Evaluation of Immune Dysregulation in an Austrian Patient Cohort Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2021, Lutz et al

MSEsperanza

MSEsperanza

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Lutz L, Rohrhofer J, Zehetmayer S, Stingl M, Untersmayr E. Evaluation of Immune Dysregulation in an Austrian Patient Cohort Suffering from Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Biomolecules. 2021; 11(9):1359. https://doi.org/10.3390/biom11091359

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

Abstract
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a severe multi-systemic disease characterized by debilitating fatigue that is not relieved by rest. The causes of the disease are still largely unexplained, and no causative treatment is currently available. Changes in the immune response are considered as fundamental in the development of ME/CFS. Thus, we aimed to evaluate the immunological profile of ME/CFS patients in a retrospective data analysis.

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.
 
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MSEsperanza said:
The study had no control group but compared the results for each parameter to norm values used for laboratory diagnosis.
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I deliberately have not looked at the article itself because I want the possibilities of a diagnostic test and a treatment to last a little longer in my imagination, before it goes back to just being a potentially interesting result that requires a lot more research.
 
Regarding the mannose-binding lectin levels:

this study said:
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
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It is not clear from that the paper or the supplementary tables if the 32.1% of the ME/CFS patients had MBL levels less than 50 ng/ml. The normal range given in paper's supplementary table 1 is '<300 ng/ml' - possibly it was meant to be >300 ng/ml. From what I can find, MBL levels are typically over 1000 ng/ml in healthy people (1 ng/ml = 1ug/L)
Frustratingly, the paper doesn't present the actual results in a way that allows us to see what they actually found. I'd love to see a scattergram of the actual MBL levels.

I do think it's interesting.


Some background on MBL:
https://medlineplus.gov/genetics/condition/mannose-binding-lectin-deficiency/#inheritance
Mannose-binding lectin deficiency is thought to affect approximately 5 to 10 percent of people worldwide; however, many affected individuals have no signs or symptoms related to low mannose-binding lectin levels.
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So, if the 32.1% frequency in this Austrian study is correct, it's possible that the MBL deficiency is substantially more common in people diagnosed with ME/CFS.

https://onlinelibrary.wiley.com/doi/full/10.1111/j.0300-9475.2004.01392.x
In many populations, MBL deficiency is the most common immunodeficiency described to date, and numerous clinical studies have established an association between MBL deficiency and disease susceptibility
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Between age groups, we found that serum MBL levels maintained within a narrow range from a mean of 2050 to 2160 µg/l until the age group 31–40 years old and declined to a mean of 1466 µg/l in the last age group 41–57 years old.
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MBL is an acute-phase protein of hepatic origin that can bind through multiple lectin domains to repeating mannose and N-acetylglucosamine sugar motifs characteristically displayed in high density on bacteria, fungi, viruses and protozoa but not on mammalian cells [4]. After binding to a pathogen, MBL undergoes a conformational change, associated molecules such as the MBL-associated serine proteases (MASP-1 and MASP-2) [5, 6] become coordinately activated, resulting in the initiation of complement activation via a third pathway, known as the lectin pathway, in an antibody- and C1-independent fashion.
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https://pubmed.ncbi.nlm.nih.gov/11256742/
Serum levels of MBL are influenced by three mutations clustered in exon 1 of the gene and are further modulated by various promoter region polymorphisms. The exon 1 mutations lead to secondary structural abnormalities of the collagenous triple helix and a failure to form biologically functional higher order oligomers. There is an increased incidence of infections in individuals with such mutations and an association with the autoimmune disorders SLE and rheumatoid arthritis. Nevertheless, MBL genotyping of various populations has led to the suggestion that there may be some biological advantage associated with absence of the protein. These and other findings suggest that the concept of MBL as a protein involved solely in first line defence is an oversimplification and the protein should rather be viewed as having a range of activities including disease modulation.
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As others have said the data reporting is too sketchy to know quite what to make of the findings. Many of their patients had something out of range in their test results but it was different things for different people, apart from just one larger group with low MBL (which is large enough to be interesting). Hard to interpret. Were those with frank immune deficiencies simply misdiagnosed? Can all the different types and severities of immune deficiencies lead to a common pathway to ME? Can having ME lead to developing all sorts of immune deficiencies in some and to immune activation in others?

