jnmaciuch
Senior Member (Voting Rights)
I agree, I think it takes too many leaps trying to frame the findings as significant for tons of diseases
Peripheral neurons, CRH, and sickness behavior
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jnmaciuch
Senior Member (Voting Rights)
Though to your general point @Hutan about some negative feedback loop being at play here with the ME/CFS autopsy findings, I do think that has a good chance of being relevant. I’ve posted earlier in this thread that there are known mechanisms of regulating CRH production within a cell—the more stimulation it receives to produce CRH, the more the suppression mechanism ramps up. So if we’re thinking that the findings of reduced CRH in severe ME/CFS autopsies are because of some negative feedback, I think that does end up being helpful. Because it tells us that the specific CRH+ population looked at in the autopsy studies is affected. So either the problem starts at these CRH neurons, or theyre one of the brain regions receiving continuous input from somewhere else.
In which case it might be useful to look at this other CRH+ population in the BNST. Maybe the brain stem as well. If those are also depleted, it would tell us that the problem probably isn’t starting in any of those brain regions, but somewhere upstream that relays to all of them. Which would probably be either the dorsal root ganglion, or actual immune signaling somewhere. That might be something the Netherlands team would be interested in, though I think funding is going to be the most immediate hurdle for them to pick up new questions.
Edited to fix a typo
In which case it might be useful to look at this other CRH+ population in the BNST. Maybe the brain stem as well. If those are also depleted, it would tell us that the problem probably isn’t starting in any of those brain regions, but somewhere upstream that relays to all of them. Which would probably be either the dorsal root ganglion, or actual immune signaling somewhere. That might be something the Netherlands team would be interested in, though I think funding is going to be the most immediate hurdle for them to pick up new questions.
Edited to fix a typo
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Yes, agreed. There is CRH production outside the hypothalamus eg Wikipedia:
Just noting for anyone looking up 'BSNT' that it's 'BNST'.
'bed nucleus of the stria terminalis'
(I've remembered it from a paper because I thought they were talking about 'brainstem' for a bit, and it's not.
Just noting for anyone looking up 'BSNT' that it's 'BNST'.
'bed nucleus of the stria terminalis'
(I've remembered it from a paper because I thought they were talking about 'brainstem' for a bit, and it's not.
V.R.T.
Senior Member (Voting Rights)
CRH is synthesised in T Lymphocytes? That's interesting if its not Wikipedia telling porkies.
[Edit: found this paper https://www.sciencedirect.com/science/article/abs/pii/016557289390262W]
Lots of interesting brain regions to look into too. We haven't seen the full CRH autopsy paper yet have we?
Looking at the NIH study, I see that Supplementary Data 17 includes the data for all the aptamers they measured in CSF. There are 1303 protein targets listed, but it doesn't seem like orexin was one of them.
Bragee et al 2026 was another study that looked at proteins in CSF of ME/CFS patients. Again doesn't look like HCRT is one of the 902 proteins listed in the supplementary file.
Maybe there's a study out there that tested it. But it might also be that CSF orexin has never been measured in an ME/CFS study.
jnmaciuch
Senior Member (Voting Rights)
They used aptamers? I remembered it was mass spec
As far as I can tell, MS was used for the metabolite analysis, while the proteins were measured using aptamers:
And just one quick note from a 2026 paper:
Chronic fatigue syndrome in MS: an endogenous response pattern to an immunological challenge mediated by orexin/hypocretin? (2026, Hildebrandt)
Chronic fatigue syndrome in MS: an endogenous response pattern to an immunological challenge mediated by orexin/hypocretin? (2026, Hildebrandt)
SugarSquared
Senior Member (Voting Rights)
Well, something needs to be done about that.
jnmaciuch
Senior Member (Voting Rights)
Ah okay that makes more sense. If the aptamers were “optimized for human serum” that may be why orexin was omitted. that’s a shame
[Edit: it looks like the second study was mass spec. Usually there’s a QC step for filtering out analytes above a certain level of missingness across samples (generally lower concentration proteins that fell below level of detection). I’d be curious if orexin was detected but filtered out at this step]
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V.R.T.
Senior Member (Voting Rights)
Who do we know in the research world with the tech, funding and inclination to do this?
jnmaciuch
Senior Member (Voting Rights)
Had some idle thoughts about whether steroids would be expected to suppress sickness behavior in the context of normal infection (focusing specifically on the parts that more commonly overlap with ME/CFS symptoms like fatigue/malaise/activity reduction/cognitive impairment). If I was just going off of the papers posted in this thread, it would be a reasonable thing to expect since glucocorticoids are well known to suppress 1) endogenous CRH production and 2) a broad array of different cytokines, both of which seem to be necessary components of “sickness behavior” in normal infection.
