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12 pages, 787 KiB

Open AccessArticle

The SNP rs2298383 Reduces ADORA2A Gene Transcription and Positively Associates with Cytokine Production by Peripheral Blood Mononuclear Cells in Patients with Multiple Chemical Sensitivity

by Attilio Cannata, Chiara De Luca, Liudmila G. Korkina, Nadia Ferlazzo, Riccardo Ientile, Monica Currò, Giulia Andolina and Daniela Caccamo

Int. J. Mol. Sci. 2020, 21(5), 1858; https://doi.org/10.3390/ijms21051858 - 9 Mar 2020

Cited by 6 | Viewed by 4420

Abstract

Systemic inflammation and immune activation are striking features of multiple chemical sensitivity (MCS). The rs2298383 SNP of ADORA2A gene, coding for adenosine receptor type 2A (A2AR), has been involved in aberrant immune activation. Here we aimed to assess the prevalence of this SNP [...] Read more.

Systemic inflammation and immune activation are striking features of multiple chemical sensitivity (MCS). The rs2298383 SNP of ADORA2A gene, coding for adenosine receptor type 2A (A2AR), has been involved in aberrant immune activation. Here we aimed to assess the prevalence of this SNP in 279 MCS patients and 238 healthy subjects, and its influence on ADORA2A, IFNG and IL4 transcript amounts in peripheral blood mononuclear cells of randomly selected patients (n = 70) and controls (n = 66) having different ADORA2A genotypes. The ADORA2A rs2298383 TT mutated genotype, significantly more frequent in MCS patients than in controls, was associated with a three-fold increased risk for MCS (O.R. = 2.86; C.I. 95% 1.99–4.12, p < 0.0001), while the CT genotype, highly prevalent among controls, resulted to be protective (O.R. = 0.33; C.I. 95% 0.224–0.475, p < 0.0001). Notably, ADORA2A mRNA levels were significantly lower, while IFNG, but not IL4, mRNA levels were significantly higher in TT MCS patients compared with controls. A significant negative correlation was found between ADORA2A and both IFNG and IL4, while a significant positive correlation was found between IFNG and IL4. These findings suggest that A2AR defective signaling may play a relevant role in PBMC shift towards a pro-inflammatory phenotype in MCS patients. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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15 pages, 1680 KiB

Open AccessArticle

Identification of MOR-Positive B Cell as Possible Innovative Biomarker (Mu Lympho-Marker) for Chronic Pain Diagnosis in Patients with Fibromyalgia and Osteoarthritis Diseases

by William Raffaeli, Valentina Malafoglia, Antonello Bonci, Michael Tenti, Sara Ilari, Paola Gremigni, Cristina Iannuccelli, Chiara Gioia, Manuela Di Franco, Vincenzo Mollace, Laura Vitiello, Carlo Tomino and Carolina Muscoli

Int. J. Mol. Sci. 2020, 21(4), 1499; https://doi.org/10.3390/ijms21041499 - 22 Feb 2020

Cited by 28 | Viewed by 6760

Abstract

Fibromyalgia (FM) diagnosis follows the American College of Rheumatology (ACR) criteria, based on clinical evaluation and written questionnaires without any objective diagnostic tool. The lack of specific biomarkers is a tragic aspect for FM and chronic pain diseases in general. Interestingly, the endogenous [...] Read more.

Fibromyalgia (FM) diagnosis follows the American College of Rheumatology (ACR) criteria, based on clinical evaluation and written questionnaires without any objective diagnostic tool. The lack of specific biomarkers is a tragic aspect for FM and chronic pain diseases in general. Interestingly, the endogenous opioid system is close to the immune one because of the expression of opioid receptors on lymphocytes membrane. Here we analyzed the role of the Mu opioid receptor on B lymphocytes as a specific biomarker for FM and osteoarthritis (OA) patients. We enrolled three groups of females: FM patients, OA patients (chronic pain control group) and healthy subjects (pain-free negative control group). We collected blood samples to apply immunophenotyping analysis. Written tests were administrated for psychological analysis. Data were statistically analyzed. Final results showed that the percentage of Mu-positive B cells were statistically lower in FM and OA patients than in pain-free subjects. A low expression of Mu-positive B cell was not associated with the psychological characteristics investigated. In conclusion, here we propose the percentage of Mu-positive B cells as a biological marker for an objective diagnosis of chronic pain suffering patients, also contributing to the legitimacy of FM as a truly painful disease. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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14 pages, 1672 KiB

Open AccessArticle

Activation of Transposable Elements in Immune Cells of Fibromyalgia Patients

by Tamara Ovejero, Océane Sadones, Teresa Sánchez-Fito, Eloy Almenar-Pérez, José Andrés Espejo, Eva Martín-Martínez, Lubov Nathanson and Elisa Oltra

Int. J. Mol. Sci. 2020, 21(4), 1366; https://doi.org/10.3390/ijms21041366 - 18 Feb 2020

Cited by 12 | Viewed by 6732

Abstract

Advancements in nucleic acid sequencing technology combined with an unprecedented availability of metadata have revealed that 45% of the human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically necessary. Dysregulation of TEs, including human retroviral endogenous sequences [...] Read more.

