Tag: autoimmunity

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)

Advancing research on regulatory autoantibodies targeting GPCRs: Insights from the 5th international symposium

Abstract:

The 5th International Symposium on Regulatory Autoantibodies Targeting GPCR (RAB-GPCRs) advanced the understanding of the significant role played by autoantibodies targeting G-protein-coupled receptors (GPCRs) in various human diseases. Once considered passive markers, RAB-GPCRs are now recognized as active modulators of cellular signaling, immune regulation, and inflammation.

The symposium highlighted their involvement in multiple prominent pathologies, including autoimmune diseases, cardio- and cerebrovascular diseases, and neuroimmunologic disorders such as myalgic encephalomyelitis/chronic fatigue syndrome and post-COVID-19 syndrome (ME/CFS/PCS), as well as solid organ and hematopoietic stem cell transplantation (SOT/HSCT). Experts from rheumatology, immunology, and neurology presented interdisciplinary discussions on the potential of RAB-GPCRs as biomarkers and therapeutic targets. Advances in screening methods, biomarker identification, and therapeutic strategies were shared, emphasizing their diagnostic potential and application in novel therapeutic interventions.

This report summarizes key insights from the symposium, particularly focusing on the modulatory properties of RAB-GPCRs and their relevance in both immune-mediated diseases and other pathologies (e.g., vascular, degenerative) that are traditionally not considered primarily immune-mediated. Ongoing research is expected to further establish these autoantibodies as crucial components in disease modulation and systems biology contexts, offering new opportunities for precision medicine and improved clinical outcomes in immune-related disorders.

Source: Cabral-Marques O, Schimke LF, Moll G, Filgueiras IS, Nóbile AL, Adri AS, do Vale FYN, Usuda JN, Corrêa YLG, Albuquerque D, Nava RG, Santos RS, Dias HD, Silva HF, Marconi PB, Catar R, Adu-Gyamfi M, Wang P, Khan TA, Hackel AM, Leheis A, Stähle A, Müller A, Schmidt C, Radunovic C, Adjailia EB, Grasshoff H, Humrich JY, Menz J, Fourlakis K, Winziers M, Jäpel M, Wegner MV, Lamprecht P, Nieberding R, Akbarzadeh R, Arnold S, Jendrek S, Klapa S, Augustin S, Biedermann S, Schinke S, Scheerer P, Endres M, Schulze-Forster K, Paul F, Yu X, Sotzny F, Sakmar TP, Banasik M, Haghikia A, Hoffmann MH, Veprintsev D, Witte T, Dalmolin RJS, Ochs HD, Heidecke H, Scheibenbogen C, Shoenfeld Y, Riemekasten G. Advancing research on regulatory autoantibodies targeting GPCRs: Insights from the 5th international symposium. Autoimmun Rev. 2025 Jun 19:103855. doi: 10.1016/j.autrev.2025.103855. Epub ahead of print. PMID: 40543860. https://www.sciencedirect.com/science/article/pii/S1568997225001156 (Full text)

How pandemics reshape our brain: Common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration

Highlights:

  • Fatiguing syndromes affect millions of patients in the United States and globally, but are grossly underserved in the clinic and in the contemplative design of basic research.
  • Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem metabolic-immune-inflammatory disorder. Although research on this condition is in its infancy, it appears to involve the immune system and central nervous system malfunction, with cellular oxidative stress as a predominant feature.
  • Approximately half of the cases of long-haul coronavirus disease 2019 meet the diagnostic criteria for ME/CFS, burgeoning the number of affected individuals.
  • Recent strides in neurobiology have yet to transfer the understanding of the neurodegenerative aspects, and potential for neuroprotection, of ME/CFS.
  • ME/CFS may represent a useful paradigm and research model for the study of the impact of sustained oxidative stress on the central nervous system and the body at large.

