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Cytokines in the Cerebrospinal Fluids of Patients with CFS/ME

A.B.

Senior Member
Messages
3,780
Cytokines in the Cerebrospinal Fluids of Patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis

Peterson D., Brenu E.W., Gottschalk G., Ramos S., Ngyuen T., Staines D., Marshall-Gradisnik S.

Objectives: Previous research has provided evidence for dysregulation in peripheral cytokines in patients with Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME). To date only one study has examined cytokines in cerebrospinal fluid (CSF) samples of CFS/ME patients. The purpose of this pilot study was to examine the role of cytokines in CSF of CFS/ME patients.

Methods: CSF was collected from 18 CFS/ME patients and 5 healthy controls. The CSF samples were examined for the expression of 27 cytokines [interleukin (IL)-1β, IL-1ra, IL-2, IL-4, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p70, IL-13, IL-15, IL-17, basic FGF, eotaxin, G-CSF, GM-CSF, IFN-γ, IP-10, MCP-1 (MCAF), MIP-1α, MIP-1β, PDGF-BB, RANTES, TNF-α and VEGF] using the bio-plex human cytokine 27-plex assay.

Results: Of the 27 cytokines examined, only IL-10 was significantly reduced in the CFS/ME patients in comparison to the controls.

Conclusions: This preliminary investigation suggests that perturbations in inflammatory cytokines in the CSF of CFS/ME patients may contribute to the neurological discrepancies observed in CFS/ME.
 
Last edited:

Scarecrow

Revolting Peasant
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Scotland
The other Hornig et al. paper due to be published soon is expected to show increased IL-10. This is a sample of 60, I think, and as with the plasma study, short and long-duration patients were subgrouped. However,
The spinal fluid, interestingly enough, showed a very different pattern. It showed a consistent profile of immunological dysregulation in CFS, regardless of duration of illness. Dr. Lipkin identified increased IL-10 and IL-13 levels suggesting enhanced Th2 activation and increased IL-1B, IL-5 and IL-17 suggesting Th1 (proinflammatory) activation. Dr. Lipkin was obviously intrigued by the differences in cytokine findings between spinal fluid and blood.
http://simmaronresearch.com/2013/09...markers-few-viruses-chronic-fatigue-syndrome/
 

August59

Daughters High School Graduation
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Location
Upstate SC, USA
This seems a little concerning to me that cytokine testing of CSF from 2 different labs has different results?

Could there be this much variance in testing methods? I've always been suspicious of the accuracy of many lab test (I'm referring to high throughput labs though!)

I suppose the selection criteria could have an impact? The Lipkin CSF study was divided into subsets?
 

nandixon

Senior Member
Messages
1,092
The other Hornig et al. paper due to be published soon is expected to show increased IL-10. This is a sample of 60, I think, and as with the plasma study, short and long-duration patients were subgrouped. However,


The authors of the paper in the original post mention a 2005 study that found increased IL-10 as well:
Only one study has reported changes in IL-10 in the CSF of CFS/ME patients, and these were increased [37]. This finding is in contrast to our present findings and this may be due to the heterogeneity of the disease, different analytical methods and the presence of divergent patient subgroups.

Reference 37 is here:
Spinal Fluid Abnormalities in Patients with Chronic Fatigue Syndrome

(Fukuda criteria was used for diagnosing CFS in both studies.)
 

Marky90

Science breeds knowledge, opinion breeds ignorance
Messages
1,253
Lol my doctor said you couldnt test for cytokines, and she has a research project on cytokines. Im confused. Is it correct that cytokines are understudied?

Very interesting papers btw.
 

Never Give Up

Collecting improvements, until there's a cure.
Messages
971
After seeing the Younger findings of intrapatient Leptin/cytokine/fatigue variability, one would think that every researcher would implement similar design strategies when looking at cytokines, they are transient little things, after all.
 

