Assessment of the Role of CD8+ T Cells in ME/CFS.

[IrisRV]

Have you had positive PCRs or just antibody tests though?

I had all the high antibody tests but after years of antibiotics and antivirals, I've just lost confidence that a chronic infection is the cause at least for me. It just seems like my immune system doesn't know which way is up anymore and has lost all regulation. But I could be wrong. Would love to be if it meant we had a root cause and a cure.

I've had positive PCR tests where such tests are accurate. For others I have high antibody tests. Antivirals have worked wonders for me, so I'm comfortable that for me, uncontrolled viruses are an issue. With all the immune abnormalities and pathogens I have, I couldn't say what is cause and what is effect.

I have no problem with the idea that chronic infections are not an issue for some PWME. We currently have no clue what is at the root of this illness -- or much of anything else for that matter, so there could be all kinds of variations.

An immune system that doesn't know which way is up does seem to be a common factor. It's what got us there and what's keeping us there that's in question. It may even be that different causes and different maintaining factors are leading us all to the same place. Hopefully the research of the next 5 years will give us a better idea of what's going on.

 

[Remy]

Antivirals have worked wonders for me, so I'm comfortable that for me, uncontrolled viruses are an issue.

Except that there are solid reasons AVs would help that are unrelated to uncontrolled viral infections too. So a positive response only means *something* shifted, but what? Maybe just the inflammation in the brain calmed down because you inhibited the microglial cells.

I am not saying you definitely do or don't have active viral infections because I have no idea. I just think that we need to be careful of ruts in our thinking and stay open to all the possibilities. I'm sure we agree on that point though.

 

[IrisRV]

Except that there are solid reasons AVs would help that are unrelated to uncontrolled viral infections too. So a positive response only means *something* shifted, but what? Maybe just the inflammation in the brain calmed down because you inhibited the microglial cells.

Sure, that could be. At the very least, it could be a contributing factor. One thing that makes me comfortable with the idea of active viruses for me is that when I stay off AVs for a couple of years, my symptoms start coming back and my viral titres rise. That shouldn't happen if the AVs are only about inhibiting microglial cells.

I'm currently on LDN, which is a microglial inhibitor, and off AVs. My viral titres are starting to climb and my symptoms are getting worse. So while microglial inhibition seems to be helping, it's not doing everything AVs did. My particular immune dysfunctions do make me more susceptible to new and reactivating viruses, so it's not like active viral infections are improbable in my case.

Of course, that's still no guarantee that viruses are a problem. Unfortunately, there's no guarantee of much of anything with this illness. We're going with the best clues we can get for my particular case, and treating based on my symptoms and lab results, not some general ME protocol. Neither my doctor, nor I, is claiming that the treatments I get based on my labs are the right treatments for PWME in general.

Absolutely we agree about ruts. I'm lucky that my specialist is not a thinker-in-ruts. When the activated microglia information came out, she put me on LDN as a microglial inhibitor, and raised my dose when it wasn't working as well as Valcyte for some symptoms. When she took me off AVs she said we'll see if the LDN can handle my symptoms or if I'll still need to go back on AVs at some point. Based on the latest labs, it looks like I'll be back on AVs within the year... but we'll see. She's always coming up with new things as the knowledge base improves.

 

[Remy]

that when I stay off AVs for a couple of years, my symptoms start coming back and my viral titres rise. That shouldn't happen if the AVs are only about inhibiting microglial cells.

The AVs aren't just about the microglial cells. That was just one example of how they are immunomodulatory. Valtrex, for example, also modulates adenosine, the hibernation molecule. That might be a much stronger effect than microglial inhibition alone.

If we are talking about antibody titers rising, all that says to me is antibody dysregulation. It doesn't necessarily say to me rising levels of viruses because it isn't measuring the viruses, it's measuring the antibodies.

What has happened to turn the overactive immune response back on to provoke symptoms? Is it increased viral load? Maybe. Or is it something else altogether? I wonder.

So do you turn IgM positive then? Or have physical outbreaks like @Strike me lucky?

You know, I'm sure, that they have to be "real" titers, ratios like Lerner used to use for EBV to make a quantitative assessment on viral load. A 12 on an ELISA test is evidence of a stronger antibody response than a 4, but it's not proportionally 3x worse. The difference might look like a lot on paper but be insignificant in the body as a whole sea. ELISA is qualitative (positive vs negative) vs titer tests which are serial dilutions.