Archeological findings from the bubonic plague era onward have demonstrated how pandemics can exert selective pressures, as will be highlighted. In particular, the short-term survival advantage during pandemics of individuals with greater immune “plasticity” comes at the cost of increased susceptibility to autoimmunity. Certain viral infections appear to trigger persistent immune system dysregulation, leading to broad autoimmunity and a sequelae of multisystem pathophysiologies with diverse symptoms long after the virus is cleared.

Human coronavirus 2019 (HCoV-19) is the most recent virus that appears to have elevated the incidence of autoimmune diseases in infected individuals. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an autoimmune, multisystem fatiguing syndrome affecting approximately 20 million people globally, representing 1.3% of adults in the United States.1, 2 It involves metabolic, immune, and inflammatory processes, with central nervous system (CNS) dysfunction and cellular oxidative stress being prominent features. Notably, about half of long-haul coronavirus disease 2019 (COVID-19) cases meet the diagnostic criteria for ME/CFS, potentially doubling or tripling its prevalence.

This article highlights ME/CFS, a nascent research area, as a model for neurological pathophysiological outcomes resulting from persistently high oxidative stress levels. Patients with ME/CFS, many who have had this condition for decades, form an underutilized patient population for this study.

A second objective of this Research Highlight is to correct recent reports that have attempted to “retrofit” principles and outcomes from other neurologic diseases to ME/CFS. This has led some neuroscientists to extrapolate erroneously that ME/CFS is not a neurodegenerative disorder. However, substantial evidence indicates that autoimmune ME/CFS is a neurodegenerative disease.

Source: Herman ME. How pandemics reshape our brain: common links and targets between long-haul COVID-19, myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), oxidative stress, and neurodegeneration. Neuroprotection. 2025; 1–8. doi:10.1002/nep3.70007 https://onlinelibrary.wiley.com/doi/10.1002/nep3.70007 (Full text)

 

HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab

Abstract:

This article summarizes the case of 30-year-old male diagnosed with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) and its longitudinal follow-up, which provided a secondary diagnosis of Multiple Sclerosis (MS) eight years later. The most impactful result was his response to rituximab treatment after the systematic failure of prior treatments.

Although the expression of endogenous retroviral proteins has been associated with autoimmunity, the patient did not show increased expression of the toxic protein HERV (human endogenous retrovirus)-W ENV, a target of the ongoing clinical trials with temelimab in MS and long COVID-19 cases. However, genome-wide HERV transcriptome analysis by high density microarrays clearly revealed a distinct profile in the patient’s blood supportive of an altered immune system.

Limitations of the study include sub-optimal frequency of magnetic resonance imaging to monitor lesion progression, and similarly for reassessment of HERV profiles after rituximab. Overall, the coincidence of HERV alterations and the impactful response to rituximab presents the possibility of additional, more specific, therapeutic targets encoded by other HERV elements yet to be discovered.

Source: Martín-Martínez E, Gil-Perotin S, Giménez-Orenga K, Barea-Moya L, Oltra E. HERV Dysregulation in a Case of Myalgic Encephalomyelitis and Multiple Sclerosis Responsive to Rituximab. Int J Mol Sci. 2025 May 20;26(10):4885. doi: 10.3390/ijms26104885. PMID: 40430026; PMCID: PMC12111851. https://pmc.ncbi.nlm.nih.gov/articles/PMC12111851/ (Full text)

Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19 (PASC)

Summary:

  • Immune dysregulation is a key aspect of post-acute sequelae of coronavirus disease 2019 (PASC), also known as long COVID, with sustained activation of immune cells, T cell exhaustion, skewed B cell profiles, and disrupted immune communication thereby resulting in autoimmune-related complications.
  • The gut is emerging as a critical link between microbiota, metabolism and overall dysfunction, potentially sharing similarities with other chronic fatigue conditions and PASC.
  • Immunothrombosis and neurological signalling dysfunction emphasise the complex interplay between the immune system, blood clotting, and the central nervous system in the context of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection.
  • Clear research gaps in the design of PASC studies, especially in the context of longitudinal research, stand out as significant areas of concern.