Surprisingly they didn't compare short- and long-term illness duration. At least one other study has found differences in immune markers (different ones from the ones investigated in the present study I think), i.e. activation in short duration and exhaustion in long duration illness, and the present study had a large subgroup with "immune deficiency" and a smaller subgroup with "immune activation" so that would have been interesting to look at.

In that context, it would also have been interesting to have had a more thorough investigation into how the subgroups matched phenotypes. Does the "immune deficient" subgroup match the phenotype that catches every infection going and, conversely, does the "immune activated" subgroup match the never-catch-anything group?

In the same vein - though they probably didn't have the necessary data to do this in the present study - would their subgroups match the react-badly-to or get-a-boost from vaccination groups?
 
Ravn said:
As others have said the data reporting is too sketchy to know quite what to make of the findings. Many of their patients had something out of range in their test results but it was different things for different people, apart from just one larger group with low MBL (which is large enough to be interesting). Hard to interpret. Were those with frank immune deficiencies simply misdiagnosed? Can all the different types and severities of immune deficiencies lead to a common pathway to ME? Can having ME lead to developing all sorts of immune deficiencies in some and to immune activation in others?
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Yes, there's so many questions.

It even seems possible that low levels of MBL might be a protective response to intra-cellular parasites
The ambiguous role of mannose-binding lectin (MBL) in human immunity
7.2. MBL in infectious diseases caused by intracellular pathogens (the paradox)
The paradox, i.e., “high MBL levels increase diseases susceptibility and low MBL levels protect,” came into light when MBL was found to have predisposing effect on the infectious diseases involving leprosy and visceral leishmaniasis, both caused by the intracellular parasites [98,99]. These patients had considerably high sMBL levels in comparison to the controls. In unison, the higher prevalence of variant alleles observed in controls than in patients suggest the advantageous role of functional MBL deficiency in these controls. This unexpected frequency was explained by the fact that intracellular parasite is dependent on the phagocytosis to invade the host cells and use opsonization by complements to enter the phagocytes through complement receptors. Therefore, the presence of low MBL levels in the controls will consequently lower the probability of parasitization because of the reduction in the complement-mediated phagocytosis [98]. This could be the plausible rationale behind the few exceptions that have surplus existence of low MBL phenotypes across the globe, suggesting that these geographic areas must be prone to the intracellular parasitism. Therefore, any mechanism that diminishes C system activation would be favorable conferring the selective advantage to those individuals carrying the variant alleles and low MBL levels [71,100]. The mechanism was proposed to be similar to sickle cell anemia, where the sickle cell gene was found to provide protection against malaria that ultimately leads to the selective advantage to the carriers of sickle cell allele [101]. Overall, this suggests that low sMBL levels provide protection against intracellular pathogens.
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Hutan said:
It even seems possible that low levels of MBL might be a protective response to intra-cellular parasites
The ambiguous role of mannose-binding lectin (MBL) in human immunity
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Interesting that you found that. Going through the thread I was just about to remark that MBL is generally thought of as protector against extracellular toxin producing bacteria like staph aureus and if anything might be a bad thing when it comes to intracellular pathogens.

If pathogens have anything to do with ME then it is almost certainly intracellular pathogens such as viruses.

I still think there is a huge worry over cohort bias. And my overriding thought is that anyone seriously interested in the immunology of ME would not publish a retrospective study like this, unless it was done on a population-based cohort with matched controls gathered independently of the project objectives. Such a cohort exists at CureME. Sadly, with the CureME team out of DecodeME they may not be able to continue providing such resource.

It is time the ME research community got its act together on these things.
 
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