Hornig/Lipkin cytokine study out now - press release

[lansbergen]

Sufferers from what?

I will PM you.

 

[Daisymay]

Why are they blocked?; what is blocking them?; why do they remain persistently blocked?; what is the effect of the blockage? (i.e. does the blockage stimulate or inhibit the receptor?); why are so many cytokine receptors apparently blocked simultaneously? (i.e. do the various cytokine receptors have enough similarities or shared features such that they could be inhibited by a single protein or other single item?)

Interesting idea. Has this sort of scenario been found in other diseases do you know?

 

[Bob]

Interesting idea. Has this sort of scenario been found in other diseases do you know?

I have no idea. But receptor inhibition is something I've thought about in the past because I've wondered if it could potentially explain why blood tests are normal in ME patients despite experiencing apparent endocrine abnormalities, orthostatic intolerance, and autonomic nervous system dysfunction. But I'd be surprised if so many different types of receptors would be inhibited in a single disease. If it was the case of widespread receptor inhibition, by whatever mechanism, then perhaps this would have been noticed in research by now?

 

[adreno]

I have no idea. But receptor inhibition is something I've thought about in the past because I've wondered if it could potentially explain why blood tests are normal in ME patients despite experiencing apparent endocrine abnormalities, orthostatic intolerance, and autonomic nervous system dysfunction. But I'd be surprised if so many different types of receptors would be inhibited in a single disease. If it was the case of widespread receptor inhibition, by whatever mechanism, then perhaps this would have been noticed in research by now?

Quite a few receptors have been shown to be inhibited by autoantibodies, for example acetylcholine and norepinephrine receptors in OI.

 

[Daisymay]

I have no idea. But receptor inhibition is something I've thought about in the past because I've wondered if it could potentially explain why blood tests are normal in ME patients despite experiencing apparent endocrine abnormalities, orthostatic intolerance, and autonomic nervous system dysfunction. But I'd be surprised if so many different types of receptors would be inhibited in a single disease. If it was the case of widespread receptor inhibition, by whatever mechanism, then perhaps this would have been noticed in research by now?

Did you see Prof Klimas's slides in her recent talk where I think it was in GWI they looked at Gordon Broderick's network diagrams and seemed to find that one cytokine being out of kilter was pivotal to the others being out of kilter so could it be that surprisingly few things could be out of kilter yet have a profound influence across a range of bodily systems and with the likes of these network diagrams it may be possible to work this out?

 

[Bob]

Did you see Prof Klimas's slides in her recent talk where I think it was in GWI they looked at Gordon Broderick's network diagrams and seemed to find that one cytokine being out of kilter was pivotal to the others being out of kilter so could it be that surprisingly few things could be out of kilter yet have a profound influence across a range of bodily systems and with the likes of these network diagrams it may be possible to work this out?

Yes, agreed. (Not that I have an expert knowledge of immunology!) It seems to me that there is a cascade of subtle and interconnected immune abnormalities at work in ME.

I did see Klimas' presentation, but the quality of the image was poor in the video, so I couldn't make much sense of it. But it seems like an interesting theory that Klimas is working on, via a very sopphitcated computational model created by Gordon Broderick. If I understood it correctly, I think Klimas is working towards trialing a drug that will block IL-1.

These are my notes from another thread:

@ 45 mins.
Drug Trials:
Klimas wants to trial FDA approved drug (biological response modifier) that blocks IL-1 (cytokine). Computational data points towards blocking IL-1. Not able to get it past review board, because drug is toxic, and review boards don't appreciate the severity of ME. Lost 5 years due to not getting grant proposals past review boards. Requires phase I funding from private donors. Will, instead, look at other less optimal drugs (used for rheumatoid arthritis?) which she expects to get through review boards, but frustrated that she can't test the drug she wants to.

 

[alex3619]

Thank you for you reply professor Edwards.

Alex do you refer to this article?
Post-exertion malaise in chronic fatigue syndrome: symptoms and gene expression.
Fatigue: Biomedicine, Health & Behavior. 2013 Oct 2. doi: 10.1080/21641846.2013.838444.
Meyer JD, Light AR, Shukla SK, Clevidence D, Yaled S, Stegner AJ, Cook DB

Actually I was referring to some unpublished research, the details of which I do not really know. It was discussed at a seminar last year that was videod and is somewhere on PR. What it Sweden?

