Infection -> Epigenetic Change -> Systemic Inflammation = ME/CFS

Belbyr

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https://link.springer.com/article/1...VsU0eTcVqUKOJTBzkj1n6_F8K-pVrB9hpnJKG8A#Sec23

"In this paper, it has been shown that, while the aetiology of CFS/ME is currently unknown, there is strong evidence of this illness being associated with a wide range of biological abnormalities, most notably in the neuroendocrine, autonomic, neurological, bioenergetic, redox and immunological domains. It has also been seen that epigenetic variation in immune response genes plays a major role in determining the development of DAMPs post-infection, which is pertinent from the perspective of the aetiology of the illness as the production or presence of these molecules can ‘convert’ an acute pathogenic infection into a state of escalating chronic systemic inflammation, which in turn can give rise to many of the reported symptoms and biological abnormalities."
 

ljimbo423

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Really interesting review. Here is the abstract-

Abstract
A model of the development and progression of chronic fatigue syndrome (myalgic encephalomyelitis), the aetiology of which is currently unknown, is put forward, starting with a consideration of the post-infection role of damage-associated molecular patterns and the development of chronic inflammatory, oxidative and nitrosative stress in genetically predisposed individuals.

The consequences are detailed, including the role of increased intestinal permeability and the translocation of commensal antigens into the circulation, and the development of dysautonomia, neuroinflammation, and neurocognitive and neuroimaging abnormalities.

Increasing levels of such stress and the switch to immune and metabolic downregulation are detailed next in relation to the advent of hypernitrosylation, impaired mitochondrial performance, immune suppression, cellular hibernation, endotoxin tolerance and sirtuin 1 activation.

The role of chronic stress and the development of endotoxin tolerance via indoleamine 2,3-dioxygenase upregulation and the characteristics of neutrophils, monocytes, macrophages and T cells, including regulatory T cells, in endotoxin tolerance are detailed next.

Finally, it is shown how the immune and metabolic abnormalities of chronic fatigue syndrome can be explained by endotoxin tolerance, thus completing the model.
 

ljimbo423

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There is also a detailed write up on how they think the IDO pathway Robert Phair is researching becomes up-regulated-

I&ONS and the development of endotoxin tolerance via IDO upregulation

Chronic I&ONS can also provoke the development of endotoxin tolerance by inducing the transcriptional activation of IDO (Kim et al. 2015c; Wichers and Maes 2004) leading to upregulation of the kynurenine pathway, aryl hydrocarbon receptor (AhR) activity and increased levels of TGF-β1 (Bessede et al. 2014; Wirthgen and Hoeflich 2015) and IL-10 (Alexeev et al. 2016; Lanis et al. 2017) via well documented mechanisms (reviewed (Wirthgen and Hoeflich 2015)).


The upregulation of AhR activity is of interest given data presented in the previous section as increased activity of this cytosolic transcription factor leads to upregulation of RelB and non-canonical NF-κB signalling (Salazar et al. 2017; Vogel et al. 2013). Mechanistically, these effects appear to be mediated by transcriptional upregulation of RelB (de Souza et al. 2014;

Thatcher et al. 2007) and subsequent physical engagement between RelB and AhR to produce dimers capable of modulating the expression of NF-κB-sensitive genes (Vogel et al. 2008). AhR-upregulated RelB also stimulates and maintains the transcription of miR-146a (Zago et al. 2014, 2017).

This is of importance as miR-146a is a dominant player in the development and maintenance of the hypo-inflammatory environment characteristic of endotoxin tolerance (Banerjee et al. 2013; Nahid et al. 2009).

Mechanistically, this inhibitory effect is enabled by suppressing TLR signalling pathways by reducing the translation of TNF receptor associated factor 6 (TRAF6), interleukin-1 receptor-associated kinase 1 (IRAK1), IRAK2 and interferon regulatory factor 3 (IRF3), which are positive adaptor kinases of MyD88-mediated signalling and hence their inactivation results in reduced activity of both NF-κB and IRF3 (Nahid et al. 2011) (reviewed (Testa et al. 2017)).


The upregulation of TGF-β1 also results in upregulated non-canonical NF-κB signalling (Pallotta et al. 2011; Shi and Massague 2003). Increased activation of this cytokine also upregulates pseudokinase IRAK-M (Pan et al. 2010; Srivastav et al. 2015; Standiford et al. 2011). This is significant because IRAK-M would appear to be the ‘master regulator’ of the TLR pathway suppression characteristic of the state of endotoxin tolerance in PMBCs (del Fresno et al. 2007; Escoll et al. 2003; Stiehm et al. 2013; van’t Veer et al. 2007; Wiersinga et al. 2009).

