Preprint Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome, 2025, Rachael Bashford-Rogers et al

[Mij]

Abstract

Fibromyalgia syndrome (FMS) is a chronic pain disorder characterised by widespread musculoskeletal pain, fatigue, and cognitive dysfunction, with no definitive biomarkers or mechanism-based treatments. Emerging evidence suggests that immune dysregulation may contribute to the FMS pathogenesis, particularly involving B cells, which have been implicated in autoantibody production and neuronal sensitisation.

However, whether peripheral B cell tolerance, a critical safeguard against autoimmunity, is compromised in FMS remains unknown. Here, we combined high-resolution B cell receptor (BCR) repertoire sequencing, deep immunophenotyping, and functional assays in a well-characterised FMS cohort to uncover profound defects in peripheral B cell tolerance.

We reveal significant defects in peripheral B cell tolerance in FMS, including: (1) impaired naïve B cell anergy, marked by elevated CD21, CD22, and CD24 expression; (2) exaggerated proliferative responses and rapid CD24 downregulation upon stimulation; and (3) altered BCR selection patterns, with increased IGHV6-1/IGHJ6 usage, skewed class switching toward IGHA1, and enhanced clonal expansion. These features closely resemble immune pathology profiles observed in classical autoimmune diseases.

These findings redefine FMS as a disorder of immune dysregulation, with defective B cell tolerance contributing to disease mechanisms. The convergence of interferon-driven B cell activation, clonal expansion, and autoantibody production suggests shared pathways with classical autoimmune diseases.

Our study provides a foundation for mechanism-based diagnostics and targeted immunomodulatory therapies, offering new avenues for intervention in this debilitating condition.
LINK

 

[Hutan]

There's been a bit of mention of increased IGHV (immunoglobulin heavy chain) usage lately, click on the tag to see the papers.
Also note mention of neuronal sensitisation from the periphery and interferon.

This paper looks like it is worth a read I think, I haven't got to it yet. From a UK team.

 

[jnmaciuch]

I will delve into this more when I have a chance. One thing that confused me off the bat is this claim in the introduction:

Interferons (IFNs), particularly IFN-γ, are consistently upregulated in FMS and may drive both neuronal sensitization and immune dysfunction.

The sentence has no citation (and none of the preceding or following sources mention it). And I was just looking at this meta-analysis which claims that 6 studies did not find consistent increase of IFN-γ in fibro.

And looking at the study itself, there's nothing that seems to implicate interferon directly, so I'm quite confused why they even mentioned it in the abstract as if their study shows something along those lines. In the intro they cite several studies showing the effects of type I interferons (mostly alpha & beta) on B-cells, so perhaps they're trying to argue that the differences seen in this study model after those type I interferon-associated changes in other illnesses. Though they barely bring it up for one sentence in the discussion to even try to tie it back in.

 

[Jonathan Edwards]

I sense a paper designed to fit a favored theory but it does look worth detailed discussion. CD24 comes up again.

 

[wigglethemouse]

I sense a paper designed to fit a favored theory but it does look worth detailed discussion. CD24 comes up again.

Is it worth forwarding the paper to Prof Cambridge as this is in her interest area? Another chance for tea and biscuits and a natter.

 

[Jonathan Edwards]

Good plan Batman.

 

[SNT Gatchaman]

If I've read correctly there seem to be some opposite findings to those in ME/CFS, eg In vitro B cell experiments explore the role of CD24, CD38, and energy metabolism in ME/CFS (2024)

Upon stimulation, the naïve B cells more readily reduced their CD24 expression, a known negative regulator of B cell activation, and exhibited exaggerated proliferative responses.

We also confirmed the dysregulation of CD24 expression on B cells from ME/CFS patients. Purified B cells from healthy donors exposed to agonists in transwell cultures showed a sharp decrease (~50%) of CD24+ B cells during the first 3 days of culture, but loss of CD24 from cultured B cells from ME/CFS patients was significantly “delayed” following stimulation, with a high proportion of cultured B cells from ME/CFS patients showing a continued expression of CD24 compared with B cells from healthy donors.

The lag in loss of CD24 from a high percentage of ME/CFS B cells may reflect their relatively slower rate of entry into the cell cycle compared with B cells from HC.

There are both similarities and differences in this FM paper wrt naive B-cell proportions (increased in both) and class-switching (FM = up, ME = down), compared to Deep phenotyping of post-infectious myalgic encephalomyelitis/chronic fatigue syndrome (2024)

Most notably, FMS patients had a significantly higher proportion of naïve B cells at day 0 (p-value=0.0053) and significantly lower proportions of plasmablasts (p-values<0.03).

Memory B cells and Plasmablasts were also more proliferative, with evidence of dysregulated clonal expansions, class-switching (skewed toward IGHA1) and somatic hypermutation, and altered selection patterns (increased IGHV6-1/IGHJ6 usage) resembling autoimmune diseases.

There were increased naïve B-cells and decreased switched memory B-cells in blood of PI-ME/CFS participants. However, contrary to prior published work, there was no consistent pattern of autoimmunity.