Category: Fibromyalgia

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

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.

Source: Rachael Bashford-Rogers, Alexander Long, Antonio Choi Chiu et al. Defective peripheral B cell tolerance leads to dysregulated B cell responses in Fibromyalgia Syndrome, 18 June 2025, PREPRINT (Version 1) available at Research Square [https://doi.org/10.21203/rs.3.rs-6836742/v1] https://www.researchsquare.com/article/rs-6836742/v1 (Full text)

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

Abstract:

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.

Source: Karla R. Sanchez, Jamie Burgess, Qin Zheng, Uazman Alam, Harvey Neiland, Richard Berwick, David Andersson, Samantha Korver, Anne Marshall, Andreas Goebel, Xinzhong Dong. The sensitising effect of IgG in fibromyalgia syndrome is mediated by Mrgprb2 in mast cells. bioRxiv 2025.05.15.652596; doi: https://doi.org/10.1101/2025.05.15.652596 https://www.biorxiv.org/content/10.1101/2025.05.15.652596v1.full (Full text)

Fibromyalgia syndrome—am I an autoimmune condition?

Abstract:

Assessments of serum-autoantibodies in fibromyalgia syndrome (FMS) date back to the 1980s and have yielded inconsistent results. Based on a new passive transfer paradigm, since 2021 causative involvement of immunoglobulin G–mediated autoimmunity in severe FMS has been demonstrated in several studies, which have included UK, Swedish, and Canadian patients. These findings open the path to the development of novel diagnostic and immune-therapeutic approaches.

Autoantibody targets and downstream mechanisms and the molecular processes that translate infection-, toxicity-, or stress-triggers into the FMS immune response in genetically or otherwise vulnerable individuals require study. These results in FMS also suggest that other chronic pain conditions or nonpainful symptom-based disorders may similarly be caused by noninflammatory minimally destructive autoantibody-mediated autoimmunity, thus offering hope for large groups of patients.

Source: Goebel A. Fibromyalgia syndrome-am I an autoimmune condition? Pain Rep. 2025 Jul 2;10(4):e1270. doi: 10.1097/PR9.0000000000001270. PMID: 40612406; PMCID: PMC12226001. https://pmc.ncbi.nlm.nih.gov/articles/PMC12226001/ (Full text)

Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review

Abstract:

Fibromyalgia (FM) is a chronic disease characterized by widespread musculoskeletal pain of unknown etiology. The condition is commonly associated with other symptoms, including fatigue, sleep disturbances, cognitive impairment, and depression. For this reason, FM is also referred to as FM syndrome. The nature of the pain is defined as nociplastic according to the latest international classification and is characterized by altered nervous sensitization both centrally and peripherally. Psychosocial conditions have traditionally been considered critical in the genesis of FM. However, recent studies in animal models and humans have provided new evidence in favor of an inflammatory and/or autoimmune pathogenesis.

In support of this hypothesis are epidemiological data of an increased female prevalence, similar to that of autoimmune diseases, and the frequent association with immune-mediated inflammatory disorders. In addition, the observation of an increased incidence of this condition during long COVID revived the hypothesis of an infectious pathogenesis. This narrative review will, therefore, discuss the evidence supporting the immune-mediated pathogenesis of FM in light of the most current data available in the literature.

Source: Paroli M, Gioia C, Accapezzato D, Caccavale R. Inflammation, Autoimmunity, and Infection in Fibromyalgia: A Narrative Review. Int J Mol Sci. 2024 May 29;25(11):5922. doi: 10.3390/ijms25115922. PMID: 38892110; PMCID: PMC11172859. https://pmc.ncbi.nlm.nih.gov/articles/PMC11172859/ (Full text)

Is fibromyalgia an autoimmune disorder?

