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A comparison of sex-specific immune signatures in Gulf War illness and CFS

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Published:25 June 2013

A comparison of sex-specific immune signatures in Gulf War illness and chronic fatigue syndrome

Anne Liese Smylie, Gordon Broderick, Henrique Fernandes, Shirin Razdan, Zachary Barnes, Fanny Collado, Connie Sol, Mary Ann Fletcher and Nancy Klimas
Background

Though potentially linked to the basic physiology of stress response we still have no clear understanding of Gulf War Illness (GWI), a debilitating condition presenting complex immune, endocrine and neurological symptoms.

Here we compared male (n = 20) and female (n = 10) veterans with GWI separately against their healthy counterparts (n = 21 male, n = 9 female) as well as subjects with chronic fatigue syndrome/ myalgic encephalomyelitis (CFS/ME) (n = 12 male, n = 10 female).
Methods

Subjects were assessed using a Graded eXercise Test (GXT) with blood drawn prior to exercise, at peak effort (VO2 max) and 4-hours post exercise.

Using chemiluminescent imaging we measured the concentrations of IL-1a, 1b, 2, 4, 5, 6, 8, 10, 12 (p70), 13, 15, 17 and 23, IFNgamma, TNFalpha and TNFbeta in plasma samples from each phase of exercise. Linear classification models were constructed using stepwise variable selection to identify cytokine co-expression patterns characteristic of each subject group.

Results

Classification accuracies in excess of 80% were obtained using between 2 and 5 cytokine markers.
Common to both GWI and CFS, IL-10 and IL-23 expression contributed in an illness and time-dependent manner, accompanied in male subjects by NK and Th1 markers IL-12, IL-15, IL-2 and IFNgamma.

In female GWI and CFS subjects IL-10 was again identified as a delineator but this time in the context of IL-17 and Th2 markers IL-4 and IL-5.

Exercise response also differed between sexes: male GWI subjects presented characteristic cytokine signatures at rest but not at peak effort whereas the opposite was true for female subjects.

Conclusions

Though individual markers varied, results collectively supported involvement of the IL-23/Th17/IL-17 axis in the delineation of GWI and CFS in a sex-specific way.

The complete article is available as a provisional PDF. The fully formatted PDF and HTML versions are in production.

I might be wrong - couldn't see it - but haven't we been discussing this somewhere else? Thanks :)
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
We still have no clear understanding of Gulf War Syndrome (GWS), also called Gulf War Illness (GWI), although evidence is mounting of immunological dysfunction in this population that may be potentiated by response to stress whether psychological, chemical or other. Indeed clinical presentation of GWS overlaps strongly with that of another stress-
mediated illness: Chronic Fatigue Syndrome/myalgic encephalomyelitis (CFS/ME) [4,5].
Dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis has been linked to the pathophysiology of GWI [6-8] and CFS [9]. Associated pathophysiology includes hypersensitivity of normal cytokine feedback to the HPA axis [10] as well as the expected stress-induced release of neuropeptides such as NPY and its mediation of innate immune response and cortisol levels [11].

From the main paper (link above at bottom of abstract). I noticed that Broderick is on this paper - so are we saying that CFS is a 'stress-mediated' condition now then? I mean is this were we are still heading - the interpretation. After all these years, that 'stress' responses are still in the main running for an explanation. Am not entirely naive of course - I realise that this is indeed in the running - but you don't often come across such a 'neat' summation. And of course 'stress responses' are responses to infections as well as responses to being unable to recover from that infection. It was just something that immediately stood out for me. Anyway, back to the paper....
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
I dare say folk might want to discuss the 'exercise challenge':

Exercise challenge
Immune response was stimulated with a standard Graded eXercise Test (GXT) using a Vmax
Spectra 29c Cardiopulmonary Exercise Testing Instrument, Sensor-Medics Ergoline 800 fully
automated cycle ergometer, and SensorMedics Marquette MAX 1 Sress ECG. According to
the McArdle protocol [35] subjects pedaled at an initial output of 60 watts for 2 minutes, followed by an increase of 30 watts every 2 minutes until the subject reached: 1) a plateau in maximal oxygen consumption (VO2); 2) a respiratory exchange ratio >1.15; or 3) the subject stopped the test. A first blood draw was conducted prior to exercise following a 30-minuterest. Second and third blood draws were conducted upon reaching peak effort (VO2 max) and at 4-hours post exercise respectively.
Summary statistics describing the exercise capacity in terms of the weight-adjusted maximum VO2 measured in L/min/kg are presented for each group in Additional file 1: Table S1. Results indicate a decline in the average maximum VO2 achievable with healthy controls performing best and CFS subjects faring the worst. This trend achieved statistical significance in the male subjects (p = 0.04) with healthy male subjects performing better than both illness groups. In light of this finding we suggest that results presented here be interpreted as immune response at maximum perceived exertion but not necessarily at equivalent exercise intensity.
We consider reduced exercise capacity to be another symptom of GWI and CFS. The characteristic immune response patterns measured at maximum perceived exertion capture this implicitly as well as a host of other more discriminating features of both illnesses.

