Soluble IL-2R impairs muscle cell mitochondrial respiration in fatigued individuals with post-acute sequelae of COVID-19, 2024, Peterson Brown

This looks like it might be the major paper for the week to discuss.

Signalling? Potential link with FOXP4 / FOXP3?

Despite the methodological issues commented on in thread Tolerability and Efficacy of s.c. IgG Self-Treatment in ME/CFS Patients with IgG/IgG Subclass Deficiency: A Proof-of-Concept Study (2021, Journal of Clinical Medicine) their finding was that "responders" had lower sIL-2r.

 

sIL-2r is elevated in a number of conditions, including sarcoidosis as noted by Mij. Recent review article —

The soluble IL-2 receptor α/CD25 as a modulator of IL-2 function (2024)
Juliane Lokau; Lynn M. Petasch; Christoph Garbers

The pleiotropic cytokine interleukin-2 (IL-2) is an integral regulator of healthy and pathological immune responses, with the most important role in regulating the homeostasis of regulatory T cells. IL-2 signalling involves three distinct receptors: The IL-2 receptor α (IL-2Rα/CD25), IL-2R β , and IL-2R γ / γ c . While IL-2R β and γ c are essential for signal transduction, IL-2Rα regulates the affinity of the receptor complex towards IL-2.

A soluble form of the IL-2Rα (sIL-2Rα) is present in the blood of healthy individuals and increased under various pathological conditions. Although it is known that the sIL-2Rα retains its ability to bind IL-2, it is not fully understood how this molecule affects IL-2 function and thus immune responses.

Here, we summarize the current knowledge on the generation and function of the sIL-2Rα. We describe the molecular mechanisms leading to sIL2Rα generation and discuss the different IL-2 modulating functions that have been attributed to the sIL-2Rα. Finally, we describe attempts to utilize the sIL2Rα as a therapeutic tool.

Link | PDF (Immunology) [Open Access]

 

It has also been highlighted in pain "catastrophising" studies —

Elevated circulating soluble interleukin-2 receptor sCD25 level is associated with prefrontal excitatory-inhibitory imbalance in individuals with chronic pain: A proton MRS study (2024)
Ma; Subramaniam; Yancey; Farrington; McGlade; Renshaw; Yurgelun-Todd

Aberrant neuronal excitability in the anterior cingulate cortex (ACC) is implicated in cognitive and affective pain processing. Such excitability may be amplified by activated circulating immune cells, including T lymphocytes, that interact with the central nervous system. Here, we conducted a study of individuals with chronic pain using magnetic resonance spectroscopy (MRS) to investigate the clinical evidence for the interaction between peripheral immune activation and prefrontal excitatory-inhibitory imbalance.

In thirty individuals with chronic musculoskeletal pain, we assessed markers of peripheral immune activation, including soluble interleukin-2 receptor alpha chain (sCD25) levels, as well as brain metabolites, including Glx (glutamate + glutamine) to GABA + (γ-aminobutyric acid + macromolecules/homocarnosine) ratio in the ACC.

We found that the circulating level of sCD25 was associated with prefrontal Glx/GABA + . Greater prefrontal Glx/GABA + was associated with higher pain catastrophizing, evaluative pain ratings, and anxiodepressive symptoms. Further, the interaction effect of sCD25 and prefrontal Glx/GABA + on pain catastrophizing was significant, indicating the joint association of these two markers with pain catastrophizing.

Our results provide the first evidence suggesting that peripheral T cellular activation, as reflected by elevated circulating sCD25 levels, may be linked to prefrontal excitatory-inhibitory imbalance in individuals with chronic pain. The interaction between these two systems may play a role as a potential mechanism underlying pain catastrophizing. Further prospective and treatment studies are needed to elucidate the specific role of the immune and brain interaction in pain catastrophizing.

Link | PDF (Brain, Behavior, and Immunity)

 

And paediatric functional somatic disorders —

Inflammatory Markers in Children and Adolescents with Functional Somatic Disorders: A Systematic Review (2024)
Hansen, Anne Sofie; Rask, Charlotte Ulrikka; Kallesøe, Karen Hansen

Functional somatic disorders (FSDs) are common in children and adolescents. Findings suggest that low-grade inflammation has a role in the development and maintenance of pediatric FSDs. This systematic review included studies with original data on systemic inflammatory markers in children and adolescents with an FSD compared to individuals without an FSD.

