We can get Peginterferon Lambda now!!!

Learner1

Senior Member
Messages
5,896
Likes
10,679
Location
Pacific Northwest
@Nuno Thanks for explaining. I was trying to understand this claim " it's very important to remember that shutting down the SARS-CoV-2 and Enterovirus B infection is going to restore gut health and normal immune function."

So, from what you're saying, it's actually nothing to restore gut health or normal immune function, though I'm sure treating the viruses would be a step in the right direction.
 
Messages
28
Likes
68
Location
Indiana, US
why would peg interferon help clear infections when yrs of antivirals cant? the only way to eradicate EBV from the body is bone marrow transplant. they have done studies on this.

what do you guys think of BC007?
Perhaps I did not convey myself properly and for that I do sincerely apologize. Here is a much more in depth explanation:

Type I and Type II interferons (alpha, beta, gamma, etc) are VERY visible in the body, very hard to miss. They act ALL over the place as part of our innate immune response.

The reason why we never knew about Type III, which is Lambda, is because it only works in a few places in the body. So it took us a while to find it.

These interferons work based on their cell receptor counterparts. Lots of cells in the body have IFN cell surface receptors for IFN alpha for instance.

So IFN alpha works on all the cells w/ that receptor, again, it's on MANY cells in the body.

When they discovered Type III (lambda), they first noted that it was just reacting in the barrier sites of the body, and that corresponded w/ the lambda cell receptor IFNLR-1

They actually did not know it wasn't redundant. They thought it was just another interferon, w/ limited usage.

Turns out, it's NOT redundant. It's necessary. It may not be used to clear out pathogens all over the body. But it's actually the most important IFN for epithelial cells in barriers.

If we look at the angle of Enterovirus in ME/CFS, and how the persistence in the intestinal epithelium is the root cause of everything.

The infected intestinal epithelial cells do NOT use Type I or Type II IFN receptors. They mostly use Type III, lambda.

For a while, I think it was assumed that these epithelial cells would respond equally Type I or Type III ifn...

So to answer your question - Using any other antiviral method, valtrex, acyclovir DOES temporarily sometimes help some. Specifically, IFN alpha will result in a lot of antiviral activity. Apparently enough to get many well again... But later relapse because you didn't destroy the root. We see this with Chia.

The root, the primary reservoir where a pathogen has its "HQ" set up, is where lambda comes in.

Regarding your EBV concern - I know EBV doesn't just go away. But my point is, a subset of patients have either a chronic EBV or have chronic increasing titers (generally IgG). When lambda gets rid of said pathogen/enterovirus - the immune system should have room to breathe again. EBV usually reactivates. As you mentioned it hibernates. It is a "smart virus". So lambda will likely not kill EBV for good. BUT it will allow your immune system to properly get your CEBV (if you have it) to recalibrate and cause EBV to go into a latent state again and hopefully causing your high titers to decrease overtime. The key take away here is: EBV is likely not the PRIMARY CAUSE of MECFS. It is a pathogen/enterovirus, which caused an EBV reactivation. We should view EBV reactivation as a symptom, not a cause.
 

sometexan84

Senior Member
Messages
1,004
Likes
1,828
Can you please explain how shutting down these infections is going to populate one's but with bacteria they may have inadvertently killed off by antibiotics, other drugs and dietary choices, kill off malicious opportunistic bacteria, candida, or other viruses, and repair the gut lining?

And, if one is immunodeficient and,/or has autoimmunity, how is this stuff going to magically make the immune system behave normally and get rid of autoimmune antibodies?

Thank you for explaining.
I think it's important to clarify "immunodeficient".

So, I think enough has been published by now that we can agree we all have an immunodeficiency. Primary immunodeficiency is one type.. this is genetic, it is rare, and it involves immune dysfunction that you just have, regardless of a virus.

Someone w/ a Primary immunodeficiency can certainly get ME/CFS. But again, this is rare. And a treatment like Interferon or antivirals is not going likely to cure this.

ME/CFS is typically secondary (acquired) immunodeficiency. The dysfunctional immune system goes hand in hand w/ the autoimmunity we have.