Indeed, the weight of evidence suggests that increased activity of this enzyme alone is sufficient to maintain an LPS-induced hypo-inflammatory state in human macrophages and monocytes (van’t Veer et al. 2007). This is unsurprising given that this molecule can inhibit TLR signalling at multiple levels. TGF-β1 has been established as an indispensable element in the development of endotoxin tolerance-associated SHIP upregulation (Sly et al. 2004; Yang et al. 2015).

This may be of particular relevance from the perspective of a putative explanatory model of CFS aetiology as elevated levels of this cytokine in PMBCs and whole blood are a common finding in patients diagnosed according to narrow international consensus criteria and correlate with the severity of a range of symptoms (Blundell et al. 2015; Wyller et al. 2017). Once again, it is noteworthy that this phenomenon is not observed in patients diagnosed according to broader schema which are not internationally recognised such as the ‘alternative CDC criteria’ (Clark et al. 2017).


Upregulated IL-10 also exerts negative effects on TLR signalling by increasing the ubiquination and proteasome-mediated degradation of a range of MyD88-dependent signalling effector molecules such as IRAK-4 and TRAF6 ultimately resulting in reduced phosphorylation and activity of inhibitor of kappa B kinase (IKK), p38 and JNK (Chang et al. 2009).

IL-10 is produced by monocytes, macrophages, Tregs and Th2-polarised T cells in a state of endotoxin tolerance, and suppresses the CD8 T and CD4 Th1 type cell response making an indispensable contribution to the development of an anti-inflammatory environment (Jiang and Chess 2006; Littman and Rudensky 2010).

The indispensable contribution of IL-10 to the development of endotoxin tolerance (Liu et al. 2011b; Quinn et al. 2012) is of importance from the perspective of this paper as the upregulation of this cytokine is a common observation in CFS patients (Roerink et al. 2017; Wong et al. 2015).


It should be noted that once activated, IDO activity can be maintained by two positive feedback mechanisms. First, TGF-β can target its cellular receptor leading to the upregulation of NF-κB-RelB signalling leading to further transcription of IDO (Pallotta et al. 2011; Shi and Massague 2003). Second, IDO-activated AhRs can in turn upregulate the transcription of IDO1 (the gene that encodes IDO) via genomic and non-genomic routes (Li et al. 2016b; Litzenburger et al. 2014). Hence once activated, IDO upregulation could be protracted or even chronic.


In addition, there is evidence obtained from human studies that chronic or intermittent translocation of LPS into the systemic circulation can induce a state of tolerance and alternative activation in macrophages and monocytes characteristic of endotoxin tolerance via the activation of IDO, kynurenine and the AhR (Banerjee et al. 2013; del Campo et al. 2011; del Fresno et al. 2008; Pena et al. 2011; Wisnik et al. 2017). Given the existence of LPS translocation in CFS, this mechanism could also contribute to the development of a chronic state resembling endotoxin tolerance.


The importance of IDO activation in the development of endotoxin tolerance is further emphasised by data confirming that interactions between the AhR, kynurenine and TGF-β1 are responsible for the polarisation of activated naïve T cells into the Treg phenotype by the presentation of antigen by tolerogenic antigen-presenting cells (Gandhi et al. 2010; Mezrich et al. 2010). Such phenotypic presentations are considered below.


IDO2 is a homologue of IDO (also known as IDO1), being an immunomodulatory enzyme which catalyses L-trytophan; like IDO1, IDO2 is also located on chromosome 8 in humans but IDO2 is not as widely expressed as IDO1 and IDO2 has a distinct signalling role (Metz et al. 2007; Cha et al. 2018). B cell IDO2 expression has recently been identified as being an essential mediator of autoreactive B and T cells in autoimmune responses (Merlo and Mandik-Nayak 2016; Merlo et al. 2016, 2017). It seems likely, therefore, that IDO2 may be found to play an important role in ME/CFS.
 
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ljimbo423

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Just to be clear, the recitation by Morris & Maes is at complete odds with Phair's metabolic trap hypothesis, which has IDO2 impaired and IDO1 (IDO) inhibited as a consequence.
That's really interesting, I didn't realize that, thanks for pointing that out. Which one of the theories are you more inclined to agree with or do you think both are wrong?
 