I know you're not saying that your treatments are right for everybody. I think you choose the treatments that make you better, no matter what. I definitely still think the antimicrobials have benefit for our population and help people with symptoms. It was just that one statement at the beginning that I thought was a bit bold given how much we still have to learn about *why* they are helping.

I hope it's clear that I'm not criticizing your treatment choices but just pondering.

 

[Cort]

Sure, that could be. At the very least, it could be a contributing factor. One thing that makes me comfortable with the idea of active viruses for me is that when I stay off AVs for a couple of years, my symptoms start coming back and my viral titres rise. That shouldn't happen if the AVs are only about inhibiting microglial cells.

I'm currently on LDN, which is a microglial inhibitor, and off AVs. My viral titres are starting to climb and my symptoms are getting worse. So while microglial inhibition seems to be helping, it's not doing everything AVs did. My particular immune dysfunctions do make me more susceptible to new and reactivating viruses, so it's not like active viral infections are improbable in my case.

Of course, that's still no guarantee that viruses are a problem. Unfortunately, there's no guarantee of much of anything with this illness. We're going with the best clues we can get for my particular case, and treating based on my symptoms and lab results, not some general ME protocol. Neither my doctor, nor I, is claiming that the treatments I get based on my labs are the right treatments for PWME in general.

Absolutely we agree about ruts. I'm lucky that my specialist is not a thinker-in-ruts. When the activated microglia information came out, she put me on LDN as a microglial inhibitor, and raised my dose when it wasn't working as well as Valcyte for some symptoms. When she took me off AVs she said we'll see if the LDN can handle my symptoms or if I'll still need to go back on AVs at some point. Based on the latest labs, it looks like I'll be back on AVs within the year... but we'll see. She's always coming up with new things as the knowledge base improves.

How have you done on long term Valcyte? I know somebody who's been on it for years now. He's doing great but every time he goes off of it the bug comes back...

 

[Cort]

Ive read similar research showing low cd8 t cell function along with the low nk function, so a double whammy when trying to control infections. I have also seen others on cfs forums have either nk or cd8 function low or both low.

I assume both probably occur due to some type of immune exhaustion and autoinflammatory effects of other parts of the immune system causing increased inflammation.

Its hard to know when these issues occur in cfsme ie straight away or after a certain time period as most arent diagnosed or even tested for nk function etc until they have been ill for quite some time.

Any ideas for immune exhaustion others have found helpful?

Drug companies are working on drugs for immune exhaustion. Not sure what they are though.

 

[weyland]

If we are talking about antibody titers rising, all that says to me is antibody dysregulation. It doesn't necessarily say to me rising levels of viruses because it isn't measuring the viruses, it's measuring the antibodies.

What would be the mechanism here? My understanding (which is admittedly really poor in this area) is that overall antibody levels for a given antigen will be determined by the amount of B cell clones present producing the antibodies, and those clones expand either due to antigenic stimulation or malignancy. Is there another mechanism besides those two that can cause clonal expansion of B cells?

For me, this theory definitely doesn't ring true. Most of my serologies are normal, and even on my enterovirus antibody panels only a single serotype is highly elevated (1:640), the rest that I have been exposed to are at the expected level for past infection. (1:40)

 

[weyland]

Guess I should have read a bit before posting. It looks like the nonspecific polyclonal B cell response can do what you're saying, though again this is due to the response to a pathogen.

 

[Remy]

Guess I should have read a bit before posting. It looks like the nonspecific polyclonal B cell response can do what you're saying, though again this is due to the response to a pathogen.

Haha! All you were going to get from me was a mechanism "through T cell dysregulation"...but your article is much more specific and clear!

FWIW, I am in no way saying that this is applicable to everyone with MECFS. I just spent a LONG time trying to stimulate my immune system to fight all these infections I tested positive for (EBV, CMV, HHV6, Parvo, Lyme etc etc) only to discover through cytokine testing and stimulated lymphocyte testing that my immune system was already in overdrive. It just seems like we need to identify the subgroups better before having any hope of a treatment, or Dog hope, a cure.

 

[IrisRV]

If we are talking about antibody titers rising, all that says to me is antibody dysregulation. It doesn't necessarily say to me rising levels of viruses because it isn't measuring the viruses, it's measuring the antibodies.

