ME/CFS Research Published 2 – 8 January 2024

The weekly research round-up includes recent publications about ME/CFS and Long Covid. We highlight studies that have particularly caught our attention.

RESEARCH INDEX

The ME Association maintains a comprehensive index of published research on ME/CFS and Long Covid that is free to use and updated weekly.

VIEW THE ME/CFS AND LONG COVID RESEARCH INDEX

Audio Commentary by Dr Katrina Pears

There have been nine new ME/CFS studies and twenty-one new Long Covid studies.

We have highlighted one of the ME/CFS studies in more detail below:

Paper two (2) looks at exploring the use of inflammation, immunity and receptor-based biomarkers for evaluating the progression of ME/CFS. This is a follow up study from this research group who have previously reported that antibodies to beta2-adrenergic (anti-β2AdR) and muscarinic acetylcholine (anti-M4) receptors demonstrate sensitivity to the progression of ME/CFS (Gravelsina et al., 2022). 

This study included: 30 patients with mild ME/CFS, 72 moderate, 31 severe and 54 healthy controls. The study looked at characterising a range of inflammatomes, immunome markers and receptor-based biomarkers. These were: interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-21, Il-23, IL-6, IL-17A, Activin-B, immunome (IgG1, IgG2, IgG3, IgG4, IgM, and IgA), and receptor-based biomarkers (anti-M3, anti-M4, and anti-β2AdR). We have listed the role of each of the biomarkers studied at the end of this blog.

The study found that the association between inflammatomes and immunome markers should be studied in further detail as well as developing individualised treatment plans based on these results. The study also found that:

For the autoantibodies studies, anti-M4 showed significant differences between the healthy controls and patients with different severity degrees of ME/CFS. Although, this did not increase with disease severity.
Compared to the control group, the increase in the level of anti-β2AdR was also statistically significant.
Significant intergroup differences have also been observed for IL-2, IL-21, and IL-6 for all severities compared to controls.
For the immune biomarkers, that IgG4 levels decreased with increasing severity. With a less pronounced effect being seen for IgA.
IgM levels were seen to increase in ME/CFS compared to controls. With a similar effected being seen for IgG3 and IgG1.
The association between inflammatome and immunome markers is broader and stronger in the severe group.
Statistical analysis through principal component analysis allowed separation of components associated with inflammatome, immunome, and receptor biomarkers.
Statistical analysis through random forest modelling demonstrates an accuracy of over 90% for splitting healthy controls and those with ME/CFS, and 45% accuracy for splitting healthy controls and different severity groups. For this, anti-β2AdR was shown to be the most relevant marker.
Overall, the biomarkers which were shown to be the most important for separating groups were: anti-β2AdR, anti-M4, IgG4, IL-2, and IL-6.

This is an interesting study with not only a large set of biological markers investigated, but also the fairly large patient sample size which spans all severities (although not the very extremely severe). These findings could have important implications in finding a diagnostic biomarkers.

Interestingly, patients were firstly assessed with the Fukuda criteria and then confirmed diagnosis of ME/CFS with the International Consensus Criteria. This ensures a strict diagnosis, as the Fukuda criteria alone is not robust enough, as it is heavily criticised in its use to diagnosis ME/CFS, especially when used in research. Problems with the Fukuda criteria include: post-exertional malaise (PEM) is not compulsory which leads to misdiagnosis, and it is not easy to use on a clinical level (a review on the contrasting case definitions has been written by Brown et al., 2013). 

There are very few negatives to this study. The authors were very strict on their inclusion/exclusion criteria. Despite the thorough research presented, longitudinal studies are really needed to monitor the transition between severity groups and the progression of ME/CFS.

In the Long Covid reference section this week, you may also be interested in Paper four (4) which shows that Muscle abnormalities worsen after post-exertional malaise (PEM). There is an easy to understand news article on this research here.

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Overview of the inflammatomes, immunone markers and receptor-based biomarkers studied in this research:

Interferon (IFN)-γ: is a cytokine that plays an important role in inducing and modulating an array of immune responses. It is involved in the activation of macrophages to increase phagocytosis (an important part of nutrition in unicellular organisms), tumoricidal properties, and intracellular killing of pathogens, particularly bacteria and fungi. 
Tumor necrosis factor (TNF)-α: is an inflammatory cytokine produced by macrophages/monocytes during acute inflammation and is responsible for a diverse range of signalling events within cells, leading to necrosis (death of body tissue) or apoptosis (programmed cell death).
Interleukin (IL)-2: one of a family of polypeptides that mediate interactions between leukocytes. It stimulates proliferation and enhances function of other T-cells, natural killer (NK) cells and B-cells.
Interleukin (IL)-21: is a pleiotropic cytokine with actions on a broad range of lymphoid, myeloid and epithelial cells. These actions include effects on proliferation, survival, differentiation and function.
Interleukin (IL)-23: is a member of the IL-12 family of cytokines with pro-inflammatory properties. Its ability to potently enhance the expansion of T helper type 17 (Th17) cells indicates the responsibility for many of the inflammatory autoimmune responses.
Interleukin (IL)-6:  is a multifunctional cytokine that plays a central role in host defense due to its wide range of immune and hematopoietic activities and its potent ability to induce the acute phase response.
Interleukin (IL)-17A: promotes inflammation by inducing various proinflammatory cytokines and chemokines, recruiting neutrophils, enhancing antibody production, and activating T cells. It plays a role in allergic reponses.
Activin-B: is involved in the control of inflammation and muscle mass. It has previously been proposed as a novel biomarker for ME/CFS (Lidbury et al., 2017).
Immunome (IgG1, IgG2, IgG3, IgG4, IgM, and IgA): this is the name given to all genes and proteins that constitute to the immune system collectively.
Immunome IgG1: is the most abundant IgG subclass in human sera and is important for mediating antibody responses against viral pathogens. 
Immunome IgG2: plays a role in protection against protein antigens but is predominantly responsible for anticarbohydrate IgG responses against bacterial capsular polysaccharides.
Immunome IgG3: is associated with enhanced control or protection against a range of intracellular bacteria, parasites, and viruses. 
Immunome IgG4: is thought to be involved in antigen disposal, which decreases inflammation or protect against type I hypersensitivity by inhibiting IgE activity, as well as prevent type II and III hypersensitivity by blocking immune complex formation.
Immunome IgM: antibodies secreted by B cells participate in both neutralization and clearance of pathogens in addition to initiating inflammatory reactions against pathogens through the complement pathway.
Immunome IgA: is the most abundant type of antibody in the body, comprising most of the immunoglobulin in secretions and a significant amount of circulating immunoglobulin. In secretions, it serves to protect the mucosal tissues from microbial invasion and maintain immune homeostasis with the microbiota
Receptor-based biomarkers- anti-M3: controls smooth muscle contractions in the blood vessels, lungs and gastrointestinal tract. It is located in many glands and helps to stimulate secretion.
Receptor-based biomarkers- anti-M4: are found to be possibly associated with the ‘PBC-chronic active hepatitis overlap' syndrome.
Receptor-based biomarkers- anti-β2AdR: have been reported to enhance the anti-inflammatory properties in some organs and tissues.