Evaluation of immune dysregulation in an Austrian patient cohort suffering from ME/CFS

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A study with Dr. Stingl as a co-author found immune-dysregulation in pwME.

https://www.mdpi.com/2218-273X/11/9/1359/htm

1.Abstract

(...) As part of the routine workup for ME/CFS patients, a differential blood count, leukocyte subtyping, and quantification of immunoglobulins and IgG subclasses, as well as a complement analysis, was performed. Out of 262 ME/CFS patients, 64.9% had a reduction or deficiency in at least one of the listed immune parameters. In contrast, 26.3% showed signs of immune activation or inflammation. A total of 17.6% of the ME/CFS patients had an unclassified antibody deficiency, with IgG3 and IgG4 subclass deficiencies as the most common phenotypes. Reduced MBL (mannose-binding lectin) levels were found in 32% of ME/CFS patients, and MBL deficiency in 7%. In summary, the present results confirmed the relevance of immune dysfunction in ME/CFS patients underlining the involvement of a dysfunctional immune response in the disease. Thus, immune parameters are relevant disease biomarkers, which might lead to targeted therapeutic approaches in the future.

2. Materials and methods

A retrospective data analysis was conducted on medical data of ME/CFS patients treated during the study period March 2019 to August 2020. ME/CFS was diagnosed by a specialized neurologist based on exclusion of other medical conditions associated with profound fatigue and based the IOM criteria for the diagnosis G93.3 ME/CFS.(...)

In case of a suggestive history, immunodiagnostics were performed as part of the routine workup for ME/CFS patients including a differential blood count, leukocyte subtyping, immunoglobulins and IgG subclasses, as well as a complement analysis. During the 18-month study period, 351 ME/CFS patients over 18 years of age were followed-up.(...)

The final evaluation was based on immunodiagnostic data of 262 ME/CFS patients independent of gender distribution. All values were compared to defined laboratory norm levels
(...)

3. Results

(...)
Out of the total number of 262 ME/CFS patients, 170 (64.9%) have a reduction or deficiency in at least one of the listed immune parameters. In contrast, 69 of the patients (26.3%) showed signs of immune activation or inflammation, characterized by the increase of one of the evaluated immune parameters
(...)
IgA, as well as total IgG levels, were decreased in 6.5% of all patients. IgM levels were below the norm values in 4.9% of ME/CFS patients. The most prominent reduction of the IgG subclasses was found for IgG3 in 8% of the patients and for IgG4 in 4.9% of the patients. Reduced MBL levels were detected in 32.1% of all patients, and reduced C3c levels in 16% of all patients
(...)
We observed an unclassified antibody deficiency in 17.6% of all patients. On the level of immunoglobulins and IgG subclasses, the highest percentage was found for an isolated IgG3 subclass deficiency found in 5.7% of all patients. In addition, 2.7% of patients suffered from an isolated IgG4 subclass deficiency and 2.7% of all patients were diagnosed with selective IgA deficiency. MBL deficiency was diagnosed in 6.9% of all patients

(...)
The largest number of patients (n = 8) revealed immunoglobulin reduction with reduced CD3-CD16+CD56+ NK (natural killer) cell counts.
(...)
Elevated levels of CD8-CD57+ NK cells were found in 23 patients and higher levels of CD4+ T-cells were detected in 12 patients. Only four patients had an increase in CD8+ T-cells. When evaluating humoral immune parameters, an increase was found mainly in IgG2 (n = 13). Elevated levels of complement parameters were rarely observed; C3 elevation was observed in one patient and C4 in three patients.
(...)


4. Discussion
(...)
Previous studies have highlighted the link between immune dysfunction and ME/CFS development [
6,8,9,15,16,24]. These previous results are confirmed in a comprehensive immune evaluation of 262 ME/CFS patients, revealing mostly a reduction or even immunodeficiency in over 64% of all patients.
(...)
Another remarkable finding in our study is the high frequency of MBL deficiency. In our study, the cut-off level for MBL was defined at <50 ng/mL. Reduced MBL levels were seen in 32.1% of ME/CFS patients, representing the most frequently reduced immune parameter. MBL deficiency, being defined as MBL levels below 50 ng/mL, in combination with severe or recurrent infections, was found in 7%. This highlights the high frequency of MBL deficiency in ME/CFS patients, as MBL deficiency with a cut off value < 100 ng/mL is assumed to be found in 4% of the Caucasian population [
16]. Up to this point, the data on MBL deficiency in ME/CFS patients is still limited. A previous study using a cut-off value <100 ng/mL for MBL deficiency found that 15% (n = 43 of 293) of ME/CFS patients were affected by this immunodeficiency. In general, ME/CFS patients had lower MBL levels than healthy controls, and more than half reported an increased susceptibility to upper and lower respiratory tract infections [16].
(...)
In summary, the present results confirm the relevance of immune dysfunction in ME/CFS patients underlining the involvement of a dysfunctional immune response in the disease. Thus, immune parameters are relevant biomarkers in ME/CFS patients to identify patients with potential responses to immune-modulating treatment for future targeted therapy of ME/CFS.
 

Pyrrhus

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Thanks so much, @Martin aka paused||M.E., for posting this (Lutz et al 2021) study from Austrian neurologist Michael Stingl and colleagues! You did an excellent job of quoting the main points.

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These sorts of immune abnormalities have been reported over many years but, with the exception of NK cells and T cells, they are not discussed that often.

Perhaps they are not discussed because it's not really clear what these abnormalities mean. And perhaps they are not discussed because immunologists routinely dismiss such abnormalities as "non-diagnostic".