To fix everything, we have to fix the root cause of the immune dysfunction.

The intestinal epithelial cells and the gut microbiome have a direct impact on immune system function.

Note: The hyperlinks embedded are often a reference for the material listed beneath it as well. So sentences and sections below the initial hyperlink are likely to correspond from that first initial hyperlink. I didn't want to keep adding the same link multiple times.


Enterovirus causes autoimmunity via Treg dysregulation

Tregs and Self Tolerance - Unregulated antigen-presenting cell activation by T cells breaks self tolerance.
Self tolerance means controlling autoimmunity

Removal of a subset of Tregs impairs immune homeostasis and causes T cell proliferation and autoimmune disease.

Tregs (T regulatory cells) maintain peripheral tolerance, and control autoreactive and excessive immune responses

Enterovirus significantly decreases the FOXP3 expression in highly activated Tregs. So this is Enterovirus removing a very important subset of Tregs.

The same FOXP3 Treg dysregulation is also found in Type I Diabetes, which is strongly thought to be caused from persistent Enterovirus

Foxp3(+) Tregs are a major regulator of immune homeostasis through their immunosuppressive function

Also regulator of inflammation


Enterovirus causes autoimmunity, inflammation, and intestinal permeability via Th17 dysregulation

Note: I didn't have time to clean up this section, and edit/organize it. So this section of notes is pretty raw. Hope to come back and clean up a little bit.

Inflammatory T helper 17 (Th17) cells modulate the activity of autoimmune response

IL-17Fduring exercise, increases in controls, but not in ME/CFS
  • IL-17F is produced from Th 17 cells, also innate immune cells and epithelial cells
  • If epithelial cells are infected (as well as the innate immune cells in the lamina propria), IL-17 production may no longer be operational here
  • And If Th17 cells are dysfunctional, then it would explain the lack of IL-17F production. If healthy controls produce IL-17F during exercise, it must be protective.
  • “IL-17A” is sometimes called “IL-17”
  • IL-17F has the ability to product defensins and other antimicrobial peptides
  • Defensins and microbial peptides might help w/ PEM
  • Defensins are produced by cells of the innate immune system and epithelial cells. Enterovirus infection of epithelial cells and innate immune cells in lamina propria won’t produce microbial peptides like they’re supposed to
Th17 - major dysfunction of Th17 cells in ME/CFS patients
  • Th17 cells are a subpopulation of CD4 T lymphocytes
  • Th17 regulates viral or bacterial infections and the microbiota
  • Th17 helps maintain mucosal barriers and with pathogen clearance at mucosal surfaces
  • Also been implicated in autoimmune and inflammatory disorders. The loss of Th17 cell populations at mucosal surfaces has been linked to chronic inflammation and microbial translocation
  • Th17 promotes integrity of mucosal epithelial barriers. And play a role in induction of autoimmune disease
  • This could explain the increased bacterial translocation following exercise, which would explain pro-inflammatory situation, which would explain increased sickness behavior.
  • The Th17 immune response protects hosts from pathogens at epithelial and mucosal tissues including the skin, lung, and intestine
If a virus is tropic for intestinal epithelial cells (Enterovirus, SARS), it causes cell damage and loosens the normally impermeable barrier that keeps bacteria in the intestinal lumen


Gut Dysbiosis causes autoimmunity. Enterovirus perpetuates Gut Dysbiosis

Disruption of gut microbial homeostasis (dysbiosis) leads to the breakdown of host immune tolerance

This particular study focuses on Type 1 diabetes (T1D) and Hashimoto's thyroiditis (HT), which are being increasingly linked to persistent Enterovirus

Chronic/persistent (but NOT acute) viral infection in the GI tract negatively alters gut microbiome, leading to dysbiosis.

Chronic/persistent (but NOT acute) viral infection in the GI tract results in widespread changes in inflammatory signaling pathways, and host immunity.



Enterovirus causes immune dysfunction, and viral reactivation

EBV Reactivation is known to occur in Enterovirus/MECFS and SARS-CoV-2/Long Covid.

