The immunological inconsistency in the IDO trap theory

[nerd]

There is one thing in the IDO theory I can't figure out - the inconsistent piece that actually makes me suspect that there is something more complex going on. Here is the story, extending what I wrote in the original IDO post, if you aren't familiar with the Ron Davis research yet.

As a reference point, I use the immunological findings of Selin et Gil. Their findings suggest an issue with CD8+ T cell differentiation. This differentiation process is driven by MHC class 1 (MCH-I). This is why I assume that MHC-I inhibition plays a role in CFS/ME pathology.

MHC-I can be manipulated by viruses to suppress antigen presentation to cytotoxic T cells. EBV, for instance, does this via the late lytic BILF1 gene (10.4049/jimmunol.1102462). But EBV also manipulates MHC-I-channeled antigen transport in and from the ER via the lytic BNFL2a gene (10.1074/jbc.M111.237784).

Since there is also a high count of CD8+CD4+ double-positives (DPs), I suspect that it actually is a thymocyte differentiation issue since the thymus is the only place where these DPs naturally exist before they can be differentiated to either CD8+ via MHC-I or CD4+ via MHC-II. I assume that the downregulation of MHC-I could inhibit the CD8+ differentiation and lead to more DPs and fewer CD8+ single-positive T cells. But this only works when apoptosis of the DPs is inhibited since they normally go into apoptosis when no MHC complex is presented (10.1126/science.1067833).

Here is the point. IDO function downregulates MHC-I (10.1016/j.humimm.2003.11.004). Interventions that upregulate IDO also downregulate MHC-I (10.1371/journal.pone.0045491). IDO inhibitors restored MHC-I function of genetically modified IDO-upregulated cells. This is the inconsistency. If no pathogen is involved, how can there be both, low MHC-I and low IDO function?

Prof. Ron Davis based his theory on genetic findings of CFS/ME patients and concluded that IDO2 might be dysfunctional. Is it possible that the opposite is the case? Maybe the IDO2 is overactive? After all, I didn't see sufficient evidence that indicates a complete loss of function of the gene. I will have another look at the involved SNPs to determine how likely an inverse scenario is. One clinical trial on Kynurenine seems to be underway (OMF). I expect their results soon since it's been over a year now. If they find a negative outcome for kynurenine as compared to placebo, it would support the theory that IDO function is already hyperactive.

But if a pathogen is involved, EBV could use this mechanism by inducing IDO via p38/MAPK and NF-κB (10.1128/JVI.03678-13). Fortunately, these two pathways are easy targets for therapeutical interventions such as Reishi and Ivermectin. However, IDO upregulation or kynurenine still wouldn't help.

I also mentioned the options of IVIG and Norepenephire for IDO upregulation, but this might be counterproductive in the long term, by exacerbating the dysbalanced lymphocyte profile, not to mention the overlapping side effects with CFS/ME symptoms. Naltrexone might be different, but there just isn't any evidence suggesting a direct interaction with IDO. Even the norepinephrine regulation of Naltrexone is speculative since it only happened selectively in the referenced study (10.1016/0006-8993(85)90794-2), and there might be different results for LDN.

There is one last explanation for IDO dysfunction I could find, and that is TLR-9. TLR-9 (but not TLR-3) induction can upregulate IDO activity (10.4049/jimmunol.0901577). Antiviral and antibacterial immune responses utilize TLR-9. Interestingly, chronic TLR-9 activation might lead to the suppression of CTLA-4 and T cell activation and proliferation in the spleen (10.1002/eji.200535602). CTLA-4 is most dominantly present in CD4+ and not in CD8+ (10.1038/gene.2013.57). CTLA-4 SNPs are associated with infectious-onset CFS/ME (10.3389/fimmu.2020.00578). So if TLR-9 was elevated or chronically hyperactive, why don't we see abnormalities in the CD4+ profile? Maybe because nobody looked in the spleen?

Regardless, TLR-9 only explains an upregulation of IDO, but not a downregulation. EBV can downregulate TLR-9 via its lytic BGLF5 gene (10.4049/jimmunol.0903120). HPV-16 can downregulate TLR-9 (10.4161/onci.27257). Viral pathology seems to make more sense than a tryptophan-accumulation-induced IDO trap.

This is just connecting dots, nothing more. Maybe you can contribute something to the inconsistencies I notice. Maybe you can find more viral interactions with TLR-9 or the IDO enzymes I could add. I'd be open to a discussion about what the missing puzzle piece might be.

 

[nerd]

Giving it another thought, there is one explanation left, namely a synergistic coinfection of Toxoplasma gondii and a virus such as EBV. T. gondii is a parasitic eukaryote that blocks IDO1 activity (10.1038/s41419-019-1420-9). EBV blocks MHC-I, as mentioned above. T. gondii doesn't depend on IDO dysregulation for its survival, so it wouldn't matter when another pathogen triggers its activation. EBV doesn't depend on IDO suppression either, but lytic activity might be more noticeable due to the lack of immune suppression.

