Tag: review

The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity

Abstract:

The prevalence of autoimmune diseases in contemporary human populations poses a challenge for both medicine and evolutionary biology. This review explores how the ancestral human leukocyte antigen class II (HLA-II) haplotypes DR2-DQ6, DR4-DQ8 and DR3-DQ2 could play a central role in susceptibility to these diseases.

We propose that these haplotypes, selected in historical contexts of high infectious pressure, may have been maintained because of their ability to elicit strong T-cell responses against pathogens; however, that antigenic promiscuity may be associated with an increased tendency toward immune hyperreactivity in modern environments. This hyperreactivity, involving proinflammatory cytokines including interferon-gamma (IFN-γ), could contribute to the breakdown of tolerance and the emergence of autoimmunity and related clinical phenomena (e.g., Long COVID, myalgic encephalomyelitis/chronic fatigue syndrome and post-vaccination syndromes), although the evidence for the latter remains limited.

Finally, we discuss how chronic infections, immunotherapies, vaccination, obesity and chronic physical stressors may exacerbate this susceptibility and consider the therapeutic implications of integrating HLA-II profiling into clinical practice.

Source: Ruiz-Pablos M, Paiva B, Zabaleta A. The origin of autoimmune diseases: is there a role for ancestral HLA-II haplotypes in immune hyperactivity. Front Immunol. 2025 Dec 4;16:1710571. doi: 10.3389/fimmu.2025.1710571. PMID: 41425584; PMCID: PMC12711860. https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2025.1710571/full (Full text)

Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex disorder marked by persistent fatigue and cognitive impairments, often termed “brain fog.” Emerging evidence suggests that immunosenescence, age- or stress-related deterioration of immune function, plays a pivotal role in the pathogenesis of cognitive dysfunction in ME/CFS.

Immunosenescence induces chronic low-grade inflammation (inflammaging); alters T-, NK-, and B-cell function; and promotes the release of senescence-associated secretory phenotype (SASP) factors. These changes are proposed to cerebral blood flow (CBF) regulation, may impair endothelial nitric oxide production, and may contribute to blood-brain barrier (BBB) breakdown. Consequently, brain hypoperfusion and oxidative stress are associated with impaired neuronal energy metabolism and synaptic plasticity, particularly in memory-related networks such as the default mode and fronto-hippocampal systems. This results in reduced ATP availability, excitotoxicity, and neurotransmitter imbalance, contributing to cognitive decline.

The review proposes an “immune-vascular-cognitive axis” linking peripheral immune aging to central neural dysfunction. It further highlights therapeutic strategies-such as cytokine blockade, nitric oxide enhancement, immune modulation, and acupuncture-that may ameliorate neurovascular impairments and cognitive symptoms. Understanding this integrative mechanism may offer new pathways for targeted intervention in ME/CFS.

Source: Xu H, Luo Y, Wu X. Immunosenescence-Driven Hemodynamic Dysregulation and Cognitive Impairment in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: An Integrative Perspective. Compr Physiol. 2026 Feb;16(1):e70098. doi: 10.1002/cph4.70098. PMID: 41527963. https://pubmed.ncbi.nlm.nih.gov/41527963/

Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a disabling clinical condition, whose hallmark characteristic is post-exertional malaise (PEM). It can affect many organs and systems, leading to severe impairment of patients’ quality of life. Although numerous post-infectious, immunological, neurological, metabolic, and endocrine alterations have been documented, neither a definitive diagnostic marker nor approved treatments are available. The etiology and pathophysiology remain incompletely understood; however, emerging evidence suggests that the gut microbiome plays a role in immune responses and the development of ME/CFS.

It is hypothesized that specific disturbances in gut microbiome composition, known as dysbiosis, may compromise the integrity of the intestinal barrier. This consequently leads to translocation of microbial components, which further triggers an immune response and systemic inflammation complicating the clinical presentation of ME/CFS. Furthermore, in terms of the so-called gut-brain axis, microbiome changes may lead to distinct neurocognitive impairments observed in ME/CFS patients.