Hmm... I wonder if PEM is another characteristic of both illnesses...
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Reading the results, let me see if I have this right.

In the Healthy Controls - cytokine expression rose across all time points - i.e. rest and during and after exercise - for females; but not for males (at least not of statistical significance).

That's interesting, in and of itself, don't you think? Leads me to wonder why.... but I don't suppose we need to go there.

Will keep reading. Need a rest now though :)
 
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15,786
I noticed that Broderick is on this paper - so are we saying that CFS is a 'stress-mediated' condition now then? I mean is this were we are still heading - the interpretation. After all these years, that 'stress' responses are still in the main running for an explanation.
I think every ailment is going to involve a "stress response" (presumably they mean a biological one) - to the infection, or the physical trauma, or the immune dysfunction. Stress response is starting to smell like one of those terms that doesn't mean a damn thing, except maybe "something's wrong" and/or "we don't know".
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
From a biologist's point of view, a stressor is something that purturbs a biological system, so a stress response is a change in a biological system. The vague definition of stress in most places confuses the issue. How if they are talking HPA dysregulation then they should say that and not call it a stress response, and similarly for other specific stressors and biological perturbations. The term "stress response" is starting to smell like a dead rat to me too, and I hated dissecting rats at uni.
 

Marco

Grrrrrrr!
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2,386
Location
Near Cognac, France
Hi Firestorm

Its all a bit of a mess really isn't it?

Actually the standout point for me was this from the review of immune findings :

Furthermore Carlo-Stella et al. (2006) [19] investigated cytokine gene polymorphisms and found significant differences in TNFα and IFNγ genotypes in CFS subjects suggesting that they might be genetically predisposed to differences in inflammatory response.

From my latest 'blog' :

The work of Julia Newton’s team at Newcastle university examining fatigue and autonomic dysfunction in ME/CFS and the autoimmune disease primary biliary cirrhosis has been discussed here recently.

Regarding fatigue in primary biliary cirrhosis Medscape states :

“The etiology of fatigue is unclear; although some evidence suggests that abnormalities of the hypothalamic-pituitary-adrenal axis, decreased release of serotonin, and increased production of proinflammatory cytokines (ie, interleukin-1 [IL-1], interleukin-6 [IL-6], tumor necrosis factor-α [TNF-α] ) may be responsible.”

Medscape

Intriguingly, a just published paper (Raszeja-Wyszomirska et al, 2013) reports the association between polymorphisms in TRAF1-C5 – a gene regulating TNF-a with ‘sickness behaviour’ – fatigue, mental and physical function and mood in patients with primary biliary cirrhosis. This finding appears to parallel increased polymorphisms in a TNF-a promoter gene in ME/CFS patients (Carlo-Stella et al, 2006) which led the researchers to comment :

“We hypothesize that CFS patients can have a genetic predisposition to an immunomodulatory response of an inflammatory nature probably secondary to one or more environmental insults of unknown nature.”

Read more: The Immune System and Neuroinflammation: Part IV of the Neuroinflammatory Series in ME/CFS Continues http://www.cortjohnson.org/blog/201...t-v-of-the-neuroinflammatory-series-in-mecfs/

You're quite chummy with Julia Newton? Think she'd be interested?
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Hi Firestorm

Its all a bit of a mess really isn't it?

Actually the standout point for me was this from the review of immune findings :



From my latest 'blog' :



You're quite chummy with Julia Newton? Think she'd be interested?

I might like the lady, Marco, but never met her or talked to her, my friend. Give it whirl I'm sure she'd take a look. Seems very receptive to me. Was an interesting blog you wrote. I just got it in my inbox. Thanks :)
 

Marco

Grrrrrrr!
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2,386
Location
Near Cognac, France
I might like the lady, Marco, but never met her or talked to her, my friend. Give it whirl I'm sure she'd take a look. Seems very receptive to me. Was an interesting blog you wrote. I just got it in my inbox. Thanks :)


I know you have particular sense of humour and I was just playing on your frequent use of the first names of researchers.

Just a little fun.

Glad you 'liked' the blog - but please read it in context of the series if you haven't already.