Highlights:

  • Certain aspects of FM are still controversial, including pathophysiology, which remain a subject of debate
  • FM shares many clinical features, sometimes designing overlapping diseases, with other conditions, including, chronic fatigue syndrome (CFS), sick building syndrome (SBS), post-COVID syndrome, and many others
  • Anti-GPCR (anti- G protein-coupled receptor antibodies), autoantibodies directed against the autonomic nervous system receptors, have been detected in the serum of patients with FM, and their titers correlated with clinical symptoms
  • Fibromyalgia belongs to nociplastic pain which means that the central nervous system is the driving force behind this pain mechanism, and the key phenotypic features include widespread pain, fatigue, and sleep, memory, and mood disturbances

Abstract:

Fibromyalgia (FM) is a multifactorial syndrome which includes not only widespread pain and stiffness, now recognized as major symptoms, but also numerous other somatic, emotional, and neuropsychic manifestation. The lack of specific validated biological and instrumental biomarkers has made FM a condition of unexplained medical significance, and its pathophysiology remains controversial and subject to debate. The current hypothesis regarding the pathogenesis of FM proposes that its development is influenced by various mechanism, including genetic predisposition, stressful life events, inflammatory processes, and cognitive-emotional factors. However, despite the extensive research conducted to date, the available data do not provide a clear understanding of the pathogenesis of FM.
In this article, we report the opposing viewpoints of two leading experts who debate the question of whether FM is an autoimmune disease, based on scientific data regarding this condition. Both perspectives are discussed and the latest evidence on the pathophysiology of FM is reported to provide a comprehensive understanding of this complex syndrome.
Source: Clauw D, Sarzi-Puttini P, Pellegrino G, Shoenfeld Y. Is fibromyalgia an autoimmune disorder? Autoimmun Rev. 2024 Jan;23(1):103424. doi: 10.1016/j.autrev.2023.103424. Epub 2023 Aug 25. PMID: 37634681. https://www.sciencedirect.com/science/article/pii/S1568997223001581 (Full text)

Patient experiences of remote consulting with chronic fatigue syndrome/myalgic encephalomyelitis and fibromyalgia: a qualitative study

Abstract:

Background: Remote and digital consulting in primary care has rapidly expanded since March 2020. It is important to understand patient experiences, particularly for those living with complex long-term conditions, to identify how care can best be delivered, including within the remote space.

Aim: To explore the experiences of people living with chronic fatigue syndrome/myalgic encephalomyelitis (CFS/ME) and fibromyalgia when consulting remotely in primary care.

Design & setting: Semi-structured interviews with patients living with CFS/ME and fibromyalgia in general practice in England.

Method: Semi-structured interviews were carried out with 13 participants. The interviews were transcribed and analysed thematically according to a Foucauldian theoretical framework.

Results: All participants highlighted needing to feel believed by clinicians. Many reported difficulties with telephone and online consulting owing to the lack of physical communication. Positive outcomes were reported when there was a good relationship with a clinician. Continuity in care and recognising the complexity of these conditions were also considered important.

Conclusion: This study allowed people living with CFS/ME and fibromyalgia to describe their experiences when consulting remotely. Participants highlighted needing to feel listened to and felt they benefited from an ongoing relationship with a clinician although this was difficult to achieve when consulting remotely. Some advantages of remote consulting were reported, particularly when symptoms were troublesome. Flexible access systems, with a range of consultation modalities or preferred clinician(s) availability, could improve healthcare encounters, particularly given the increased use of remote consulting in primary care.

Source: Leach H, Eccles A, Chew-Graham CA, Atherton H. Patient experiences of remote consulting with chronic fatigue syndrome/myalgic encephalomyelitis and fibromyalgia: a qualitative study. BJGP Open. 2025 Apr 24;9(1):BJGPO.2024.0079. doi: 10.3399/BJGPO.2024.0079. PMID: 39191480; PMCID: PMC12137999. https://pmc.ncbi.nlm.nih.gov/articles/PMC12137999/ (Full text)

The gut microbiota promotes pain in fibromyalgia

Highlights:

• Transplanting gut microbiota from women with fibromyalgia into mice induces pain
• It also induces immune activation, metabolomic changes, and reduced skin innervation
• Gut microbiota promotes pain through several mechanisms
Summary:

