JAX Research on Immune Profiles in ME/CFS is now available

[Hufsamor]

https://jaxmecfs.com/2019/12/27/jax...GVjx5xE2FtINFh8t-SCVsioYtoprphdkzFGV9ssRi9avg

Finally and importantly, we utilized these immune profiling parameters in a machine learning classifier and were able to correctly identify ME/CFS patients from healthy controls with high sensitivity and accuracy. As patients often wait years to receive an ME/CFS diagnosis since there are currently no clear diagnostic tools to identify the disease, the development of an immune profile classier could aid as a biomarker to diagnose the disease.

 

[Hufsamor]

Overall, we did not find differences in the overall numbers of monocytes, B cells, or T cells, but the ratio of two major subsets of T cells, namely the CD4+ to CD8+ T cell ratio, was increased in ME/CFS patients compared to healthy controls. This CD4+ to CD8+ ratio is known to change due to normal aging, and interestingly, when the study groups were split by age into those younger than 50 years and those older than 50 years, this difference in the CD4+ to CD8+ ratio was seen only in the subjects who were younger than 50 years of age, suggesting an accelerated aging phenotype in people with ME/CFS.

 

[Hufsamor]

There was also a major difference seen between healthy controls and ME/CFS patients in the Th17 cell subset, which is involved in responding to bacteria and is also a culprit in several autoimmune and chronic inflammatory conditions. These cells are also resident in mucosal tissues, and play a major role in the immune response to both bacterial infections and to the microbiota (the trillions of bacteria that live in our bodies). The frequency of these cells was significantly higher in ME/CFS patients compared to healthy controls, yet their functionality was decreased in ME/CFS patients. We will write a separate article on this topic as it is more complex than this summary. However, we think this suggests a chronic activation of Th17 cells in ME/CFS which induces an “exhausted” state where the cells are more dysfunctional due to their chronic stimulation.

 

[Hufsamor]

There was also a major difference seen in the mucosal-associated invariant T (MAIT) cells in ME/CFS patients compared to healthy controls. MAIT cells selectively respond to a broad range of bacteria, which we will discuss in more detail in a separate article. While the MAIT cell frequency did not differ between ME/CFS and controls, the functionality of these cells was profoundly different between the two groups and included a reduced production of cytokines. It is possible that these changes in Th17 and MAIT cells are associated with differences in the composition of the microbiota of the ME/CFS patients, and that a disruption in the microbiota causes chronic activation of these subsets and an exhausted state in ME/CFS patients. Interestingly, we also noted that regulatory T cells (Tregs) were increased in ME/CFS patients compared to controls. Tregs function to suppress excessive chronic immune responses, so this is consistent with our finding that there appears to be chronic activation of major T cell subsets in ME/CFS patients.

 

[pattismith]

Overall, we did not find differences in the overall numbers of monocytes, B cells, or T cells, but the ratio of two major subsets of T cells, namely the CD4+ to CD8+ T cell ratio, was increased in ME/CFS patients compared to healthy controls. This CD4+ to CD8+ ratio is known to change due to normal aging, and interestingly, when the study groups were split by age into those younger than 50 years and those older than 50 years, this difference in the CD4+ to CD8+ ratio was seen only in the subjects who were younger than 50 years of age, suggesting an accelerated aging phenotype in people with ME/CFS.

This is what I found in my lymphocytes when I had them tested 2 years ago, a very high CD4/CD8 ratio with low CD8.

 

[andyguitar]

we also noted that regulatory T cells (Tregs) were increased in ME/CFS patients compared to controls. Tregs function to suppress excessive chronic immune responses, so this is consistent with our finding that there appears to be chronic activation of major T cell subsets in ME/CFS patients.

I think this is the most interesting finding.

 

[SlamDancin]

I’ve been speaking with Dr Unutsmaz. We’ve discovered some very interesting things while discussing possible relative meanings of these findings. IIRC MAIT cells and the mucosa in general, the connective tissue and membranes/(gut-liver-brain-Axis membranes) are the primary places to find MAIT cells. They say just in the summary it’s primarily a gut dysbiosis problem but MAIT cells are highly enriched in the liver as well for example. Anyways twice I recall the Doctor giving me props for a good idea so I think I was firing on all cylinders that day.

 

[SlamDancin]

I think this is the most interesting finding.

Not the first time either
@nandixon

 

[wigglethemouse]

@mariovitali have you looked at the role of MAIT cells in the liver?

but MAIT cells are highly enriched in the liver as well for example.

 

[ljimbo423]

This is a link to the abstract and full paper-https://www.biorxiv.org/content/10.1101/2019.12.23.887505v1.full

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating disorder of unknown etiology, and diagnosis of the disease is largely based on clinical symptoms.

We hypothesized that immunological disruption is the major driver of this disease and analyzed a large cohort of ME/CFS patient or control blood samples for differences in T cell subset frequencies and functions.

