Hornig/Lipkin cytokine study out now - press release

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@Jonathan Edwards

I'm trying to understand. So a couple of these cytokines are high enough to reflect that some physiological problem is definitely going on somewhere in the body and these cytokine results in short duration do reflect this quite clearly? So even though the cytokines themselves are not at levels to cause symptoms ( I read that they don't correlate with symptoms) these findings are adequately reflective of something going on biologically elsewhere to make this very significant? Any chance you could give a 101 how we know these could reflect that something else is happening. I'm trying to understand how the difference between short duration and healthy controls is enough to show this to doctors and researchers.

I had thought that the increase compared to controls in short duration and then the drop in long duration was also significant. Do you think this paper will be taken notice of really seriously in the medical community?
Take as an example the biochemical changes in the blood in RA. It is very hard to measure TNF but it is now reasonably reliable and we have several bits of evidence indicating that TNF actually causes pain and exhaustion, as well as bone damage. In the old days we measured ESR, which is mostly a reflection of fibrinogen levels which go up because IL-6 has gone up. And IL-6 goes up partly because TNF goes up and it also contributes to B cell activation and disease. But fibrinogen probably does not do anything much.

Basically, immunological diseases set off very complex networks of signals and in each disease it is a different subset of these signals that actually causes trouble. And what you can measure may not be the signals that cause the trouble. What this study is saying is that if you listen at the door of the immune system you can definitely hear some plotting of crime inside, but you don;t know which of the people speaking is going to go out and commit it. And after 3 years they are still committing the crime (because the PWME is still ill) but they are no longer even talking about it - something like that.

So there is no suggestion from Dr Hornig and Dr Lipkin that they have found the mechanism here - just some incriminating evidence. But that is where we need to start. I asked Dr Lipkin about blocking IL-17 in Bristol, rather jokingly, and he said no way would he say he had enough evidence to do that. (He may be more sensible than me.)
 
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Professor Edwards
Regarding these findings, does it assist with the rituximab trial? For example, people who have been ill less than 3 years or more than three years? Or, does it have no assistance to the rituximab trial?
It seems to be telling us that whatever biomarkers we look for that might help us identify who might respond to rituximab we should look for them both in <3yr and >3yr cases and analyse separately. It might possibly turn out to mean that rituximab is more likely to work early on but to be honest as soon as we find something that works we are going to want to use it before 3 years. And I do not think it necessarily means that a B cell treatment would not work later. For instance the shift at 3 years might indicate a shift from IgM mediated events to IgG mediated disease. It might be the IgG that matters and remains treatable. The early cytokines might reflect a 'smokescreen' from IgM mediated events that do not actually cause symptoms. I am not saying I think that is a likely idea but all sorts of things could explain thee shifts. As I said in response to Marco, I agree that immune exhaustion does not sound terribly plausible.
 

A.B.

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Regarding B cells and Rituximab, they say this:

Our observation that the levels of CD40L were both decreased and dissociated from normal intercytokine regulation early in the course of illness in ME/CFS is intriguing. CD40L (CD154), a TNF superfamily transmembrane protein found on immune (especially CD4+ T cells), endothelial, and smooth muscle cells, is essential for regulation of B cell maturation and isotype switching (37); however, abnormally high levels have been associated in some studies with risk of adverse neurovascular events (38) as well as mild cognitive impairment (39) and Alzheimer’s disease (40). Of potential relevance for ME/CFS, constitutive CD40L deficiency (X-linked hyperimmunoglobulin M syndrome) not only is associated with susceptibility to recurrent infections of the sinuses and pulmonary tracts but also can present with a pattern of cognitive and neurologic decline that is unexplained by the presence of any known pathogen or clear clinical signs of encephalitis (41).
We found significantly different levels of CD40L in the short duration versus long-duration subgroups, and an uncoupling of CD40L levels with other cytokines in the short-duration subgroup. To our knowledge, only one other study has evaluated CD40L levels in patients with ME/CFS and found low levels (as did we, in the shortduration
patients) (48). CD40L plays an important role in B cell maturation (49). There is indirect evidence that B cells play an important role in ME/CFS (50), although not all studies have found abnormalities of B cell phenotype or function (51, 52). Most studies indicate a higher frequency of autoantibodies in the illness (53), and a randomized trial of a monoclonal antibody that targets B cells has demonstrated symptom improvement in some patients (54).
CD40L is decreased in short term patients and increased in long term patients.
 
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alex3619 said:
greeneagledown said:
Why isn't C-Reactive Protein and/or sed rate elevated in short-duration patients if they have so much cytokine inflammation? Makes me wonder if maybe these two tests don't measure inflammation as effectively as has traditionally been thought
These are two of many markers. I haven't seen a list since I was at uni but its much longer than that. Its just these are two that are clinically useful in a wide range of conditions.Any ideas, @Jonathan Edwards?
CRP and ESR only measure inflammation that includes IL-6 production. That is quite a wide range but by no means all sort. CRP does not go up in lupus a lot of the time.