Cheers
 

SOC

Senior Member
Messages
7,849
I'm glad to see research actively looking at more than simple single point data under nonstressed (meaning without a change or challenge to the system) conditions. The human body is a sophisticated dynamic system with unbelievably complex control systems helping it adjust to change. My husband and I (engineers that we are) have been saying for years that ME/CFS is a control system problem -- we get an infection and our bodies under-react (or over-react); we change position and our bodies don't adjust vasoconstriction and BP properly; we go out in the heat and our bodies don't adapt correctly; we exercise and all hell breaks loose. It's not the condition, it's the change our bodies are not handling well.
 

Firestormm

Senior Member
Messages
5,055
Location
Cornwall England
Reading the results, let me see if I have this right.

In the Healthy Controls - cytokine expression rose across all time points - i.e. rest and during and after exercise - for females; but not for males (at least not of statistical significance).

That's interesting, in and of itself, don't you think? Leads me to wonder why.... but I don't suppose we need to go there.

Will keep reading. Need a rest now though :)

Must get back to this today. I was pondering the above, and read I think on Marco's blog that estrogen might have something to do with this greater expression in females. Will have to read his blog more carefully...
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
I'd rather they used the term 'challenge' than stress-test, but don't much mind what they call it, so long as they test patients in the context of physical or mental exertion, rather than at rest.

This is unconvincing:

Results indicate a decline in the average maximum VO2 achievable with healthy controls performing best and CFS subjects faring the worst. This trend achieved statistical significance in the male subjects (p = 0.04) with healthy male subjects performing better than both illness groups
What they mean by 'trend' is that there wasn't a significant difference between patients as a whole and controls. There was among men, though only at p=0.04. Not sure how well patients and controls were matched on activity/deconditioning levels? These are very small samples and I wonder how well they will replicate

Chris Snell's work found no sig difference between CFS patients and controls at the first exercise test (and his latest, soon-to-be published work presented at the FDA workshop found no difference in peak output at the second test either).

Overall, these are very small samples and a '>80%' classification accuracy isn't very impressive (>90% might be), especially as that's specific to this small sample and there's a real danger of 'overfitting' the classification model to this particular set of subjects. Until it's been replicated on an independent sample, it doesn't mean that much, and I like to think the authors say as much in the full paper and are planning a replication.
 

Bob

Senior Member
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16,455
Location
England (south coast)
Chris Snell's work found no sig difference between CFS patients and controls at the first exercise test (and his latest, soon-to-be published work presented at the FDA workshop found no difference in peak output at the second test either).

Have I misunderstood something here, Simon? I thought that Chris Snell was a proponent of the two day VO2 max test for ME patients? Are you saying otherwise?
 

alex3619

Senior Member
Messages
13,810
Location
Logan, Queensland, Australia
I'm glad to see research actively looking at more than simple single point data under nonstressed (meaning without a change or challenge to the system) conditions. The human body is a sophisticated dynamic system with unbelievably complex control systems helping it adjust to change. My husband and I (engineers that we are) have been saying for years that ME/CFS is a control system problem -- we get an infection and our bodies under-react (or over-react); we change position and our bodies don't adjust vasoconstriction and BP properly; we go out in the heat and our bodies don't adapt correctly; we exercise and all hell breaks loose. It's not the condition, it's the change our bodies are not handling well.

Exactly SOC, the nervous system, hormones and immune system are all regulatory systems - all control systems.
 

Simon

Senior Member
Messages
3,789
Location
Monmouth, UK
Have I misunderstood something here, Simon? I thought that Chris Snell was a proponent of the two day VO2 max test for ME patients? Are you saying otherwise?
He is saying otherwise, check out his talk at the FDA, the key slide is near the end.

Or rather what he is now saying is no difference in V02max (the original finding was based on n=6!), though he now finds a decrease in efficiency in at the anaerobic threshold. This could be very interesting, on the other hand it really needs replicating given that the VO2max claim didn't hold up. We should learn a lot more when the paper comes out.
 

Bob

Senior Member
Messages
16,455
Location
England (south coast)
He is saying otherwise, check out his talk at the FDA, the key slide is near the end.

Or rather what he is now saying is no difference in V02max (the original finding was based on n=6!), though he now finds a decrease in efficiency in at the anaerobic threshold. This could be very interesting, on the other hand it really needs replicating given that the VO2max claim didn't hold up. We should learn a lot more when the paper comes out.

Thanks for that Simon. That's interesting because many ME advocates are heavily promoting the two-day VO2 max test as a definitive biomarker test. I had assumed that there was good evidence behind it. I'll have to have a closer look at it. Thanks for the pointers towards Snell's presentation.