Sanchez et al. (2025)
- Authors: Karla R. Sanchez, Jamie Burgess, Qin Zheng, Uazman Alam, Harvey Neiland, Richard Berwick, David Andersson, Samantha Korver, Anne Marshall, Andreas Goebel, Xinzhong Dong
- Institutes: Department of Pain Medicine, Institute of Life Course and Medical Sciences, University of Liverpool, Liverpool, UK, The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Wolfson Centre for Age-Related Diseases, King’s College London, London, UK, The Walton Centre NHS Foundation Trust, Liverpool, UK
- Publisher: bioRxiv
- Link: DOI
Summary
This research identifies a specific neuro-immune bridge—the MRGPRX2 receptor—that translates immune activity into chronic pain in fibromyalgia. By pinpointing mast cells as the critical link between circulating antibodies and sensory hypersensitivity, the study shifts the view of fibromyalgia toward a peripheral autoimmune disorder. This discovery opens the door for developing targeted drugs that could block this pain pathway at its source.
What was researched?
This study investigated whether mast cells and the MRGPRX2 receptor mediate the pain-sensitizing effects of patient-derived immunoglobulin G (IgG) in fibromyalgia syndrome (FMS).
Why was it researched?
While previous research demonstrated that FMS symptoms could be transferred to mice using patient IgG, the specific cellular and molecular targets through which these antibodies cause pain remained unknown.
How was it researched?
Researchers utilized a passive transfer model, injecting human FMS-IgG into mice with and without mast cells or the Mrgprb2 receptor (the rodent version of MRGPRX2). They also analyzed human skin biopsies for mast cell density and tested the activation of human mast cell lines by patient-derived antibodies.
What has been found?
FMS-IgG binds directly to and activates mast cells via the MRGPRX2 receptor, triggering the release of inflammatory mediators such as IL-6. Mice lacking this receptor were entirely protected from the mechanical and cold pain hypersensitivity induced by patient antibodies, and human FMS skin samples showed significantly higher mast cell density compared to controls.
Discussion
The study demonstrates that mast cells are essential for the development of pain in the FMS-IgG model, though they do not appear to mediate other symptoms like bowel dysfunction. As a preprint, these findings await final validation through the peer-review process.
Conclusion & Future Work
The researchers conclude that MRGPRX2 on mast cells is a critical mediator of autoantibody-induced pain in fibromyalgia. This finding suggests that inhibiting mast cells or the MRGPRX2 receptor represents a promising new therapeutic strategy for the condition.