Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights... 2024 Jahanbani et al

[Andy]

Full title: Longitudinal Cytokine and Multi-Modal Health Data of an Extremely Severe ME/CFS Patient with HSD Reveals Insights into Immunopathology, and Disease Severity

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) presents significant challenges in patient care due to its intricate multisystem nature, comorbidities, and global prevalence. To address these complexities, we employed a comprehensive approach, integrating longitudinal cytokine profiling with extensive clinical, health, textual, pharmaceutical, and nutraceutical data, and performed personalized analyses using AI.

Focusing on an exceptionally severe ME/CFS patient with hypermobility spectrum disorder (HSD) and marginal symptom improvements, our study highlights the dynamic nature of symptoms, severity, triggers, and modifying factors. As part of this study, we introduced an updated platform and two applications, ME-CFSTrackerApp, and LexiTime, facilitating real-time symptom tracking and enhancing physician-patient communication.

Our longitudinal cytokine profiling underscores the significance of Th2-type cytokines and synergistic activities between mast cells and eosinophils, leading to skewing of Th1 toward Th2 immune responses in ME/CFS pathogenesis, especially in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major comorbidities. Additionally, our data reveal potential roles of BCL6 and TP53 pathways in ME/CFS etiology and emphasize the importance of investigating low-dose drugs with partial agonist activity in ME/CFS treatment. Our analyses underscore the patient-centered care approach for better healthcare management.

Abstract only at time of posting, https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1369295/abstract

 

[Hutan]

Fereshteh Jahanbani1*, Justin C. Sing2, Rajan D. Maynard1, Shaghayegh Jahanbani3, Janet Dafoe4, Whitney Dafoe4, Nathan Jones1, Kelvin J. Wallace1, Azuravesta Rastan1, Hannes Rost2, Holden Maecker5, Michael P. Snyder6, Ronald W. Davis4

Presumably Whitney Dafoe is the patient. A few red flags and a lot of vagueness in that abstract. I've liked Jahanbani's work in the past though, I'll wait to see the full paper.

 

[Hubris]

Our longitudinal cytokine profiling underscores the significance of Th2-type cytokines and synergistic activities between mast cells and eosinophils, leading to skewing of Th1 toward Th2 immune responses in ME/CFS pathogenesis, especially in cognitive impairment and sensorial intolerance

I think this part could be interesting. My worst symptom by far is cognitive impairment and eosinophil activation is one of the most consistent markers in my illness. Eosinophilic cationic protein is consistently elevated in my blood (10x over normal values) and eosinophils are found in my gut biopsy also consistently.

I think for very severe patients this kind of longitudinal analysis is the way to go.

 

[SNT Gatchaman]

Now published. (Though someone didn't do a good job on the proofing as there's a long duplicated passage.)

 

[SNT Gatchaman]

The application they created for symptom tracking is at https://me-cfstrackerapp.su.domains/

As a companion to our work, a web-based application was developed to allow patients to create an electronic journal of their symptoms, medications, and life events. The application was built using a stack of a Node.js front end and a Python back end and deployed on a secure server hosted at Stanford. The deployment is configured to guarantee constant uptime and cross-browser compatibility to ensure accessibility. Cross-browser compatibility and responsive design were prioritized to facilitate seamless usage across various devices, enhancing the accessibility and user experience. To promote widespread usage and accessibility, MECFSTrackerApp is freely available for use. Users can navigate to the application using the provided link “https://mecfstrackerapp.su.domains”, where they can benefit from its features without any cost.