Advancements in nucleic acid sequencing technology combined with an unprecedented availability of metadata have revealed that 45% of the human genome constituted by transposable elements (TEs) is not only transcriptionally active but also physiologically necessary. Dysregulation of TEs, including human retroviral endogenous sequences (HERVs) has been shown to associate with several neurologic and autoimmune diseases, including Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). However, no study has yet addressed whether abnormal expression of these sequences correlates with fibromyalgia (FM), a disease frequently comorbid with ME/CFS. The work presented here shows, for the first time, that, in fact, HERVs of the H, K and W types are overexpressed in immune cells of FM patients with or without comorbid ME/CFS. Patients with increased HERV expression (N = 14) presented increased levels of interferon (INF-β and INF-γ) but unchanged levels of TNF-α. The findings reported in this study could explain the flu-like symptoms FM patients present with in clinical practice, in the absence of concomitant infections. Future work aimed at identifying specific genomic loci differentially affected in FM and/or ME/CFS is warranted. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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20 pages, 2803 KiB

Open AccessArticle

Cell-Based Blood Biomarkers for Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

by Daniel Missailidis, Oana Sanislav, Claire Y. Allan, Sarah J. Annesley and Paul R. Fisher

Int. J. Mol. Sci. 2020, 21(3), 1142; https://doi.org/10.3390/ijms21031142 - 8 Feb 2020

Cited by 18 | Viewed by 10353

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those [...] Read more.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a devastating illness whose biomedical basis is now beginning to be elucidated. We reported previously that, after recovery from frozen storage, lymphocytes (peripheral blood mononuclear cells, PBMCs) from ME/CFS patients die faster in culture medium than those from healthy controls. We also found that lymphoblastoid cell lines (lymphoblasts) derived from these PBMCs exhibit multiple abnormalities in mitochondrial respiratory function and signalling activity by the cellular stress-sensing kinase Target Of Rapamycin Complex 1 (TORC1). These differences were correlated with disease severity, as measured by the Richardson and Lidbury weighted standing test. The clarity of the differences between these cells derived from ME/CFS patient blood and those from healthy controls suggested that they may provide useful biomarkers for ME/CFS. Here, we report a preliminary investigation into that possibility using a variety of analytical classification tools, including linear discriminant analysis, logistic regression and receiver operating characteristic (ROC) curve analysis. We found that results from three different tests—lymphocyte death rate, mitochondrial respiratory function and TORC1 activity—could each individually serve as a biomarker with better than 90% sensitivity but only modest specificity vís a vís healthy controls. However, in combination, they provided a cell-based biomarker with sensitivity and specificity approaching 100% in our sample. This level of sensitivity and specificity was almost equalled by a suggested protocol in which the frozen lymphocyte death rate was used as a highly sensitive test to triage positive samples to the more time consuming and expensive tests measuring lymphoblast respiratory function and TORC1 activity. This protocol provides a promising biomarker that could assist in more rapid and accurate diagnosis of ME/CFS. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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26 pages, 4375 KiB

Open AccessArticle

An Isolated Complex V Inefficiency and Dysregulated Mitochondrial Function in Immortalized Lymphocytes from ME/CFS Patients

by Daniel Missailidis, Sarah J. Annesley, Claire Y. Allan, Oana Sanislav, Brett A. Lidbury, Donald P. Lewis and Paul R. Fisher

Int. J. Mol. Sci. 2020, 21(3), 1074; https://doi.org/10.3390/ijms21031074 - 6 Feb 2020

Cited by 50 | Viewed by 10824

Abstract

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular [...] Read more.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is an enigmatic condition characterized by exacerbation of symptoms after exertion (post-exertional malaise or “PEM”), and by fatigue whose severity and associated requirement for rest are excessive and disproportionate to the fatigue-inducing activity. There is no definitive molecular marker or known underlying pathological mechanism for the condition. Increasing evidence for aberrant energy metabolism suggests a role for mitochondrial dysfunction in ME/CFS. Our objective was therefore to measure mitochondrial function and cellular stress sensing in actively metabolizing patient blood cells. We immortalized lymphoblasts isolated from 51 ME/CFS patients diagnosed according to the Canadian Consensus Criteria and an age- and gender-matched control group. Parameters of mitochondrial function and energy stress sensing were assessed by Seahorse extracellular flux analysis, proteomics, and an array of additional biochemical assays. As a proportion of the basal oxygen consumption rate (OCR), the rate of ATP synthesis by Complex V was significantly reduced in ME/CFS lymphoblasts, while significant elevations were observed in Complex I OCR, maximum OCR, spare respiratory capacity, nonmitochondrial OCR and “proton leak” as a proportion of the basal OCR. This was accompanied by a reduction of mitochondrial membrane potential, chronically hyperactivated TOR Complex I stress signaling and upregulated expression of mitochondrial respiratory complexes, fatty acid transporters, and enzymes of the β-oxidation and TCA cycles. By contrast, mitochondrial mass and genome copy number, as well as glycolytic rates and steady state ATP levels were unchanged. Our results suggest a model in which ME/CFS lymphoblasts have a Complex V defect accompanied by compensatory upregulation of their respiratory capacity that includes the mitochondrial respiratory complexes, membrane transporters and enzymes involved in fatty acid β-oxidation. This homeostatically returns ATP synthesis and steady state levels to “normal” in the resting cells, but may leave them unable to adequately respond to acute increases in energy demand as the relevant homeostatic pathways are already activated. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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16 pages, 1593 KiB