I don't actually think there is likely to be that much 'inflammation' of a traditional sort in ME but it looks as if there may well be cytokine involving immune reactions. There are lots of immune disease where there is no typical inflammation - immune thrombocytopenia, Grave's disease, anti-phispholipid syndrome etc etc. To understand what is going on here I think we have to move beyond simple terms like inflammation and deal with specific cellular interactions. That requires a considerable knowledge of immunology so it isn't much help in general discussion I am afraid!
 

Simon

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IFN-gamma Odds ratio of 100, and viral infection

[fancy statistical modelling showed that] proinflammatory cytokines had a prominent association with short-duration ME/CFS (Table 2). This association was markedly elevated for interferon-γ (IFNγ), with an OR of 104.77 (95% CI, 6.975 to 1574.021; P = 0.001)
So this is a remarkable finding: odds ratios that high are pretty rare, and even the very lowest in the confidence interval range (of 7) is impressive. It suggests that the precise level of IFN-gamma is very predictive of whether a patient is a short or long duration case.

It's also quite surprising given the modest difference in average levels between short and long duration:
upload_2015-2-28_20-55-44.png


I'm honestly not sure why the difference between the high odds ration and smaller difference in average levels.

So what's the significance?
the authors said:
The marked association of IFNγ with the early phase of illness that was detected through logistic regression modeling is consistent with a viral trigger or disrupted immune regulatory networks.

IFNγ is a product of activated T cells [particularly CD8+ and CD4+ T helper 1 (TH1) cells], natural killer cells, as well as activated macrophages in the periphery (15, 16) and microglia in the central nervous system (1719). IFNγ may disrupt immune cell homeostasis, resulting in a TH2-type skew and greater vulnerability toward the development of certain types of autoimmune responses (2023).
It's worth bearing in mind also that buried amongst these averaged findings will be PWME whose illness didn't follow from a viral infection..
Worth noting that half of the sample came from the NIH/'XMRV' cohort where all cases had a viral-like onset. Let's say half of the remaining cohort (CFI one) also had a viral-like onset and three-quarters of cases, but not all, probably have a viral-like illness. Certainly the NIH cohort means this sample is enriched for patients with a viral onset.

IFN-gamma driving fatigue?
Some studies in ME/CFS (7), but not all (2426), have found plasma levels of IFNγ to be elevated, with effects restricted to males in one study (27). Postviral fatigue in West Nile virus infection has also been reported to be associated with elevations of IFNγ (28). Individuals experiencing more severe fatigue as part of an acute sickness response to infection have been noted to have specific genetic polymorphisms in IFNG (29).
The Dubbo studies (ref 29) found that the link with IFN-gamma was in the acute phase of the illness (glandular fever, or whatever), not once people had developed CFS. And @Jonathan Edwards said earlier on this thread he didn't think the cytokine levels generally were high enough to be causing symptoms.

IFN-gamma drives faster tryptophan degradation, causes cognitive problems?
the authors said:
IFNγ may accelerate degradation of tryptophan, resulting in depletion of the neurotransmitters serotonin and melatonin in the central nervous system through activation of indoleamine-2,3-dioxygenase, a rate-limiting enzyme in the kynurenine pathway. Activation of this pathway also results in increased levels of quinolinic acid, a neurotoxic compound that acts as an agonist at glutamatergic [NMDA (N-methyl-d-aspartate)] receptors (3032). Psychomotor changes, including cognitive problems (deficits of memory and attention) as well as affective disturbances, are correlated with changes in the kynurenine pathway in disorders ranging from Alzheimer’s disease (33) to major depression (34). We hypothesize that IFNγ-mediated lesions in kynurenine metabolism may culminate in the depression and psychomotor retardation that contribute to disability in some patients with ME/CFS (3436).
Which is quite dramatic. I wonder if there is a way of testing this?
 

msf

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That's interesting, I was looking for a possible mechanism that might cause serotonin depletion, as this would seem to be at least responsible for many of the ME symptoms I have.
 

nandixon

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That's interesting, I was looking for a possible mechanism that might cause serotonin depletion, as this would seem to be at least responsible for many of the ME symptoms I have.
One possibility is presented in this paper which was the topic of this thread by @Simon:
Immune-induced model of CFS - Interleukin-1 in brain may trigger fatigue (2014)

I gave a post on that same thread here in an attempt to give a simple explanation of the paper and, possibly, the practical implications for treatment.
 

cigana

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I would just like to mention that maybe we need a bit of caution in interpreting cytokines as the cause of our symptoms. Firstly from my own experience (and I realise this is N=1), I have had many cytokines tested and many of them have been raised. By treating with a combination of nexavir and abx, I was able to normalise all cytokines for a period of around 6 months - but none of my symptoms improved.

So I take this study, which shows PWC's feel ill no matter whether their cytokines are raised or lowered, as evidence that cytokines are likely not responsible for our symptoms.
 

alex3619

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EDIT - although of course we don't know if all the abnormalities are pathogenic - some may be (necessary) responses to pathology, so it will have an element of trial and error as usual, as of course does (much) formal research.
This is one of the concerns. Are the cytokine changes causing symptoms, which appears unlikely, or in response to something else?