Wishful

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The inhibited IDO hypothesis doesn't match my observations, which is that my symptoms increase with increased cerebral TRP, and also with events that would increase IFN-g (and thus IDO). Since there are now two opposing hypotheses, perhaps some researcher can test whether IDO (and kynurenine production) is elevated in ME patients and correlates with symptom severity.

One thing in the paper caught my attention: it mentioned cardolipin released in the cells being increased in ME patients. I had to look that up, since it's new to me. It's a molecule critical for mitochondrial membranes, and affects mitochondrial function. It's affected by T2. I've been looking for explanations for why T2 resets something in my ME, in a way that a single dose switches it one way, and that effect abruptly switches back after 21 days. Maybe cardolipin fits that, though there's not much known about T2's effect on it.
 

S-VV

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Not to be nitpicky, but they talk about a state of lps tolerance, which is the opposite to inflammation.

For example, this shift is mediated in part by an increased activity of PPARy, which is widely considered to be anti-inflammatory, and Sirt1, which is a target for life extension
 

Wishful

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The IDO1-IDO2 story is pretty complex. I came across:

Glial and tissue-specific regulation of Kynurenine Pathway dioxygenases by acute stress of mice.
Dostal CR1,2, Carson Sulzer M3, Kelley KW1,4,5, Freund GG1,4,5, McCusker RH1,4,5.
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Abstract
Stressors activate the hypothalamic-pituitary-adrenal (HPA) axis and immune system eliciting changes in cognitive function, mood and anxiety. An important link between stress and altered behavior is stimulation of the Kynurenine Pathway which generates neuroactive and immunomodulatory kynurenines. Tryptophan entry into this pathway is controlled by rate-limiting indoleamine/tryptophan 2,3-dioxygenases (DOs: Ido1, Ido2, Tdo2). Although implicated as mediating changes in behavior, detecting stress-induced DO expression has proven inconsistent. Thus, C57BL/6J mice were used to characterize DO expression in brain-regions, astrocytes and microglia to characterize restraint-stress-induced DO expression. Stress increased kynurenine in brain and plasma, demonstrating increased DO activity. Of three Ido1 transcripts, only Ido1-v1 expression was increased by stress and within astrocytes, not microglia, indicating transcript- and glial-specificity. Stress increased Ido1-v1 only in frontal cortex and hypothalamus, indicating brain-region specificity. Of eight Ido2 transcripts, Ido2-v3 expression was increased by stress, again only within astrocytes. Likewise, stress increased Tdo2-FL expression in astrocytes, not microglia. Interestingly, Ido2 and Tdo2 transcripts were not correspondingly induced in Ido1-knockout (Ido1KO) mice, suggesting that Ido1 is necessary for the central DO response to acute stress. Unlike acute inflammatory models resulting in DO induction within microglia, only astrocyte DO expression was increased by acute restraint-stress, defining their unique role during stress-dependent activation of the Kynurenine Pathway.

For the inhibited IDO hypothesis, which cells would be involved, since it does make a difference? My hypothesis of ME involves activated microglial cells producing excess IDO which converts more TRP into kynurenines, specifically the nastier ones such as quinolinic acid.
 

Learner1

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I am actually starting to see a little light at the end of the tunnel that tells me we may have some treatments in the near future.
By all means, let's figure out how to measure if this is indeed going on and figure out how it can be treated (or what we can try got thr next 10 years before their are perfrct answers.)

This is all very interesting as an academic discussion, but it would be useful to know what we can measure to look at these hypotheses in real time.

For example, my kynurenine and quinolonic acid are normal, as is the ratio between them. When they've been high, I've been deficient in B6.

How do we meaure what's going on in the IDO pathways and whether we are stuck?

How do we measure is LPS are in our blood steam causing problems, and if so, what do we do about them?

And how do we make sense of what is going on with cytokines? My IL-10 is measurable, but fairly low, IFN-gamma is quite high, as are IL-12, 17, and 18. These are the only cytokines that looked significant. All others were low.

And how do genes like the KIR locus, HLA, IDO, etc. play into all of this? How do we measure what they are doing and make interventions that will cause them to behave better if they are misbehaving?

Sorry to sound a bit cranky, here, but it would be nice to get well sooner, rather than later....
 

Learner1

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It is. I have come a long way, by reading and interpreting the research that's out there.

It does not seem prudent to wait 30 years for all of this research to be complete and properly translated into clinical standards of care with a big red now around it.

