Drs. Liisa Selin and Anna Gil receive grant of $2.5 for research into ME/CFS

[Sushi]

Press release:

This NIH RO1 grant, titled “Altered T cell Responses in ME/CFS” allows the researchers to examine the role of aberrant T cell responses in the immunopathogenesis of ME/CFS patients. Selin and Gil's recent research findings could point to potential biomarkers, treatments and ways of tracking response to therapy for the disease, things that have been sorely missing.

 

[Rebeccare]

Here's a video of their presentation to the Mass ME/CFS & FM Association Research Club a few months back:

 

[nerd]

Very promising research!

Since they found a lot of microbiotic antigens in their antigen matching analysis, I wonder if this is just "debris" from the microbiome or how specific the matched motifs are. Maybe a normally healthy microbiome combined with inflammation and/or a leaky gut can contribute to the T cell dysbalance?

Since they talk about IL-10 involvement and IL-10 Ab therapy, here is a piece I wrote last year about the role of viral IL-10 for reactivations and fatigue.

IL-10 deserves a special mentioning because of its diverse CFS significance under different conditions and experiments. Consistent with previous studies, a 1-year longitudinal study didn't show persistent cytokine findings either (10.1186/1479-5876-10-88). Persistent, however, was a reduced NK cell activity. Moreover, their term 2 data shows a correlation between reduced mitogen-induced IL-10 levels and a normalization of IL-2, IFN-γ, and TNF-α levels. This indicates that the season of the year might influence an exclusive common factor of these cytokines' deviations in the studied long-term CFS patients. Under this assumption, inconsistent single-term findings are not surprising. A study on exercise-induced IL-10 showed that IL-10 gene expression increases while its concentration remains relatively unaffected (pmid:24974723). This indicates that IL-10 might need to be differentiated to become a reliable biomarker for CFS. Another study on Cerebrospinal Fluids (CSF) of CFS patients determined IL-10 to be the only among 27 cytokines that showed significantly reduced concentrations in CSF compared to controls (10.1155/2015/929720). Contrary to the assessment of Yang et al. that IL-10 would be supported as a positively correlating marker by the majority of CFS authors, I could not confirm this by reading through the referenced literature. Even though significant, the results are completely inconsistent amongst each other.

In an effort to cross-reference the role of IL-10 in EBV infections, vIL-10 has to be mentioned. vIL-10 has similar homology to the human IL-10 variant (hIL-10) but differs in certain pathway functions. vIL-10 is not an exclusive feature of EBV but is also encoded by other viruses, especially types of herpes (10.1128/JVI.01098-09). A great difference between hIL-10 and vIL-10 is the significantly compromised STAT3 phosphorylation of vIL-10, which can lead to elevated immune-inflammatory feedback. The IC50 of vIL-10 on hIL-10's pSTAT3 signaling is almost reached at about half of the overall IL-10 concentration, which is also the lower boundary of vIL-10 alone. This means that at >50% IL-10 concentration, there is 1/4 - 1/3 of the expected pSTAT3 signaling as one would expect by an undifferentiated IL-10 measurement.

A study on vIL-10 in the context of System Lupus Erythematosus (SLE) showed that vIL-10 can be found in significantly higher concentrations in SLE patients (10.3389/fimmu.2018.02198). SLE is significantly associated with EBV in multiple ways (e.g. antibody levels) (10.1007/s10238-018-0535-0). There is also initial evidence for EBV to cause SLE (pmid:17121489). Jog et al. further showed that vIL-10 correlates with IgA antibodies to EBV viral capsid antigen. This is an indicator for EBV reactivations. vIL-10 doesn't seem to directly correlate with hIL-10, though. This means that vIL-10 would not explain any deviations of measured hIL-10 levels if research actually differentiates overall IL-10. But the inhibition of the STAT3 phosphorylation would limit hIL-10's regulatory effect on monocytes.

