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

[Remy]

J Immunol Res. 2016;2016:9064529. doi: 10.1155/2016/9064529. Epub 2016 Jan 4.
A Preliminary Comparative Assessment of the Role of CD8+ T Cells in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis and Multiple Sclerosis.

Brenu EW1, Broadley S2, Nguyen T3, Johnston S3, Ramos S1, Staines D1, Marshall-Gradisnik S3.
Author information


Abstract

Background. CD8+ T cells have putative roles in the regulation of adaptive immune responses during infection. The purpose of this paper is to compare the status of CD8+ T cells in Multiple Sclerosis (MS) and Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). Methods. This preliminary investigation comprised 23 CFS/ME patients, 11 untreated MS patients, and 30 nonfatigued controls. Whole blood samples were collected from participants, stained with monoclonal antibodies, and analysed on the flow cytometer. Using the following CD markers, CD27 and CD45RA (CD45 exon isoform 4), CD8+ T cells were divided into naïve, central memory (CM), effector memory CD45RA- (EM), and effector memory CD45RA+ (EMRA) cells. Results. Surface expressions of BTLA, CD127, and CD49/CD29 were increased on subsets of CD8+ T cells from MS patients. In the CFS/ME patients CD127 was significantly decreased on all subsets of CD8+ T cells in comparison to the nonfatigued controls. PSGL-1 was significantly reduced in the CFS/ME patients in comparison to the nonfatigued controls. Conclusions. The results suggest significant deficits in the expression of receptors and adhesion molecules on subsets of CD8+ T cells in both MS and CFS/ME patients. These deficits reported may contribute to the pathogenesis of these diseases. However, larger sample size is warranted to confirm and support these encouraging preliminary findings.
PMID:
26881265
[PubMed - in process]
PMCID:
PMC4736227
Free PMC Article

 

[IrisRV]

There is discussion of this paper on this thread.

 

[Strike me lucky]

So a dummed down version, in MS increase in immune markers compared to controls and cfsme were reduce immune markers compared to healthy controls??

Is that other peoples understanding of it???

 

[weyland]

So a dummed down version, in MS increase in immune markers compared to controls and cfsme were reduce immune markers compared to healthy controls??

Is that other peoples understanding of it???

After reading a bit about the specific markers they found reduced my interpretation is that it's a sign of immune activation in ME. Loss of those markers is seen on activated T cells.

 

[Remy]

After reading a bit about the specific markers they found reduced my interpretation is that it's a sign of immune activation in ME. Loss of those markers is seen on activated T cells.

Immune activation, not deficiency...how verrrry interesting!

 

[Strike me lucky]

In the CFS/ME patients CD127 was significantly decreased on all subsets of CD8+ T cells in comparison to the nonfatigued controls.

This is the part where i read it as cfsme having reduced/decreased immune markers.

Im not sure i understand how its immune activation?? Or am i missing something, this brain of mine isnt 100% so im probably having a boy look when i read it.

 

[weyland]

Im not sure i understand how its immune activation?? Or am i missing something, this brain of mine isnt 100% so im probably having a boy look when i read it.

I included some references in the other thread linked above.

Recently, much attention has been attributed to another mechanism causing CD127 downregulation, namely, T-cell activation. Downregulation of CD127 by T-cell-activating factors has been also demonstrated in a number of animal and in vitro models [14]. Correspondingly, we and many other investigators reported decreased levels of CD127 expression on CD4+ and CD8+ T-cells in AIDS [15, 16]. Downregulation of CD127 on entire CD4+ T-cell pool (not only infected CD4+ T-cells) was demonstrated to reflect the status of chronic immune activation characteristic for lentiviral infection [17]. Decreased CD127 levels in HIV-infected individuals are strongly related to increased rate of disease progression, increased T-cell death resulting in CD4+ T-cell loss, and impairment of protective functional immunity [18, 19]. Similarly, we found significantly decreased CD127 on CD4+ T-cells in patients with noninfectious chronic inflammatory diseases characterized by T-cell activation, namely, perennial allergy and asthma [20]. Similarly, alterations of CD127 expression were reported in rheumatoid arthritis patients [21]. Moreover, experimental blockade of CD127 in arthritis mice resulted in significant clinical improvement [22].