Jonathan Edwards

"Gibberish"
Messages
5,256
There are several things missing from this paper that make it difficult to interpret. We are not told how CSF was obtained from 5 healthy people (and why no more). We are not given any data on most of the cytokines and even for the IL-10 we are not give the p value as far as I can see. We are not told about statistical methods, like whether Bonferoni was used.

For me, interpretation of data like this starts when you have lots of comparator findings to give you a feel for the territory - as a pharmacologist would look for a dose response curve. A single data point is hard to make sense of. As I have mentioned before in the context of the Hornig/Lipkin study, I personally think histograms with error bars are a problem for making use of data like these. I think it should all be done with scatter plots so that we can see population overlap and bimodality and lots more.
 
Messages
7
Regarding sample size, may be its a pilot study.

Does anyone find connection with JNK interesting? Anybody using Xeljanz?
I ask this because from where I see it, even if you inhibit JNK, you would still need to upregulate IL-10, unless IL-10 levels and JNK levels work via a feedback loop. How one can do that? Hence, if anyone is using Xeljanz, one can very roughly extrapolate the idea into, just take Xeljanz or you need more than that.
 

Jon_Tradicionali

Alone & Wandering
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291
Location
Zogor-Ndreaj, Shkodër, Albania
Lipkins finding was right actually.

Increased il10 is a feature of CFS. It is a mediator of chronic viral infection and EBV, CMV and herpesviruses in general produce il10 mimicking proteins in order to promote chronic persistence. It is a very important part of CFS pathogenesis and one which could yield similar results to that of HepC and HCMV which were shown to be eliminated once it's mediators were inhibited. Il10 is the protein responsible for viral persistence and Tcell exhaustion, which has been shown time and time again in CFS patients. I've absolutely no idea why more focus has not been set on this protein considering it fits the bill in every way possible.
 

Jon_Tradicionali

Alone & Wandering
Messages
291
Location
Zogor-Ndreaj, Shkodër, Albania
But Lipkin and Peterson both found diminished IL-10?

"Dr. Lipkin identified increased IL-10"
http://simmaronresearch.com/2013/09...markers-few-viruses-chronic-fatigue-syndrome/

"IL-10 and IL-17A secretion was elevated at T2 in comparison to the T1 and T3"
http://mecfsassist.weebly.com/blog/...s-decreased-immune-function-in-mecfs-patients

"Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10"
http://niceguidelines.blogspot.co.uk/2011/05/immunological-abnormalities-as.html?m=1


A quick google search yields multiple study results of increased IL-10. Including studies by Lipkin, Peterson and others also.

Below is a model used to prove this:

"Elevated levels of systemic IL-10 have been associated with several chronic viral infections, including HCV, EBV, HCMV and LCMV. In the chronic LCMV infection model, both elevated IL-10 and enhanced infection of dendritic cells (DCs) are important for viral persistence.......
Collectively these data point to enhanced infection of DCs as a key trigger of the IL-10 induction cascade resulting in maintenance of elevated IL-10 expression in CD4 T cells and inhibition of LCMV-specific CD4 and CD8 T cell proliferation."

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0090855

To make things more interesting, rituximab depletes IL-10 producing B cells which explains remission and cessation of rituximab results in rapid repopulation of IL-10 producing B cells, which explains relapse.

The anti-cancer drug cyclophosphamide being trialed by Fluge/Mella also inhibits IL-10.

These two cancer drugs both inhibit iL-10 and produce remission in many patients. It is this exact mechanism that I propose produces the remission.
 

nandixon

Senior Member
Messages
1,092

That particular blog report turned out to be premature/incorrect, since when the study it's referring to was actually published, the level of IL-10 in cerebrospinal fluid was found to be low.

Here's the actual published study:
Cytokine network analysis of cerebrospinal fluid in myalgic encephalomyelitis/chronic fatigue syndrome

And there's a Phoenix Rising thread about it here:
CFI Spinal Fluid study from Lipkin and Hornig is out.
 

halcyon

Senior Member
Messages
2,482
I'm not sure what's up with that quote. You can see in the figures from the Lipkin CSF study that IL-10 was diminished compared to controls. I believe there weren't any significant IL-10 differences found in the blood study.