The survey on vIL-10 summarizes multiple of the exclusive effects of the viral IL-10 homolog (10.1128/JVI.01098-09). According to their summary, the immunosuppressive properties of vIL-10 provide EBV enhanced survivability in the human organism. In contrast to hIL-10, vIL-10 also lacks the stimulatory capability of thymocyte and mast cell proliferation, as well as MHC II surface expression on B cells. Besides the 1000-fold lower IL-10R1 affinity, vIL-10 also showed an equally reduced potential of inhibiting IL-2 (pmid:8992974). Moreover, the BCRF1 gene also showed great inhibitory effects on IFN-y synthesis in human PBMCs (10.1126/science.2173142). According to Slobedman et al. opinion, EBV's gain of the BCRF1 gene, which encodes the IL-10 homology, most likely enhances latent infection.

Interestingly, hIL-10 antibodies, as they are common in pathology for determining IL-10 levels are not completely specific to hIL-10. A western blot showed a certain affinity to vIL-10 (10.3389/fimmu.2018.02198). In total, vIL-10 probably shows rather low concentrations in the blood. Unfortunately, I could not find any data to relatively quantify both homologs in test groups beyond arbitrary units. However, EBV doesn't need wide systemic proliferation for systemic symptoms to happen. Localized residues would be sufficient as a trigger after exertion when IL-10 proliferation is naturally amplified, as it has been shown with athletic controls (pmid:24974723). After all, this might be the reason for the elevated gene expression but this is speculative. I imagine that this localized immune-suppressive dynamic of vIL-10 could be a catalyst for true reactivations and new infections of all kinds of pathogens. Surprisingly, the same vIL-10 dynamic has been shown for CAEBV (10.1086/517260), which means impaired NK cell activity, a lack of cytotoxicity, and reduced IFN-γ levels.

Given the assumption that vIL-10 plays a role in EBV-induced CFS, IFN-γ would be a physiological and desirable response, despite the fatigue that it induces. Similarly, NK cell and cytotoxic support would be adverse to the relatively new BCRF1 adaptation of the EBV virus. EBV mutants that lack BCRF1 and BNLF2a - the two genes responsible for vIL-10's synthesis - can not sufficiently evade pre-latent and lytic immune response for an encoding of latent genes into further lymphocytes (10.1371/journal.ppat.1002704). Even though a therapy that targets vIL-10 might not be able to eliminate viral residues, it might block the reactivating process (i.e. the lytic phase) of EBV and thereby inhibit the further proliferation of EBV's latent B cell reservoir (10.1016/j.virusres.2010.08.012). One theoretical consideration would be the use of vIL-10-targeted monoclonal antibodies since they would not show any affinity towards hIL-10. Common IL-10 antibodies most likely will not work, though, because of the higher affinity to hIL-10. This only works in vitro with knockout concentrations.

Increased TGF-β levels would further support the latent-lytic reactivation of EBV (10.1128/JVI.01197-10), but also impair NK cell activity (not count) due to its complementary function with IL-10. This dynamic has been shown to be part of the pathogenesis of HIV (10.1186/s12879-018-2991-2), and to affect the energy metabolism, including glycolysis (10.3389/fimmu.2018.01364). Hence, a normalization of TGF-β levels might be beneficial when they are elevated.

First and foremost, the question is if vIL-10 can be detected in the EBV subgroup of CFS patients. The similarities with the pathology of CFS are remarkable. This includes effects on IL-1β, IL-2, NK cell activity, cytotoxicity, particularly the gradually declining IFN-γ levels that occasionally seem to flare up again or remain mildly elevated for CFS patients. Unfortunately, I could not find any data on JAK/STAT3 signaling in CFS patients to support this theory, which would be the next-best indicator I presume.

 

[bread.]

Given you have low cd8, would low dose IVIG not make sense?

 

[nerd]

Given you have low cd8, would low dose IVIG not make sense?