 

[Dolphin]

Figure 3 Proposed Framework for Personalized Severity Assessment in ME/CFS to Capture Variation in ME/CFS Severity and Life Impairment across Patients and Time. (A)Illustrates the dynamic range of the ME/CFS severity scale based on the disease’s impact on all aspects of the patient’s life, including occupational, educational, social, and personal spheres. (B) Depicts the impact of mild to severe ME/CFS on the patient’s life. Mild: maintained about 80% of pre-ME/CFS functional capacity, as well as full-time employment with limitations due to post-exertional malaise (PEM). Moderate: pre-ME/CFS functional capacity, unable to hold part-time work, with increased limitations in activity, progressing to severe: inability to hold any job, primarily house and bedbound. (C) Shows the patient’s functioning ability significantly degrading from extremely severe A to D, highlighting ME/CFS’s profound impact at this level. Severe nutritional deficiencies led to Gastrostomy tube (G-tube) and Peripherally inserted central catheter (PICC Line) Line use. Sensory intolerance intensified, making it impossible for the patient to tolerate others in his room. At stage D, communication loss and internet access loss intensified social isolation.

https://twitter.com/user/status/1777351143300993354

 

[Hutan]

Severity levels
Figure 3 gives an interesting definition of severity levels, with additional sub levels added for extremely severe. I like the definitions of the milder levels. I'm not sure about the difference between Very Severe and Extremely Severe A, which seems to have a lot to do with being able to speak and write and being able to get to the bathroom for toileting and washing. To me, there's a big leap between those two levels; I think some people might not be able to get to the bathroom but can still speak, and that's a pretty fundamental difference. I think you'd need to do a study on the capabilities of a lot more people who are bedridden than just one to determine if the levels at the worst end of the spectrum apply more generally. Of course, I understand why the authors wanted to differentiate levels for this particular individual, in order to correlate health variables, but just noting that they may not be generalisable.


Blog word analysis
There's quite a lot of content about analysing the patient's blogs, in terms of word frequency and so on. I find it a bit irrelevant - basically, they had some new tools to do it, and so they did it. They say:

Additionally, employing natural language processing and open AI tools like ChatGPT, as well as the development of LexiTime application for textual data processing, including sentiment analysis and topic modeling, holds significant implications for ME/CFS research, particularly for patients with extreme severity who may face challenges in verbal communication

I think, however, if you want to find out how someone is feeling about their health status, there are easier ways to find out, so I question the idea that this 'holds significant implications for ME/CFS research'.
Edit to add - for example, when I am feeling better, I am more likely to write more complex things, often critical things, and have a bit more strength to be angry about things that should be better. I don't think there is a clear correlation about the sentiment of my written words and my health status.

 

[Hutan]

Cytokines
Levels of cytokines that were different between two disease levels, Extremely Severe A and Extremely Severe D (the difference being largely in the capability to listen to speech, read and write on a keyboard):

To investigate cytokines linked with disease severity, Z-scores were computed for the 80 measured cytokines between the patient’s improvement to ‘Extremely Severe A’ (Jan 21) and the average of the preceding eight time points when his health was assessed at ‘Extremely Severe D’ (Supplementary Table S1). Cytokines of interest were identified based on absolute z-scores deviating by 1 standard deviation or more from the mean (Table 2), enabling the identification of subtle changes in cytokine patterns across time points that may be associated with transitions in health severity from extreme severe D to A. Among 80 cytokines, ten exhibited a Z-score of +1 or more, including HGF (4.80), Leptin (3.61), MIF (3.08), ENA78 (1.37), GROA (1.25), IL2 (1.19), CCL17 (1.10), CCL21(1.04), FGF2 (1.0), and TPO (1.0). Additionally, 14 cytokines showed a z-score value of -1 or less including CCL11 (-2.75), MCP1 (-2.27), IL28A(-2.17), CXCL9 (-2.10), IL5 (-2.08), MIP1D (-2.06), SFAS (-1.90), VEGF (-1.79), CCL27 (-1.71), IL9 (-1.51), IL6 (-1.29), MCP4 (-1.20), IL10 (-1.18), IL4 (-1.11) (Table 2; Supplementary Table S1). Among these 24 cytokines, only nine exhibited statistically significant changes with an absolute z-score > 1 and p-value <= 0.05. These include HGF (z-score: 4.80, p-value: 1.60E-06), Leptin (z-score: 3.61, p-value: 0.0002), MIF (z-score: 3.08, p-value: 0.002), CCL11 (z-score: -2.75, p-value: 0.005), MCP1 (z-score: -2.27, p-value: 0.023), IL28A (z-score: -2.17, p-value: 0.029), CXCL9 (z-score: -2.11, p-value: 0.035), IL5 (z-score: -2.08, p-value: 0.035), and MIP1D (z-score: -2.06, p-value: 0.039) (Figure 4C, Table 2). This limited 9-plex cytokine panel effectively distinguished ‘Extremely Severe A’ from ‘Extremely Severe D’ (Figures 4C, D). Out of these 14 cytokines, only HGF, LEPTIN, and MIF withstood an FDR adjustment of 10% (Table 2; Supplementary Table S1).

