longer taking chlorella or my mushroom mix. I'm also taking a break from LDN but was thinking of starting it back up again.

I should have said that I take this cocktail with another cocktail of antibiotics and antivirals.

 

[knackers323]

@knackers323
There are two major modes of operation of the immune system: the Th1 mode and the Th2 mode (there is also the Th17 mode, but we won't go into that here).

The immune system switches into Th1 mode when it wants to fight pathogens that live inside our cells; such pathogens include viruses, and certain species of intracellular bacteria like Chlamydia pneumoniae which lives inside human cells.

The immune system switches into Th2 mode when it wants to fight pathogens that live outside our cells; such extracellular pathogens include most bacteria.

So depending on the infection you have, your immune system needs to be in the right Th1 or Th2 mode.

Unfortunately, the immune system is not very good at working in both Th1 and Th2 at the same time. So if the immune system is working hard in Th2, then is will only be working quite weakly in Th1, and vice versa.

This leads to the concept of the Th1 / Th2 balance of your immune system: that is, you immune system is a bit like a pendulum that can swing between Th1 and Th2. When your immune system is working hard in Th1 mode, then Th2 will be weak, and when your immune system is working hard in Th2 mode, then Th1 will be weak.

In general, it has been shown that ME/CFS patients are permanently swung too far into the Th2 mode, which means we have difficulty in fighting of viruses, intracellular bacteria like Chlamydia pneumoniae.

That is why doctors try to use Th1 boosting immunomodulators to bring us back towards the Th1 side of the pendulum, so that we can fight off the viruses thought to be driving ME/CFS.

Thank you for the explanation. But what is causing it to shift to a th2 response?

If it is switching there wouldn't that mean it is trying to kill an outer cellular bacteria? And by pulling it away from that we would be letting that infection grow?

 

[Hip]

Thank you for the explanation. But what is causing it to shift to a th2 response?

Well that's the million dollar question. But if you read the info in my post above, you see that reactivated herpes family viruses are capable of pushing the body towards Th2, so that could part of the answer. Toxic mold exposure also shifts to Th2 (ref: here) and many ME/CFS patients were exposed to mold (ref: here), so that may be another part of the answer. There may well be more than one factor that shifts ME/CFS patients towards Th2.

If it is switching there wouldn't that mean it is trying to kill an outer cellular bacteria? And by pulling it away from that we would be letting that infection grow?

What I wrote about the cortisol cycle in the above post may answer this concern.

 

[heapsreal]

Well that's the million dollar question. But if you read the info in my post above, you see that reactivated herpes family viruses are capable of pushing the body towards Th2, so that could part of the answer. Toxic mold exposure also shifts to Th2 (ref: here) and many ME/CFS patients were exposed to mold (ref: here), so that may be another part of the answer. There may well be more than one factor that shifts ME/CFS patients towards Th2.



What I wrote about the cortisol cycle in the above post may answer this concern.

I also recall that herpes viruses can turn down the bodies interferon production and thus lower nk function, so probably the same mechanisms. I think this is why there has been some success with interferron inducers.
So to add more confusion to your th1/2 theory throw in the interferron and nk function into the mix??

 

[Hip]

to add more confusion to your th1/2 theory throw in the interferon and nk function into the mix??

Interferon gamma (IFN-γ) is already in the mix, because IFN-γ is a standard Th1 cytokine which is released during the TH1 response.

Th1 mode cytokines = IFN-γ, IL-2 and IL-12
Th2 mode cytokines = IL-4, IL-10

IFN-γ is very important during coxsackievirus B infections, as IFN-γ knock out mice were unable to fight off coxsackievirus B, and this infection rapidly killed them (ref: here).

Interferon alpha and delta are effective against enterovirus / coxsackievirus B, as Dr Chia's research demonstrated, but these 2 interferons are not automatically released by the Th1 response, but rather are released by the presence of pathogens themselves (though the mechanisms are not well understood; one mechanism is the presence of dsRNA from pathogens, which triggers the release of interferons).