Source: Adhikari, A., Maddumage, J., Eriksson, E.M., Annesley, S.J., Lawson, V.A., Bryant, V.L. and Gras, S. (2024), Beyond acute infection: mechanisms underlying post-acute sequelae of COVID-19 (PASC). Med J Aust, 221: S40-S48. https://doi.org/10.5694/mja2.52456 https://onlinelibrary.wiley.com/doi/full/10.5694/mja2.52456 (Full text)

Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study

Abstract:

Background: Since the pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has become the leading trigger for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Evidence indicates that autoimmunity plays an important pathophysiological role. We aimed to evaluate the effectiveness of IA treatment in post-COVID ME/CFS patients.

Methods: This pre-post study included 20 post-coronavirus disease 2019 (COVID) ME/CFS patients found to have elevated β2 adrenergic autoantibodies (β2 AR-AB) between October 2022 and October 2023. Patients, with a median disease duration of 22 months (IQR: 15-31), were treated with five immunoadsorption sessions at Charité – Universitätsmedizin Berlin, Germany. Seven were male and 13 female, with a median age of 40 years (IQR: 36-51). The primary end point was the change in the Short Form (36) Health Survey physical functioning domain (SF36 PF) from baseline to four weeks post immunoadsorption. Key symptoms were assessed via questionnaires over six months. Handgrip strength and EndoPAT® measurements were used to evaluate muscle fatigue and vascular dysfunction. Seven patients who worsened after an initial response received a second cycle.

Findings: The treatment was generally well tolerated, reducing total immunoglobulin G by 79% (CI: 73-84%) and β2 AR-AB by 77% (CI: 58-95%). Patients demonstrated a mean increase in the SF36 PF of 17.75 points (CI: 13.41-26.16), with the greatest improvement occurring between months two and three, and significant gains maintained through month six. 14/20 (70%) patients were categorized as responders with an increase in the SF36 PF of ≥ ten points. Further lasting improvements were reported in fatigue, post-exertional malaise, pain, cognitive, autonomic, and immunological symptoms. Female patients had increased repeat handgrip strength at month six.

Interpretation: Immunoadsorption may improve symptoms in post-COVID ME/CFS patients. The beneficial effects of IgG depletion suggest a significant role for autoantibodies and disturbed B-cell function in the condition’s pathophysiology.

Funding: Funded by The Federal Ministry of Education and Research and the Weidenhammer Zöbele Research Foundation.

Source: Stein E, Heindrich C, Wittke K, Kedor C, Rust R, Freitag H, Sotzny F, Krüger A, Tölle M, Grabowski P, Scheibenbogen C, Kim L. Efficacy of repeated immunoadsorption in patients with post-COVID myalgic encephalomyelitis/chronic fatigue syndrome and elevated β2-adrenergic receptor autoantibodies: a prospective cohort study. Lancet Reg Health Eur. 2024 Dec 12;49:101161. doi: 10.1016/j.lanepe.2024.101161. PMID: 39759581; PMCID: PMC11699797. https://pmc.ncbi.nlm.nih.gov/articles/PMC11699797/ (Full text)

Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing

Abstract:

The pathogenesis of Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains unclear, though increasing evidence suggests inflammatory processes play key roles. In this study, single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) was used to decipher the immunometabolic profile in 4 ME/CFS patients and 4 heathy controls.

We analyzed changes in the composition of major PBMC subpopulations and observed an increased frequency of total T cells and a significant reduction in NKs, monocytes, cDCs and pDCs. Further investigation revealed even more complex changes in the proportions of cell subpopulations within each subpopulation. Gene expression patterns revealed upregulated transcription factors related to immune regulation, as well as genes associated with viral infections and neurodegenerative diseases.

CD4+ and CD8+ T cells in ME/CFS patients show different differentiation states and altered trajectories, indicating a possible suppression of differentiation. Memory B cells in ME/CFS patients are found early in the pseudotime, indicating a unique subtype specific to ME/CFS, with increased differentiation to plasma cells suggesting B cell overactivity. NK cells in ME/CFS patients exhibit reduced cytotoxicity and impaired responses, with reduced expression of perforin and CD107a upon stimulation. Pseudotime analysis showed abnormal development of adaptive immune cells and an enhanced cell-cell communication network converging on monocytes in particular.