Certainly when you're using a secondary measure like antibodies, there is the question of whether the flaw is in the primary condition (viral load) or the secondary measure (antibody production). We simply can't know at this point.

We are putting together the clues for me as best we can given there's no way to get definitive evidence. Since my antibody production appears to be impaired based on immune data, for me the possibility of unstimulated antibody overproduction seems less likely than the possibility of an increased antibody demand as reason for the antibody increase when I'm off AVs. Of course, the less likely possibility could still be true, but we're doing the best we can with the evidence we have so far. Both the doctor and I are willing to change directions if the evidence becomes stronger in another direction.

So do you turn IgM positive then? Or have physical outbreaks like @Strike me lucky?

I was IgM or PCR positive for new infections. IgM antibodies are produced at the beginning of an initial infection. They aren't produced during a reactivation or a chronic infection because the IgG antibodies already exist at that point. The only commonly measured antibody response you get with a reactivation is an IgG antibody increase.

Barring antibody dysregulation causing random increase in certain disease-specific antibodies, IgG antibodies should only increase when there is an increased demand, a need to beat down a reactivation of a latent infection. Generally, disease-specific IgG antibodies decrease over time, hence the need for the shingles vaccine (chicken pox booster) later in life.

I have had multiple shingles outbreaks, and symptoms consistent with HHV6 and EBV reactivation. I do not go back on AVs immediately upon seeing antibodies rise. We wait for symptoms to occur also. We are beginning to question that strategy, however, since I invariably do get symptoms within a few months. It has yet to happen that my antibodies rise but my body kicks the infection back into latency without the use of AVs.

You know, I'm sure, that they have to be "real" titers, ratios like Lerner used to use for EBV to make a quantitative assessment on viral load.

Yes, Lerner is the one who first recognized and treated herpesviral reactivations in me. He had no doubt whatsoever based on his testing. My current doctor doesn't use qualitative tests, either. My docs have always used quantitative tests. I believe both Lerner and Klimas know what they're doing in that respect.

It was just that one statement at the beginning that I thought was a bit bold given how much we still have to learn about *why* they are helping.

I hope it's clear that I'm not criticizing your treatment choices but just pondering.

I understand. I probably could have worded that first statement better. My doctor never said my immune pattern is absolutely a sign I'm fighting an infection my immune system can't handle. She said that my immune patterns looks like those of people who are fighting an infection their immune systems can't handle. Not quite the same thing. I could, theoretically, have the same immune pattern for another reason.

Since it's not just a question of antibody titres increasing, but also other measures -- certain immune cell numbers and ratios, cytokine patterns, and I dunno what else -- our best plan at this point is to use treatments that help people with similar immune profiles to mine. If they work, we stick to them. It's the best we've got. There could be any number of reasons why various treatments work. AVs could work for reasons entirely different from those medicine currently thinks are correct. But they work for people with chronic infections and they work for me. I'm satisfied with that for now, and am hoping for better information relatively soon.

 

[IrisRV]

How have you done on long term Valcyte? I know somebody who's been on it for years now. He's doing great but every time he goes off of it the bug comes back...

That's my experience. I can do about 2 years off before I start getting symptoms again and my titres start climbing. We're trying to find ways to stretch that with immune/inflammation treatments and Valtrex because Valcyte can be hard on the liver. So far all my liver function labs have been good, but I'm going to need that liver for another couple of decades, so we're trying to treat it as nicely as possible.

My uncle was on Valcyte a very long time (8-10 years straight, I think) starting with the IV form. He's been off all AVs for 5-7 years so far and appears to be completely cured. He only had mild ME, though.

My daughter is fully functioning with a lot of symptomatic treatment. She also manages with 2 years on and 2 years off. Valtrex during the 2 years off seems to help. Lerner had some reason for that. Something to do with the different AVs acting on different parts of the virus, I think. So he felt you needed the Valcyte to shove CMV/HHV6 back into latency, but once you were there Valtrex could help keep it in latency longer.

Frankly, I feel best when I'm on Valcyte, whatever the reason. My current doc is just not comfortable keeping me on it continuously for decades.

 

[Remy]

Barring antibody dysregulation

That's a really high bar though.

I understand about IgM/IgG. And I understand that "conventional" doctors think that highly elevated IgG levels are meaningless whereas our doctors are using them as a sign of a reactivated infection...but what if they are wrong? They certainly were in my case.