Alternatively, it might be a coinfection of T. gondii in the past with any virus that has similar immune evasion mechanisms as EBV and can reliably persist with cell cycle manipulation only. In this case, the IDO pathology would be retained without any further infections and without immune recognition.

Cell cycle regulation therapy could fix this though. Don't let the latent virus disrupt apoptosis or autophagy, then the problem should resolve itself. When the virus infects new cells, these lack the T. gondii pathology, so there wouldn't be any synergistic effect. One exception would be when a virus "learns" from the coinfected cell's pathology and "becomes" a new strain that actually suppresses IDO as well, which could theoretically happen, though seems unlikely to happen in so many patients at the same time.

 

[Wishful]

How solid is the evidence that you're basing your hypotheses on? To me it seems that for every paper that finds low x or elevated y, there's another study that finds no such abnormalities, or at least no study that verifies it. Papers that do seem to show potential markers for ME seem to be based on small studies, which could be showing just a downstream effect of ME on a small subset of PWME. It's hard for me to get too excited about complex theories based on minimal actual verified data.

I haven't found the IDO trap hypothesis very compelling.

I think the mystery of ME is more likely to be solved by finding some definite marker for ME and following that upstream to find out what is causing that abnormality, or by accidentally finding a reliable treatment and then figuring out why it works. I was hoping that cumin would be that 'loose thread' that leads to the answer, but it's only worked for me (and maybe one other person).

Another possible lead to the answer would be a significant outbreak of ME somewhere. If "80% of people who contracted strain 34rz of virus y developed ME within two weeks", that might help researchers ... especially if it also worked on mice or fruit flies.

 

[Rufous McKinney]

I'd be open to a discussion about what the missing puzzle piece might be.

Do you have an opinion regarding the Mechanical Basis theories? Do you see a means thru which that interfaces with the IDO trap theory?

 

[nerd]

How solid is the evidence that you're basing your hypotheses on?

Do you mean my thymus hypothesis? A lot of background research has flown into this theory. More than I could put into this comment. It would get off-topic. I think the thymus is a very likely participator in CFS/ME pathology until there is evidence that shows otherwise. It's not rock-solid. The hypothesis would explain a whole range of autoimmune diseases that surprisingly share almost the same immunological profile as CFS/ME, except for the serology.

There are other explanations as well, such as the bone marrow, which supplies the thymus with progenitors. Another even less likely scenario would be pathology in the nervous system since its cells don't produce MHC-I. This wouldn't explain the DPs though. So it's completely speculative.

But the relevant information for this topic is MHC-I since this is the major identifier specific for CD8+. So it doesn't really matter which hypothesis is correct as long as the findings of Selin et Gil are. And their findings seem to be reproducible among studies, as they say. They also give an explanation why other authors haven't found the same profile - because they didn't use ordered CD4+ and CD8+ concentration measurements but categorically ones. And their humoral immune mediator findings seem to be consistent with other findings so far, e.g. on Foxp3+ (10.1186/1479-5876-9-81).

Do you have an opinion regarding the Mechanical Basis theories? Do you see a means thru which that interfaces with the IDO trap theory?

Cervical spinal stenosis and whiplash injury are differential-/co-diagnoses. In both cases, OCF surgery would help. It might lead to partial to full remission (if it is a differential diagnosis). But it also comes with risks. And it might not help patients without this co-diagnosis at all. One possibility would be a latent neck cervical spine infection or some kind of pathology located there. It's not untypical to develop tissue damage in the neck region during certain viral infections such as COVID-19. It might also be due to small fiber pathology which is associated with chronic whiplash disorders (10.1002/ejp.1549).

I think the OCF is only trying to treat a systemic problem by applying a localized structural fix where the issues manifest most dominantly. it's like removing an organ because one autoimmune condition manifests there most dominantly. But removing the organ doesn't fix the causality. Removing the colon of colitis patients won't fix the autoimmune disease, but it might still help a lot with the primary symptoms.

 

[pattismith]

I was interesting in testing for MHC-I deficiency, as my T lymphocytes CD8 are always in the low limit.

The test is MHC class I (HLA-A, B, C) expression by flow cytometry, but I don't know where to do such a test...

I suppose it's easier to check for HLA class I typing to see if there is any problem ...

It is usually diagnosed when HLA class I serological typing is unsuccessful;

Clinical and immunological aspects of HLA class I deficiency | QJM: An International Journal of Medicine | Oxford Academic (oup.com)

Immunodeficiency Search

 

[nerd]

I suppose it's easier to check for HLA class I typing to see if there is any problem ...

As far as I know, HLA tests would try to quantify MHC expression, but this wouldn't show MHC binding activity. You could have normal MHC expression but your CD8+ could be limited by suppressed MHC-I activity. After all, it's not really the production of MHC-I (or a genetic HLA condition) that inhibits its interactions. Maybe HLA-A/B/C antibodies still work, I'm not sure.

In the laboratory, they have different options to show the binding affinity. Here is an article from a supplier.