The response to cortisol is dependent on the ratio of alpha to beta corticoid receptors, at least in part. They thought we might have more beta corticoid receptors. We await the full paper being published before we can see what the evidence is and evaluate it. Its intriguing though, as if so it would make ME a different kind of Addisons Disease.

 

[alex3619]

If it was the case of widespread receptor inhibition, by whatever mechanism, then perhaps this would have been noticed in research by now?

I am not sure about this. You can find what you are looking for if it exists. If you are not looking for something and its not obvious you are relying on chance to find it.

I have long been enchanted by the notion of a cAMP/Ca++ imbalance in us. Its still somewhat speculative. These two are intracellular messengers, and if there is a frank imbalance, a triggered imbalance or a circadian imbalance then cellular hormone responses, including to cytokines, would be off.

In fact my third model of CFS (I think) which I never discussed much, and perhaps my second (its been so long, circa 2000) relied on Ca++ imbalances. Since that time I became more aware this can induce cAMP imbalances. These models are probably obsolete but I was left with curiosity about these mechanisms.

 

[Jonathan Edwards]

B cells have cortisol receptors and CD40L could be telling us about the flip side of whatever feedback pathway is being blocked. CD40 is all about shifting the threshold of sensitivity to specific signals. The whole thing could be downstream of some glitch in HPA feedback and that might be remarkably difficult to pin down because of multiple back-up pathways. As an illustration it has been known that autoantibodies in Graves' disease are responsible for strange things like nodular swellings along the front of the shin (pretibial myxoedema) presumably through some strange blockage of a feedback cycle but despite people looking for a mechanism for fifty years as far as I know nobody understands how it actually works.

 

[Gijs]

Thank you Alex. It is interesting. We have so many, many, many abnormalities sometimes i think what the F... How can this all be, there must be 1 reason.

 

[Gijs]

I still believe all these immune problems are secondarily. Cortisol ''dysfunction'' could explain many of these.

 

[Marco]

How about this (bearing in mind there's limited data and I know sod all about the immune system).

We have two distinct immune patterns. (a) For those with illness duration under three years we have upregulation of numerous pro and anti-inflammatory cytokines. (b) Post three years we have a less dramatic downregulation of certain cytokines including the anti-inflammatory IL10. One of the study cohorts was the XMRV one which we can assume was populated with PWME reporting viral onset.

I'll make the unfounded assumption that most of the under three year patients came from this viral onset cohort.

Perhaps the (b) pattern preceded (a)?

We have pretty consistent evidence of autoimmune dysregulation (enhanced sympathetic activity and possibly attenuated parasympathetic activity) in ME/CFS along with initial suggestions of neuroinflammation.

An established pattern of neuroinflammation (perhaps due to autoimmunity in some) could potentially cause frontal lobe dysfunction (as frequently found) leading to reduced autonomic inhibition and reduced (vagal) parasympathetic activity. This in turn downregulates the vagus mediated cholinergic anti-inflammatory pathway including production of anti-inflammatory IL10. In the absence of infection we have brain immune activation without peripheral immune activation.

Next, along comes a common virus and bang - the already primed microglia pump out cytokines without the braking effect of the anti-cholingergic pathway resulting in an exaggerated and prolonged immune response. The 'flu from hell' is in fact a sign of rather than the cause of the underlying problem?

 

[anne_likes_red]

@Gijs I think Alex is referring to the studies mentioned in Dr Bansal's talk posted here a few months ago.

 

[voner]

How about this (bearing in mind there's limited data and I know sod all about the immune system).

We have two distinct immune patterns. (a) For those with illness duration under three years we have upregulation of numerous pro and anti-inflammatory cytokines. (b) Post three years we have a less dramatic downregulation of certain cytokines including the anti-inflammatory IL10. One of the study cohorts was the XMRV one which we can assume was populated with PWME reporting viral onset.

I'll make the unfounded assumption that most of the under three year patients came from this viral onset cohort.

Perhaps the (b) pattern preceded (a)?

We have pretty consistent evidence of autoimmune dysregulation (enhanced sympathetic activity and possibly attenuated parasympathetic activity) in ME/CFS along with initial suggestions of neuroinflammation.

An established pattern of neuroinflammation (perhaps due to autoimmunity in some) could potentially cause frontal lobe dysfunction (as frequently found) leading to reduced autonomic inhibition and reduced (vagal) parasympathetic activity. This in turn downregulates the vagus mediated cholinergic anti-inflammatory pathway including production of anti-inflammatory IL10. In the absence of infection we have brain immune activation without peripheral immune activation.