I assume you're referring to IVIg's effect on CD8+ T cells' cytotoxic and antigen-specific activation (10.1182/blood-2012-07-445007). For autoimmune diseases, the suppressed autoantigen response would hence increase CD8+ levels again. But this is more a side effect of the therapeutic intervention. Because even the elevated levels of CD8+ T cells would have inhibited antigen-specific activity, which is necessary for pathogen-feedback as well.

It becomes even counterproductive if we assume a pathogenically-relevant MHC class I involvement. The circumstance that CD8+CD4+ levels are elevated speaks for the theory that the thymus is somehow causally involved and that there is an activity in the thymus that alters the T cell maturation. MHCs are involved in the thymocyte maturation process. For example, if residual EBV activity inhibited MCHs in the thymus via EBV's BDLF3 gene (10.1128/JVI.02183-15), it could explain why CD4+CD8+ thymocytes don't mature into CD8+ naive T cells.

 

[bread.]

I assume you're referring to IVIg's effect on CD8+ T cells' cytotoxic and antigen-specific activation (10.1182/blood-2012-07-445007). For autoimmune diseases, the suppressed autoantigen response would hence increase CD8+ levels again. But this is more a side effect of the therapeutic intervention. Because even the elevated levels of CD8+ T cells would have inhibited antigen-specific activity, which is necessary for pathogen-feedback as well.

It becomes even counterproductive if we assume a pathogenically-relevant MHC class I involvement. The circumstance that CD8+CD4+ levels are elevated speaks for the theory that the thymus is somehow causally involved and that there is an activity in the thymus that alters the T cell maturation. MHCs are involved in the thymocyte maturation process. For example, if residual EBV activity inhibited MCHs in the thymus via EBV's BDLF3 gene (10.1128/JVI.02183-15), it could explain why CD4+CD8+ thymocytes don't mature into CD8+ naive T cells.

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223861

 

[bread.]

What is even more interesting regarding CD8, which I looked into a bit over the years is that a high CD8 leads to increased gut permeability which would before the CD 8 exhaustion (a lengthy process with intermittent deteoriation due to infection, vaccines etc) actually happened lead to a vicious circle. Th17 which is connected to gut permeability and many other pro and anti inflammatory actions is increased in me/cfs as well (?), my bet would be that this is a mechanism that tries to restore whacked barrier functions in gut and bbb. If this would be correct one would have to find a way to inhibit the increased gut permeability due to raised cd8 before one tries to increase cd8 systemically, if that makes any sense. That the most severe patients (like myself) and a high total number of me/cfs patients have an EDS phenotype would further strengthen this hypotheses as barrier functions are an issue in EDS even without infection.

 

[nerd]

https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0223861

This study shows an increased CD8+-CD4+ ratio only due to a decrease in CD4+. IVIg therapy decreased CD4+ or CD8+ T cell proliferation in PAD and SAD subgroups respectively. I don't see how this would help CD8+ maturation, proliferation, or function.

that a high CD8 leads to increased gut permeability which would before the CD 8 exhaustion

Is there any evidence that high CD8 levels occur during or before the initial phase of CFS/ME? You know, "leaky gut" can have many causes. Inflammation and pathogens are among them. If you eat something bad, you could already develop this condition.

if that makes any sense

I don't follow. When and how would CD8 levels be raised in CFS/ME patients?

 

[bread.]

This study shows an increased CD8+-CD4+ ratio only due to a decrease in CD4+. IVIg therapy decreased CD4+ or CD8+ T cell proliferation in PAD and SAD subgroups respectively. I don't see how this would help CD8+ maturation, proliferation, or function.



Is there any evidence that high CD8 levels occur during or before the initial phase of CFS/ME? You know, "leaky gut" can have many causes. Inflammation and pathogens are among them. If you eat something bad, you could already develop this condition.



