Jonathan Edwards
Senior Member (Voting Rights)
I like that idea @jnmaciuch . I am boating again but will add some thorts later.
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Genetics: OLFM4
- Thread starter Hutan
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Very interesting! How would we test the hypothesis that type I interferons are involved in ME/CFS?Looking through the candidate list again, I think there's an interesting thread that ties several of the top genes together, which is regulation of type I (alpha/beta) interferon signaling.
OLFM4
No directionality info from eQTLs.
PEBP1
TRIM38 (type I interferons are one of the main products of TLR and cGAS-STRING/viral RNA sensing)
KLHL20
E3-ubiquitin ligases are typically associated with degradation of interferon, but it might not be so cut and dry.
ZNFX1
I'll note that though this is an interferon-stimulated gene, it's activity as a dsRNA sensory would also trigger interferon.
And interestingly, PRDX6, a cousin of PRDX5--which is inhibited by itaconate to allow type I interferon production in macrophages
Itaconate modulates immune responses via inhibition of peroxiredoxin 5 - Nature Metabolism
Itaconate is shown to non-covalently inhibit the antioxidant enzyme peroxiredoxin 5 in macrophages, thereby modulating the production of mitochondrial peroxide and enhancing the type I interferon production.www.nature.com
The BTNs could also be part of the story via their regulatory effect on TLRs. Plus TLR/type I interferon signaling utilizes MAPK signaling, which potentially implicates ZNF322 (increased) and SUDS3 (increased).Plus PTGIS (decreased expression), since prostaglandins are known to inhibit interferon signaling in some contexts.
Just throwing things at a wall to see what sticks based on the assumption that at least some of these genes are actually affected by the identified SNPs. The directionality of most of these (where eQTL data is provided) seems to generally be in the direction of enhanced interferon in ME/CFS (either increased expression in genes that are positive regulators or decreased in genes that are negative regulators), so that would be some weak evidence against the idea that these SNPs are driven by [edit: poorer protection in ME/CFS cases] against viral infections.
[Edit: and acknowledging that I’m probably biased here since I already think there’s a good case for type I interferons in ME/CFS]
jnmaciuch
Senior Member (Voting Rights)
I unfortunately can't give details about projects involving data from another research group, but I can say that I'm already on the case and have reasons to be encouraged so far
(I know, the most annoying response to hear from a researcher!) Speaking in generalities, there are a couple ways this could be assessed depending on the specific hypothesis. Measurements in the blood have turned up nil so far, so if type I interferon is involved, that negative finding at baseline has to be explained.
The options for type I interferon are basically:
1) Interferon only reaches detectable levels in the blood transiently, i.e. during active PEM.
2) Interferon production is limited to certain tissues and does not reach the bloodstream.
It could potentially be a combination of both as well, if interferon production starts from a trigger in the tissue and eventually increases in concentration until it reaches the blood during PEM. One option is to run high-sensitivity assays for interferon on blood samples from pwME in active PEM, which probably would probably be quite difficult to arrange but is potentially doable for a team of able-bodied researchers who can drive around for home visits.
The second option, which could potentially provide more mechanistic insight but would be much more technically involved, is to collect (and possibly culture) cells from the tissues you think are affected and measure interferon before and after some stimulation. Measuring interferon directly can sometimes get difficult depending on your experimental setup, so initial screens might look at the expression of interferon-stimulated genes, which tend to give a more robust signal.
Kitty
Senior Member (Voting Rights)
If they're standard assays, it might not be unsurmountable for moderately affected people with access to a general hospital.
I have to have bloods taken every fortnight at the moment, so I drive 15 minutes to the hospital, park next to it, wheel in to the phlebotomy dept next to the reception desk, take a ticket and wait for my number to come up. The whole thing (waiting included) never takes more than 10 minutes.
It's so streamlined I could do it in pretty nasty PEM. You don't even have to talk to anyone except for giving your DoB; I swear they get paid by the number of vials they fill, they never even look up from what they're doing.
jnmaciuch
Senior Member (Voting Rights)
They’re not standard assays, unfortunately, though if it’s possible to find enough people that can travel while in PEM then sample collection could just happen as normal. If it gets funded by one of the charities maybe they could be convinced to include funds to pay for a driver to make the trek as painless as possible. Or at least one could dream.