Naïve and memory T-cells express high levels of CD127, while effector cells are CD127lo and retention of the receptor is thought to influence the development of memory cells. Reduced expression of CD127 has been associated with markers of disease severity in HIV infection and other chronic viral infections as well as in various cancers. In HIV infection, decreased CD127 expression on T-cells is correlated with reduced CD4+ T-cell counts, increased viral replication and immune activation. The loss of IL-7 activity, due to decreased CD127 expression, may contribute to the observed loss of CD8+ cytotoxic T lymphocyte (CTL) activity in HIV infection. The downregulation of CD127 expression in HIV infection may be due to host (e.g. IL-7, IL-4, immune activation) and/or viral (e.g.HIV-tat) factors and mechanisms of receptor regulation may differ by cell type. In addition, the expression of a soluble form of CD127 (sCD127) has been shown to be increased in HIV infection. This protein may affect IL-7 activity in vivo and therefore may have implications for IL-7-based therapies which are currently being tested in clinical trials. Understanding how CD127 is regulated during HIV infection will provide insight for the development of novel therapeutics to improve immune function and anti-viral T-cell activity.

Interestingly a recent study has found IL-7 to be deficient in ME patients.

Similarly the other marker they found is also decreased during activation:

In summary, the overall conclusion from the current data is that leukocyte activation results in decreased surface expression of PSGL-1 and decreased leukocyte adhesion to P-selectin under both static and dynamic conditions. The decrease in PSGL-1 surface-expression occurs along with the appearance of PSGL-1 in the supernatants. It is unclear at this time whether PSGL-1 release is the result of a novel divalent cation-dependent sheddase or some other mechanism. Finally, though much remains to be determined about the in vivo regulation of PSGL-1 expression, these findings indicate an entirely novel means by which leukocyte-leukocyte, leukocyte-platelet, and leukocyte-endothelial interactions, and thus many facets of the inflammatory response, may be regulated.

 

[Strike me lucky]

I included some references in the other thread linked above.

Still clear as mud lol. Your links showing its from viral infections, do you think this is probably indicating some viral infection in cfsme or possibly retrovirus??





Interestingly a recent study has found IL-7 to be deficient in ME patients.

Similarly the other marker they found is also decreased during activation:

 

[bobby]

@Strike me lucky I read this study a while ago, and this is what I understood:

They compared MS patients to ME patients (+ healthy controls) because there seemed to be something abnormal going on with CD8+ T cells in both diseases. CD8+ T cells are responsible for getting rid of viruses and other harmful pathogens. The study did show there was something going wrong with these T cells, but the ME vs MS profiles turned out opposite to each other, so have very different consequences.

- in ME patients they saw an exhausted profile, with low CD127 (= a part of IL-7) and low alpha4beta1 (aka VLA-4 or Very Late Antigen-4).

- in MS patients they saw a hyperactive profile, with high CD127, high alpha4beta1, etc. (I honestly didn't focus on the details of the MS part, only the things that were similar to ME).

As far as I've understood, VLA-4 is a sort of transportation method for T cells. In MS VLA-4 is increased, which makes T cells able to cross the blood/brain barrier, with damaging effects to the body.

In ME VLA-4 is reduced, which the researchers aren't sure yet how to interpret, but they think this could explain why many ME patients have viral persistance and/or viral reactivation of some sort. They supposed that if VLA-4 is too low, T cells aren't able to get where they are supposed to be getting, to kill off pathogens in specific places in the body. (In my head that means party time for old viruses and pathogens all over the place. When the cat's away, the mice will play. But that's just my imagination running wild!)

CD127 or Interleukin-7 plays an important role in development of B-cells (amongst other things). No idea what too little IL-7 would do to our B-cells, but we know by now that our B-cells are not working as they should be (cfr. Rituximab research).

 

[Strike me lucky]

@Strike me lucky I read this study a while ago, and this is what I understood:

They compared MS patients to ME patients (+ healthy controls) because there seemed to be something abnormal going on with CD8+ T cells in both diseases. CD8+ T cells are responsible for getting rid of viruses and other harmful pathogens. The study did show there was something going wrong with these T cells, but the ME vs MS profiles turned out opposite to each other, so have very different consequences.

- in ME patients they saw an exhausted profile, with low CD127 (= a part of IL-7) and low alpha4beta1 (aka VLA-4 or Very Late Antigen-4).

- in MS patients they saw a hyperactive profile, with high CD127, high alpha4beta1, etc. (I honestly didn't focus on the details of the MS part, only the things that were similar to ME).

As far as I've understood, VLA-4 is a sort of transportation method for T cells. In MS VLA-4 is increased, which makes T cells able to cross the blood/brain barrier, with damaging effects to the body.