Natural killer cells: it says here that NK cells are activated in response to interferons or macrophage-derived cytokines. So that means that NK cells will be activated by IFN-γ from the Th1 response, but clearly NK cells can also be activated independently of the Th1 response.

I generally feel better after a few days of taking NK cell activation boosters, and get no side effects at all from them. I think an NK cell boosting cocktail of supplements might be beneficially added to the Th1 boosting supplements, for increased antiviral efficacy.

The NK cell activation booster cocktail I have used is along these lines:

NK Cell Activation Boosters:
Siberian ginseng
Gynostemma pentaphyllum
Arabinogalactan
Transfer factor
B12 methylcobalamin sublingual
Echinacea
Glutamine
Cat's claw
Cordyceps
Sulforaphane
Proboost

 

[heapsreal]

Interferon gamma (IFN-γ) is already in the mix, because IFN-γ is a standard Th1 cytokine which is released during the TH1 response.

Th1 mode cytokines = IFN-γ, IL-2 and IL-12
Th2 mode cytokines = IL-4, IL-10

IFN-γ is very important during coxsackievirus B infections, as IFN-γ knock out mice were unable to fight off coxsackievirus B, and this infection rapidly killed them (ref: here).

Interferon alpha and delta are effective against enterovirus / coxsackievirus B, as Dr Chia's research demonstrated, but these 2 interferons are not automatically released by the Th1 response, but rather are released by the presence of pathogens themselves (though the mechanisms are not well understood).


Natural killer cells: it says here that NK cells are activated in response to interferons or macrophage-derived cytokines. So that means that NK cells will be activated by IFN-γ from the Th1 response, but clearly NK cells can also be activated independently of the Th1 response.

I generally feel better after a few days of taking NK cell activation boosters, and get no side effects at all from them. I think an NK cell boosting cocktail of supplements might be beneficially added to the Th1 boosting supplements, for increased antiviral efficacy.

The NK cell activation booster cocktail I have used is along these lines:

NK Cell Activation Boosters:
Siberian ginseng
Gynostemma pentaphyllum
Arabinogalactan
Transfer factor
B12 methylcobalamin sublingual
Echinacea
Glutamine
Cat's claw
Cordyceps
Sulforaphane
Proboost

Did u get an increase in nk function and or numbers with that protocol?

From memory as its been awhile since i read much about it but interferons can be further broken down, alpha, beta amd gamma and probably more. I think alpha and beta were anti inflammatory and gamma was pro inflammatory. Some of the interferon inducers eg cycloferon stimulated mostly the anti inflammatory interferons so supposedly one didnt feel sick like when one uses straight interferon therapy. After saying that i dont think its was 100% specific and was different amongst individuals.

For me cycloferon did have a calming type of an effect which at a guess was anti inflammatory as i felt the effects within the first day or 2 of using them, but others who have tried cyclo have felt worse so maybe it was increasing the pro inflammatory interferons more?? I did have 1 nk function test while on cycloferon and it greatly increased my nk activity which was most of the time between 1-6 (13-34 normal range), cyclo increase this to 51. But nk bright cells they find that function poorly in cfs/me and mine were crap also, did not improve with cyclo. But cyclo was promising to see that response in a test as well as having symptom improvements from it. But cyclo doesnt seem to work forever and i guess like most immune mods needs to be cycled off and on.

Im currently using AHCC and inosine, when i have done a couple more months on this im thinking of trying cycloferon again for 2 months. All depends on finding a reliable source as the company i was getting it from stopped and other places were unreliable.

I think its a good idea throwing a few things at the immune system but i think its good to try them individually first to see if they have an effect on their own and then after finding a good group of treatments then roll the dice( still refining a good group of immune supps). Also be good to be able to have a few things to alternate every few months to avoid tolerance and keep that dam immune system working.

cheers!!!

 

[Hip]

Did u get an increase in nk function and or numbers with that protocol?

I have never been tested for NK function, and given the cost of these NK function tests in the US, I don't think I will be splashing out on one any time soon! I have not seen these NK function tests anywhere in UK; I wish the UK NHS would give me such as test though.