I don't follow. When and how would CD8 levels be raised in CFS/ME patients?

re low dose ivig:

„Our data also support the anti-inflammatory and anti-proliferative immunomodulatory effects of long-term IRT in PAD patients but paradoxically appear to enhance pro-inflammatory IFN-γ production in CD4 and CD8 T-cells upon α-CD3/CD28 stimulation for SAD patients alone. This may describe an enhanced T-cell functional recovery to produce IFN-γ post-IRT that renders SAD patients less vulnerable to common pathogens, leading to a reduced state of activation and proliferation“

 

[nerd]

This may describe an enhanced T-cell functional recovery to produce IFN-γ post-IRT that renders SAD patients less vulnerable to common pathogens, leading to a reduced state of activation and proliferation

This seems to be quite speculative to me. Even if IFN-γ signaling functionally recovers somehow, I don't see why this would be indicative of a causal improvement. IFN-γ is just one of many cytokines that are abnormal in CFS/ME patients. Of course, it might be worth looking into it, just like many other things. But from my perspective, their results don't support IVIg as a primary CFS/ME therapy.

 

[gbells]

Here's a video of their presentation to the Mass ME/CFS & FM Association Research Club a few months back:

It's interesting but I don't think it will get her a ME biomarker or lead to a cure. This is because while she mentions that viruses cause this disorder her treatment strategy of using checkpoint inhibitors will have the same type of effect of rituximab, suppressing symptoms while the underlying disease progresses.

Wow, $2.5 million to run a few lab tests. That's expensive.

I can't even say if this award is meaningful for NIH who normally funds $15 million per year in ME research. I won't assume it is an increased budget. However, it is an accomplishment for any researcher to get an NIH grant for ME which are hard to get.

 

[nerd]

It's interesting but I don't think it will get her a ME biomarker or lead to a cure.

They have achieved sufficient statistical significance to suggest a diagnostic method based on cytokine profiling. This isn't the first positive finding suggesting different kinds of profiling-based tests. If a single biomarker isn't specific enough, a combination of multiple ones can solve this. It isn't much different in rheumatology. But medicine is reluctant to introduce complex and expensive testing into their guidelines, especially if it's based on such small studies. Not to speak of the gender-specific issue. Medicine doesn't even want to introduce gender-specific dosages of common medicine. So women usually overdose. Feminists prefer other topics to speak about. In Germany, they primarily debate about whether to put an "*in" behind every subject that could potentially address women. I'm glad this language sexism problem doesn't exist in English.

Regarding a cure, I agree with you. Maybe they have luck. Because you need luck if there is no causal methodology. But maybe they'll analyze the thymuses of their patients and find something similar as in MG. They already talk about this possibility. This makes me hopeful that they also might find something more casual, so we end up with a therapeutic guideline as with MG, which is the typical immunological treatment plan plus thymectomy plus symptomatic treatment. If a CFS/ME patient tries to get a standard immunological treatment because most studies show that this is an immunological disease, they are ridiculed and patronized.

 

[bread.]

Regarding a cure, I agree with you. Maybe they have luck. Because you need luck if there is no causal methodology. But maybe they'll analyze the thymuses of their patients and find something similar as in MG. They already talk about this possibility.

Who and where are they talking about it?

This seems to be quite speculative to me. Even if IFN-γ signaling functionally recovers somehow, I don't see why this would be indicative of a causal improvement. IFN-γ is just one of many cytokines that are abnormal in CFS/ME patients. Of course, it might be worth looking into it, just like many other things. But from my perspective, their results don't support IVIg as a primary CFS/ME therapy.

What other things are you referring to if I may ask?

 

[nerd]

Who and where are they talking about it?

In the webinar

What other things are you referring to if I may ask?

Basically, any abnormal cytokine finding they mention in the webinar, e.g. CD8+ T cell count, Foxp3, IL-17, IL-10, CD107a/b, IL-9, etc.

 

[Pyrrhus]

Related discussion:

Dr. Amy Proal interviews Dr. Liisa Selin about T cell exhaustion and viral activity in ME/CFS
https://forums.phoenixrising.me/thr...xhaustion-and-viral-activity-in-me-cfs.86179/

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