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Cytokines: Explaining what they are and how they might relate to ME/CFS

Discussion in 'Phoenix Rising Articles' started by Phoenix Rising Team, Jan 20, 2014.

  1. Phoenix Rising Team

    Phoenix Rising Team

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    Andrew Gladman takes a brief look at what cytokines are and how they might relate to our disease - exploring some of the research that is indicating their involvement in disease pathways...

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    Interferon Alpha By Nevit Dilmen
    [GFDL or CC-BY-SA-3.0]
    Wikimedia Commons

    In recent years ME/CFS research has turned the spotlight on several areas, such as autoimmunity, the cardiovascular system and the autonomic nervous system.

    While it is fair to say that much remains unknown about their function and behaviour, cytokines have a role to play in all these areas and they are being talked about with increasing regularity.

    What are cytokines?

    The term 'cytokine' encompasses quite a few diverse families of proteins, peptides and glycoproteins which are secreted primarily by the different cells of the immune system. However, there are many other cells that release cytokines and that then trigger an immune response.

    They act as signalling molecules between cells and fundamentally regulate the hosts' immune response primarily to infection, inflammation and trauma – and for this reason they are often described as immunomodulating agents.

    Once secreted by the cell, cytokines can function in one of two ways. The first, known as autocrine, means that the cytokine binds to a receptor on the cell surface of the same cell secreting the cytokine, triggering further responses within that cell. The second, known as paracrine, is when the secreted cytokine binds to a receptor on the cell membrane of an adjacent cell triggering further responses within that cell.

    Types of cytokine

    There is still a dispute between biochemists as to what does and does not constitute a cytokine. The following list encompasses quite well the accepted family groups, but whilst these titles are now partly redundant, many of the terms are still commonly used. It should be noted that these classifications are non-exclusive - meaning that a cytokine, for example interlukin 2, can be classed both as an interlukin and a lymphokine:

    Interlukins: Initially this term referred to signalling molecules which were primarily targeted towards leukocytes, however many newly discovered cytokines are given this name regardless of targeted cell. This family are for the most part produced by Helper T-cells.

    Lymphokines: Produced almost exclusively by lymphocytes, they often aid B-cells in producing antibodies.

    Monokines: Produced almost exclusively by Monocytes such as macrophages. Many monokines are also classed as chemokines.

    Interferons: Primarily involved in antiviral immune responses, but they can also be secreted in response to a bacterial or parasitic infection and furthermore can help fight tumours.

    Chemokines: Mediate the movement of many cells involved in the immune response (chemotaxis). This is important to ensure cells of the immune system migrate to the area of the infection.

    Fundamentally, studying cytokine levels in sick people gives us a snapshot into the functional status of that patient's immune system at a given point in time.

    The study of cytokines has consistently helped in the differentiation of pathogenic and autoimmune based diseases, for example, but this is only possible by understanding a little more of the specific function that certain cytokines exhibit and imagining how these cytokines react with cells to produce changes that can be observed on an organism level.

    Function of cytokines…

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    The left branch represents the cells of the adaptive immune response which involves B and T cells. This diagram shows many of the cells discussed later in this article in relation to what produces which cytokine.

    The most important part of a cytokine is not in the binding that it makes to a cell (as briefly described above), but the changes that it has the ability to cause within that cell.

    It is worth remembering that even the more in-depth explanation of the effects many of the more common cytokines can have is still something of an oversimplification.

    In truth, cytokines are still at the forefront of much research to discover their numerous functions and the different effects they can induce in different cells.

    One common misconception I must address at this point is the notion that the presence or finding of cytokines automatically means there is inflammation present.

    While this may be true in many instances, certain pro-inflammatory cytokines, for example, can in fact can also exhibit anti-inflammatory properties.

    To save space, I have attached a non-exhaustive list that I hope you might find helpful. It details the common function of those cytokines you are likely to encounter in research papers and articles.

    It may be worth referring to this list when I now begin to discuss specific cytokine findings in relation to CFS/ME research. But do note that there are many functions of cytokines we still do not yet fully understand.

    CFS/ME researchers whose work has indicated key cytokine involvement

    Professor Ian Lipkin

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    Professor Ian Lipkin

    Lipkin revealed in a CDC telephone broadcast in September 2013, a range of findings that may relate to the immune profile of ME/CFS patients. Simon covered these exciting developments in his Phoenix Rising article and transcript: Lipkin finds biomarkers not bugs.

    While the main purpose of the study was to determine is there was any consistent viral or bacterial agents to be found, it also involved a more extensive examination of cytokine profiles and it is here that the potential biomarkers were discovered.