In ME VLA-4 is reduced, which the researchers aren't sure yet how to interpret, but they think this could explain why many ME patients have viral persistance and/or viral reactivation of some sort. They supposed that if VLA-4 is too low, T cells aren't able to get where they are supposed to be getting, to kill off pathogens in specific places in the body. (In my head that means party time for old viruses and pathogens all over the place. When the cat's away, the mice will play. But that's just my imagination running wild!)

CD127 or Interleukin-7 plays an important role in development of B-cells (amongst other things). No idea what too little IL-7 would do to our B-cells, but we know by now that our B-cells are not working as they should be (cfr. Rituximab research).

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?

 

[bobby]

Any ideas for immune exhaustion others have found helpful?

No idea, sorry... What I do know is that a similar autoinflammatory effect is found in various auto-immune illnesses. As we know, there is no cure for any of them, but what I think they usually do in the case of autoimmune disease is agressively suppress the entire immune system. This results in less illness related symptoms, but makes you extremely prone to all kinds of infections/viruses.

I can't remember where I've heard this, but there's this theory that says part of our immune system is exhausted, and part of it is in overdrive. This makes it very difficult to tackle either the exhaustion or the overdrive reaction. Whatever boosts or strenghtens the immune system (= vs exhaustion) will make the part in overdrive even stronger. And whatever soothes the overdrive will further paralyze the exhausted part.

 

[weyland]

Still clear as mud lol. Your links showing its from viral infections, do you think this is probably indicating some viral infection in cfsme or possibly retrovirus??

It's hard to say from this research exactly what the cause is, but I think it's very much compatible with past viral research findings.

I don't think this represents immune exhaustion. I think it's a result of dysregulation. As mentioned above, IL-4 can cause downregulation of CD127 expression:

Signaling via the IL-7 receptor complex (IL-7Ralpha/CD127 and IL-2Rgamma/CD132) is required for T-cell development and survival. Decreased CD127 expression has been associated with persistent viral infections (e.g. HIV, HCV) and cancer. Many IL-2Rgamma-sharing (gammaC) cytokines decrease CD127 expression on CD4+ and CD8+ T cells in mice (IL-2, IL-4, IL-7, IL-15) and in humans (IL-2, IL-7), suggesting a common function. IL-4 is of particular interest as it is upregulated in HIV infection and in thyroid and colon cancers. The role of IL-4 in regulating CD127 expression and IL-7 activity in human thymocytes and mature CD8+ T cells is unknown and was therefore investigated. IL-4 decreased CD127 expression on all thymocyte subsets tested and only on naïve (CD45RA+) CD8+ T cells, without altering membrane-bound CD127 mRNA expression. Pre-treatment of thymocytes or CD8+ T cells with IL-4 inhibited IL-7-mediated phosphorylation of STAT5 and decreased proliferation of CD8+ T cells. By downregulating CD127 expression and signaling on developing thymocytes and CD8+ T cells, IL-4 is a potential contributor to impaired CD8+ T-cell function in some anti-viral and anti-tumor responses. These findings are of particular consequence to diseases such as HIV, HCV, RSV, measles and cancer, in which CD127 expression is decreased, IL-7 activity is impaired and IL-4 concentrations are elevated.

This is the same pattern that is found in ME, high IL-4 and low IL-7.

 

[Cort]

Immune activation, not deficiency...how verrrry interesting!

Yes, indeed! I just finished a blog for Simmaron on immune exhaustion - not activation! (lol)

 

[Cort]

@Strike me lucky I read this study a while ago, and this is what I understood:

They compared MS patients to ME patients (+ healthy controls) because there seemed to be something abnormal going on with CD8+ T cells in both diseases. CD8+ T cells are responsible for getting rid of viruses and other harmful pathogens. The study did show there was something going wrong with these T cells, but the ME vs MS profiles turned out opposite to each other, so have very different consequences.

- in ME patients they saw an exhausted profile, with low CD127 (= a part of IL-7) and low alpha4beta1 (aka VLA-4 or Very Late Antigen-4).

- in MS patients they saw a hyperactive profile, with high CD127, high alpha4beta1, etc. (I honestly didn't focus on the details of the MS part, only the things that were similar to ME).

As far as I've understood, VLA-4 is a sort of transportation method for T cells. In MS VLA-4 is increased, which makes T cells able to cross the blood/brain barrier, with damaging effects to the body.

In ME VLA-4 is reduced, which the researchers aren't sure yet how to interpret, but they think this could explain why many ME patients have viral persistance and/or viral reactivation of some sort. They supposed that if VLA-4 is too low, T cells aren't able to get where they are supposed to be getting, to kill off pathogens in specific places in the body. (In my head that means party time for old viruses and pathogens all over the place. When the cat's away, the mice will play. But that's just my imagination running wild!)