And Lyme can actually turn IgM positive and negative over time. Can viral infections do this too? I don't know. Would the doctor just call it a new infection? I had chicken pox twice and that was supposed to be impossible.

ETA: Viral infections apparently can turn IgM positive as well on reactivation.

Likewise, @Strike me lucky shows good immunity to herpes zoster on testing...but clearly that is not keeping his shingles in check well enough. So what is really going on here? Million dollar question. Maybe trillion!

I also think that if the basis behind Lerner's treatment model was *entirely* correct, it would have worked for more people. Lerner was positive in my case too...and he was apparently wrong.

And I also think that if you are treating within a paradigm, you tend to see those patterns everywhere. Surely I'm as guilty of this as anyone else in my health evolution. It's not a criticism, but an observation on human nature. If your only tool is a hammer, everything looks like a nail. But you have to have a treatment model or you may as well spit into the wind.

Some people treat infections for years without seeing much of any progress, thinking their immune systems are bunk and might be wholly surprised to find out they are really dealing with an immune storm instead. I just want to stay open to the possibilities.

 

[IrisRV]

@Remy, those are all good questions.

I am fortunate that I don't have to assume a bunk immune system. I have had a lot of immune testing so I know certain parts of my immune system are bunk -- low CD8+ cell numbers, low NK cell function, low IgM, low IgG and I don't know what else. I'll have to ask my specialist next time I see her, but I consider it quite possible that some of my immune data suggests other parts may be upregulated.

I in no way support randomly throwing immune boosters at anyone. The immune system is too complex to classify it as universally downregulated or universally upregulated. It could be that some parts are down and others are up. You could do a lot of harm using a medication that boosts the part of your immune system that is already upregulated, or suppresses the part that is downregulated.

I got no immune treatment of any kind until I developed specific immune conditions for which there is a focused treatment. I don't take anti-pathogens unless I have both symptoms and the best pathogen testing available at the moment. I get plenty of other treatments -- OI, hormonal, sleep, anti-inflammatory. I have been advised to try changing my diet and to increase my antioxident intake.

I think where you may be making a mistake is in assuming that my doctor and I are working with only one paradigm and that we are making assumptions about my condition instead of using data to inform our decisions. My specialist is always keeping an eye on new developments and running lots of tests. She changes my treatment when she sees something she thinks might help my specific condition. We are keeping our eyes and minds open.

We understand there are multiple possible explanations for some of my test results, but we are taking the sum total of the data we have and chosing the most likely explanation for me. While it's possible that over-production of disease-specific antibodies could result from an immune system in overdrive, for me that is unlikely because my overall immunoglobulin production is low which makes under-production more likely than over-production.

The sad truth is that we know essentially nothing about what is going on in this disease. We know we have different responses to different things -- that there is no known single treatment that works for us all. It could be that different things are going on at different phases in the illness. There may be a number of subsets, or even more likely, several different diseases currently under the CFS heading. The treatments could be very different for the different conditions.

The best we can do right now is get the best information we can about our own specific condition and find a specialist with a big treatment toolbox. We treat according to what we know about our own bodies, not the body of some other PWME. We have to do some guessing because the absolute answers don't exist. The trick is to make the most informed guess you can based on symptoms, testing, and the best available research. And donate to the research groups making real progress in figuring out WTH is going on.

 

[Remy]

my overall immunoglobulin production is low which makes under-production more likely than over-production.

My total IgG levels are low overall too...so what's confusing is that we (as a group) share some markers, others not.

For example, I've always had good NK cell function and an abnormally high number of CD8 T cells. This is pretty unusual from what I've read on these forums over the years.

I think where you may be making a mistake is in assuming that my doctor and I are working with only one paradigm and that we are making assumptions about my condition instead of using data to inform our decisions.

If we have inadequate tests, we can't make informed decisions because we have bad data by definition. You know what they say about garbage in, garbage out. You *have* to make assumptions because there aren't enough concrete facts. We all do, unfortunately.

And I'm not saying that you couldn't change tack or that you are necessarily stuck in the infection paradigm...but that's certainly the paradigm that you are currently using to treat and that has been most successful for you (and many others).