I recall that the earliest reports mentioned IgG1 and IgG3 deficiencies, but this study found IgG3 and IgG4 deficiencies. I don't think the earlier reports looked at MBL deficiency, so this finding of MBL deficiency seems significant. I believe @pattismith has investigated MBL deficiency in other discussions.

In my case, I have the following low antibody levels:
  • total IgM (selective IgM deficiency)
  • IgG3
(I have not tested for MBL.)

I have heard that some patients with these immune abnormalities are being given a diagnosis of Common Variable Immune Deficiency (CVID), although I'm not sure that's the best diagnosis...
 

Wishful

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Perhaps they are not discussed because it's not really clear what these abnormalities mean.
No one likes appearing ignorant, so they discuss anything but whatever they don't really understand. :meh:

Did they do any comparisons with people who were also less active than normal? Our low-activity lifestyles probably have a measurable effect on various body functions, including immune function.

The abnormalities may be symptoms rather than part of the mechanism of ME. Trying to treat the deficiencies might improve some symptoms, such as increased susceptibility to infections, but my guess is that it won't treat ME itself.

ME research really does need this sort of data though, so good work on their part. :thumbsup:
 

Wishful

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Correlation with severity might show something more interesting. Likewise comparisons between people with various forms of ME, such as those who don't have physical limitations vs those that do, and those who become more susceptible to infections vs those who don't.
 
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@Wishful

Thats kinda philosophical isnt it. Is the Immune Dysregulation/Exhaustion the cause or the result of CFS/ME.

I think at first its the cause and then the result even more dramatically if you get it.
 
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As I can say for myself, I don't have an Ig deficiency but my MBL is below the detection limit (I have a homogeneous polymorphism on that gene) and low NK count and function, low T-cell function but lymphocytosis and almost no b-cells.

That is definitely not the consequence of my inactivity but surely the consequence of pathogens “hitting” the immune system. I've written a summary in the Amy Proal thread and think PolyBio is just right.

@Wishful I talked now with three lab docs about cytokines because of my cytokinic profile which differs a bit from what I expected (RANTES normal, no IFN-g activity) and they all said that cytokines are in general not a very good marker because they fluctuate and many things can cause them to rise or fall. But as I repeated the tests and some cytokines are elevated over time they all said that it clearly showed an inflammatory response of my immune system. To whatever.

I think to persistent pathogens.
 

Treeman

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I have panhypogammaglobulinemia and some auto anti bodies. It's possible to me that my immune cells are being negatively influenced by some infectious organism. I used to get recurrent shingles out brakes when I could work, but now I can't and spend 95% of my day resting and laying down they have subsided.

"In summary, the present results confirm the relevance of immune dysfunction in ME/CFS patients underlining the involvement of a dysfunctional immune response in the disease. Thus, immune parameters are relevant biomarkers in ME/CFS patients to identify patients with potential responses to immune-modulating treatment for future targeted therapy of ME/CFS."

The treatment I have requested and been turned down for (as I'm not ill enough! I think they meant I'm not dying.....) is IVIG. I know some one within ME/CFS who used to get monthly subcutaneous injections and they said it was the only thing that improved their health, having a healthy persons immunoglobulin's in their system. This could also be what is showing in Prusty's work?

There has been a global shortage of the immunoglobulin, however this recent news in the UK may in time help UK blood supplies to be used to make life-saving drug | Phoenix Rising ME/CFS Forums

I have also read, some pwME have tried this treatment and it didn't help.

But I'm all for trying every immune-modulating treatment in an attempt to return my health.
 
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Agree, but if the immune system is working well, it will do it its self. Its like the chicken and the egg, only we cant see either of them.
That's true. I only think it might often be more difficult to treat the immune system. But of course, in case of for example an enteroviral infection immune modulation is the only weapon we have.
 
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Agree, but if the immune system is working well, it will do it its self. Its like the chicken and the egg, only we cant see either of them.
Just wanted to say the question with egg and Chicken is resvoled. Before the Chicken there was the egg. The mother of this Egg was not a Chicken (genetically). Also called Evolution :D

And your right if the Immune system IS working it will regulate itself as it fking normally should.

But multiple infections is not normal.

I personally think treating the Immune Dysregulation/Exhaustion is treating the cause.

As i said its the cause AND consequence.

The inital cause might happend years before, too much stress at once, Nutrition defiency, multiple infections overwhelming. An unlucky chain of Events in a short period.
 

Treeman

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But multiple infections is not normal.
I think this is normal. We can have cold viruses, other viruses and other types of infections e.g. bacteria all at the same time. This is can be a problem according to Amy Proal and other professionals for ME/CFS people. From personal experience, I can say that catching a number of colds did worsen my ME/CFS.

I think it's maybe not normal to react like pwME.
 
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Virus in Latency is normal, Good gut bacteria is normal. Lytic infection is NOT normal. (According to Lerner the cause.)

"Its not normal to react like pwME" Well obviously otherwise their were no chronic lytic infections.

Well PEM is due to Mitochondrial Fragmentation and Lactate Accumulation.
You cant solve PEM without solving the chronic infection.
 

Wishful

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Well PEM is due to Mitochondrial Fragmentation and Lactate Accumulation.
You cant solve PEM without solving the chronic infection.
I don't know what PEM is due to, but cumin solved my PEM. I've been a couple of years PEM-free now. The cuminaldehyde seemed to stop the PEM symptoms within hours (or was it less than an hour?), so I don't think that fits 'solving chronic infection'. Influencing the immune response seems faster and thus a better fit.

One possibility for how cuminaldehyde worked is as a lipoxygenase inhibitor, which one paper claimed might work as an antiinflammatory agent. However, LOX also produces pro-resolving mediators, which are antiinflammatory, so I'm confused about whether LOX is good or bad (or maybe both). It does influence immune activity in some way, so that might be how it worked on my PEM.