We found that the ratio of CD4+ to CD8+ T cells and the proportion of CD8+ effector memory T cells were increased, whereas NK cells were reduced in ME/CFS patients younger than 50 years old compared to a healthy control group.

Remarkably, major differences were observed in Th1, Th2, Th17 and mucosal-associated invariant T (MAIT) T cell subset functions across all ages of patients compared to healthy subjects. While CCR6+ Th17 cells in ME/CFS secreted less IL-17 compared to controls, their overall frequency was higher.

Similarly, MAIT cells from patients secreted lower IFNγ, GranzymeA and IL-17 upon activation. Together, these findings suggest chronic stimulation of these T cell populations in ME/CFS patients. In contrast, the frequency of regulatory T cells (Tregs), which control excessive immune activation, was higher in ME/CFS patients.

Finally, using a machine learning algorithm called random forest, we determined that the set of T cell parameters analyzed could identify more than 90% of the subjects in the ME/CFS cohort as patients (93% true positive rate or sensitivity).

In conclusion, these multiple and major perturbations or dysfunctions in T cell subsets in ME/CFS patients suggest potential chronic infections or microbiome dysbiosis. These findings also have implications for development of ME/CFS specific immune biomarkers and reveal potential targets for novel therapeutic interventions.

While the causes of ME/CFS are likely to be multifactorial, a common history of initial infectious agents, including viral (e.g. EBV) and bacterial (e.g. Lyme Disease) infections, have been associated with triggering the disease (Hickie et al., 2006;Katz et al., 2009).

Notice they say Lyme disease and EBV, etc, have been associated with "triggering" the disease, NOT causing it.

Changes in Th17 cell frequency and function in ME/CFS disease
We hypothesized that ME/CFS patients may also have disruptions within effector T cell subsets resident in mucosal tissues such as Th17 cells, which respond to bacterial infections or microbiota and are also linked to autoimmune diseases (Milner et al., 2010;Pandiyan et al., 2019).

Changes in Frequency of MAIT cells in ME/CFS
Mucosal-associated invariant T (MAIT) cells are a subset of the non-classical T cell population and defined by an invariant T cell receptor that is triggered by riboflavin metabolites produced by bacteria, including commensal microbiota (Tastan et al., 2018;Godfrey et al., 2019). Similar to the Th17 subset, we hypothesized that dysbiosis in the gut microbiome or prior bacterial infections may result in changes in MAIT cell frequencies or function.

In addition, the proportion of CMV/EBV infection among healthy controls and ME/CFS patients was not significantly different in either age group (data not shown).

 

[SlamDancin]

@mariovitali have you looked at the role of MAIT cells in the liver?

I can tell you they seem to be associated with response to long term alcohol damage in an inflammatory nature and that’s almost certainly another translocation of bad bacteria and a breakdown of membranes.

 

[mariovitali]

@mariovitali have you looked at the role of MAIT cells in the liver?

There are many references of MAIT cells and Liver involvement. Recall also that Ron Davis found metabolites occuring from breakdown of colllagen and this could be related to Liver fibrosis. Derya Unutmaz is aware of the Liver Injury hypothesis (and i also sent to him the Fibroscans suggesting Liver fibrosis of some ME patients) but from what i can tell he is looking more into the Gut Microbiome, along with Amy Proal.

My question is since we have a link between the Liver and the Gut, why are we only look at the Gut and not the Liver? For example, impaired bile acids metabolism can lead to disruption of the gut microbiome. Also it is possible that the gut microbiome can affect liver function. For more see below :

Linking the gut and liver: crosstalk between regulatory T cells and mucosa-associated invariant T cells

The gut–liver axis is increasingly considered to play a vital part in the progression of chronic inflammatory gut and liver diseases. Hence, a detailed understanding of the local and systemic regulatory mechanisms is crucial to develop novel therapeutic approaches. In this review, we discuss in-depth the roles of regulatory T cells (Tregs) and mucosal-associated invariant T cells (MAITs) within the context of inflammatory bowel disease, primary sclerosing cholangitis, and non-alcoholic steatohepatitis. Tregs are crucial in maintaining peripheral tolerance and preventing autoimmunity. MAIT cells have a unique ability to rapidly recognize microbial metabolites and mount a local immune response and act as a ‘biliary firewall’ at the gut and biliary epithelial barrier. We also outline how current knowledge can be exploited to develop novel therapies to control the propagation of chronic gut- and liver-related inflammatory and autoimmune conditions.

https://link.springer.com/article/10.1007/s12072-018-9882-x

 

[SlamDancin]

Role in the immune systemEdit
Because the epithelium is often under external stress and is somewhat delicate, the lamina propria hosts many immune cells.[4] In the intestinal tract the immune system must have tolerance to the normal intestinal flora, yet respond to pathogenic microorganisms. Imbalance of this causes inflammation diseases such as inflammatory bowel disease.[10] The lamina propria’s richness in macrophages and lymphoid cells makes it a key place for immune responses to occur. It forms part of the barrier that protects internal tissues from external pathogenic microorganisms, especially from the gastrointestinal tract.[11]

The myofibroblasts in the lamina propria make it a very important contributor of inflammation and wound healing responses. Myofibroblasts are capable of releasing cytokines and chemokines in response to stress. Also their contractile capacity may help pull tissue together in the wound healing mechanism.[7]

This is part of what I sent to the Doctor. The Lamina Propria is connective tissue based part of all mucosa based tissue contained in all major membranes of the body. Oh and the main host of MAIT cells in the body.