    The main finding was the emergence of two possible subsets within the patient cohort, differentiated by the duration of illness. In those ill for less than three years the disease profile seemed to lean more towards an allergy type response – with increased number of eosinophils.

    And, whilst cytokine findings are often very difficult to interpret, Lipkin expressed confidence in the additional finding of a consistent up-regulation in the production of Interlukin 17 within this same subset (IL17 is produced by T-helper cells and has a pro-inflammatory effect while recruiting further neutrophils).

    The second subset identified were those who have been ill for a more prolonged period of time. In this group it appears that the ‘allergy’ aspect of the disease had run its course and was replaced by a chronic immune dysregulation phase.

    The key findings in this second group were decreases in the serum levels of Interleukin’s 17, 2, 8 and also in TNF-alpha. Inteterlukin 2 is produced by a vast array of cells and has a stimulating effect upon T, B and NK cells; and if the findings outlined in this research hold true, then it is clear to see that a down-regulation in the levels of IL-2 could have a negative effect upon the immune response of a patient.

    Interlukin 8 is also produced by quite a large variety of cells and acts as a chemokine, aiding in the recruitment of neutrophils. A down-regulation in Il-8 is also therefore going to have a negative impact upon the immune competency of a patient.

    But perhaps the most interesting finding for me was the observed down-regulation of TNF-Alpha. TNF-A is known universally as a strongly pro-inflammatory cytokine, and finding it to be decreased is therefore quite odd - if we were to assume ME/CFS is an inflammatory disease. Though it is worth noting that TNF-A has many other functions aside from stimulating inflammation, including activation of the endothelium and also inducing the release of other cytokines.

    As with all research, this data would need to be replicated before being considered reliable, thought there do appear to be several promising and very unexpected leads among the preliminary revelations. It’s clear that such cytokine findings in the absence of any infectious agent point quite strongly towards an ongoing process of disruption involving the immune system.

    Perhaps autoimmunity will be more clearly linked to ME/CFS in the future, and this apparent change over time in cytokine activity could be an indicator of this: it is well known that many diseases such as Lupus and Multiple Sclerosis change over time, with disease activity often flaring and remitting quite unpredictably and causing disruption to functional ability. I speculate, but maybe what we are seeing here is the first observation of such a process in our own condition?

    Dr Nancy Klimas

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    Dr. Nancy Klimas

    There have been many studies exploring cytokine levels within CFS/ME but one such study that I wanted to highlight, came from Klimas and focused upon the plasma cytokine levels of female patients.

    The interesting aspect of this study for me, was the wide array of cytokines studied, some 16 in total, but the downside was the sample size. While 40 patients may seem adequate, much larger samples are really now required for research into CFS/ME to better gain wider acceptance.

    However, Klimas found numerous cytokines were elevated, including interlukins 1, 4, 5, 6 and 12. Interlukin 1 is pro-inflammatory and stimulates endothelial activation. This might be seen as something of a challenge to the results talked about above, where TNF-A was found to be down-regulated - TNF-A also stimulates endothelial activation – but perhaps this likely indicates a greater degree of cytokine dysfunction.

    Interlukin 5 interestingly recruits eosinophils, as discussed above, where it appeared that eosinophils might play a larger role during the initial illness period and then decrease their involvement over time – unfortunately we do not know the illness duration for patients from the Klimas study.

    Interlukin 5 also stimulates an isotype switch to IgA and Interlukin 4 also stimulates an isotype switch, but to IgE. With the two isotype switching cytokines acting in opposition to one another it would also indicate dysregulation of the immune system.

    Three cytokines in this patient sample were found to be decreased: Interlukins 8, 13 and 15. Interlukin 8 was also found to be down-regulated by the Lipkin study, this is therefore a reasonably promising finding and deserves further investigation.

    Interlukin 13 functions primarily as an anti-parasitic agent, but it also stimulates another isotype switch to IgE, and this additional down-regulation adds to the evidence of immune system irregularity. And finally, Interlukin 15 stimulates NK cell and cytotoxic T-cell proliferation also dampening down immune system activity.

    Contradictory to the Lipkin studies preliminary announcement above, the Kilmas study found TNF-A to be at normal levels. However, and whilst we await publication of the Lipkin paper (due by the end of March 2014 it is believed), given the sample sizes of each study, the Lipkin results appear to show greater reliability.

    Conclusion…

    From the evidence presented, it is clear that there is much to be learnt about the disease process of ME/CFS from cytokine findings alone. The vast array of dysfunction and dysregulation strongly imply an ongoing process, one that is likely self perpetuating.