This review offers the readers a broad perspective on the topic on ME/CFS, with a particular emphasis on the interplay between the gut microbiome and disease mechanisms. Last but not least, recent data on potential treatment strategies for intestinal dysbiosis in ME/CFS patients have been included.

Source: Nikolova R, Donchev D, Vaseva K, Ivanov IN. Gut Microbiome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): Insights into Disease Mechanisms. Int J Mol Sci. 2025 Dec 31;27(1):425. doi: 10.3390/ijms27010425. PMID: 41516296; PMCID: PMC12785659. https://pmc.ncbi.nlm.nih.gov/articles/PMC12785659/ (Full text)

Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis

Abstract:

Individuals with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) frequently report pronounced cognitive difficulties, yet the empirical literature has not fully characterised how discrete components of working memory are affected. Given that working memory serves as a foundational system supporting complex cognitive processes, differentiating performance across verbal and visual modalities provides critical insight into which higher-order functions may be most vulnerable. This systematic review/meta-analysis aimed to synthesise current research to investigate how ME/CFS impacts working memory systems.

Using PRISMA guidelines, a systematic search of 6 databases was undertaken (MEDLINE, CINAHL, Web of Science Core Collection, PubMed, EMBASE and PsycINFO). Initially, 10 574 papers were imported and following screening 34 studies of good to strong quality met the inclusion criteria. A series of random effects models were utilised to analyse working memory.

Results indicated a significant difference and large effect size between ME/CFS individuals and controls on verbal working memory tasks; however, no significant difference in visual working memory performance was found between the groups. Following the breakdown of these subsystems into span/attentional control tasks and object/spatial tasks, these results remained consistent.

These findings contribute to the body of ME/CFS research by articulating where specific working memory deficits lie. Specifically, they show that individuals with ME/CFS have impaired verbal memory performance. This knowledge can guide future research targeting higher-order verbal cognition and underscores the importance of recognising cognitive manifestations within ME/CFS clinical care.

Source: Penson M, Kelly K. Evaluating working memory functioning in individuals with myalgic encephalomyelitis/chronic fatigue syndrome: a systematic review and meta-analysis. Psychol Health Med. 2026 Jan 8:1-30. doi: 10.1080/13548506.2025.2606183. Epub ahead of print. PMID: 41504224. https://pubmed.ncbi.nlm.nih.gov/41504224/

Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease?

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating multisystem illness with unknown etiology. An estimated 17-24 million people representing approximately 1% of the population are afflicted worldwide. In over half of cases, ME/CFS onset is associated with acute “flu-like” symptoms, suggesting a role for viruses. However, no single virus has been identified as the only etiological agent.

This may reflect the approach employed or more strongly the central dogma associated with herpesviruses replication, which states that a herpesvirus exists in two states, either lytic or latent. The purpose of this review is to address the role that abortive lytic replication may have in the pathogenesis of ME/CFS and other post-acute viral infections and also to raise awareness that these syndromes might be poly-herpesviruses mediated diseases.

Source: Ariza ME, Mena Palomo I, Williams MV. Does Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Represent a Poly-Herpesvirus Post-Virus Infectious Disease? Viruses. 2025 Dec 16;17(12):1624. doi: 10.3390/v17121624. PMID: 41472292. https://www.mdpi.com/1999-4915/17/12/1624 (Full text)

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has garnered substantial scientific and clinical interest, due to its rising global prevalence and significant pathophysiological overlap with post-acute COVID-19 syndrome (PACS). This review systematically elucidates the prevailing diagnostic criteria, summarizes recent advances in understanding the potential pathophysiological mechanisms, and evaluates pharmacological and non-pharmacological interventions, and symptom-based assessment and management strategies.

Methods: A comprehensive literature search was conducted across PubMed, Web of Science, Embase, and the Cochrane Library for articles published from inception to August 2025.