And from the Enterovirus Foundation

“Enterovirus infections can trigger dormant viruses to reactivate, such as HHV6, Epstein Barr Virus, CMV, and chickenpox– all herpes viruses”

To get more specific…

Dysfunctional CD8+ T Cells allow for EBV re-activation.

In the acute EBV infection, CD8+ T cells have a CD45RO+CD45RA− which control the virus.

But in later EBV infection, like re-activation, the CD45RA switches, and becomes positive. So reactivation is controlled by CD45RO+CD45RA+ CD8+ T cells.

And if we go back to the Enterovirus in Type I Diabetes, it was shown that enterovirus-infected patients w/ T1D had decreased CD8+ CD45RO+CD45RA+ T cell population.

And back to the more general…

Enterovirus causes Th1/Th2 imbalance, which leads to EBV reactivation.

EBV reactivation from reduced Th1 (cellular immunity), and from reduced Immune surveillance

Enterovirus is Th2 dominant, leading to reduction in Th1.

That’s why Dr. John Chia uses Oxymatrine, as it increases antiviral Th1 cytokines (IFN-γ and IL-2). Reduced Th2 cytokines (IL-4 and IL-10) and why some people have seen improvement on LDN, as it helps restore Th1/Th2 balance.

And referencing back to the CD8+ T cells… these are part of Th1 immunity. So you can see how that all fits.



Enterovirus (and gut dysbiosis) leads to intestinal permeability, leading to more autoimmunity, infections, etc

Gut dysbiosis has been associated w/ “sickness behavior” and chronic fatigue, where CFS and severe mental illness patients have increased circulating levels of the tight-junction protein zonulin, the endotoxin LPS, the gut related systemic inflammatory proteins LBP and sCD14, antibodies against endotoxins, and the acute phase protein A-1-AT.

Zonulin is a tight-junction protein and key regulator of intestinal permeability, with increased circulating levels suggesting a compromised intestinal barrier

Density of Enterovirus in intestines correlates w/ circulating levels of zonulin

One member of Phoenix Rising said they used a Zonulin inhibitor (antagonist) for about 3 months and it greatly improved gut symptoms and decreased Zonulin in serum by half.

Persistent Enterovirus infection is associated with increased intestinal permeability and inflammation; both pronounced in mice and children with type 1 diabetes



Restoring Immunity

Once we remove the enteric infection in the intestinal epithelium, and restore gut microbiome, our immune system will recalibrate and return to normal.

The immune system will no longer be controlled by any of the elements mentioned above. Th1/Th2/Th17 balance will restore. Gut homeostasis will no longer be disrupted. Intestinal mucosa will be able to completely heal w/ no more intestinal permeability. Self-tolerance can return to normal. etc etc etc



Further Reading:

This goes over how the intestinal epithelium and gut microbiota interact w/ one another, and how they influence T-cell differentiation, intestinal permeability, the innate and adaptive immune system, Tregs, inflammation, cytokines, autoimmunity, etc.

https://www.nature.com/articles/s41422-020-0332-7



B cells

The GI tract microbiome modulates B cell differentiation, maturation, and activation

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5845559/

Didn’t have time to complete this section on B cells, and how they’re involved in autoimmunity, immune dysfunction, and how enteric viruses and microbiota alter them. Hope to come back later are update.
 

Learner1

Senior Member
Messages
5,896
Likes
10,679
Location
Pacific Northwest
My explanation needs more work, I know. I need to add and fix some sections, and I need to throw in summaries to help explain the connections.

For now, that's what I've got
Your lengthy explanation is very well thought out and admirable in effort.

I still have a few questions, not just for myself, but for others whose land I've seen and whose stories I'm familiar with...