    As discussed in relation to the work of Professor Lipkin, there has never been a universally acknowledged infectious cause of ME/CFS, and the numerous infectious agents in patients might appear to be a product of the dampened immune response rather than a causative problem.

    We therefore have to look beyond an infectious cause and perhaps consider a self perpetuating autoimmune process. Other autoimmune diseases such as Lupus have similar cytokine profiles to those outlined in this article - there is however still a wide degree of variation even within a well defined disease such as Lupus.

    In Lupus patients with significant thrombocytopenia of the skin, TNF-Alpha is often measurably increased relative to the normal range, whereas in Lupus patients with significant lymphandeopathy or nervous system involvement, often TNF-Alpha serum levels are within normal range. Demonstrating the difficultly cytokines can present even within a single, well-defined disease such as Lupus. It is therefore easier to acknowledge the challenge such findings present to researchers.

    While cytokine findings are an important piece of the greater ME/CFS puzzle, it must be remembered that they are only that. Cytokines have a tendency to fluctuate wildly from one day to another, even in otherwise healthy patients.

    They are also prone to changing prior to the symptomatic onset of an infection – therefore in a small sample size, a simple cold in 2 or 3 patients can drastically change the results of a study. Having said all this, the findings from the two pieces of research I have chosen to feature, should not I think be understated. They present firm evidence of an immunological problem in ME/CFS patients and provide new roads and avenues for further exploration and research.

    If replicated and proved consistent, not only do these abnormalities have the potential to prove a useful bio-marker, they also go some way to aiding our understanding of the disease mechanism at the heart of the disease and perhaps even aiding in the development of treatments in the future.


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  2. teefy

    teefy

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    "The vast array of dysfunction and dysregulation strongly imply an ongoing process, one that is likely self perpetuating".

    Self perpetuating - exactly.

    An initiating trigger event, either sudden or cumulative, disrupts the hypothalmic-pituitary-adrenal axis, creating a dysfunctional state of excitation.

    Over-stimulation of parts of the immune system (the allergy-like response), in combination with hormonal irregularities, creates oxidative stress and cellular damage, including damage to mitochondrial cells.

    These effects lead to a wide range of symptoms varying according to individual susceptibilities and onset conditions, but will always include fatigue and a degree of multi-systemic poor functioning and, especially in long-term patients, impairment of other parts of the immune system, which weaken the body's capacity to constrict latent pathogens, which can then become reactivated.

    The combinatory effects of reactivated pathogens and multi-systemic vulnerabilities serve to prevent the HPA axis from returning to it's pre-initiating state of equilibrium, perpetuating the dysfunctional state, and alongside amplification from dysfunctional responses to new inputs like stress, exertion, new viruses, etc, a resultant condition of self-perpetuating feedback becomes established: a state of autocatalysis.
    Legendrew likes this.
  3. WNM

    WNM

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    Nice review of cytokines Andrew. I would only suggest that you cover more that just 2 studies on cytokines in ME/CFS. There have been so many studies, with so many different findings, that it is very easy to cherry pick and support any bias. However all need to be considered to reach an objective view.

    http://www.ncbi.nlm.nih.gov/pubmed?term=((((chronic%20fatigue%20syndrome)%20OR%20myalgic%20encephalomyelitis)%20NOT%20depression)%20AND%20cytokine)%20AND%20immune

    For instance a common view in the literature atm supported by research from several different groups is that a subgroup of patients have elevated pro-inflammatory cytokines in blood. The Maes team have further correlated this with immune responses to LPS (i.e. gut bacterial translocation). Notably a subgroup of patients may also have slightly increased CRP. Interestingly there is also new evidence that the Treg/IL-10 anti-inflammatory response is up-regulated in ME/CFS, and perhaps simultaneously with pro-inflammatory markers. This is of notable contrast to most auto-immune disorders but has recently been found to occur during ageing, and is perhaps consistent with a compensatory response to chronic inflammation.
  4. Simon

    Simon

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    Thanks, Andrew
    I think that's a very important point. Rheumatoid Arthritis is another case like Lupus, with a clear role for TNF-alpha yet still they have problems detecting consistent changes - even measuing cytokines in joint fluid rarther than blood. Studying cytokines is very hard indeed.
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  5. WNM

    WNM

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    Currently most cytokine studies are limited in their scope. Until you study cytokines at a network level you can't get an idea of the overall immune response. For this reason the Klimas study discussed by Andrew is good. And they have taken it further in what I think this is one of the best cytokine studies in ME/CFS so far:

    http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2939140/
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  6. Legendrew

    Legendrew Content team

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    Yes, I wish I could have included a few more of the papers revolving around cytokines and ME but felt that going into depth on too many papers might get a little long-winded so decided instead to focus on two of the most rigorous studies; Lipkin's having the largest cohort and the Klimas' study having the best breath of cytokines.