I've chatted with some residents before about what steroids do and don't help with, and most didn't have much experience giving steroids to someone with a run-of-the-mill viral infection (for obvious reasons). When they have been used for some severe infection-related complications, it was suggested that they can have some effect on fever, can help with breathing problems, and will improve some lab values like CRP, but they generally aren't taking away the feeling of being ill. Though, to be fair, that’s usually not the primary symptom being asked about and monitored when someone is hospitalized with an infection so the anecdotal evidence should be taken with an extra grain of salt.
For sake of thoroughness I looked for some papers that assessed the effect of steroids on sickness behavior symptoms in common infections. General consensus from a small trial and a meta-analysis seems to be that they don't really improve the particular symptoms I listed, supporting the anecdotal evidence.
It’s an interesting contradiction and maybe solving it can clarify some things for ME/CFS if the same sickness behavior pathways are involved.
From the type 1 narcolepsy papers I linked earlier in the thread it seems that having 10% of the normal CRH production of a healthy person doesnt inhibit sickness symptoms or affect cortisol, so maybe we shouldn’t be surprised that suppressing CRH with glucocorticoids doesn’t strongly suppress sickness behavior in this context either.
In terms of reconciling the piece about steroids broadly suppressing lots of different immune pathways, I think the only thing that makes sense is if the particular immune signals that mediate fatigue/malaise/activity reduction in actual infections are the few that aren’t steroid-responsive. Steroids readily penetrate the BBB and pretty much every other part of the body, so we can rule out the possibility that steroids don’t affect sickness behavior because they just aren’t reaching where the relevant signaling happens.
It’s been known for a while that NFkB is the main immune mediator inhibited by glucocorticoids. Which does help eliminate several options since that one is pretty central to a lot of immune signaling cascades. I will have to dig more into whether it’s necessary for CXCL10 induction in endothelial cells, which was highlighted in the Blank et al. Cell Immunity paper.
I've chatted with some residents before about what steroids do and don't help with, and most didn't have much experience giving steroids to someone with a run-of-the-mill viral infection (for obvious reasons). When they have been used for some severe infection-related complications, it was suggested that they can have some effect on fever, can help with breathing problems, and will improve some lab values like CRP, but they generally aren't taking away the feeling of being ill. Though, to be fair, that’s usually not the primary symptom being asked about and monitored when someone is hospitalized with an infection so the anecdotal evidence should be taken with an extra grain of salt.
For sake of thoroughness I looked for some papers that assessed the effect of steroids on sickness behavior symptoms in common infections. General consensus from a small trial and a meta-analysis seems to be that they don't really improve the particular symptoms I listed, supporting the anecdotal evidence.
A small trial evaluating whether steroids taken during lower respiratory tract infection improved symptom intensity and duration. The only symptoms with statistically significant improvement were chest pain and "activity disturbance.” Fatigue and the feeling of being ill/malaise were not different. So mixed effects here for our sickness behavior symptoms. The authors note that this population likely had some selection bias for people that were overenthusiastic about the effects of the medication (>80% said that they would take the drug again in the placebo arm). That bias might actually be helpful here, though, since it shows that there isn't a significant reported improvement in many of the symptoms we’re interested in even in a particularly optimistic cohort
pmc.ncbi.nlm.nih.gov
This is a Cochrane meta-analyses for use of steroids in infectious mononucleosis. Some contradictory evidence for sore throat and fever. No effect for fatigue and difficulty concentrating (one study reported fatigue improvement but it was in combination with anti-virals).
pmc.ncbi.nlm.nih.gov
Effect of Oral Prednisolone on Symptom Duration and Severity in Nonasthmatic Adults With Acute Lower Respiratory Tract Infection: A Randomized Clinical Trial - PMC
Does a moderate dose of oral corticosteroid reduce the duration or severity of acute lower respiratory tract infection in adults without asthma presenting to primary care? In this randomized trial of 401 adults with symptoms of acute lower ...
pmc.ncbi.nlm.nih.gov
This is a Cochrane meta-analyses for use of steroids in infectious mononucleosis. Some contradictory evidence for sore throat and fever. No effect for fatigue and difficulty concentrating (one study reported fatigue improvement but it was in combination with anti-virals).