Regarding your EBV concern - I know EBV doesn't just go away. But my point is, a subset of patients have either a chronic EBV or have chronic increasing titers (generally IgG). When lambda gets rid of said pathogen/enterovirus - the immune system should have room to breathe again. EBV usually reactivates. As you mentioned it hibernates. It is a "smart virus". So lambda will likely not kill EBV for good. BUT it will allow your immune system to properly get your CEBV (if you have it) to recalibrate and cause EBV to go into a latent state again and hopefully causing your high titers to decrease overtime. The key take away here is: EBV is likely not the PRIMARY CAUSE of MECFS. It is a pathogen/enterovirus, which caused an EBV reactivation. We should view EBV reactivation as a symptom, not a cause.
It's not just EBV, it's all the other herpes family viruses, too. My experience is it's like playing "whack a mole" between them bsdrd on stressors on the immune system.

So, is lambda going to actively keep them all at bay? What about the next stressor that causes the next one to reactivate?
I think it's important to clarify "immunodeficient".

So, I think enough has been published by now that we can agree we all have an immunodeficiency. Primary immunodeficiency is one type.. this is genetic, it is rare, and it involves immune dysfunction that you just have, regardless of a virus.

Someone w/ a Primary immunodeficiency can certainly get ME/CFS. But again, this is rare. And a treatment like Interferon or antivirals is not going likely to cure this
According to the CDC, primary immunodeficiency is not always genetic - this is from their website.

"People with primary immunodeficiency (PI) have an immune system that does not work correctly. This means that people with PI are more likely to get and become severely ill from infections. There are more than 400 types of PI that vary in severity, which affects how early they are detected."

I have run into several ME/CFS patients who have significant immunodeficiency, and many of us have a diagnosis of common variable immune deficiency. The last immunologist I saw told me I would likely be getting replacement immunoglobulin therapy the rest of my life. No one has found a genetic reason for mine. It would be very nice from my point of view not to have to have a $5,000 treatment every 3-4 weeks for the rest of my life, though it's greatly helped me increase function. I'm all ears for any cure here.
To fix everything, we have to fix the root cause of the immune dysfunction.
Well, that would be nice. No one knows what the root cause is.
The intestinal epithelial cells and the gut microbiome have a direct impact on immune system function.
That's true. However, each of our microbiomes has over 30 trillion cells of over 1,000 unique species of bacteria, plus viruses, fungi, biofilms, macrophages, etc. Scientists have not unravelled all the complexity to understand how to manipulate it, though humans have created antibiotics, other drugs, and pesticides which kill off various microbiome constituents.
Enterovirus causes autoimmunity, inflammation, and intestinal permeability via Th17 dysregulation
That may be. How do we all know we have an enterovirus in our gut?

Epstein Barr also causes autoimmunity, inflammation and intestinal disease. It also uses Th17 and IL17.

https://doi.org/10.3390/v13071272

https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC6040775/


Enterovirus causes autoimmunity via Treg dysregulation

Tregs and Self Tolerance - Unregulated antigen-presenting cell activation by T cells breaks self tolerance.
Self tolerance means controlling autoimmunity

Removal of a subset of Tregs impairs immune homeostasis and causes T cell proliferation and autoimmune disease.

Tregs (T regulatory cells) maintain peripheral tolerance, and control autoreactive and excessive immune responses

Enterovirus significantly decreases the FOXP3 expression in highly activated Tregs. So this is Enterovirus removing a very important subset of Tregs.
Epstein Barr affects Tregs, too.

https://pubmed.ncbi.nlm.nih.gov/19319950/

That’s why Dr. John Chia uses Oxymatrine, as it increases antiviral Th1 cytokines (IFN-γ and IL-2). Reduced Th2 cytokines (IL-4 and IL-10) and why some people have seen improvement on LDN, as it helps restore Th1/Th2 balance
This is not appropriate for everyone - I tend to have very high IFN-g and low IL4 and IL10... Not sure that's desirable...

Restoring Immunity

Once we remove the enteric infection in the intestinal epithelium, and restore gut microbiome, our immune system will recalibrate and return to normal.