This makes intuitive sense to me but that is probably meaningless.
Two thoughts and you've probably already had both of them but just in case you havent:
Chris Armstrong's team are/were doing a study that involved sampling people in active PEM with home visits iirc, so he might be a good person to consult on the logistics of that.
I know LIINC have a lot of tissue samples from pwLC, perhaps they have some of the tissues you theorise are affected? But of course access is a problem and probably not possible to know which test subjects experience PEM.
Anyway glad you're on the case and encouraged that you're encouraged. I look forward to hearing more when you can share it!
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chillier
Senior Member (Voting Rights)
Looking through the candidate list again, I think there's an interesting thread that ties several of the top genes together, which is regulation of type I (alpha/beta) interferon signaling.
OLFM4
No directionality info from eQTLs.
PEBP1
TRIM38 (type I interferons are one of the main products of TLR and cGAS-STRING/viral RNA sensing)
KLHL20
E3-ubiquitin ligases are typically associated with degradation of interferon, but it might not be so cut and dry.
ZNFX1
I'll note that though this is an interferon-stimulated gene, it's activity as a dsRNA sensory would also trigger interferon.
And interestingly, PRDX6, a cousin of PRDX5--which is inhibited by itaconate to allow type I interferon production in macrophages
Itaconate modulates immune responses via inhibition of peroxiredoxin 5 - Nature Metabolism
Itaconate is shown to non-covalently inhibit the antioxidant enzyme peroxiredoxin 5 in macrophages, thereby modulating the production of mitochondrial peroxide and enhancing the type I interferon production.
The BTNs could also be part of the story via their regulatory effect on TLRs. Plus TLR/type I interferon signaling utilizes MAPK signaling, which potentially implicates ZNF322 (increased) and SUDS3 (increased).Plus PTGIS (decreased expression), since prostaglandins are known to inhibit interferon signaling in some contexts.
Just throwing things at a wall to see what sticks based on the assumption that at least some of these genes are actually affected by the identified SNPs. The directionality of most of these (where eQTL data is provided) seems to generally be in the direction of enhanced interferon in ME/CFS (either increased expression in genes that are positive regulators or decreased in genes that are negative regulators), so that would be some weak evidence against the idea that these SNPs are driven by [edit: poorer protection in ME/CFS cases] against viral infections.
[Edit: and acknowledging that I’m probably biased here since I already think there’s a good case for type I interferons in ME/CFS]
One thing I'm trying to get my head around is to what extent the 'immunological' and 'neurological' parts of the genetics story are compartmentalised. For example is there a inteferon response happening within the neurons (or glia) themselves or would something like that be happening elsewhere and affecting neurons through cell interactions etc.
None of these genes here have particular neuron specificity as far as I can tell. However, PEBP1 can supposedly be degraded into ' hippocampal cholinergic neurostimulating peptide (HCNP)'
and KLHL20, much like RABGAP1L and ARFGEF2 regulates vesicle trafficking between in the region between golgi and membrane - and is supposedly involved in neurite development.
Maybe it is significant that the decode genes may moonlight with roles both in neurite development and immunological responses
jnmaciuch
Senior Member (Voting Rights)
That’s the drop of blood study, yeah? Definitely worth reaching out, thanks for the reminder.
No worries, I believe so. I found these two links from a quick google. I think there is more info on S4ME but I am brain fogged right now!
SPOT ME: Serial Pediatric Omics Tracking for ME/CFS
Exploring the pathology of pediatric ME/CFS (13-18 years) using a case-control, longitudinal approach with clinical and omics methods.
www.omf.ngo
OMF Scientist Receives Grant for ME/CFS research from the NHMRC in Australia - Open Medicine Foundation
Open Medicine Foundation is excited to announce that our Science Liaison, Christopher Armstrong, PhD has received a grant of $784,000 for ME / CFS research from the National Health and Medical Research Council (NHMRC) in Australia. The NHMRC is the primary agency of the Australian Government...
www.omf.ngo
Edit: Found the thread https://www.s4me.info/threads/seria...ary-observational-study-2024-armstrong.41567/
jnmaciuch
Senior Member (Voting Rights)
That’s definitely something I’m interested in—part of what drew me to the type I interferon response is that it is nearly universal across cell types, and thus could potentially explain PEM triggered by both muscle activity and cognitive activity for some pwME. It seemed to fit quite well since we already know that mtDNA release triggered in muscle during exercise elicits a mild type I interferon response in healthy people, and interferon therapy side effects are remarkably similar to PEM symptoms.
