Deep Sequencing of BCR Heavy Chain Repertoires in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, 2025, Ryback et al

[forestglip]

Do you mind listing what those 3 studies were? The first thing that comes to mind to check is whether all of them were done after Covid started.

This thread's study, plus the following two:

Plasma proteomic profiling suggests an association between antigen driven clonal B cell expansion and ME/CFS, 2020, Lipkin et al

IGHV3-23/30 and immunoglobulin kappa variable region 3–11 were significantly associated with ME/CFS without sr-IBS.

Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome, 2021, Sato et al

By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.

The first one isn't exactly the same as the other two since they couldn't discriminate between IGHV3-23 and IGHV3-30, and the ME/CFS group seemed to have individuals with both very high and very low amounts of the combination of these gene segments:

Whilst 12 patients had extremely high levels (>100,000) of IGHV3-23/30, only 3 patients had extremely low levels (<25,000) of this protein.

I'm going to have to reread that one. I think I had misread before as it being IGHV3-23/30 on the BCR, but looks like it's actually antibodies in the first paper, with the following two being BCRs.

Here's the Ryback et al paper referencing the previous two studies:

BCR repertoire sequencing in ME/CFS and healthy controls (HCs) previously identified increased use of several Immunoglobulin Heavy Chain V (IGHV) gene segments in ME/CFS patients: IGHV-3-30 and IGHV3-30-3 gene usage was elevated in ME/CFS, particularly in patients who reported an infectious onset to their illness (19). The authors suggest this IGHV gene signature may represent a shared infection-elicited response among those ME/CFS patients.

This result putatively fits a signature of dysregulated IGHV3-30/IGHV3-23 antibody detected by plasma proteomic profiling (20).

With regard to COVID timing - I'm not sure about the Lipkin paper, though it was published near the start of the pandemic (2020), so the sample collection might have been before it. Sato et al says this:

Cohort 1 comprised patients recruited to NCNP hospital from October 2015 to December 2016. [...] To validate the results of BCR repertoire analysis, new patients with ME/CFS were recruited from NCNP hospital from January 2017 to November 2019, which comprised cohort 2

Ryback et al samples were from the CureME biobank, but I don't see dates of collection.

 

[SNT Gatchaman]

Tag for ighv

 

[jnmaciuch]

This thread's study, plus the following two:


The first one isn't exactly the same as the other two since they couldn't discriminate between IGHV3-23 and IGHV3-30, and the ME/CFS group seemed to have individuals with both very high and very low amounts of the combination of these gene segments:


I'm going to have to reread that one. I think I had misread before as it being IGHV3-23/30 on the BCR, but looks like it's actually antibodies in the first paper, with the following two being BCRs.

Here's the Ryback et al paper referencing the previous two studies:



With regard to COVID timing - I'm not sure about the Lipkin paper, though it was published near the start of the pandemic (2020), so the sample collection might have been before it. Sato et al says this:


Ryback et al samples were from the CureME biobank, but I don't see dates of collection.

Thanks! The conclusion from Sato et al. is exactly what I was going to say—none of these results look particularly like the BCR repertoires I’ve seen from a known auto-antibody mediated disease. What they do indicate to me is slightly differential efficacy of long term B cell response to vaccination or a pathogen encountered in the last few years. IGHV3-30 comes up specifically for SARS-CoV-2 spike protein, and since it is one of the more commonly used genes, I would imagine it could come up for seasonal viruses as well. Which might still point us towards underlying immune pathways in ME/CFS that regulate B cell responses, but a bit non-specifically at that.

 

[SNT Gatchaman]

IGHV3-30 comes up specifically for SARS-CoV-2 spike protein, and since it is one of the more commonly used genes, I would imagine it could come up for seasonal viruses as well.

Eg Longitudinal Multi-omics Analyses Identify Responses of Megakaryocytes, Erythroid Cells, and Plasmablasts as Hallmarks of Severe COVID-19 (2020) —

Analysis of immunoglobulin heavy-chain variable region (IGHV) family subunits showed a preponderance of specific V regions in COVID-19 patients compared with in controls, e.g., IGHV3-30 and IGHV3-23 were overrepresented in PBs and neutrophil-like cells during disease. In summary, we observed an increase in B cell clonality in COVID-19, and there was an increase of memory B cells and PBs, dominated by the IgA and IgG isotypes and a skewed use of the IGHV gene early during the disease course.

 

[forestglip]

I'm not sure about the Lipkin paper, though it was published near the start of the pandemic (2020)

Noting that they do say the exact date in Milivojevik/Lipkin 2020:

Blood samples were collected into BD VacutainerTM Cell Preparation Tubes (CPT) with sodium citrate anticoagulant between June and October 2014, and centrifuged to pellet red blood cells.

 

[hotblack]

Ryback et al samples were from the CureME biobank, but I don't see dates of collection.

I remember that 2019/20 winter before covid they were collecting but obviously stopped, as I had been scheduled to give more blood. I’m not sure exactly when they restarted but Caroline was doing limited home visits later in 2021 IIRC.

The Ryback paper mentions it uses the same samples as Dibble et al, published in Jan 2024 but that doesn’t mention dates either.

Would there have been time for the Biobank to collect, process, distribute and the team do their processing and research and write it up all in that window? Would there have been enough samples collected? And presumably unless there’s other requirements the Biobank get the older samples out into use first?

So I’d guess pre covid samples are most likely.