The literature search identified 1374 articles. After assessment, a total of 15 studies met the inclusion criteria. In total, 41 serum or plasma cytokines were assayed in a population of 696 children and adolescents. Altered cytokine levels in patients with FSDs were reported in 12 studies, whereas three studies found no significant differences when comparing patients with FSDs and controls.

The cytokine levels were significantly elevated in nine studies (i.e., IL-2, IL-6, IL-8, IL-12 (p70), CRP, hsCRP, IP-10, MCP-1, sTIM-3, sCD25 and TNF-α). The findings indicate that inflammatory response may have a role in the pathophysiology of pediatric FSDs. However, the included studies showed limited quality with potential risk of bias, small study populations and a narrow spectrum of included FSDs, which limits the generalizability of the results.

To further explore the potential link between inflammatory markers and pediatric FSDs, future research using a longitudinal study design is recommended.

Link | PDF (Children) [Open Access]

 

Thanks MIJ and SNT
This is a paper from mostly a University of Kentucky team, with varied backgrounds but a substantial focus on muscle biology.
NIH funding

They appear to have started with the idea that there is something in the blood of people with PASC that causes mitochondrial dysfunction:

They then tested substances in the blood of people with PASC, to find out which ones affected mitochondria,

They say that they found reduced mitochondrial content, impaired muscle function and elevated sIL-2R-a

 

On the methods:
People were eligible to participate as soon as 4 weeks after the Covid-19 infection, and they just had to report ongoing fatigue. The average time after the positive test for the acute illness was only 59 days.

And the healthy controls were mostly historic pre-pandemic samples in a biobank.

Those are quite small sample sizes - only 11 for PASC. There was an unusually high percentage of male subjects.

So, whatever they find, unless there is a very clear distinction, it's not going to be super conclusive due to possible issues related to sample size and storage (does fresher material have higher levels of IL-2R-a than material stored for a while in a biobank?).

 

On the results:

Activity
At this early stage of the illness, muscle size, fibre composition, and muscle strength were still similar to the healthy controls.
Three participants (27%) reported no change in activity after infection, of which two had been highly active, and one was intermediately active prior to infection.

Mitochondrial analyses - Reduced mitochondrial content claim

Note that the sample size was even smaller for these investigations - only 7 people with PASC.

There's the Supplemental Fig 1C above. Yeah, there does look to be a higher percentage of intermediate intensity samples, and they go on to say that it was mostly in Type 2 muscle fibres. But here is Supplemental Fig 1E, with the Type 2 muscle fibres:

That's pretty underwhelming. There are really only 3 PASC people with a higher percentage of intermediate intensity fibres, and the sample size is so small.

They go on to investigate mitochondrial function further:

They found:

I think there might be something there in Figures 2A and 2B. There is overlap between PASC and the controls though, perhaps not everyone in the small PASC group has the same thing causing their fatigue.

Here are Figures 2E and 2F:

Again, maybe there's something there with lower CS (which they say is a proxy for mitochondria content) and CCO (which they say is a proxy for complex IV activity), but there is overlap. Note that the proxy for complex IV activity is not statistically significant here, but they note later (see SNT's post above (#3) where the authors say

So, they are potentially hanging their hat on a molecule that reduces complex-IV activity, but a reduction in complex-IV activity wasn't significant in the muscle biopsies. Maybe it would be significant with a bigger and better characterised sample?

That's interesting. The two pictures of PASC mitochondria do indeed seem to have a lot more of what are identified as autophagosomes near them than the one picture from a healthy control. But, the difference is not quantified.

So, they quantified the amount of subunits of the complexes in the electron chain. Here are the charts:


And yep, with a bigger and better characterised sample, maybe there would be reductions in the complexes. But, this is not strong evidence.

So, it's frustrating. This is potentially important study, looking at mitochondria in muscles. But, it's so underpowered, and the requirement to have had fatigue for 4 weeks after Covid-19 is a pretty low bar when it comes to cohort selection.

The paper then goes on to look at sIL-2R levels.

 

On the sIL-2R finding:
They tested a lot of things (65), IL-2R on the left does look interesting.

They investigated the impact of SIL2R and IL-2 (separately) on the oxygen consumption rate of a type of muscle cell in the Seahorse machine.

Figure 4 certainly is interesting. That's a big difference in oxygen consumption rate. They went on to find lower complex IV activity and lower complex III protein levels.