Fibromyalgia is a prevalent syndrome characterized by widespread pain in the absence of evident tissue injury or pathology, making it one of the most mysterious chronic pain conditions. The composition of the gut microbiota in individuals with fibromyalgia differs from that of healthy controls, but its functional role in the syndrome is unknown. Here, we show that fecal microbiota transplantation from fibromyalgia patients, but not from healthy controls, into germ-free mice induces pain and numerous molecular phenotypes that parallel known changes in fibromyalgia patients, including immune activation and metabolomic profile alterations. Replacing the fibromyalgia microbiota with a healthy microbiota substantially alleviated pain in mice. An open-label trial in women with fibromyalgia (Registry MOH_2021-11-04_010374) showed that transplantation of a healthy microbiota is associated with reduced pain and improved quality of life. We conclude that altered gut microbiota has a role in fibromyalgia pain, highlighting it as a promising target for therapeutic interventions.
Source: Cai W, Haddad M, Haddad R, Kesten I, Hoffman T, Laan R, Westfall S, Defaye M, Abdullah NS, Wong C, Brown N, Tansley S, Lister KC, Hooshmandi M, Wang F, Lorenzo LE, Hovhannisyan V, Ho-Tieng D, Kumar V, Sharif B, Thurairajah B, Fan J, Sahar T, Clayton C, Wu N, Zhang J, Bar-Yoseph H, Pitashny M, Krock E, Mogil JS, Prager-Khoutorsky M, Séguéla P, Altier C, King IL, De Koninck Y, Brereton NJB, Gonzalez E, Shir Y, Minerbi A, Khoutorsky A. The gut microbiota promotes pain in fibromyalgia. Neuron. 2025 Apr 18:S0896-6273(25)00252-1. doi: 10.1016/j.neuron.2025.03.032. Epub ahead of print. PMID: 40280127. https://www.cell.com/neuron/fulltext/S0896-6273(25)00252-1 (Full text)

HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity

Abstract:

Research of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and fibromyalgia (FM), two acquired chronic illnesses affecting mainly females, has failed to ascertain their frequent co-appearance and etiology. Despite prior detection of human endogenous retrovirus (HERV) activation in these diseases, the potential biomarker value of HERV expression profiles for their diagnosis, and the relationship of HERV expression profiles with patient immune systems and symptoms had remained unexplored.

By using HERV-V3 high-density microarrays (including over 350k HERV elements and more than 1500 immune-related genes) to interrogate the transcriptomes of peripheral blood mononuclear cells from female patients diagnosed with ME/CFS, FM, or both, and matched healthy controls (n = 43), this study fills this gap of knowledge. Hierarchical clustering of HERV expression profiles strikingly allowed perfect participant assignment into four distinct groups: ME/CFS, FM, co-diagnosed, or healthy, pointing at a potent biomarker value of HERV expression profiles to differentiate between these hard-to-diagnose chronic syndromes.

Differentially expressed HERV-immune-gene modules revealed unique profiles for each of the four study groups and highlighting decreased γδ T cells, and increased plasma and resting CD4 memory T cells, correlating with patient symptom severity in ME/CFS. Moreover, activation of HERV sequences coincided with enrichment of binding sequences targeted by transcription factors which recruit SETDB1 and TRIM28, two known epigenetic silencers of HERV, in ME/CFS, offering a mechanistic explanation for the findings.

Unexpectedly, HERV expression profiles appeared minimally affected in co-diagnosed patients denoting a new nosological entity with low epigenetic impact, a seemingly relevant aspect for the diagnosis and treatment of this prevalent group of patients.

Source: Giménez-Orenga K, Martín-Martínez E, Nathanson L, Oltra E. HERV activation segregates ME/CFS from fibromyalgia while defining a novel nosologic entity. Elife. 2025 May 8;14:RP104441. doi: 10.7554/eLife.104441. PMID: 40338225. https://elifesciences.org/articles/104441 (Full text)

Recognizing the role of fibromyalgia in post-exertional malaise

Letter:

The recent opinion by Charlton et al. published in Trends in Endocrinology & Metabolism [] provides a thought-provoking discussion of the overlap between long coronavirus disease (long-COVID) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), emphasizing the centrality of post-exertional malaise (PEM) as a shared mechanism.