Interferon signaling from brain tissue has been implicated in dementia and lupus, and the former also has some evidence of mtDNA release from neurons mediating that signaling. I guess the million dollar question is whether it can occur in brain tissue without leading to the memory loss or psychosis seen in either of those conditions.
Perhaps it’s an issue of concentration? Or of also having neurological predispositions that make the “cracks” more likely to show and compound into other problems under mildly upregulated interferon signaling (I think @hotblack was theorizing a similar “cracks in the system under duress” idea in the context of brain metabolism on another thread).
[Edit: or interferon signaling may not be causative for the main problems in either dementia or neurolupus, it just contributes to additional fatigue/brain fog sometimes recorded in those conditions]
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Yann04
Senior Member (Voting Rights)
When extremely severe, I experienced both those symptoms. (Memory loss more as in inability to form new memories, like I have entire weeks where a month after I could remember absolutely nothing from them but a “feeling”.)
jnmaciuch
Senior Member (Voting Rights)
That’s really interesting, thanks for sharing. And does support the idea that it might be concentration dependent. I have similar “memory holes” from the years I was more moderate, and I’m sure that’s only a fraction of what is experienced by the more severe.
I wonder if in dementia it’s actually a two-part phenomenon: something preventing new memories from being made (perhaps something influenced by interferon) and something that destroys neurons harboring older memories (which doesn’t happen in ME/CFS, as far as it aware, though I could be wrong).
I hadn’t previously heard of pwME experiencing any psychosis—that’s very useful to know. That’s probably because the people who experience it are the least able to communicate online. And, I’m sure, many pwME might feel that it will be used against them by psychosomatic proponents.
Yann04
Senior Member (Voting Rights)
Yes. It’s actually somewhat commonly talked about on private groups for severe people. But rarely brought up publicly lest get institutionalised. Perhaps it’s also just a natural consequence of having very little visual or auditory stimulation like your brain starts compensating by making stuff up.
Utsikt
Senior Member (Voting Rights)
There’s a Norwegian team called the Moser Group (by the nobel winners) that works on how memory is formed.
Moser Group - Kavli Institute for Systems Neuroscience - NTNU
Kavli Institute's Space and memory Group
www.ntnu.edu
See e.g. this:
It’s way above my understanding, but I remember a news article where they explained that memories are stored in sequences of events that are determined based on events that stand out. These events are like tying knots on a string with pearls that keeps groups of pearls together (as distinct memories). The knots (specific activation of neurons) are always unique.
If the brain has very little stimuli, maybe there are very few knots so memories aren’t formed properly? Pure speculation by me.
jnmaciuch
Senior Member (Voting Rights)
Very valuable, thank you for sharing. It seems I have some chatting to do with a member of my former department that studies neurolupus
jnmaciuch
Senior Member (Voting Rights)
It’s very possible, though I did have something similar to what @Yann04 described when I was more moderate—stretches of months where I knew that something happened but the details aren’t so clear later on. I think I just didn’t connect it to “memory loss” until this discussion (and it was probably milder than what severe pwME describe). I definitely had plenty of stimulation even though I was housebound. It might be worthwhile to have a more detailed survey on that across severitiesThere’s a Norwegian team called the Moser Group (by the nobel winners) that works on how memory is formed.
Moser Group - Kavli Institute for Systems Neuroscience - NTNU
Kavli Institute's Space and memory Group
See e.g. this:
It’s way above my understanding, but I remember a news article where they explained that memories are stored in sequences of events that are determined based on events that stand out. These events are like tying knots on a string with pearls that keeps groups of pearls together (as distinct memories). The knots (specific activation of neurons) are always unique.
If the brain has very little stimuli, maybe there are very few knots so memories aren’t formed properly? Pure speculation by me.
hotblack
Senior Member (Voting Rights)
That’s perhaps a grand word for what I’m doing
Really interesting thoughts on potential things which could tie the identified contributors together. So if these are all factors which would increase the chance of a runaway process, or spin little cogs in a way which makes it more likely, what’s the actual process or cog?