Our analysis also identified the estrogen-related receptor alpha (ESRRA)-APP-CD74 signaling pathway as a potential biomarker for ME/CFS in peripheral blood. In addition, data from the GSE214284 database confirmed higher ESRRA expression in the monocyte cell types of male ME/CFS patients. These results suggest a link between immune and neurological symptoms.

The results support a disease model of immune dysfunction ranging from autoimmunity to immunodeficiency and point to amyloidotic neurodegenerative signaling pathways in the pathogenesis of ME/CFS. While the study provides important insights, limitations include the modest sample size and the evaluation of peripheral blood only.

These findings highlight potential targets for diagnostic biomarkers and therapeutic interventions. Further research is needed to validate these biomarkers and explore their clinical applications in managing ME/CFS.

Source: Sun Y, Zhang Z, Qiao Q, Zou Y, Wang L, Wang T, Lou B, Li G, Xu M, Wang Y, Zhang Z, Hou X, Chen L, Zhao R. Immunometabolic changes and potential biomarkers in CFS peripheral immune cells revealed by single-cell RNA sequencing. J Transl Med. 2024 Oct 11;22(1):925. doi: 10.1186/s12967-024-05710-w. PMID: 39394558. https://translational-medicine.biomedcentral.com/articles/10.1186/s12967-024-05710-w (Full text)

Autoimmunity’s enigmatic role: exploring the connection with myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complicated, heterogeneous condition distinguished by post-exertional neuroimmune exhaustion and multisystem symptoms. Its complexity poses challenges for physicians, researchers and those inflicted by its presence. Due to conflicting evidence and limiting consensus, the association and contribution autoimmunity serves in the pathophysiology or aetiology of ME/CFS is yet to be confirmed. This systematic review synthesises the currently available data to clarify the role autoimmunity has in the pathogenesis of ME/CFS and explore the therapeutic limitations.

Methods: This systematic review was conducted in accordance with the PRISMA and Cochrane guidelines. Full-text articles containing the primary key terms “Autoimmunity/Autoimmune” and “ME/CFS” were included provided their suitability to the inclusion and exclusion criteria.

Results: Ten publications investigating the role of autoimmunity in ME/CFS were examined. One investigated the role of cytokine signalling; Three investigated the genetic nature of autoimmunity in ME/CFS patients; One examined the immune lineage of ME/CFS patients; Six investigated the presence and role of autoantibodies in ME/CFS patients.

Conclusion: The findings generated from this systematic review highlight inconsistent and insufficient evidence to classify ME/CFS as an autoimmune disease. Additionally, it further emphasises the complexity of ME/CFS and highlights the challenges in distinguishing autoreactivity from deregulatory processes. Future research is urgently needed to advance the development of diagnostic and treatment strategies.

Source: Batham J, Dwyer J, Eaton-Fitch N, Marshall-Gradisnik S. Autoimmunity’s enigmatic role: exploring the connection with myalgic encephalomyelitis/chronic fatigue syndrome. BMC Immunol. 2024 Oct 1;25(1):62. doi: 10.1186/s12865-024-00657-5. PMID: 39354352. https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-024-00657-5 (Full text)

Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances.

A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH. As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology.

It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene. In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress.

Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.

Source: Manuel Ruiz-Pablos, Bruno Paiva, Aintzane Zabaleta. Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis. Front. Immunol., 08 July 2024, Sec. Viral Immunology, Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1422940 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available.

Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease’s multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances.

This comprehensive model not only advances our understanding of ME/CFS’s pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease’s complexity and the multifaceted approach required for its study and management.

Source: Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol. 2024 Jun 3;15:1386607. doi: 10.3389/fimmu.2024.1386607. PMID: 38887284; PMCID: PMC11180809. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180809/ (Full text)