Here, we suggest that fibromyalgia should be included in the discussion, given the established role of PEM in this condition []. In addition, fibromyalgia not only shares symptomatic and mechanistic overlaps with ME/CFS, but also offers a complementary perspective on the pathophysiology of PEM. Considering that PEM is a key symptom in both fibromyalgia and long COVID, exploring skeletal muscle function in fibromyalgia could provide complementary insights into the muscle-specific alterations that contribute to this debilitating phenomenon.

Source: Giollo A, Salvato M, Doria A. Recognizing the role of fibromyalgia in post-exertional malaise. Trends Endocrinol Metab. 2025 Mar 11:S1043-2760(25)00045-1. doi: 10.1016/j.tem.2025.02.005. Epub ahead of print. PMID: 40074568. https://www.cell.com/trends/endocrinology-metabolism/abstract/S1043-2760(25)00045-1

Mitochondrial structural alterations in fibromyalgia: a pilot electron microscopy study

Abstract:

Objectives: The pathogenesis of fibromyalgia (FM), characterised by chronic widespread pain and fatigue, remains notoriously elusive, hampering attempts to develop disease modifying treatments. Mitochondria are the headquarters of cellular energy metabolism, and their malfunction has been proposed to contribute to both FM and chronic fatigue. Thus, the aim of the current pilot study, was to detect structural changes in mitochondria of peripheral blood mononuclear cells (PBMCs) of FM patients, using transmission electron microscopy (TEM).

Methods: To detect structural mitochondrial alterations in FM, we analysed PBMCs from seven patients and seven healthy controls, using TEM. Patients were recruited from a specialised Fibromyalgia Clinic at a tertiary medical centre. After providing informed consent, participants completed questionnaires including the widespread pain index (WPI), symptoms severity score (SSS), fibromyalgia impact questionnaire (FIQ), beck depression inventory (BDI), and visual analogue scale (VAS), to verify a diagnosis of FM according to ACR criteria. Subsequently, blood samples were drawn and PBMCs were collected for EM analysis.

Results: TEM analysis of PBMCs showed several distinct mitochondrial cristae patterns, including total loss of cristae in FM patients. The number of mitochondria with intact cristae morphology was reduced in FM patients and the percentage of mitochondria that completely lacked cristae was increased. These results correlated with the WPI severity. Moreover, in the FM patient samples we observed a high percentage of cells containing electron dense aggregates, which are possibly ribosome aggregates. Cristae loss and possible ribosome aggregation were intercorrelated, and thus may represent reactions to a shared cellular stress condition. The changes in mitochondrial morphology suggest that mitochondrial dysfunction, resulting in inefficient oxidative phosphorylation and ATP production, metabolic and redox disorders, and increased reactive oxygen species (ROS) levels, may play a pathogenetic role in FM.

Conclusions: We describe novel morphological changes in mitochondria of FM patients, including loss of mitochondrial cristae. While these observations cannot determine whether the changes are pathogenetic or represent an epiphenomenon, they highlight the possibility that mitochondrial malfunction may play a causative role in the cascade of events leading to chronic pain and fatigue in FM. Moreover, the results offer the possibility of utilising changes in mitochondrial morphology as an objective biomarker in FM. Further understanding the connection between FM and dysfunction of mitochondria physiology, may assist in developing both novel diagnostic tools as well as specific treatments for FM, such as approaches to improve/strengthen mitochondria function.

Source: Israel L, Furer V, Levin-Zaidman S, Dezorella N, Brontvein O, Ablin JN, Gross A. Mitochondrial structural alterations in fibromyalgia: a pilot electron microscopy study. Clin Exp Rheumatol. 2024 Jun;42(6):1215-1223. doi: 10.55563/clinexprheumatol/3l0ihz. Epub 2024 Jun 28. PMID: 38966946. https://www.clinexprheumatol.org/abstract.asp?a=21119 (Full text available as PDF file)