Steroids for symptom control in infectious mononucleosis - PMC
Infectious mononucleosis, also known as glandular fever or the kissing disease, is a benign lymphoproliferative disorder. It is a viral infection caused by the Epstein‐Barr virus (EBV), a ubiquitous herpes virus that is found in all human societies ...
pmc.ncbi.nlm.nih.gov
It’s an interesting contradiction and maybe solving it can clarify some things for ME/CFS if the same sickness behavior pathways are involved.
From the type 1 narcolepsy papers I linked earlier in the thread it seems that having 10% of the normal CRH production of a healthy person doesnt inhibit sickness symptoms or affect cortisol, so maybe we shouldn’t be surprised that suppressing CRH with glucocorticoids doesn’t strongly suppress sickness behavior in this context either.
In terms of reconciling the piece about steroids broadly suppressing lots of different immune pathways, I think the only thing that makes sense is if the particular immune signals that mediate fatigue/malaise/activity reduction in actual infections are the few that aren’t steroid-responsive. Steroids readily penetrate the BBB and pretty much every other part of the body, so we can rule out the possibility that steroids don’t affect sickness behavior because they just aren’t reaching where the relevant signaling happens.
It’s been known for a while that NFkB is the main immune mediator inhibited by glucocorticoids. Which does help eliminate several options since that one is pretty central to a lot of immune signaling cascades. I will have to dig more into whether it’s necessary for CXCL10 induction in endothelial cells, which was highlighted in the Blank et al. Cell Immunity paper.
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Jonathan Edwards
Senior Member (Voting Rights)
All I can give is an anecdote from 50 years ago. I was badly affected by EBV and reached a state in which I was in delirium once or twice a day, could not swallow my own saliva and had to be supported to get to the toilet. My mental activity did not go further than short periods of listening to light music on the radio. In the end I got sufficiently dehydrated that I didn't even get to the toilet. My parents, both physicians, and one a virologist who later took over the UK EBV central service, suggested to our GP that the time had come to try some prednisolone in the hope of at least allowing me to maintain fluid intake at home.
Within 24 hrs I was feeling generally quite well and never looked back. I probably had the prednisolone for five days or so.
I have other anecdotes relating to patients with rheumatoid on steroids who were unaware of their severe and in some cases fatal staphylococcal infections. Steroids have a predictably dramatic effect on joint pain and swelling equivalent to TNF inhibitors. They also improve fatigue with RA.
But I think the question is a good one.
Maybe we should try to separate out an ME/CFS-specific version of sickness behvaiour features and call it something a bit different.
jnmaciuch
Senior Member (Voting Rights)
That’s not the only anecdote I’ve heard of steroids seeming to bring someone back from the brink—probably what inspired all those trials of steroids in IM to begin with. The meta-analysis seems pretty clear though. So it must come down to a difference in what drives severe cases like yours vs. the average case selected for these trials.
Maybe TNF is just the simple answer here. It would track with steroids having a strong effect on NFkB. TNF, IL-6, and IL-1B can all separately induce fever, so I think it would be no surprise if fatigue had a similar rotating cast across different contexts, some of which were steroid responsive and some such were not.
If I’m recalling correctly, anti-TNF isnt a first line therapy for lupus. Do steroids also improve fatigue when used there? My impression is that SLE fatigue can be pretty intractable to all the first line therapies even when there’s dramatic improvement in other symptoms and signs.
It would also explain not noticing staph infections on steroids—TNF is nearly always induced in innate responses but especially strongly in bacterial infections. Were respiratory viruses also missed frequently or is it possible there was something specific about staph?
In my head I’ve just been calling it “feeling like crap”. Someone else can probably come up with a more elegant name
SugarSquared
Senior Member (Voting Rights)
Hahaha, I love it!
Jonathan Edwards
Senior Member (Voting Rights)
Anti-TNF agent were banned early on for lupus because it is quite common for them to induce ANA. Large complex lupus like brain, skin and kidney is not TNF mediated, or IL-6, as apparent from the lack of CRP rise. Small complex lupus like joint and pleura does involve TNF and a CRP rise but the ANA observation stopped people using anti-TNF. And yes, lupus fatigue often fails to respond to steroids. Is lupus fatigue 'sickness behaviour'? Is ME/CFS fatigue? All these questionsare relevant and tricky. I quite like Feeling Like Actual CRAP (FLAC) as a working terminology.
jnmaciuch
Senior Member (Voting Rights)
Found this paper which provided some interesting insight:
pmc.ncbi.nlm.nih.gov
It started with the hypothesis that steroids might not affect interferon signaling, since interferon stimulated genes have been shown to remain elevated in SLE patients treated with steroids despite improvement in disease index. Contrary to the hypothesis they found that IFN-B and interferon-stimulated gene production (including IP-10/CXCL10, which was shown in a mouse study to mediate sickness behavior) in cultured macrophages was strongly suppressed by Dexamethasone. This was despite all the known mediators of the IFN response (STAT1/STAT2/IRF9 and other IRFs) still being produced and phosphorylated as normal, so the interference must come right at the last step of TF binding to chromatin. This would be in contrast with NFkB signaling, where steroids induce some potent inhibitors well upstream.