The comparison is only between the two disease levels, with no reference to normal ranges for humans. Using values relating to being more than one standard deviation away from the mean, 24 cytokines were different, with only 9 of those also having significant p values. I think there is a significant typo in this section, because they then talk about 14 cytokines, when I think they mean the 9 cytokines. Only three of the cytokines that were more than one SD different and statistically significant and that survived a false discovery rate (taking into account the fact that 80 cytokines that were measured): HGF, Leptin and MIF.

HGF - increased 4.8 SDs, p value 1.6E-06
Leptin - increased 3.61 SDs, p value 0.0002
MIF - increased 3.08 SDs, p value 0.002
It is noted that all of these three were correlated with improvements in the health of the subject
They note in the discussion:

It’s essential to acknowledge that the observed cytokine elevation at the healthiest time point may be influenced by factors beyond health improvement, such as extended fasting hours, medication, infection, or trauma.

HGF - Hepatocyte Growth Factor - info from wikipedia
It is involved in the response to tissue damage.

Hepatocyte growth factor is secreted by platelets,[8] and mesenchymal cells and acts as a multi-functional cytokine on cells of mainly epithelial origin. Its ability to stimulate mitogenesis, cell motility, and matrix invasion gives it a central role in angiogenesis, tumorogenesis, and tissue regeneration.[9]

Interestingly,

HGF may further play a role as an indicator for prognosis of chronicity for Chikungunya virus induced arthralgia. High HGF levels correlate with high rates of recovery.[14]

I'm surprised that the authors of this study didn't note that association. The authors say:

The varied physiological role of HGF (hepatocyte growth factor) suggests that an increase level may reduce ME/CFS symptom severity through tissue repair (116), anti-inflammatory effects, enhanced energy metabolism (117), neuroprotection (118, 119), improved blood circulation (120), immune modulation (121), and antioxidant properties (122–124). Further research into HGF’s role in ME/CFS is warranted due to inconsistencies across studies (117–121).

I'm not sure what they mean by 'inconsistencies across studies' - none of the studies cited seem to be about ME/CFS.

Leptin - info from wikipedia

As one of the major signals of energy status, leptin levels influence appetite, satiety, and motivated behaviors oriented towards the maintenance of energy reserves (e.g., feeding, foraging behaviors).

The amount of circulating leptin correlates with the amount of energy reserves, mainly triglycerides stored in adipose tissue. High leptin levels are interpreted by the brain that energy reserves are high, whereas low leptin levels indicate that energy reserves are low, in the process adapting the organism to starvation through a variety of metabolic, endocrine, neurobiochemical, and behavioral changes.[7]

The authors of this paper say:

Elevated leptin may positively impact ME/CFS by enhancing mental clarity, focus, mood, emotional well-being, metabolic regulation, energy production and utilization, neuroendocrine hormonal balance, motivation and immune function (109–114). Our current findings, indicating a negative correlation between plasma leptin and disease severity, differ from previous studies (42, 43), potentially attributed to the longitudinal nature of our research and variations in severity scales. Furthermore, the observed rise in leptin levels in the latest time point may be associated with slight changes in BMI (41, 115).