CD127 or Interleukin-7 plays an important role in development of B-cells (amongst other things). No idea what too little IL-7 would do to our B-cells, but we know by now that our B-cells are not working as they should be (cfr. Rituximab research).

Thanks Bobby

To put another twist on this...in the spinal fluid study comparing MS, ME/CFS and healthy controls my understanding was that both ME/CFS and MS patients exhibited immune downregulation relative to the healthy controls. The really interesting thing was that the ME/CFS and MS patients showed markedly different kinds of immune downregulation. In fact a case could be made that the ME/CFS and MS patients were more different from each other than from the healthy controls.

Both MS and ME/CFS patients showed an upregulation of a chemokine that brings immune cells in the brain - apparently to fight off an infection. The MS patients had higher levels than the ME/CFS patients. Both could be fighting off an infection but in different ways or rather the the infection could have sparked a different immune response.

I'm going to have a blog pretty soon on a person who did really well on an MS drug - for awhile.

 

[Cort]

No idea, sorry... What I do know is that a similar autoinflammatory effect is found in various auto-immune illnesses. As we know, there is no cure for any of them, but what I think they usually do in the case of autoimmune disease is agressively suppress the entire immune system. This results in less illness related symptoms, but makes you extremely prone to all kinds of infections/viruses.

I can't remember where I've heard this, but there's this theory that says part of our immune system is exhausted, and part of it is in overdrive. This makes it very difficult to tackle either the exhaustion or the overdrive reaction. Whatever boosts or strenghtens the immune system (= vs exhaustion) will make the part in overdrive even stronger. And whatever soothes the overdrive will further paralyze the exhausted part.

I wouldn't be surprised at all. Ultimately they'll have to figure out what is up and what is down try to manipulate each or even better - find what if putting them both out of sync - and deal with that.

 

[IrisRV]

Any ideas for immune exhaustion others have found helpful?

All I have for you is that my ME/CFS specialist, who is an immunologist, says my immune profile looks like immune exhaustion from something viral it can't clear. The result is that some parts of the immune system are downregulated (exhausted), so other parts are upregulated (in overdrive) trying to compensate -- making one hot mess.

FWIW, I have low NK cell function (this is new), low CD8+ cell numbers, low IgM, bottom of range IgG, with some subclass deficiencies. Of the 18 cytokines tested, 15 are way, way out of range. In some cases they are orders of magnitude (10X, 100x, 1000x) out of range -- and not in one direction. Some are very, very high and some are very, very low.

 

[Remy]

looks like immune exhaustion from something viral it can't clear.

I wonder how she can possibly know this though?

I'm not saying it's wrong, but just that it seems like that is a pretty bold statement when objective signs of active infections have been very hard to find in many of us. We're unfortunately still working on assumptions here for way too long.

It seems just as likely to be immune system dysregulation from maybe, actually, clearing the infection and forgetting to turn off properly. Maybe.

 

[IrisRV]

I wonder how she can possibly know this though?

I'm not saying it's wrong, but just that it seems like that is a pretty bold statement when objective signs of active infections have been very hard to find in many of us. We're unfortunately still working on assumptions here for way too long.

It seems just as likely to be immune system dysregulation from maybe, actually, clearing the infection and forgetting to turn off properly. Maybe.

I don't believe she was stating it as a certainty. I think the "looks like" part means she doesn't know for sure what the cause is. She was talking to a laywoman and was probably simplifying it for me. I'm sure the full story is a great deal more complex.

Objective signs of active infections have not been hard to find in me, though. So this could be perfectly true for me while not implying that immune exhaustion is the state for all PWME.

Sure, it could also be my immune system forgetting to turn off. I don't think she was saying that it wasn't -- just that it looks like the pattern seen when fighting infections long-term.

 

[Strike me lucky]

I wonder how she can possibly know this though?

I'm not saying it's wrong, but just that it seems like that is a pretty bold statement when objective signs of active infections have been very hard to find in many of us. We're unfortunately still working on assumptions here for way too long.

It seems just as likely to be immune system dysregulation from maybe, actually, clearing the infection and forgetting to turn off properly. Maybe.

Autoimmune disorder generally targets an organ etc. Autoinflammatory is supposedly an increase in general inflammation. Guessing chronic infections that cant be cleared could cause it or hit and run theory.

If its a cause or a consequences, having some parts of the immune system down like nk and cd8 t cells are going to make us more prone to infections??

The dog is chasing its tail.

 

[Remy]

Objective signs of active infections have not been hard to find in me

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.