Time is ticking by, and none of us is getting younger, so dealing with imperfect info and translating as best we can is all we have at this point.

What are the tests available to patients, as a start?
 

ljimbo423

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From what I could understand reading this paper. It is basically saying that damage associated molecular patterns (DAMPs) in individuals post-infection, leads to "escalating chronic systemic inflammation". This causes a leaky gut, neuro-inflammation etc, and all symptoms of CFS.

That's the best this foggy brain could come up with.:)


Hence it is difficult to conclude that persistent or chronic infections are at the root of CFS/ME/SEID, but of course they could be in some patients. However, many patients have a history of a severe infection before the development of their symptoms (Gow et al. 2009; Hickie et al. 2006; Stormorken et al. 2015; White 2007; Zhang et al. 2010).
In this context it is noteworthy that the intensity of the immune response is not determined solely by the virulence or otherwise of an invading pathogen but by genetic and epigenetic variation in immune response genes (Bronkhorst et al. 2013; Morandini et al. 2016; Rautanen et al. 2015; Smelaya et al. 2016).

Epigenetic variation in immune response genes also plays a major role in determining the development of DAMPs in an individual post-infection (reviewed (Morandini et al. 2016)).

This may be pertinent from the perspective of the aetiology of CFS, as the production or presence of these molecules can at least in some circumstances ‘convert’ an acute pathogenic infection into a state of escalating chronic systemic inflammation, and hence this mechanism could conceivably underpin the development of chronic symptoms in CFS patients diagnosed according to the Fukuda criteria (Lucas and Maes 2013; Lucas et al. 2015).
Chronic engagement of TLRs by DAMPs leads to the development of a positive feedback loop, whereby increasing tissue damage caused by elevated PICs, ROS and RNS perpetuates and escalates pro-inflammatory responses, leading to a state of chronic inflammation, ONS, mitochondrial dysfunction and glial cell activation (Drexler and Foxwell 2010; Goh and Midwood 2012; Morris and Berk 2015; Piccinini and Midwood 2010).
 

Learner1

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Thanks @ljimbo423 .

So, again, what do we measure, to determine if we have the problem, and then progress in fixing it?

For example, one can do PCRs to see if certain infections are active; antioxidant levels, lipid peroxides and 8OH-dG to get an idea of oxidative stress; nitrotyrosine for nitrosative stress; a MitoSwab test for mutochindrial dysfunction; various inflammatory markers for inflammation...

The above have all been extremely helpful.

What else?
 

ljimbo423

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Thanks @ljimbo423 .

So, again, what do we measure, to determine if we have the problem, and then progress in fixing it?

For example, one can do PCRs to see if certain infections are active; antioxidant levels, lipid peroxides and 8OH-dG to get an idea of oxidative stress; nitrotyrosine for nitrosative stress; a MitoSwab test for mutochindrial dysfunction; various inflammatory markers for inflammation...

The above have all been extremely helpful.

What else?
I really wish I new, sorry.
 

Belbyr

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I agree with you Learner, time is ticking and it is aggravating to say the least. I don't think the last 13 years of my life have been a waste but it has been hard and frustrating. Some of this language can be confusing because sometimes these papers never clarify are they talking serum or intracellular... then subgroups?

When Ron Davis spoke at the last conference, he mentioned they didn't want anyone trying to medicate with these pathways. That tells me there are treatment approaches and someone knows how.

I think my biggest take away from this is, it seems everyone is converging on 'sickness behavior'. I really don't think we have some mysterious infection that was sought after for a lot of the 90's and 2000's. It seems the computational guys that have come on board around the early to mid 2010's with super computing, their models are also predicting this.

When proof in the pudding stuff comes out like this, it puts my mind more at ease knowing that we have our hands on this. We just don't have it in a choke hold yet.
 
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Theories are an important part of the process of science. But.

Theories that make everything seem to fit are CHEAP. With all due respect. Once one has a good knowledge of biology and an IQ a couple of standard deviations above normal creating plausible theories is trivial. Someone like @necessary8 can whip them up from his sickbed. It's not surprising Naviaux and Phair can come up with convincing theories. The fact the theories appear to make sense is - sadly, awfully, counterintuitively, disappointingly - not a strong clue to their truth.

Morris and Maes have made a career of theories. The longer I've been around here the more theories I can come up with too. In my view science is very hard and this approach - looking at data and creating theories - has relatively low productivity. The avenues with the most promise are about findings.