So, they are noting that higher levels of leptin were correlated with better health here, whereas others have found that they are associated with worse health in ME/CFS. They don't quote Jarred Younger's studies, I can't remember what he found. Given leptin's association with satiety and BMI, possibly the leptin finding is a downstream result of increasing BMI from previous very low levels, and so not really much to do with the underlying disease process.


MIF - basically it looks to be a pro-inflammatory molecule, involved in a range of acute and chronic inflammatory conditions. Quotes below from a paper about it:

Macrophage migration inhibitory (MIF) factor is an immunoregulatory cytokine whose effect on arresting random immune cell movement was recognized several decades ago. Despite its historic name, MIF also has a direct chemokine-like function and promotes cell recruitment. Multiple clinical studies have pointed to the utility of MIF as a biomarker for different diseases that have an inflammatory component; these include systemic infections and sepsis, autoimmune diseases, cancer, and metabolic disorders such as type 2 diabetes and obesity.

MIF also has a chemokine-like function and promotes the directed migration and recruitment of leukocytes into infectious and inflammatory sites [6]. MIF is produced by a variety of cell types that in addition to immune cells such as monocytes/macrophages, B- and T-cells include endocrine, endothelial, and epithelial cells [7]. MIF is stored in preformed, cytoplasmic pools and is rapidly released in response to such stimuli as microbial products, proliferative signals, and hypoxia [8-11]. One of the earliest physiologic functions described for MIF is to counter-regulate glucocorticoid suppression of immune cell responses [12], which is important for the regulation of the systemic inflammatory response in settings such as invasive stress or acute illness when adrenal glucocorticoid levels are high. MIF also plays a pivotal upstream role in sustaining immune cell survival by inhibiting activation-induced apoptosis. This effect serves to provide for optimal and, in some pathologic circumstances, excessive, inflammatory responses [13

The authors of this study say:

However, elevated MIF at the healthiest point may stem from factors like infection (128), glucocorticoid use (129), and trauma (130). Further investigation is needed to understand MIF’s role in ME/CFS pathophysiology, disease severity, and prognosis.

So, again, there are all sorts of confounders, and it's hard to know what to make of it.


There's a lot of talk about mast cells and eosinophils, based on differences in cytokine levels that did not reach statistical significance. It would have been very helpful if there had been some analysis of levels against normal ranges in healthy people. There is also a lot of talk about connective tissue disease. Hopefully the authors have some clues that will inspire further research, but I'm not sure that there is much we can take from this study for now, given the n=1 nature of it, and the enormous amount of confounding there will have been.

 

[Murph]

S
There's quite a lot of content about analysing the patient's blogs, in terms of word frequency and so on. ...
Edit to add - for example, when I am feeling better, I am more likely to write more complex things, often critical things, and have a bit more strength to be angry about things that should be better. I don't think there is a clear correlation about the sentiment of my written words and my health status.

I'm always pleased when I see Whitney Dafoe posting online because it suggests he's feeling a bit better. His blog is chugging along recently and he keeps popping up on my instagram. He does seem to have had a big improvement then setback at some point recently because he registered a small business a little while ago but i'm not sure it has continued. Mostly i just want him to be better but there's wider implications for the rest of us - if he is suddenly up at and at em it could be random - or it could hint that Stanford has some good ideas.

 

[alex3619]

If there is a Th2 skew, and it turns out to be important, and replicable, then there are ways to treat that, including Th1 vaccinations. Its all too speculative at this point but its worth a longer look I think. I have still to read most of this and probably wont this month.

 

[wigglethemouse]

One of the authors, Whitney Dafoe, provided some background on the creation of the severity scale that is in this paper. See post #6 by @Dolphin for the image of the scale.

