Biology subjects

Goebel, A.

Publications and source records attributed to Goebel, A..

5 recordsLinked to original sources

bioRxiv2025

Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome

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 naive 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 heavy chain 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, heavy chain 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.

immunology↗

bioRxiv2025

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

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.

immunology↗

bioRxiv2024

The biotoxin BMAA promotes mesenchymal transition in neuroblastoma cells

Mesenchymal-like cancer cells are an indicator of malignant tumors as they exhibit tumorigenic properties including downregulation of differentiation markers, and increased colony-forming potential, motility, and chemoresistance. We have previously demonstrated that the cyanobacterial biotoxin beta-methylamino-L-alanine (BMAA) is capable of influencing neural cell differentiation state through mechanisms involving the Wnt signaling pathway, suggesting the possibility that BMAA may play a role in influencing other Wnt related differentiation processes including mesenchymal transition. In this study we present evidence characterizing the effects of BMAA on mesenchymal transition in a human neuroblastoma cell line and provide support for the hypothesis that the biotoxin can promote this process in these cells by altering differentiation state, inducing changes in gene expression, and changing cellular function in manners consistent with cellular mesenchymal transition. Results of this study indicate that BMAA exposure may promote carcinogenesis through its effects on cell differentiation state in certain contexts. These results suggest that exposure to the biotoxin BMAA may be an influencing factor in chemotherapy resistance and cancer relapse in neuroblastoma.

molecular biology↗

bioRxiv2020

Disputing space-based biases in unilateral complex regional pain syndrome

There is some evidence that people with Complex Regional Pain Syndrome (CRPS) show reduced attention to the affected relative to unaffected limb and its surrounding space, resembling hemispatial neglect after brain injury. These neuropsychological symptoms could be related to central mechanisms of pathological pain and contribute to its clinical manifestation. However, the existing evidence of changes in spatial cognition is limited and often inconsistent. We examined visuospatial attention, the mental representation of space, and spatially-defined motor function in 54 people with unilateral upper-limb CRPS and 22 pain-free controls. Contrary to our hypotheses and previous evidence, individuals with CRPS did not show any systematic spatial biases in visuospatial attention to or representation of the side of space corresponding to their affected limb (relative to the unaffected side). We found very little evidence of directional slowing of movements towards the affected relative to unaffected side that would be consistent with motor neglect. People with CRPS were, however, slower than controls to initiate and execute movements with both their affected and unaffected hands, which suggests disrupted central motor networks. Finally, we found no evidence of any clinical relevance of changes in spatial cognition because there were no relationships between the magnitude of spatial biases and the severity of pain or other CRPS symptoms. The results did reveal potential relationships between CRPS pain and symptom severity, subjective body perception disturbance, and extent of motor impairment, which would support treatments focused on normalizing body representation and improving motor function. Our findings suggest that previously reported spatial biases in CRPS might have been overstated.

neuroscience↗

bioRxiv2019

Passive transfer of fibromyalgia pain from patients to mice.

Fibromyalgia syndrome (FMS) is a chronic pain condition characterized by widespread pain and tenderness1,2. The etiology and pathophysiology of fibromyalgia are unknown and there are no effective treatments. Here we show that sensory hypersensitivity in FMS is caused by autoantibodies that act by sensitizing nociceptive sensory neurons. Administration of IgG from FMS patients increased mouse pain sensitivities to stimulation with mechanical pressure and cold. In contrast, transfer of IgG depleted samples from FMS patients or IgG from healthy control subjects had no effect on pain sensitivity. Sensory nerve fibres in ex vivo skin-nerve preparations from mice treated with FMS IgG were hypersensitive to mechanical stimulation. Immunohistochemical analysis revealed that IgG from FMS patients specifically labeled satellite glial cells and myelinated fibre tracts, as well as a small number of macrophages and endothelial cells in mouse dorsal root ganglia but not skin, muscle, spinal cord and brain. Our results demonstrate that fibromyalgia pain is caused by IgG autoantibodies that sensitize peripheral nociceptive afferents neurons and suggest that therapies that reduce patient IgG titres may be effective treatments of fibromyalgia pain.

neuroscience↗