However there is the third option that they are not directly driving symptoms but driving brain immune changes (or some other mechanism) which leads to symptoms. So correcting them might work, but indirectly.If so then expect that any treatment might have to be prolonged.

I do think something like cytokines is a cause. It has to be something active. The way symptoms can wax and wane, get worse fast or improve damatically in minutes ... this is not a structural problem but a regulatory problem. Hormones or neurological signals are very likely involved.

I do think we will try what remedies are potentially available. I probably will myself. We do need to understand this more.

Cytokines and other complex interactive signal control networks are hard to figure out. Even the experts don't really understand them. Nobody should expect to get a great theoretical grasp. This is probably going to be more a case of suck it and see, though as was said at least now we have an idea of targets.
 

halcyon

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This is only one piece of the picture. It seems reasonable to expect that cytokine levels in the periphery and in the brain could be totally different. Perhaps cytokine levels in the brain are driven high initially but remain high even after the 3 year mark.
 

cigana

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I didn't see the reference in the paper about all cases being higher than controls, but presume this applies to IFN-gamma in short duration cases.

But according to my maths, the chances of any one cytokine being higher in cases than controls (assume for the 52 short duration, and compared with matched controls) are:
0.5^52 x 51=1 x 10^-14 - or one in 100,000 billion
Maybe someone could check my maths but it looks like Peter White's 'chance alone' comment is a little off.
White et al know full well how to exploit definition.
When they use a ridiculously broad umbrella definition and show that some respond to GET, then they are confident the result applies to everyone under the umbrella. When another researcher uses a better definition and shows that everyone displays some abnormality, then they are quite sure it could all have happened by chance!
Talk about double standards...
 

Sidereal

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IFNγ may accelerate degradation of tryptophan, resulting in depletion of the neurotransmitters serotonin and melatonin in the central nervous system through activation of indoleamine-2,3-dioxygenase, a rate-limiting enzyme in the kynurenine pathway. Activation of this pathway also results in increased levels of quinolinic acid, a neurotoxic compound that acts as an agonist at glutamatergic [NMDA (N-methyl-d-aspartate)] receptors (3032). Psychomotor changes, including cognitive problems (deficits of memory and attention) as well as affective disturbances, are correlated with changes in the kynurenine pathway in disorders ranging from Alzheimer’s disease (33) to major depression (34). We hypothesize that IFNγ-mediated lesions in kynurenine metabolism may culminate in the depression and psychomotor retardation that contribute to disability in some patients with ME/CFS (3436).
A key pathway in major depression but in ME/CFS? Hmm. I think this is a problem for many in the early phase of the illness when we feel viral and IFN gamma is high but in the chronic phase IFN gamma drops BELOW levels seen in normal controls.

I do appreciate that a subset of us have comorbid depression in the chronic phase of the illness so perhaps that accounts for some of the huge variance in the IFN gamma data (look at that confidence interval) but, for what it's worth, as my illness progressed, I have developed a constitutional inability to develop an actual depressive episode (= persistently low mood for at least 2 weeks) despite horrible disability/life circumstances which would make anyone depressed who still has a functioning immune system.

Of course, in order to be capable of becoming depressed you need a functioning acute phase response.

http://www.ncbi.nlm.nih.gov/pubmed/20015486

There is a reason why placebo response rates are enormous in depression trials and virtually zero in ME/CFS trials. Some have hypothesised that this is the mechanism of action by which placebo transiently dampens down inflammation and makes people feel better for a while. There is nothing to dampen down in long-term ME/CFS. Our CRP is already 0; our immune system crapped out long ago.

Anything serotonergic like 5-HTP is extra fatiguing (and elating) for me, no good at all. I know other people with mast cell activation issues who get really sick on serotonergic drugs. I haven't tried SSRIs but I expect I would respond horribly.

Psychomotor retardation by the way is more mediated by disruption of dopamine / basal ganglia than this stuff.

To my mind this study is quite useful in showing that the immune system is the wrong thing to focus on. We can't make energy normally. There is something wrong with the metabolism.
 

lansbergen

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To my mind this study is quite useful in showing that the immune system is the wrong thing to focus on. We can't make energy normally. There is something wrong with the metabolism.
I focused on the immune system and the immune modulator helped me a lot. The immune system is more than cytokine titers.
 

alex3619

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CD40L is decreased in short term patients and increased in long term patients.
Its worth noting that most or maybe all pathogenic triggers for ME, SEID, whatever, can target B cells. Maybe the early stage is marked by a B cell depletion from pathogenic assault? Or maybe the pathogens alter gene expression in infected cells?
 

Sean

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Are the cytokine changes causing symptoms, which appears unlikely, or in response to something else?
The results from this Lipkin study suggest that cytokine changes are secondary. I certainly can't recall there being any noticeable changes in my basic symptom profile around the 3 year mark.

It seems reasonable to expect that cytokine levels in the periphery and in the brain could be totally different.
I have long suspected that at least two physiological axes are worth investigating, via a range of different measures: the core-periphery axis, and the lateral axis (left-right).