Text:
New Severity Scale for ME/CFS

I wrote this new severity scale for ME/CFS about 2 years ago. I really wanted to express how severe the illness can actually get which is not at all reflected in our current mild-moderate-severe-v.severe scale. And I wanted to make it more accurate to our lives. It’s not perfect, I know, mostly because every ME/CFS patient is so different.

It’s not possible to reflect everyone’s situation perfectly or account for and all the millions of particular circumstances all ME/CFS patients face in one scale because every category would need a 50 pages long description. But I tried my best to make it as useful and inclusive as possible.

It has been changed for publication in a few ways that I don’t like, mostly making the Extremely Severe categories labelled with A, B, C, D etc because it doesn’t mean anything without having to look at the scale and read it. A more descriptive Extremely Severe category name would be more useful to us I think so you would know what it meant from the words alone or could at least remember what they meant. But there is always room for improvement and change down the road.

Also, I am now a twice published author! My MDPI manuscript - "Extremely Severe ME/CFS—A Personal Account"" and now this! Woo! I never thought any of my writing would ever be published, it’s amazing how ME/CFS changes our lives and also how we must change to adapt to the life ME/CFS imposes on us.

I really hope I did you all justice and that this may be useful for us if nothing else, for a template for moving forward to make a scale that is even better. I have already read some great ideas for improvement.

I love you all. Whitney

 

[Trish]

I think it is a good idea to expand the severity scale to include more detail at each severity level. I always seem to fall between levels, whatever scale is used.

The application they created for symptom tracking is at https://me-cfstrackerapp.su.domains/

I had a quick attempt to fill this in. I couldn't make sense of how it worked, and how one retrieves saved data for comparison over time. The questions didn't seem to relate to the words in the coloured strip sometimes, and I'm not sure what I'm supposed to be writing in the white strips.

 

[mariovitali]

Regarding elevated Hepatocyte Growth Factor (HGF) and since hepatocytes are liver cells, it is interesting that there is no mention of liver involvement. The text mentions that increased HGF was associated with fewer symptoms :

Hepatocyte Growth Factor (HGF) is a protein that has multiple roles in the body, including stimulating liver regeneration, promoting angiogenesis (the growth of new blood vessels), and acting as a mitogen for various cell types. Elevated levels of HGF can be observed in various conditions and contexts, reflecting its involvement in both physiological and pathological processes. Here are some of the causes and conditions associated with increased HGF levels:

1. Liver Regeneration and Damage

• Liver Regeneration: HGF is a key factor in liver regeneration. Its levels increase after liver injury or partial hepatectomy to stimulate hepatocyte proliferation and liver tissue regeneration.
• Liver Diseases: Chronic liver diseases, such as cirrhosis, hepatitis, and fatty liver disease, can lead to elevated HGF levels as the liver attempts to repair itself.

2. Tissue Repair and Wound Healing

• HGF plays a role in the repair of tissues other than the liver, including the skin and injured muscles. Its levels can increase in response to tissue damage or injury as part of the healing process.

3. Cancer

• Tumor Growth and Metastasis: HGF, acting through its receptor c-Met, can promote the growth and spread (metastasis) of various types of cancer. Elevated HGF levels have been observed in patients with cancers such as breast, lung, and gastric cancers.
• Paraneoplastic Syndrome: In some cases, tumors may secrete HGF, leading to elevated levels in the absence of liver or tissue injury.

4. Cardiovascular Diseases

• HGF has been implicated in the pathogenesis of cardiovascular diseases. Its levels may increase in conditions such as heart failure, myocardial infarction, and atherosclerosis, possibly reflecting its role in angiogenesis and tissue repair.

5. Kidney Diseases

• Conditions affecting the kidneys, such as chronic kidney disease and acute kidney injury, can lead to elevated HGF levels. HGF may contribute to renal tissue repair and regeneration.

6. Inflammatory Conditions

• Some inflammatory diseases and conditions can trigger an increase in HGF levels as part of the body's response to inflammation and tissue repair.