The immune system will no longer be controlled by any of the elements mentioned above. Th1/Th2/Th17 balance will restore. Gut homeostasis will no longer be disrupted. Intestinal mucosa will be able to completely heal w/ no more intestinal permeability. Self-tolerance can return to normal. etc etc etc
The microbiome is made up of over 1,000 unique citizens comprising over 30 trillion cells. For many of us, the drugs we have taken have irreversibly killed off many species in out microbiomes. For example, the majority of antibiotics kill off oxalobacter fomigenes, the bacteria in our guys that degrade oxalate toxins from the plant based foods we eat, causing a cascade of health problems including muscle and joint pain, mitochondrial dysfunction, oxidative stress, mineral depletion, osteoporosis, etc. There is no probiotic to replace this bacteria and getting rid of these built up toxins takes years. And it is a very common (but unfortunately less known) problem in ME/CFS patients.

Then there are issues like clostridium difficile, candida, SIBO, helicobacter pylori, klebsiella, blastocystis hominis roundworms, pinworms, furmicute/bacteroides imbalance, etc. In addition to mast cell degranulation and food allergies. All very vexing problems that take a great deal of effort to resolve. It's quite unlikely that any one substance will magically make these problems that are reasonably common in ME/CFS patients disappear.

So, back to our topic. Since lambda cannot cure our microbiomes, restore our immune systems, or info our autoimmunity, what exactly can we expect it to do? I think you're saying it can help kill enteroviruses for those who have them, but what about those of us with autoimmunity, immunodeficiency and a bunch of herpes viruses, any of which are reasonably common among ME/CFS patients?

Thank you for helping us understand this better.
 

sometexan84

Senior Member
Messages
1,004
Likes
1,828
Your lengthy explanation is very well thought out and admirable in effort.
Well I am glad that you admire my effort.

So, is lambda going to actively keep them all at bay? What about the next stressor that causes the next one to reactivate?
Lambda has some direct antiviral activity here... but that's not what we're going for here.

We want to treat the persistent infection causing the immune response disturbances. Lambda will do this, which indirectly will keep them at bay.

The next stressor? You mean, how do we cure your ME/CFS when you get it again. Idk. Odd question.

That may be. How do we all know we have an enterovirus in our gut?

Epstein Barr also causes autoimmunity, inflammation and intestinal disease. It also uses Th17 and IL17.
Because it's been found in most of our guts, and EBV has not. And I think that the EBV reactivation that occurs in SARS-CoV-2 is more proof of which was the chicken and which was the egg. ...... that made more sense in my head ....

Epstein Barr affects Tregs, too.
No more EBV talk. Doesn't explain everything, EBV is not a contender.

This is not appropriate for everyone - I tend to have very high IFN-g and low IL4 and IL10... Not sure that's desirable...
omg. That's not what I was trying to portray. Yes, our cytokine profiles are vastly different. That's why all the ME/CFS cytokine studies show so many conflicting things. That's not the point. Also, you MAY have a primary immunodeficiency.

It's quite unlikely that any one substance will magically make these problems that are reasonably common in ME/CFS patients disappear.
We will let you know in approx. 4 months
 

Daffodil

Senior Member
Messages
5,831
Likes
6,283
@Thebirdman333 thanks for that explanation! I agree that EBV reactivation is at play but is not the cause. Could be a trigger but not the cause - unless the abortive replication theory is right. Mine was triggered by EBV But I never had high antibodies to it.

I also agree that the problem is in the gut epithelium and the inflammation is coming from there....i think the Demeirleir tissue study showed this

However, I disagree that it is enterovirus causing this. I mean, it could, in theory, but so could any number of things.

But most of it is over my head anyway..
 

sometexan84

Senior Member
Messages
1,004
Likes
1,828
However, I disagree that it is enterovirus causing this. I mean, it could, in theory, but so could any number of things.
If we focus on all the historical outbreaks of ME/CFS, the VAST majority were poliovirus-like, or you hear "poliomyelitis", as well as enterovirus. But all the polio-like ones where polio was never found... these are all VERY likely Enterovirus.

If you were to go through all these ME/CFS outbreaks over the yrs, you'd find only a very small number of possibilities.
 