Results: Current diagnostic frameworks for ME/CFS rely primarily on clinical symptomatology and lack definitive biomarkers. Immune dysregulation, oxidative stress, mitochondrial dysfunction, and neuroinflammation are central to its pathology. Pharmacological management includes immunomodulatory treatments, antioxidant therapies, mitochondrial support, and neuroinflammation intervention. Non-pharmacological strategies such as cognitive behavioral therapy (CBT), graded exercise therapy (GET), activity pacing, and traditional Chinese medicine (TCM) complement biomedical approaches by alleviating symptom severity and promoting energy conservation.

Conclusion: Among these approaches, CBT serves as an adjunctive therapy for symptom management rather than a curative one, whereas GET is contraindicated due to its potential for harm. Comprehensive clinical assessment and management of ME/CFS requires being symptom oriented and the recognition of individual differences. Recommended directions for future research include developing biomarker-based diagnostic tools, optimizing combination therapies that target multiple pathophysiological pathways simultaneously, and integrating real-world data and digital health technologies for precise monitoring and management of ME/CFS.

Source: Fan J, Jiao J, Chang HQ, Zhong DL, Liu XB, Li J, Chen LM, Jin RJ, Wu X. Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS): diagnosis and management. J Transl Med. 2025 Dec 9. doi: 10.1186/s12967-025-07506-y. Epub ahead of print. PMID: 41366804. https://link.springer.com/article/10.1186/s12967-025-07506-y

Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multifaceted disorder characterized by persistent fatigue, post-exertional malaise (PEM), cognitive dysfunction, sleep disturbance, pain, psychological distress, orthostatic intolerance, and impaired multidimensional health status and functioning. In the absence of reliable biomarkers, standardized symptom assessment is essential for accurate diagnosis and comparability across studies.

This narrative literature review synthesized studies identified through PubMed and Web of Science up to June 2024, covering assessment instruments across major ME/CFS symptom domains. Tools were evaluated for their psychometric validity, clinical applicability, and key limitations.

Overall, existing scales demonstrate acceptable reliability but vary in sensitivity and disease specificity. Harmonized, multidimensional, and digitally or objectively validated measures are needed to improve diagnostic precision, longitudinal monitoring, and clinical translation in ME/CFS.

Source: Lu J, Sun W, Li S, Qu Y, Liu T, Guo S, Feng C, Yang T. Assessment of symptoms in myalgic encephalomyelitis/chronic fatigue syndrome: a comparative study of existing scales. Front Neurol. 2025 Nov 18;16:1618272. doi: 10.3389/fneur.2025.1618272. PMID: 41341517; PMCID: PMC12668935. https://pmc.ncbi.nlm.nih.gov/articles/PMC12668935/ (Full text)

Differential Characteristics and Comparison Between Long-COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

Long-COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome are disabling diseases characterised by ongoing fatigue, post-exertional malaise, cognitive impairment, and autonomic dysfunction. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome typically follows viral infections, whereas Long-COVID exclusively follows SARS-CoV-2 infection, with overlapping but distinct features. This review uses comprehensive searches of online databases to compare their clinical presentations, pathophysiologies, and treatments.

Both Long-COVID and ME/CFS appear to involve multifactorial mechanisms, including viral persistence, immune dysregulation, endothelial dysfunction, and autoimmunity, though their relative contributions remain uncertain. Symptom management strategies are consistent, however. Cognitive behaviour therapy has been successful, and there are minimal drug treatments. Graded exercise therapy occupies a contested place, recommending individualised pacing and multidisciplinary rehabilitation.

Common and exclusive mechanisms must be identified to formulate valuable therapies. A more significant body of research focusing on immune dysfunction as a pathogenic mechanism for advancing the disease and enabling more effective therapies and diagnostics is needed.