7. Obesity and Metabolic Syndrome

• Research has indicated that HGF levels can be elevated in individuals with obesity and metabolic syndrome, possibly reflecting systemic inflammation and endothelial dysfunction associated with these conditions.

 

[Nightsong]

Results: Longitudinal cytokine profiling revealed the significance of Th2-type cytokines and highlighted synergistic activities between mast cells and eosinophils, skewing Th1 toward Th2 immune responses in ME/CFS pathogenesis particularly in cognitive impairment and sensorial intolerance. This suggests a potentially shared underlying mechanism with major ME/CFS comorbidities such as HSD, Mast cell activation syndrome, postural orthostatic tachycardia syndrome (POTS), and small fiber neuropathy.

The logic of this simply doesn't follow to the point that I'm surprised it got past peer review. The authors resurrect the Th1/Th2 "imbalance" hypothesis - if I recall correctly a decade or so ago there were various papers claiming that such an "imbalance" was implicated in the aetiology of ME, which never made much sense and which I assumed had been abandoned.

The synergistic activity of mast cells and eosinophils upon systemic activation can skew Th1/Th2 to Th2-immune responses, leading to tissue injuries, autoimmunity, impairment of multiple organs and biological systems as well as causing exercise intolerance and post-exertional malaise in predisposed individuals. Unresolved systemic mast cell and eosinophil overactivation could contribute to the development and aggravation of ME/CFS and related multisystem disorders and comorbidities.

Oh dear. And how would this "systemic mast cell and eosinophil overactivation" correlate with the actual clinical presentation of ME/CFS? There's an awful lot of spurious hypothesising based on some often very woolly immunology all throughout this paper.

I created an account to look through some of the tracker app's questions - here's one: "How has ME/CFS symptom severity impacted your ability to hold a job?" with the possible answers being: "yes" "most of the time" "some of the time" "rarely" "no" - which isn't very clear. Also: "How would you rate your sleep quality?" with the possible answers being "not at all", "mildly", "moderately", "severely", etc - again, very unclear. And the "How do I feel compared to the last time I filled out this form" question is repeated twice and the answers are all "very restful" "restful" etc - why restfulness? There are no instructions as to what to fill in the "string" fields. There's also no privacy policy or any indication as to who will have access to the data being submitted on the site that I can see.

I was going to look at Lexitime, but the GitHub link is broken.

 

[leokitten]

What do people think about interleukin-2 inducible T-cell kinase (ITK) inhibition as a possible target for ME/CFS for an empirical drug response trial? If ME is a T-cell mediated inflammatory/immune disease with a Th2 skew this could be a promising target. Soquelitinib (formerly known as CPI-818) for example is a highly selective ITK inhibitor that modulates affected T cells back towards Th1 and has demonstrated efficacy in Th2-mediated diseases in preclinical models. I believe it’s also in early human clinical trials for certain cancers and autoimmune diseases. @Jonathan Edwards I remember you wondered if ME is a T-cell mediated disorder, and the fact that many pwME also come down with MCAS some of it seems to make sense.

 

[leokitten]

ITK inhibitors in inflammation and immune-mediated disorders, Sahu et al, 2009

Interleukin-2-inducible T cell kinase (ITK) is a non-receptor tyrosine kinase expressed in T cells, NKT cells and mast cells which plays a crucial role in regulating the T cell receptor (TCR), CD28, CD2, chemokine receptor CXCR4, and FcepsilonR-mediated signaling pathways. In T cells, ITK is an important mediator for actin reorganization, activation of PLCgamma, mobilization of calcium, and activation of the NFAT transcription factor. ITK plays an important role in the secretion of IL-2, but more critically, also has a pivotal role in the secretion of Th2 cytokines, IL-4, IL-5 and IL-13. As such, ITK has been shown to regulate the development of effective Th2 response during allergic asthma as well as infections of parasitic worms. This ability of ITK to regulate Th2 responses, along with its pattern of expression, has led to the proposal that it would represent an excellent target for Th2-mediated inflammation. We discuss here the possibilities and pitfalls of targeting ITK for inflammatory disorders.