Isn’t Jackie Cliff particularly interested in MAIT cells and their potential involvement? I seem to remember @Jonathan Edwards mentioning something. And there’s some type I interferon interactions talked about
Someone’s PhD so embargoed for a few more months
The talk of memory seems interesting too, along with ideas elsewhere in these genetic factors of either neuronal links being made or things not being cleaned up. Concepts which seem to pop up when talking about memory.
Jonathan Edwards
Senior Member (Voting Rights)
It is difficult to write cogent thoughts on a boat but another thing came to mind. Lupus has the female predominance of most autoimmune diseases squared (9=3×3). Maybe female ratio in MECFS is the other x3 that does not apply to RA or Graves and specifically involves inteferon-driven responses. No need to implicate antibodies even if lupus does involve an antibody pathway (but also dependent on interferons).
There are arguably similarities between MECFS and lupus.
There are arguably similarities between MECFS and lupus.
jnmaciuch
Senior Member (Voting Rights)
It's exactly the same as what any of us researchers and grad students are doing!That’s perhaps a grand word for what I’m doing
That's definitely the question, and it's what I've been tinkering at with my hypothesis. If I'm actually onto something re: type I interferons and not just seeing what I want to see, the question becomes "what could go wrong in interferon signaling that sustains a disease state over many years, but doesn't result in out-of-control damage a la interferonopathies or inflammatory diseases that involve interferon?"
I've talked on other threads about the two modes of interferon production:
1) an "activated" state that is mediated by highly amplified interferon production, driven by transcription factors that only get activated themselves through one of many immune "sensors"--TLRs, cytosolic DNA/RNA sensors, immune complex/antibody binding, etc. This state also simultaneously involves repressors that are activated by interferon itself, with the purpose of making sure that a highly amplified interferon response doesn't get too out of control.
2) a constitutive state, where a low basal amount of interferon and interferon-stimulated genes are constantly produced but actively kept in check by several mechanisms. This pathway always has to be a little bit active, because it's a self-perpetuating feedback loop. If the "active" response is mediated by a game of telephone across signaling molecules, this is basically making sure that someone is always at the switchboard to enable that lightning fast non-specific antipathogenic response.
The resolution of infection involves switching over from 1 to 2. My hunch, given the lack of inflammatory damage that you'd expect from constantly being in state 1, is that it's more likely to be a problem fully switching over to state 2 or keeping state 2 suppressed enough. You have enough interferon causing interferon problems, but the calvary doesn't get called in to start skewering all the tissue cells. The genetic hits basically amount to a series of points where different parts of the interferon response get amplified more than it should, or perhaps doesn't get repressed as strongly as it should.
As it happens, I'm currently working on a project about epigenetic regulation of innate immune responses to vaccination--there seems to be considerable biological variation in terms of how "primed" several of the genes involved in state 1 remain up to a year after vaccination, and this ends up being a strong determinant of vaccine protection independent of the strength of antibody response. So I definitely see this as a potential area where a pathological constitutive state of interferon production could play out, though I think every scientist has a tendency to believe that what they've previously worked on is relevant to whatever they're interested in now. I guess the only thing I can do is look for signs of this phenomenon happening and see if I prove myself wrong.
hotblack
Senior Member (Voting Rights)
Makes sense. Thanks for all the explanation. An always ready and waiting pathway that is perhaps a little too ready and always sounds particularly appealing for ME/CFS. Could it also be that this state 2 is doing something new and different it doesn’t in healthy people, rather than just a how much it’s turned up or suppressed?
Or how about it being fairly normal in itself but something else mediating or intermittently activating it, maybe along with some T cells, perhaps MAIT cells that have learned some new tricks?
MAIT cells interest me because of well, the mucosal aspect. And because I onky recently learned about them so recency and novelty bias! But I certainly experience and others talk of issues with eyes, nose, mouth, throat, even chest as well as gut.
On the idea of sampling and cell populations in specific places I think we’ve talked about brain/nerve and lymphoid tissues and the difficulties there. Has anyone tried looking at any of this in cells from mucosal tissue from somewhere like the mouth? Seems that should be easier to get at?