How much did your NK test cost, or was it just part of the free health care in Australia?

 

[heapsreal]

I have never been tested for NK function, and given the cost of these NK function tests in the US, I don't think I will be splashing out on one any time soon! I have not seen these NK function tests anywhere in UK; I wish the UK NHS would give me such as test though.

How much did your NK test cost, or was it just part of the free health care in Australia?

The nk function testing isnt a standard test here, i got it free through the Bond/griffith uni cfs/me study. Got 5 in total over 18months.

 

[Asklipia]

Just to add Curcumin as a NK Cell Activation Booster.

And MSG as causing a shift from Th1 to Th2. This also happens with folate deficiency. Which can be induced by MSG and Fake Folates for those who have a problem metabolizing different kinds of folates.

And circadian rhythms problems (many times due to the effects of blue light at the wrong time = think computer screens but not only), which also disrupt the switch between Th1 and Th2.

 

[mermaid]

Thank you for such an interesting thread! I have not explored the subject since my little experiment last winter. I got a bit scared as I didn't really know what I was doing and was worried that I had shifted it permanently into some mode that I could not get out of.

I have learnt a bit more now anyway.....thank you for some of the explanations above.

I do remember that my cortisol was low at the time as I had recently had a test.

 

[Dufresne]

Well that's the million dollar question. But if you read the info in my post above, you see that reactivated herpes family viruses are capable of pushing the body towards Th2, so that could part of the answer. Toxic mold exposure also shifts to Th2 (ref: here) and many ME/CFS patients were exposed to mold (ref: here), so that may be another part of the answer.
that shifts ME/CFS patients towards Th2.

Just a few ideas. I wonder if we shouldn't be calling this immune shift 'humoral dominance' rather than TH2 dominance. All the TH's are arms of adaptive immunity. The thing is I think our problem straddles both adaptive and innate immunity. As I think the above cited study (mold toxins and allergies) suggests, innate immune flares can lead to increased allergic (TH2) flare ups. And it might work the other way round too. with adaptive flares exacerbating innate reactions to mold and LPS toxins.

De Meirleir has stated that the bacterial problems we face from the GI tract are all intracellular. I don't think taking ABX simultaneously with Cellular immune boosters for the sake of covering the TH2 wing is warranted. Besides I don't think it's likely we could be that successful in shifting our immunity to the point that we would become TH2 deficient. If we could I think we'd find ourselves healthy. That said, antibiotics to decrease the number of gram-negative, LPS producing, bacteria in our guts is probably a great way of indirectly bettering cellular immunity. However also worth considering is the idea that De Meirleir is wrong and that cell-wall deficient bacteria can persist outside of cells and this may be a significant problem for some of us. It may be that our immune systems are right to crank up humoral immunity to combat these, but the problem might be that although the immune system knows they're there it still has difficulty finding them.

I find it most interesting that Cheney has asserted that ME/CFS and mold illness are indistinguishable. His theory of our disease revolves around a redox shift. This redox shift explains our inadequate cellular immune response as well as the energy deficit. This is a large part of why we are humoral dominant. This suggests mold toxin exposure, or even LPS translocation, can perpetuate a redox shift that keeps us ill. This sets up the perfect environment for intracellular pathogens to flourish and further tilt immunity to humoral dominance. To further support the idea that we all suffer with innate immune problems, it turns out that C4a is the only consistently found abnormality that actually worsens, indicating more inflammation, in post-exertional testing. According to Shoemaker elevated C4a strongly suggests innate immune activation.

What further illustrates the connection between innate-humoral activation and chronic cellular infections is that LLMD's testing for biotoxin susceptible haplotypes are finding that 90-95% of individuals presenting with "Lyme Disease" have the genes that appear to predispose to problems with biotoxins. And these genes are only present in about 24% of the population. Although not a scientific statement, as in peer-reviewed, it is a clinical observation that begs further attention and theorizing. Lyme becomes chronic in the presence of a redox shift and I believe it's innate humoral inflammation that causes this. It seems it's most beneficial to address both innate inflammation, LPS and/or mold induced reactions, and the pathogen at the same time.