 

[leokitten]

What do people think about interleukin-2 inducible T-cell kinase (ITK) inhibition as a possible target for ME/CFS for an empirical drug response trial? If ME is a T-cell mediated inflammatory/immune disease with a Th2 skew this could be a promising target. Soquelitinib (formerly known as CPI-818) for example is a highly selective ITK inhibitor that modulates affected T cells back towards Th1 and has demonstrated efficacy in Th2-mediated diseases in preclinical models. I believe it’s also in early human clinical trials for certain cancers and autoimmune diseases. @Jonathan Edwards I remember you wondered if ME is a T-cell mediated disorder, and the fact that many pwME also come down with MCAS some of it seems to make sense.

@Jonathan Edwards do you have any thoughts or useful insight into ITK as a target and possible ITK inhibition in ME/CFS? Like everything else to get treatments to patients would require an empirical trial without direct evidence supporting this hypothesis. In addition to the other functions mentioned above, ITK inhibitors also reduce T-cell exhaustion, so there are various bits of evidence in ME research that point to a problem in the immune system where ITK inhibition might work. A company is trialing ITK inhibition for autoimmune disorders like atopic dermatitis, so I imagine the side effect profile is decent.

 

[Jonathan Edwards]

Soquelitinib (formerly known as CPI-818) for example is a highly selective ITK inhibitor that modulates affected T cells back towards Th1 and has demonstrated efficacy in Th2-mediated diseases in preclinical models. I believe it’s also in early human clinical trials for certain cancers and autoimmune diseases. @Jonathan Edwards I remember you wondered if ME is a T-cell mediated disorder, and the fact that many pwME also come down with MCAS some of it seems to make sense.

As Nightlong said, the Th1/Th2 balance idea was a barmy speculation with no evidence base in any disease in fact about three decades ago. I had hoped it had finally died out.

Whatever ME/CFS is it ain't Th2 I would say. Not even Th1, but something to do with CD8s.

To me this is all the worst sort of immunobabble.

 

[leokitten]

@Jonathan Edwards

How about ignoring for now the semantics or specific immunobabble language of Th1/Th2 balance and, I'll try my best here I'm not an immunologist, e.g. there might be some dysfunctional regulation of ITK-mediated signaling in ME/CFS which causes dysfunction in certain NK cells, mast cells and T cells resulting in them chronically producing pro-inflammatory cytokines such as IL-2, IL-9, IL-13, etc and our disease pathology?

Role of the IL-2 inducible tyrosine kinase ITK and its inhibitors in disease pathogenesis, Lechner et al, 2020

ITK (IL-2-inducible tyrosine kinase) belongs to the Tec family kinases and is mainly expressed in T cells. It is involved in TCR signalling events driving processes like T cell development as well as Th2, Th9 and Th17 responses thereby controlling the expression of pro-inflammatory cytokines. Studies have shown that ITK is involved in the pathogenesis of autoimmune diseases as well as in carcinogenesis. The loss of ITK or its activity either by mutation or by the use of inhibitors led to a beneficial outcome in experimental models of asthma, inflammatory bowel disease and multiple sclerosis among others. In humans, biallelic mutations in the ITK gene locus result in a monogenetic disorder leading to T cell dysfunction; in consequence, mainly EBV infections can lead to severe immune dysregulation evident by lymphoproliferation, lymphoma and hemophagocytic lymphohistiocytosis. Furthermore, patients who suffer from angioimmunoblastic T cell lymphoma have been found to express significantly more ITK. These findings put ITK in the strong focus as a target for drug development.

What I also find interesting is the ppl with genetic ITK gain of function mutations acquire a disorder which results in EBV infections and severe immune dysregulation