    I'm not sure what to make of the subgroup you discuss with pro-inflammatory cytokines related to LPS. It's always so difficult given the subgroups each paper seems to find, my default position is that this sounds to be something of an after effect of the ongoing immune dysregulation but as with everything it warrants further investigation. I've never heard of elevated CRP in ME patients and this is something I personally have never had during my own illness. The idea of T-reg/IL-10 up-regulation being a response to a chronic inflammatory state makes logical sense however much of the research I've read has been relating to the absence of standard inflammation within the ME cohort.
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  7. WNM

    WNM

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    I agree, proper inflammation as assessed by typical markers (e.g. ESR, CRP and calprotectin) does not appear to commonly occur in ME/CFS. Instead there is only evidence for mild inflammation, and perhaps only in a subset of patients. Certainly when you compare the cytokine elevations occurring in infections (e.g. from influenza to bacteria sepsis) they are mild in ME/CFS; although could be higher in specific organs. CRP may also only be mildly elevated in ME/CFS as reported in 4 studies, whilst others find no difference. Note. the normal range for inflammatory markers is quite wide. The correlation between blood immune responses to LPS and inflammatory/immune markers (e.g. cytokines, elastase, etc) reported by Maes et al seems logical given the well-characterised immunogenic potential of LPS.

    I think there are many subgroups within ME/CFS. These can be better defined by studies which correlate biological markers with one another and symptoms. For instance cytokine patterns in ME/CFS have been correlated with exercise-induced symptom far, bacterial translocation (i.e. blood LPS), IBS and sudden illness onset.
  8. Valentijn

    Valentijn Activity Level: 3

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    My ESR has been constantly elevated since I got sick. CRP was elevated once when tested about 6 months ago, but not a couple months ago. I also get visible swelling, especially if I eat the wrong foods, which can be helpful when dealing with doctors :p
  9. liverock

    liverock Senior Member

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    Interesting article in this months LEF magazine 'Turn Off The Cytokine Switch' and the effect of mung beans and green tea.

    http://www.lef.org/magazine/mag2014/jan2014_Turn-Off-the-Cytokine-Switch_01.htm
  10. There are over 60,000 known cytokines and counting! To make a claim of discovery based on 16 of them is stretching it a bit I'd say.

    Dr. Horst has been cataloging them for years. Here is his site which is a truly amazing piece of work!

    http://www.copewithcytokines.org/cope.cgi
  11. lansbergen

    lansbergen Senior Member

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    I agree

    If he can not get enough money to keep it up, it will stop
  12. Legendrew

    Legendrew Content team

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    Looks interesting, don't forgot however that there is great debate as to what constitutes a cytokine. Furthermore there are certain cytokines we don't understand whatsoever currently so studying them in a patient group is pretty pointless if we wish to learn more about the disease. Searching for and documenting changes from the normal for 20 well known and understood cytokines will likely teach us a lot more than searching for 60000 cytokines just because there are that many.
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  13. user9876

    user9876 Senior Member

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    There is a drug called g-csf which promotes the growth of granulocytes including neutrophils. I believe it does causes raised IL17 but I'm not sure. It can produce flu like symptoms including joint aches and a mild fever (in healthy people, its used to stimulate cell growth in granulocyte and bone marrow donors). It also has an effect on the stem cells in the bone marrow making them easier to kill off during chemo therapy.
  14. user9876

    user9876 Senior Member

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    One question is how cytokines are detected and classified. Could it be that there are antibodies that react with something else that bind to cell receptors as if they were cytokines? Would such things be detected?
  15. Legendrew

    Legendrew Content team

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    This is a good question, the trouble we face is that the vast majority of biological interactions aren't as simple as a chemical messenger binding to a receptor causing a response. Often the process is a cascade of interactions between different proteins binding together to stimulate a response through the receptor. The story doesn't even stop there as once the receptor is bound to this often causes a conformational change within a cellular protein triggering a further cascade of responses within the cell. Obviously with such complex cascade reactions any problem at any point will result in the entire ensemble not working as intended - it then becomes a difficult task of working out where the problem lies. I think I've described it previously as a river drying up, you have to carefully work back from the result to find the dam.
  16. aimossy

    aimossy Senior Member

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    Thanks Andrew!
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