Mark Davis on T-Cells. Norwegians and cyclophosphamide. Klimas and GWI. Ron Davis and his nano-needle and red blood cells deformity findings. Younger and neuroinflammation. Maybe as an outside bet the Griffith researchers who are on another planet to everybody else with their deep dive into calcium transfer.

None of these findings are replciated and consistent. Some, like the Griffith findings, are so far unable to be replicated. But it will be from experiments that we take our biggest steps.
 

nandixon

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That's really interesting, I didn't realize that, thanks for pointing that out. Which one of the theories are you more inclined to agree with or do you think both are wrong?
I think the biochemistry as it relates to what is currently known about ME/CFS seems more likely to be on the side of IDO1 being upregulated, but the plasma or serum ratio of kynurenine to tryptophan, kyn/trp (one measure of IDO1 function), has not ever been found to be consistently either high or low among ME/CFS patients, I don't believe.

Phair originally found a low intracellular kyn/trp ratio in severe ME/CFS patients using a tracer experiment but he's not sure now whether those results are correct (and they probably weren't properly controlled anyway with respect to IDO2 and IDO1 mutations/SNPs). I think we're waiting to see if he can reproduce those results. And even if it did turn out to be correct that kyn/trp is low, intracellularly, in the severe ME/CFS patients versus controls, I think there might be a better explanation than the metabolic trap hypothesis for why that would be the case, as I posted several months ago.

And as always there's the problem of not being able to very easily tell what is actually happening biochemically in cells where it may matter the most (e.g., the brain).
 

Learner1

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When Ron Davis spoke at the last conference, he mentioned they didn't want anyone trying to medicate with these pathways.
I attended that conference and found it very depressing to hear, one after the other, the scientists saying, "Don't try this at home." It was infuriating.

The scientists don't have all the answers yet. They are reading the data, playing hunches, and running experiments. They are doing the very best they can, with the resources they have. And, the pace has been accelerating in the past 5 years, and they are coordinsting with each other. It is truly amazing, and they will crack this.

Tragically, it will be too late for some of us. Some of us are in our 50s, 60s, and 70s, and are running out of time. Others are younger, but will succumb to this disease, to cancer, etc.

We can't sit idly by, waiting in our beds to bring us perfect answers. Because we are each unique, with different genetics, environmental factors, and comorbidities, what works for one, or for the perfect patient, wont work for all of us, even after the long wait.

The more we learn about ourselves in this era of p4 medicine will help us each in our quest to get well.

It's not just one theory chosen from amongst competing theories, but using systems biology to weave together compatible theories into a body of knowledge that provides a roadmap of diagnostics and treatments to bring us back to health.
We just don't have it in a choke hold yet.
No, and we wont for many years. If we think of an analogy to cancer, if you take 50 patients all with X cancer, they will benefit from a toolbox of diagnostics and treatments that can be applied to each patient's unique situation. Treating people like widgets can be catastrophic. We need to individualize for each of us.
Theories that make everything seem to fit are CHEAP. With all due respect. Once one has a good knowledge of biology and an IQ a couple of standard deviations above normal creating plausible theories is trivial. Someone like @necessary8 can whip them up from his sickbed. It's not surprising Naviaux and Phair can come up with convincing theories. The fact the theories appear to make sense is - sadly, awfully, counterintuitively, disappointingly - not a strong clue to their truth.

Morris and Maes have made a career of theories. The longer I've been around here the more theories I can come up with too. In my view science is very hard and this approach - looking at data and creating theories - has relatively low productivity. The avenues with the most promise are about findings.
Unfortunately, there have been very few findings that are clinically applicable to all of us.

There was a recent interview with Susan Levine, who characterized ME/CFS like cancer - she thinks well find its a group of diseases with some key similarities but differences between them. Jarred Younger has found different subgroups, Stanford is looking at different subgroups, ...

This is incredibly complex. But, my doctors and I have learned a lot, and the treatments I've had, built upon some of these theories, that we've chosen when my test results seem to match theories, have been paying off, one by one. And, I, for one, have experienced huge benefits from translating and harnessing theories of Maes and Morris, Fluge and Mella, Younger, Armstrong and McGregor, Hanson and Levine, and many others. It is possible to make headway now, with thoughtful choices, and access to doctors, tests, and treatments.

There will be mistakes, but given that there's little alternative today, it's worth trying.

That's why it's good to know what tests exist to examine some of these ideas, so one is not just making educated, and not foolhardy guesses. Because, as I learned un the cancer world, there are some choices one cannot reverse. Being prudent is wise.