A shifter that wasn't included in the TH1/TH2 cocktail that I think deserves special note is wormwood (or artemisia, artesunte, etc). As Cheney stresses, it's the strongest redox shifter he's tested. For this reason it's effective against all intracellular pathogens including the herpes viruses. And if that were not enough it's one of the most effective antiparasitics too. Parasites are pathogens on the humoral side that probably need addressing if we have them.

 

[JBB]

...However also worth considering is the idea that De Meirleir is wrong and that cell-wall deficient bacteria can persist outside of cells and this may be a significant problem for some of us. It may be that our immune systems are right to crank up humoral immunity to combat these, but the problem might be that although the immune system knows they're there it still has difficulty finding them.

Possible but if they are floating around outside our cells then Dr Lipkin is finding them difficult to find too!

This is a very interesting thread.


Best wishes,

J

 

[Helen]

@Dufresne
Thanks for an interesting post. You wrote: "I find it most interesting that Cheney has asserted that ME/CFS and mold illness are indistinguishable. His theory of our disease revolves around a redox shift."
Do you have any links to Cheney where he writes about a redox shift?
You also wrote:" What further illustrates the connection between innate-humoral activation and chronic cellular infections is that LLMD's testing for biotoxin susceptible haplotypes are finding that 90-95% of individuals presenting with "Lyme Disease" have the genes that appear to predispose to problems with biotoxins. And these genes are only present in about 24% of the population."
Do you have any link you would recommend for further reading about this? Thanks in advance.

 

[Hip]

@Dufresne
Certainly the innate immune system is also involved in ME/CFS. The complement system is of course the major part of the innate immune system, and in ME/CFS patients it has, as you say, been shown that C4a in the complement system is activated after exercise, but not in healthy controls. It has also been shown that C4a is activated in chronic Lyme disease.

There are three basic pathways within the complement system: the classical pathway, the alternate pathway, and the lectin pathway. In ME/CFS, you have C4a activation within the lectin pathway, as a result of exercise.

It certainly might be a good idea to try to inhibit the lectin pathway in ME/CFS. Some time ago I was actually looking for drugs or supplements that can inhibit the complement system, and there are a few of them, including olive leaf extract, boswellic acids (from frankincense), rosmarinic acid (from rosemary and lemon balm essential oils), bladderwrack herb and Ephedra. However, these all inhibit the classical pathway and the alternate pathway, but unfortunately not the lectin pathway. I could not find any medication that inhibits the lectin pathway.

The lectin pathway of the complement system is activated when mannose-binding lectin or ficolin attaches to certain sugars found on the surface of pathogens.



But going back to the Th1 / Th2 balance: the important thing to note about the Th1 / Th2 balance is that the activation of one automatically creates an inhibition of the other. So this means that in ME/CFS, where is Th2 is over-activated, this automatically means that Th1 will be simultaneously inhibited, and since Th1 is responsible for fighting viruses, this is not good news.

 

[Asklipia]

@Dufresne

The lectin pathway of the complement system is activated when mannose-binding lectin or fcolin attaches to certain sugars found on the surface of pathogens.

All very interesting. Do you mean "ficolin"?

 

[Hip]

All very interesting. Do you mean "ficolin"?

Thanks, yes, I've corrected it.

 

[Asklipia]

Other Factors that Reduce the Th1 Response

There are also a number of other factors that can reduce the desired Th1 response, and shift to the Th2 response; these factors include:

• Prostaglandin E2 inhibits the Th1 response and IFN-alpha secretion. Fortunately, alpha acids from hops (available as Perluxan) is a very potent prostaglandin E2 inhibitor supplement (ref here). And this study states resveratrol potently reduces prostaglandin E2 in the brain.

Curcumin blocks prostaglandin E2 biosynthesis through direct inhibition of the microsomal prostaglandin E2 synthase-1.
http://www.ncbi.nlm.nih.gov/pubmed/19671757
Another way in which curcumin works on that.