Daffodil

Senior Member
Messages
5,831
Likes
6,283
but i am at the point where I dont think the triggering infection is the on-going problem. For most, I dont even think it matters. i came across some papers saying that some viruses, such as EBV, norovirus, and some others, can damage the neuromodulatory cells in the gut. I think maybe something like this is happening. The result is that digestion becomes altered. There is delay in gastric emptying. Then there is bacterial overgrowth. And then the rest follows. That is not how it is for everyone (Jen Brea for example) but ...I suspect it might be for many. I have come to believe that a number of things can somehow shift the microbiome. Severe Trauma, Vaccines, Infections, etc. I am just speculating about the neuromodulatory cells but maybe that is one way

I know there are still a million questions.......but this is kind of where my head is now, after taking antimicrobials for decades. Obviously I am heavily biased by my own experience
 
Last edited:

sometexan84

Senior Member
Messages
1,004
Likes
1,828
but i am at the point where I dont think the triggering infection is the on-going problem. For most, I dont even think it matters. i came across some papers saying that some viruses, such as EBV, norovirus, and some others, can damage the neuromodulatory cells in the gut. I think maybe something like this is happening. The result is that digestion becomes altered. There is delay in gastric emptying. Then there is bacterial overgrowth. And then the rest follows. That is not how it is for everyone (Jen Brea for example) but ...I suspect it might be for many. I have come to believe that a number of things can somehow shift the microbiome. Severe Trauma, Vaccines, Infections, etc. I am just speculating about the neuromodulatory cells but maybe that is one way
Well, a few months from now hopefully there will be news that helps clear things up.
 

sometexan84

Senior Member
Messages
1,004
Likes
1,828
I had posted this on the Discord group chat, but wanted to repost here for others.....

IFNλ cures persistent Norovirus + Norovirus can cause ME/CFS?

Wanted to share more since I've barely mentioned Norovirus. Norovirus is of the Caliciviridae family, so very close to Enterovirus and SARS-CoV-2, another ssRNA virus.

And can establish persistent infection in intestinal epithelium, like those as well.

There have been very few studies on Type III IFN Lambda against persistent enteric infections, but Norovirus is one, showing IFNλ completely clearing persistent gut infection.

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5957778/
https://www.science.org/doi/10.1126/science.1258100

Also, I had never heard about Norovirus causing ME/CFS. Then I found this blog from a nurse who developed ME/CFS after acute Norovirus infection.

I had seen a couple of individuals mention they thought theirs was from Norovirus, but this blog is a bit more definitive. Crazy!

https://www.omf.ngo/i-hope-for-trea...ition-for-this-horrible-debilitating-illness/
 
Messages
63
Likes
167
Super interesting @sometexan84 as my ME/CFS started after viral gastroentiritis. So Norovirus is one of my possible causes.

I wonder though, Enterovirus also cause viral gastroenteritis right? Apologies for taking off topic but could use some of your knowledge.

Do you know how the symptoms differ between these?
 

sometexan84

Senior Member
Messages
1,004
Likes
1,828
Super interesting @sometexan84 as my ME/CFS started after viral gastroentiritis. So Norovirus is one of my possible causes.

I wonder though, Enterovirus also cause viral gastroenteritis right? Apologies for taking off topic but could use some of your knowledge.

Do you know how the symptoms differ between these?
It's interesting to see Norovirus may have the ability to cause ME/CFS as well. Because noro is Caliciviridae, another ss+ RNA virus. (repeating this because it makes the graphic below make more sense)

But yes, all the gut viruses are known for viral gastroenteritis, including those like Rotovirus (which is actually NOT associated w/ ME/CFS)


1632447795624.png
 

Daffodil

Senior Member
Messages
5,831
Likes
6,283
they did tissue study on gut epithelium. they did not find any virus. they did second generation sequencing.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3776582/

the virus does something to shift the microbiome somehow but i do not think it is a persistent viral infection of the gut

i got this after ebv. i did tons and tons of blood tests and even cultures for ebv. never found it. at the best labs. took yrs and yrs of antivirals. even IV. did not help
 

Daffodil

Senior Member
Messages
5,831
Likes
6,283
i read that rotavirus increases motility (diarrhea) but not permeability. so perhaps that would explain why it is not associated with me/cfs