Next, along comes a common virus and bang - the already primed microglia pump out cytokines without the braking effect of the anti-cholingergic pathway resulting in an exaggerated and prolonged immune response. The 'flu from hell' is in fact a sign of rather than the cause of the underlying problem?

or there is a latent virus that opportunistically arises again... the causal question then would be what caused pattern (B) to exist or stay dominant?

 

[Marco]

or there is a latent virus that opportunistically arises again... the causal question then would be what caused pattern (B) to exist or stay dominant?

Can't be ruled out but there's no evidence for (or need for) it to date.

 

[Antares in NYC]

Yes, agreed. (Not that I have an expert knowledge of immunology!) It seems to me that there is a cascade of subtle and interconnected immune abnormalities at work in ME.

I did see Klimas' presentation, but the quality of the image was poor in the video, so I couldn't make much sense of it. But it seems like an interesting theory that Klimas is working on, via a very sopphitcated computational model created by Gordon Broderick. If I understood it correctly, I think Klimas is working towards trialing a drug that will block IL-1.

These are my notes from another thread:

Drug Trials:
Klimas wants to trial FDA approved drug (biological response modifier) that blocks IL-1 (cytokine). Computational data points towards blocking IL-1. Not able to get it past review board, because drug is toxic, and review boards don't appreciate the severity of ME. Lost 5 years due to not getting grant proposals past review boards. Requires phase I funding from private donors. Will, instead, look at other less optimal drugs (used for rheumatoid arthritis?) which she expects to get through review boards, but frustrated that she can't test the drug she wants to.

Very interesting that you mention rheumatoid arthritis. There's a potential connection here with RA and also chronic Lyme, all related to the HLA-DR4 gene allele (look for the work of Dr. Brigitte Huber). Recent genome studies on individuals that were treated for Lyme but never improved showed that those folks (about 20% of people who get Lyme) carry the HLA-DR4 gene allele. On the other hand, people who received ABX treatment and improved had the HLA-DR11 allele instead.

Their immune response was dramatically different:

- When infected, people with HLA-DR11 produced antibodies that fought the infection.
- When infected, people with HLA-DR4 overproduced cytokines, particularly interferon gamma, and no antibodies to fight the infection.

Closing the circle, HLA-DR4 is also involved in rheumatoid arthritis.

Just pure speculation on my part, but could it be we are talking about different expressions of the same issue?

PS: also the fact that most of us show very low NK cell count and function while showing signs of multiple infections makes me think of these studies on HLA-DRA.

 

[MeSci]

Very interesting that you mention rheumatoid arthritis. There's a potential connection here with RA and also chronic Lyme, all related to the HLA-DR4 gene allele (look for the work of Dr. Brigitte Huber). Recent genome studies on individuals that were treated for Lyme but never improved showed that those folks (about 20% of people who get Lyme) carry the HLA-DR4 gene allele. On the other hand, people who received ABX treatment and improved had the HLA-DR11 allele instead.

Their immune response was dramatically different:

- When infected, people with HLA-DR11 produced antibodies that fought the infection.
- When infected, people with HLA-DR4 overproduced cytokines, particularly interferon gamma, and no antibodies to fight the infection.

Closing the circle, HLA-DR4 is also involved in rheumatoid arthritis.

Just pure speculation on my part, but could it be we are talking about different expressions of the same issue?

PS: also the fact that most of us show very low NK cell count and function while showing signs of multiple infections makes me think of these studies on HLA-DRA.

My father had RA. I have often suspected a genetic link.

 

[Antares in NYC]

My father had RA. I have often suspected a genetic link.

My mom has RA!
I don't have it, though. And I don't need it! Have my hands full with ME/CFS!

 

[Aurator]

Here's the NHS's hatchet job on the Columbia Univ. study. Predictably the only "independent" expert they quote is Sharpe.

 

[rosie26]

The 'flu from hell' is in fact a sign of rather than the cause of the underlying problem?

The flu was what really locked me in to this illness, as if it turned a permanent switch. I remember an unusual flu-like cold (I don't know what it was) I got 7 years before my severe flu onset. I think that earlier one started off my mild symptoms of ME. I think the flu progresses the underlying illness and/or changes it into something else again.