Very interestingly, they found that this effect was specific to macrophages. Cultured fibroblasts did not have a blunted IFN response with steroids. They figured out that IFN-B response is resistant to Dexamethasone in cells with high GRIP1, which is a transcriptonal co-activator that anchors both the glucocorticoid receptor complex and several TFs involved in the interferon response to chromatin. They suggest that glucocorticoids might suppress interferon response only when IFN signaling has to compete with GR signaling for GRIP1. If there's plenty of GRIP1 to go around in the cell, steroids don't do much to suppress IFN signaling.
GRIP1 is glutamate receptor interacting protein 1. Human protein atlas seems to show inconsistency in where GRIP1 expression is highest across their different reference datasets. Does seem to be consistently higher in neurons than in immune cells, though. Generously speculative point being that if some symptom is caused by IFN signaling in neurons, we should expect steroids to be largely ineffective.
www.proteinatlas.org
The Type I Interferon Signaling Pathway Is a Target for Glucocorticoid Inhibition - PMC
Type I interferon (IFN) is essential for host defenses against viruses; however, dysregulated IFN signaling is causally linked to autoimmunity, particularly systemic lupus erythematosus. Autoimmune disease treatments rely on glucocorticoids (GCs), ...
pmc.ncbi.nlm.nih.gov
It started with the hypothesis that steroids might not affect interferon signaling, since interferon stimulated genes have been shown to remain elevated in SLE patients treated with steroids despite improvement in disease index. Contrary to the hypothesis they found that IFN-B and interferon-stimulated gene production (including IP-10/CXCL10, which was shown in a mouse study to mediate sickness behavior) in cultured macrophages was strongly suppressed by Dexamethasone. This was despite all the known mediators of the IFN response (STAT1/STAT2/IRF9 and other IRFs) still being produced and phosphorylated as normal, so the interference must come right at the last step of TF binding to chromatin. This would be in contrast with NFkB signaling, where steroids induce some potent inhibitors well upstream.
Very interestingly, they found that this effect was specific to macrophages. Cultured fibroblasts did not have a blunted IFN response with steroids. They figured out that IFN-B response is resistant to Dexamethasone in cells with high GRIP1, which is a transcriptonal co-activator that anchors both the glucocorticoid receptor complex and several TFs involved in the interferon response to chromatin. They suggest that glucocorticoids might suppress interferon response only when IFN signaling has to compete with GR signaling for GRIP1. If there's plenty of GRIP1 to go around in the cell, steroids don't do much to suppress IFN signaling.
GRIP1 is glutamate receptor interacting protein 1. Human protein atlas seems to show inconsistency in where GRIP1 expression is highest across their different reference datasets. Does seem to be consistently higher in neurons than in immune cells, though. Generously speculative point being that if some symptom is caused by IFN signaling in neurons, we should expect steroids to be largely ineffective.
Tissue expression of GRIP1 - Summary - The Human Protein Atlas
Summary of GRIP1 expression in human tissue. Ubiquitous cytoplasmic expression.
www.proteinatlas.org
jnmaciuch
Senior Member (Voting Rights)
Ah yes this is jogging my memory of anti TNF-induced lupus in psoriasis patients. So this would track with steroids working for problems that are NFkB mediated.
I suppose it's the same question as whether fever in a lupus flare is "sickness behavior". There must be a point where things converge and all fever is the same. It's just tracing steps to find where the paths start branching out. If we can understand a symptom in one context, that at least gives us a list of checkpoints along a route to help find where the fork is. 3 instances of fatigue (lupus, infection, and ME/CFS) that are all non-responsive to steroids is a pretty good head start.
+1 vote for FLAC
[And with that I must return to the gallows of grad school work on a weekend]
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DHagen
Senior Member (Voting Rights)
My biggest objection is that, if this takes hold and if I should ever regain the ability to listen to music, how will I ever be able to download lossless data or even open my digital library without re-traumatizing myself? FLAC has always been such a beautiful thing!