 

[Murph]

Holy smokes, this paper is huge! It contains the results of literally dozens of interesting experiments. And it is full of findings that are statistically significant, such as the elevated T-regulatory cells, shown in the graphs below.

What these graphs provide a glimpse of is how ME/CFS is particularly cruel to the young. It gives young people the immune parameters of someone much older. Older ME/CFS patients show less difference with their peers, as the peers "catch up".

I've attached the PDF of the study to this post for anyone who'd like to read it.

 

[Judee]

This CD4+ to CD8+ ratio is known to change due to normal aging, and interestingly, when the study groups were split by age into those younger than 50 years and those older than 50 years, this difference in the CD4+ to CD8+ ratio was seen only in the subjects who were younger than 50 years of age, suggesting an accelerated aging phenotype in people with ME/CFS.

Does this mean this type of testing would not be useful for ME/CFS patients over 50?

 

[pattismith]

There was also a major difference seen between healthy controls and ME/CFS patients in the Th17 cell subset, which is involved in responding to bacteria and is also a culprit in several autoimmune and chronic inflammatory conditions. These cells are also resident in mucosal tissues, and play a major role in the immune response to both bacterial infections and to the microbiota (the trillions of bacteria that live in our bodies). The frequency of these cells was significantly higher in ME/CFS patients compared to healthy controls, yet their functionality was decreased in ME/CFS patients. We will write a separate article on this topic as it is more complex than this summary. However, we think this suggests a chronic activation of Th17 cells in ME/CFS which induces an “exhausted” state where the cells are more dysfunctional due to their chronic stimulation.

Interesting to notice that ETA receptors activation (by endothelin), increases IL17 production by Th17.

Th17/IL-17 have been involved in MS and Psoriasis, and @MartinDH noticed that his psoriasis and his ME/CFS never come together. (when one shows up, the other disappears).



https://www.sciencedirect.com/science/article/pii/S0024320514002240

 

[SlamDancin]

I brought up with the Dr yesterday that MAIT cells characteristics are possibly highly tissue specific and did he think there were a lot of further information to be determined by comparing the microbiome MAIT cells with say liver MAIT or other micro environments. I am waiting to hear because it seems to be between Gut and liver this can be easily transferred and we may be looking at an exhausted immune response in the liver too. Seems in both cases we’d stand to learn a lot by expanding out the search since MAIT cells probably don’t circulate like normal T cells.

 

[Belbyr]

View attachment 35804

This may be ignorant of me, but to me these graphs don't look all the different between controls and ME/CFS.

 

[Belbyr]

Speaking of collagen... This is a test I had done within the first year of my illness (17 years old). It was 'experimental' and not a FDA/CDC approved test. Subsequent testing has not been able to show positive SSB antibodies like this one did, and every doctor I have shown the ANTI-Ku antibodies to just shrugged their shoulders and had no response. No one has tried to repeat it either.

 

[SlamDancin]

Interesting so SSB is Sjogren’s B anti but the Ku antibodies I had to look up and they are also interesting.

“Anti-Ku antibodies were found in 34 patients (0.46% of 20,600 sera positive for antinuclear antibodies), and complete data were available for 30 patients; 86.7% were female, mean age was 49 years (range, 20-73 yr). The most frequent clinical manifestations were arthralgia (77%) and Raynaud phenomenon (53%). Eleven (37%) patients had IM, 8 of them as part of an overlap syndrome defined as IM associated with connective autoimmune disease (5 systemic sclerosis [SSc], 2 Sjögren syndrome (SS), and 1 systemic lupus erythematosus [SLE]). Of 21 patients without IM, 19 had autoimmune diseases (including 6 SLE, 2 SSc, 2 SS, and 2 rheumatoid arthritis), 1 had bronchial neoplasia, and 1 had nephroangiosclerosis. Clinical features of the 9 patients with IM were myalgia (91%), proximal muscle weakness (89%), and dysphagia (36%). All had increased creatine kinase (median, 2210 U/L; range, 194-4073 U/L). Muscle biopsy showed necrosis, inflammation, and positive HLA class I immunostaining”

https://www.ncbi.nlm.nih.gov/m/pubmed/22391471/