[Preprint] The sensitising effect of IgG in fibromyalgia syndrome is mediated by Mrgprb2 in mast cells, 2025, Sanchez et al.

[SNT Gatchaman]

The sensitising effect of IgG in fibromyalgia syndrome is mediated by Mrgprb2 in mast cells

Spoiler: Authors

Karla R. Sanchez; Jamie Burgess; Qin Zheng; Uazman Alam; Harvey Neiland; Richard Berwick; David Andersson; Samantha Korver; Anne Marshall; Andreas Goebel; Xinzhong Dong

Fibromyalgia syndrome (FMS) is characterized by elevated levels of immunoglobulin G (IgG), altered bowel habits, and increased pain sensitivity, suggesting immune dysregulation, but the exact mechanism remains unclear.

Here, we found that FMS-IgG binds to mast cells in a MRGPRX2/b2-dependent manner, leading to mast cell recruitment and IL-6 secretion. Transferring serum-IgG from FMS patients to mice induced FMS-like symptoms and increased skin mast cells, indicating that FMS-IgG acts through mast cell activation.

The ablation of mice Mrgprb2 mast cells or deleting Mrgprb2 receptors prevented IgG-induced heightened sensitivity to mechanical and cold stimuli. Stimulating human LAD2 cells with FMS IgG elicited MRGPRX2-dependent IL-6 production. Consistent with mice findings, mast cell density and tryptase levels increased in human FMS skin samples compared to healthy controls.

Taken together our results suggests that FMS IgG mediates hypersensitivity via activation of mast cells bearing the MRGPRX2 receptor and that these cells are a potential therapeutic target.

Web | PDF | Preprint: BioRxiv | Open Access

 

[SNT Gatchaman]

I think we missed this back in May, but Cort has posted an article at HR — Turning the Pain up in Fibromyalgia (and ME/CFS?): The Antibody-Mast Cell Connection

 

[Jonathan Edwards]

Mast cells carry Fc gamma R1 !!

 

[SNT Gatchaman]

From the introduction —

In both humans and rodents, specific receptors expressed on mast cells, such as MRGPRX2 (humans) and Mrgprb2 (rodents), play a crucial role in mast cell activation [15,16] . These receptors, which respond to a broad range of ligands, trigger mast cell degranulation, releasing substances including cytokines (IL-6) and chemokines (CCL2) to amplify pain signals [9 ,17] and promote further mast cell recruitment [18,19]. IgG has not, been reported to directly bind to these receptors, however it can bind to Fc receptors (FcγRs) on mast cells. promoting degranulation with release of pro-inflammatory mediators such as histamine, cytokines (IL-6), and tryptase which can contribute to nociceptor sensitisation [9,20,21,22].

These processes cause hyperalgesia and allodynia, where painful stimuli are perceived as more painful, and normal stimuli are perceived as painful respectively [9,23,24]. Antidromic release of substance P from already-hyperactive sensory fibres activates mast cells to drive the release of mediators and further sensitise these fibres, perpetuating the pain phenotype [25]. We hypothesised that pro-algetic FMS IgG exerts its effect through activation of mast cells.

Spoiler: Those references are

Involvement of Mast Cells in the Pathophysiology of Pain (2021, Frontiers in Cellular Neuroscience)

Mast Cell-Mediated Mechanisms of Nociception (2015, International Journal of Molecular Sciences)

Mast cell activation: A complex interplay of positive and negative signaling pathways (2014, European Journal of Immunology)

Degranulation of Mast Cells as a Target for Drug Development (2023, Cells)

Mast cells: Versatile gatekeepers of pain (2015, Molecular Immunology)

MRGPRX2 signaling involves the Lysyl-tRNA synthetase and MITF pathway (2023, Frontiers in Immunology)

The Multifaceted Mas-Related G Protein-Coupled Receptor Member X2 in Allergic Diseases and Beyond (2021, International Journal of Molecular Sciences)

Therapeutic Potential of MRGPRX2 Inhibitors on Mast Cells (2021, Cells)

The human mast cell: functions in physiology and disease (2001, Frontiers in Bioscience-Landmark)

Mas-related G protein-coupled receptor MRGPRX2 in human basophils: Expression and functional studies (2023, Frontiers in Immunology)

FcɛRI et MRGPRX2 régulent différemment la dynamique de dégranulation des mastocytes (2018, Revue Française d'Allergologie)

IL-8 and IL-6 primarily mediate the inflammatory response in fibromyalgia patients (2016, Journal of Neuroimmunology)

Mast cell activation: A complex interplay of positive and negative signaling pathways (2014, European Journal of Immunology)

 

[wigglethemouse]

Mast cells, traditionally associated with allergic responses, are located near peripheral nerves and can influence pain sensitivity through the release of pro-inflammatory mediators such as histamine, cytokines (IL-6), and proteases (tryptase)9.

Since they were researching FM and pain, and mention mast cells locating around nerves, why doesn't anyone consider the fact that mast cells also secrete GranzmeB, which is cytotoxic, as a possible cause.

I'd really like to see researchers do some quality characterization of mast cells in much the same way they do for T cells and NK cells, and use some out of box thinking, instead of assuming cytokines etc........ Mast cells seem pretty complex and deserve better.

 

[wigglethemouse]

Mast cells carry Fc gamma R1 !!

Here is an article about "Mast cell Fcγ receptors (FcγR) for IgG" in case there is some useful information there. It also has references.

Mast cell Fcγ receptors (FcγR) for IgG – EMBRN – European Mast Cell and Basophil Research Network

embrn.eu