Source: Ivanovska M, Homadi MS, Angelova G, Taskov H, Murdjeva M. Differential Characteristics and Comparison Between Long-COVID Syndrome and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Biomedicines. 2025 Nov 17;13(11):2797. doi: 10.3390/biomedicines13112797. PMID: 41301889; PMCID: PMC12650534. https://pmc.ncbi.nlm.nih.gov/articles/PMC12650534/ (Full text)

The Role of Nuclear and Mitochondrial DNA in Myalgic Encephalomyelitis: Molecular Insights into Susceptibility and Dysfunction

Abstract:

Myalgic Encephalomyelitis (ME), also known as chronic fatigue syndrome (CFS), is a debilitating and heterogeneous disorder marked by persistent fatigue, post-exertional malaise, cognitive impairment, and multisystem dysfunction. Despite its prevalence and impact, the molecular mechanisms underlying ME remain poorly understood.
This review synthesizes current evidence on the role of DNA, both nuclear and mitochondrial, in the susceptibility and pathophysiology of ME. We examined genetic predispositions, including familial clustering and candidate gene associations, and highlighted emerging insights from genome-wide and multi-omics studies.
Mitochondrial DNA variants and oxidative stress-related damage are discussed in relation to impaired bioenergetics and symptom severity. Epigenetic modifications, particularly DNA methylation dynamics and transposable element activation, are explored as mediators of gene–environment interactions and immune dysregulation.
Finally, we explored the translational potential of DNA-based biomarkers and therapeutic targets, emphasizing the need for integrative molecular approaches to advance diagnosis and treatment. Understanding the DNA-associated mechanisms in ME offers a promising path toward precision medicine in post-viral chronic diseases.
Source: Elremaly W, Elbakry M, Vahdani Y, Franco A, Moreau A. The Role of Nuclear and Mitochondrial DNA in Myalgic Encephalomyelitis: Molecular Insights into Susceptibility and Dysfunction. DNA. 2025; 5(4):53. https://doi.org/10.3390/dna5040053 https://www.mdpi.com/2673-8856/5/4/53 (Full text)

The Gut-Brain-Immune Axis in Environmental Sensitivity Illnesses: Microbiome-Centered Narrative Review of Fibromyalgia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity

Abstract:

Environmental sensitivity illnesses-including fibromyalgia syndrome (FMS), myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), and multiple chemical sensitivity (MCS)-are chronic, disabling disorders characterized by hypersensitivity to environmental stimuli, persistent fatigue, widespread pain, and neurocognitive and autonomic dysfunction. Although their diagnostic criteria differ, increasing evidence suggests overlapping clinical features and shared biological mechanisms. A unifying hypothesis highlights the gut-brain-immune axis, where alterations in the intestinal microbiome, epithelial barrier dysfunction, and aberrant immune signaling interact with central sensitization and systemic metabolic dysregulation.

Recent studies demonstrate reduced microbial diversity, depletion of anti-inflammatory taxa (e.g., Faecalibacterium prausnitzii, Bifidobacterium), and enrichment of pro-inflammatory Clostridium species across these conditions. These shifts likely alter production of short-chain fatty acids, amino acid metabolites, and complex lipids, with downstream effects on mitochondrial function, neuroinflammation, and host energy metabolism. Moreover, emerging clinical interventions-including probiotics, prebiotics, synbiotics, and fecal microbiota transplantation-suggest a potential role for microbiome-targeted therapies, though controlled evidence remains limited.

This review synthesizes current knowledge on microbiome alterations in FMS, ME/CFS, and MCS, emphasizing their convergence on metabolic and immune pathways. By integrating microbial, immunological, and neurophysiological perspectives, we propose a microbiome-centered framework for understanding environmental sensitivity illnesses and highlight avenues for translational research and therapeutic innovation.

Source: Watai K, Taniguchi M, Azuma K. The Gut-Brain-Immune Axis in Environmental Sensitivity Illnesses: Microbiome-Centered Narrative Review of Fibromyalgia Syndrome, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome, and Multiple Chemical Sensitivity. Int J Mol Sci. 2025 Oct 14;26(20):9997. doi: 10.3390/ijms26209997. PMID: 41155291. https://www.mdpi.com/1422-0067/26/20/9997 (Full text)