 

[Wishful]

They also give an explanation why other authors haven't found the same profile -

That's an example of what I meant by unverified findings: "if you process the samples precisely this way, and process the data using precisely these mathematical methods, you'll see a clear pattern". Unfortunately, the same might apply to random data. Maybe the researchers tried hundreds of different combinations before finding one that gave their desired results. I'm not saying that the specific paper you are basing it on is faulty, but rather that any single research finding that isn't independently verified is suspect.

That being said, there are also things that 'everyone knows' ... that eventually turns out to be wrong.

The process of hypothesizing and testing is important, so I'm not suggesting against it. Even if it doesn't lead to an answer for ME, it's a good exercise that might lead to other useful findings. I just don't know how reliable the data is.

 

[Pyrrhus]

If the findings of Selin et Gil are eventually published somewhere, it would be great to add it to this discussion:

Summary of NK and T cell discussions
https://forums.phoenixrising.me/threads/summary-of-nk-and-t-cell-discussions.83170/

 

[nerd]

Here is a paper that shares a similar pathophysiological perspective.

Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?

Morris, G., Maes, M., Berk, M. et al. Myalgic encephalomyelitis or chronic fatigue syndrome: how could the illness develop?. Metab Brain Dis 34, 385–415 (2019).
doi: 10.1007/s11011-019-0388-6

IDO2 is a homologue of IDO (also known as IDO1), being an immunomodulatory enzyme which catalyses L-trytophan; like IDO1, IDO2 is also located on chromosome 8 in humans but IDO2 is not as widely expressed as IDO1 and IDO2 has a distinct signalling role (Metz et al. 2007; Cha et al. 2018). B cell IDO2 expression has recently been identified as being an essential mediator of autoreactive B and T cells in autoimmune responses (Merlo and Mandik-Nayak 2016; Merlo et al. 2016, 2017). It seems likely, therefore, that IDO2 may be found to play an important role in ME/CFS.

 

[Boba]

Viral pathology seems to make more sense than a tryptophan-accumulation-induced IDO trap.

@nerd
First of all, this very interesting and nice intellectual work. Does Rob Phair know about this?

According to your theory this could also be HPV right? I have no history of EBV, but HPV since 10 years. I developed CFS after Covid. My neck was a problem before and got worse after Covid. Burning spine etc.

 

[nerd]

First of all, this very interesting and nice intellectual work. Does Rob Phair know about this?

Thank you!

I do not think he is aware of my thoughts. Ron Davis might be.

According to your theory this could also be HPV right? I have no history of EBV, but HPV since 10 years. I developed CFS after Covid. My neck was a problem before and got worse after Covid. Burning spine etc.

Any carcinogenic herpes virus is in the focus. HPV is certainly included.

 

[Boba]

@HTester what do you think about @nerd ’s thoughts?

 

[Boba]

@nerd do hsv 1&2 effect TLR9 as well?

This work seems promising for HPV treatment. Adding this and I might be able to leave my bed in 10 years... argh

 

[nerd]

@nerd do hsv 1&2 effect TLR9 as well?

It seems so (10.1128/JVI.77.20.11158-11169.2003). In fact, some HSV reservoirs might also downregulate IDO (10.1155/2012/815465). It's also viral pathology that would lead to the IDO substrate inhibition then.

This work seems promising for HPV treatment.

It does (as many things do). I think potent antivirals are important to develop effective therapy protocols for CFS/ME.

Adding this and I might be able to leave my bed in 10 years... argh

When you can afford it. Otherwise, wait 15 more years until the patent expires.

By the way, there is a straightforward therapy for TLR-9 activation, namely CpG. It supports antiviral defense. But it's only available for laboratories.

 

[wigglethemouse]

Since there is also a high count of CD8+CD4+ double-positives (DPs),

The Selin & Gill study was a very small pilot study. The UK CureME Biobank team reported no difference with 251 ME patinets vs 107 controls and 46 with MS
https://researchonline.lshtm.ac.uk/id/eprint/4652675/1/fimmu-10-00796.pdf

 

[Boba]

By the way, there is a straightforward therapy for TLR-9 activation, namely CpG. It supports antiviral defense. But it's only available for laboratories

I need this

 

[nerd]

The Selin & Gill study was a very small pilot study. The UK CureME Biobank team reported no difference with 251 ME patinets vs 107 controls and 46 with MS

Both use a gated CD3+ subpopulation. But as far as I remember, they use different sorting mechanisms (fluorescence vs. magnetic). I would have to check to be sure. Still, it's a valid point to consider. I hope there will be a follow-up.

 

[wigglethemouse]

Both use a gated CD3+ subpopulation. But as far as I remember, they use different sorting mechanisms (fluorescence vs. magnetic). I would have to check to be sure. Still, it's a valid point to consider. I hope there will be a follow-up.

Selin & Gill received an R01 grant this year from NIH based on the pilot results, so yes, there will be a follow up.
https://reporter.nih.gov/search/e_gWv6hqxUqC-hdOxPxaaw/project-details/10185392

 

[Rufous McKinney]

I do not think he is aware of my thoughts. Ron Davis might be.

Is there any means thru which the viruses may be inducing tryptophan to accumulate? Could they be influencing this phenomenon in some way?