I, too, think AVs are still one of the best treatment options that we currently have - for either an overactive or underactive immune system alike, for the immune modulation reasons mentioned in earlier posts. But it's also clear that they aren't curing anyone fast. It's still about symptom management and I want to know what is going wrong with the immune system to require that management. And I think we've overlooked immune activation in favor of immune deficiency for too long...

 

[IrisRV]

My total IgG levels are low overall too...so what's confusing is that we (as a group) share some markers, others not.

So true! It makes it nigh-on impossible to know what this disease is. I'm thinking multiple diseases, but it could also be different phases of a single disease.

We definitely don't have the tests we need. Even if some exist, we can't get them. In medicine we're always guessing based on limited data. Our bodies are one unbelievably complex dynamic system which we can't begin to fully test.

My doctor and I are trying to do what works for me, not what works for some non-existent standard ME/CFS patient. It's the best we can do at the moment. None of it is aimed at cause, because we don't know what the cause is. It's all symptomatic treatment. I think that's all there's going to be in my lifetime, so I'm making the best of it.

And I think we've overlooked immune activation in favor of immune deficiency for too long...

I think that's true for the vast majority of the ME/CFS community. I'm not convinced it's true of the immunologists among us. They are mostly talking about dysregulated immune systems which can mean deficiency, activation, or both. They treat what they can and that's not much.

I really want to know what's going on -- what's causing so many systems to be so screwed up. We don't have the research yet, but things are changing rapidly. We'd better start getting some answers soon (in research terms). I'm going to be SO pissed if I die without my curiosity being satisfied.

 

[Strike me lucky]

Likewise, @Strike me lucky shows good immunity to herpes zoster on testing...but clearly that is not keeping his shingles in check well enough. So what is really going on here? Million dollar question. Maybe trillion

Yes im stumped. Yes good antibody response to vzv. Had chickenpox twice, once as a child and once as an adult. Before stopping famvir beginning of last year had antibody test say i had good immunity to vzv. A week at most was when viral symptoms started and shingles rash came out about 5 days after start of viral symptoms. Several minor out breaks throughout the year while on famvir. Then changing to valcyte this year and off famvir for a few days when viral symptoms started then a few days later shingles and back on famvir.

Over the years i have had other breaks from antivirals usually lasting 2 to 3 weeks before viral symptoms would start. We use to suspect cmv but now im not sure as it may have been vzv, zoster sine which is shingles/vzv without a rash. Its possible cmv was an issue as in the past was able to get one test of viral titres showing igg high enough that lerner would have considered a reactivation of cmv, i was on famvir at the time so i guess these titres could have been higher.

I think we need both adaptive and innate immunity to stop viruses reactivating and taking a hold. Common knowledge my nk function was tested very low several times with nk function at 1 or less so the buggers are doing nothing. The other common finding i have is mild to mostly moderate neutropenia, this can occur due to prolonged infections also. Its also important in fighting infections, so theres two parts of my immune system down. Im guessing my cd8 function is low as i was in the study group a few yrs ago that found low cd8 function in cfs, personal results were given for these only nk function was given to us.

So one could say i have a nk cell functional deficiency and just that could explain viruses reactivating. Or these viruses are a stronger strain compared to normal and the immune system cant suppress them and this causes immune exhaustion with low nk function etc. Or theres something else underlying causing immune suppression like a retrovirus or lyme or some other bacterial infection.

The hit and run theory is possible and maybe this can cause immune exhaustion on its own and over time making it easier to get infections.

I feel better on antivirals and abx. The only immune mod that i have had noticeable effects was cycloferon. Immunovir i had a small increase in nk numbers but i didnt feel any better from it. I have felt better short term on high doses prednisolone and low dose hc.

So after 14yrs of cfsme thats what i have come up with but these are my thoughts on my situation.

 

[Who Me?]

You're F'ed. Lol.

 

[weyland]

FWIW, I am in no way saying that this is applicable to everyone with MECFS. I just spent a LONG time trying to stimulate my immune system to fight all these infections I tested positive for (EBV, CMV, HHV6, Parvo, Lyme etc etc) only to discover through cytokine testing and stimulated lymphocyte testing that my immune system was already in overdrive.

Out of curiosity, what did your IL-10 and TGF-β levels look like?

 

[Remy]

Out of curiosity, what did your IL-10 and TGF-β levels look like?

Low and high respectively but that is all I know from memory.

I'm happy to look up some exact numbers if it would help you though. Just ask!