See above regarding the latest Peterson CSF study, "Results: Of the 27 cytokines examined, only IL-10 was significantly reduced in the CFS/ME patients in comparison to the controls."

"IL-10 and IL-17A secretion was elevated at T2 in comparison to the T1 and T3"
http://mecfsassist.weebly.com/blog/...s-decreased-immune-function-in-mecfs-patients
The increase in IL-10 secretion was following mitogenic stimulation. The next sentence states "A significant decrease was observed at T2 in the CFS/ME group for IL-10".

"Compared to healthy individuals, CFS/ME patients displayed significant increases in IL-10"
http://niceguidelines.blogspot.co.uk/2011/05/immunological-abnormalities-as.html?m=1
This study was also done by mitogenically stimulating PBMCs and then measuring the cytokine release. The Lipkin studies were just measuring systemic blood/CSF cytokine concentrations.
 

Jon_Tradicionali

Alone & Wandering
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291
Location
Zogor-Ndreaj, Shkodër, Albania
@nandixon

I was not aware Lipkin had retracted statements he had made during the CDC conference call.
It clearly states:

"However, they did find that patients had elevated levels of the TH-2 type cytokines IL-10 and IL-13 and elevated levels of four TH-1 cytokine: IL-1 beta, TNF-alpha, IL-5, and IL-17. Lipkin said this is compatible with a profile of some particular types of response that may provide insights into immunological dysregulation in Chronic Fatigue Syndrome."

http://phoenixrising.me/archives/19083

Original Transcript:
https://docs.google.com/file/d/0B-NT-7M70igudmZVSVJUTnZVclU/edit?pli=1

As for the Hornig study you linked, there is no mention of iL-10 at all. It was Petersons study which showed decreased iL-10.

The inconsistencies in iL-10 detection seem to stark and something I firmly believe deserves a deeper investigation.

@halcyon

Below is a statement by Natelson after iL-10 was found to be the only elevated cytokine in a study:

"Spotlight on IL-10…The fairly consistent finding of increased IL-10 levels in ME/CFS is interesting – no other cytokine is found to be upregulated as frequently. That finding (thankfully) fits with some other immune findings in ME/CFS. Interleukin-10, for instance, down-regulates several parts of the immune system ( Th1 cytokines, MHC class II antigens) that play a role in pathogen detection. Interestingly for the EBV theory of ME/CFS and questions of autoimmune problems IL-10 also enhances B cell survival, proliferation, and antibody production. It also appears to be an important immunoregulator in the intestinal tract. A study in mice has shown that interleukin-10 is also produced by mast cells. An NIH investigator is looking at whether mast cells play a role in CFS."

http://phoenixrising.me/archives/5223


Original study:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2849324/

As I noted above to Nadixon, iL-10 findings have been nothing short of varied from study to study. However there does seem to be a correlation of slight increase between majority of studies conducted on CFS iL-10.

One reason for this variation is provided here:

"Before exercise, CFS had lower CD40L (p<.05) but similar cytokines versus controls. In subgroups based on SF at 48 h, high SF patients (n=11) increased in IL-1β, IL-12, IL-6, IL-8, IL-10, and IL-13 (p<.05) 8 h post-ex. Low SF patients (n=8) showed post-ex decreases in IL-10, IL-13, and CD40L, and controls decreased in IL-10, CD40L, and TNFα (p<.05). Thus, in CFS, cytokine activity may vary directly with SF, which may explain prior inconsistent findings."

http://onlinelibrary.wiley.com/enhanced/doi/10.1111/j.1469-8986.2010.00978.x/

As can be seen from study above^ , cytokine findings depend on WHEN sample was taken and heavily dependant upon SF (Symptom Flare).

Test cytokines , especially iL-10, in subjects directly after excercice (which initiates symptom flare) and they will show to be quite clearly ELEVATED as this study shows.