Project: Single Cell RNA Sequencing Analysis of the Immune Cell Receptor Repertoire in Patients with ME/CFS and Post-COVID-Syndrome

[Dude]

Principal investigators
Prof. Dr. Thomas Harrer
Dr. Katja Schmidt

Organisation
University Clinic Erlangen

Funding programme
Research Funding Programme 2026

Details:
Current evidence suggests that autoimmunity plays an important role in ME/CFS and post-COVID-Syndrome (PCS) and the similarity of symptoms suggests that both share a common pathophysiology. Detection of functional GPCR autoantibodies correlated with fatigue in PCS patients but so far, it is unclear why only subgroups of patients responded to autoantibody targeting treatments. Therefore, additional biomarkers are needed to delineate the role of autoimmunity in ME/CFS and PCS and to monitor the effectiveness of immunomodulatory treatments. One promising strategy in this context is the analysis of B-cell receptor (BCR) and T-cell receptor (TCR) repertoire of ME/CFS and PCS patients to detect potentially expanded or autoreactive clones that can be targeted. In contrast to bulk sequencing, single-cell RNA sequencing (scRNA-seq) is much more sensitive for the detection of clonally expanded immune cell receptors (IRs) as it allows the delineation of the complete BCR and TCRs in single cells and can provide information regarding the differentiation state and the metabolic activity of cells with distinct BCRs and TCRs. The investigators hypothesise that scRNA-Seq of the immune receptor repertoire could be a sensitive biomarker to assess the pathogenesis of ME/CFS and PCS and to monitor the response to immunomodulatory treatments. Within this project, they seek to identify clonally expanded and potentially autoreactive BCRs and TCRs in the peripheral blood from ME/CFS and PCS patients and map these to epitopes. BCR epitope pairs will furthermore be validated in-vitro and clonally expanded immune receptors will be compared between ME/CFS and PCS patients and healthy controls. Additionally, they plan to analyse the effect of treatments such as BC007 and corticosteroids on the TCR and BCR repertoire of ME/CFS and PCS patients regarding the potential elimination or functional attenuation of expanded and potentially autoreactive immune receptors.

Single Cell RNA Sequencing Analysis of the Immune Cell Receptor Repertoire – ME/CFS Research Foundation

Current evidence suggests that autoimmunity plays an important role in ME/CFS and post-COVID-Syndrome (PCS) and the similarity of symptoms suggests that…

projects.mecfs-research.org

 

[Jonathan Edwards]

I don't see any realistic chance of this finding anything.
Everyone seems obsessed with trying to find the keys in the waste bin under the light from the hot dog stand where they didn't buy a hot dog.

 

[hotblack]

I like the idea of sequencing immune cells, there are still questions and could still be things to learn. Disappointed they start off with an opening sentence that is untrue though, it somewhat reduces confidence in the study.

 

[ME/CFS Science Blog]

I thought that Dibble (T-cell repertoires) and Ryback (B-cell repertoires) already did this, but without clear results.

 

[Jonathan Edwards]

I have never seen this technique tell us anything useful about human disease. It may be possible to measure restricted clonality in animal experiments and anti-TB cell clones can be identified in TB but searching autoimmunity with this sort of method has not taken us any further as far as I know. It is just something people know how to measure.

 

[hotblack]

I thought that Dibble (T-cell repertoires) and Ryback (B-cell repertoires) already did this, but without clear results.

Those were designed to look at very specific questions weren’t they? This may be too. But my understanding was there may be more questions that more sequencing and more well designed studies could answer?

 

[forestglip]

I don't see any realistic chance of this finding anything.
Everyone seems obsessed with trying to find the keys in the waste bin under the light from the hot dog stand where they didn't buy a hot dog.

I don't understand. Will this not allow the researchers to investigate the IGHV3-30 finding further?

 

[Jonathan Edwards]

I don't understand. Will this not allow the researchers to investigate the IGHV3-30 finding further?

It might, but they want it to 'delineate the role of autoimmunity'. The VH3 data are intriguing but I doubt anyone will get very far trying to study it in more detail. It is likely to be an indirect signal of something else and if we don't know how to track that repeating the observation won't help much.

 

[forestglip]

The VH3 data are intriguing but I doubt anyone will get very far trying to study it in more detail.

The main thing I was thinking would be testing isotypes separately. Maybe the 3-30 gene is only over-expressed in IgG cells. That'd both give a further clue and also create a stronger signal due to eliminating unrelated cells. Maybe it would also allow highlighting other genes that are upregulated due to the increased signal.

I'm not sure if the current project is set up to do anything like that.

 

[Jonathan Edwards]

The main thing I was thinking would be testing isotypes separately.

Those things would be interesting but I don't see them telling us anything about the 'role of autoimmunity'.

 

[forestglip]

Those things would be interesting but I don't see them telling us anything about the 'role of autoimmunity'.

Sure, I was just thinking about what we might be able to learn from their BCR analysis.

 

[hotblack]

Those things would be interesting but I don't see them telling us anything about the 'role of autoimmunity'.

Sure. But you and I and @forestglip are clear on that. But we’ve also wanted more information which a good study using rnaseq could tell us. That was the question I think we’ve been posing. Even if this study may not the right one to do it the technique isn’t useless?

 

[Jonathan Edwards]

Even if this study may not the right one to do it the technique isn’t useless?

It really isn't a very intelligent way to try to get crucial data, to my mind. They are looking at peripheral blood. The repertoires of T and B cells floating about in the blood is'nt terribly likely to reflect anything much directly. In RA, where there are at least data of some interest, they relate to sampling of follicles from several different target organs - joints.

 

[hotblack]

It really isn't a very intelligent way to try to get crucial data, to my mind. They are looking at peripheral blood. The repertoires of T and B cells floating about in the blood is'nt terribly likely to reflect anything much directly. In RA, where there are at least data of some interest, they relate to sampling of follicles from several different target organs - joints.

Ah okay. Thanks. So it’s not the sequencing that’s the problem but the methodology, the sampling? Can you do single cell rnaseq on immune cells gathered from particular places of interest like follicles? Where would we be interested in looking?

 

[Jonathan Edwards]

So it’s not the sequencing that’s the problem but the methodology, the sampling? Can you do single cell rnaseq on immune cells gathered from particular places of interest like follicles?

You can but you get pretty much what would be expected in the context.
We have no idea where would be of interest in ME/CFS, except conceivably gut, but biopsying gut is not without risks.