Open AccessArticle

Increased Cardiovascular Risk Associated with Chemical Sensitivity to Perfluoro–Octanoic Acid: Role of Impaired Platelet Aggregation

by Luca De Toni, Claudia Maria Radu, Iva Sabovic, Andrea Di Nisio, Stefano Dall’Acqua, Diego Guidolin, Salvatore Spampinato, Elena Campello, Paolo Simioni and Carlo Foresta

Int. J. Mol. Sci. 2020, 21(2), 399; https://doi.org/10.3390/ijms21020399 - 8 Jan 2020

Cited by 38 | Viewed by 5308

Abstract

Perfluoro–alkyl substances (PFAS), particularly perfluoro–octanoic acid (PFOA), are persisting environmental chemicals showing bioaccumulation in human tissues. Recently, exposure to PFAS has been associated with increased prevalence of cardiovascular diseases (CVDs). However, a causal role of PFAS in atherosclerosis pathogenesis is under-investigated. Here, we [...] Read more.

Perfluoro–alkyl substances (PFAS), particularly perfluoro–octanoic acid (PFOA), are persisting environmental chemicals showing bioaccumulation in human tissues. Recently, exposure to PFAS has been associated with increased prevalence of cardiovascular diseases (CVDs). However, a causal role of PFAS in atherosclerosis pathogenesis is under-investigated. Here, we investigated the effect of PFOA exposure on platelets’ function, a key player in atherosclerosis process. PFOA accumulation in platelets was evaluated by liquid chromatography-mass spectrometry. Changes in platelets’ membrane fluidity and activation after dose-dependent exposure to PFOA were evaluated by merocyanine 540 (MC540) and anti P-Selectin immune staining at flow cytometry, respectively. Intracellular calcium trafficking was analyzed with Fluo4M probe, time-lapse live imaging. Platelets’ aggregation state was also evaluated with Multiplate^® aggregometry analyzer in 48 male subjects living in a specific area of the Veneto region with high PFAS environmental pollution, and compared with 30 low-exposure control subjects. Platelets’ membrane was the major target of PFOA, whose dose-dependent accumulation was associated in turn with increased membrane fluidity, as expected by a computational model; increased activation at resting condition; and both calcium uptake and aggregation upon activation. Finally, exposed subjects had higher serum and platelets levels of PFOA, together with increased aggregation parameters at Multiplate^®, compared with controls. These data help to explain the emerging association between PFAS exposure and CVD. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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26 pages, 1623 KiB

Open AccessArticle

by Alessandro Micarelli, Andrea Cormano, Daniela Caccamo and Marco Alessandrini

Int. J. Mol. Sci. 2020, 21(1), 156; https://doi.org/10.3390/ijms21010156 - 25 Dec 2019

Cited by 14 | Viewed by 5893

Abstract

Genetic polymorphisms as well as environmental exposures to chemical compounds, iatrogenic, psychological, and physical trauma may play a pathophysiological role in multiple chemical sensitivity (MCS) olfactory complaints, given that xenobiotic metabolism is influenced by sequence variations in genes of metabolizing enzymes. Thus, the [...] Read more.

Genetic polymorphisms as well as environmental exposures to chemical compounds, iatrogenic, psychological, and physical trauma may play a pathophysiological role in multiple chemical sensitivity (MCS) olfactory complaints, given that xenobiotic metabolism is influenced by sequence variations in genes of metabolizing enzymes. Thus, the aim of the present study was to depict—by means of multiple regression analysis—how different genetic conditions, grouped according to their function as well as clinical background and environmental exposure may interfere with those olfactory complaints referred by MCS patients. Therefore, MCS patients after gene polymorphism sequencing, the olfactory-related quality of life score—calculated by means of the Questionnaire of Olfactory Disorder in forty-six MCS patients—have been found to significantly rely on the phase I and II enzymes score and exposure to previous compounds and surgical treatments. The present work—implementing for the first time a genetic-acquired factors model on a regression analysis—further reinforces those theories, positing MCS as a complex, multifactorial, disease in which the genetic risk related to phase I and II enzymes involved in xenobiotic detoxification, olfactory, and neurodegenerative diseases play a necessary, but probably not sufficient role, along the pathophysiological route of the disease. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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16 pages, 641 KiB

Open AccessArticle

Machine Learning to Understand the Immune-Inflammatory Pathways in Fibromyalgia

by Laura Andrés-Rodríguez, Xavier Borràs, Albert Feliu-Soler, Adrián Pérez-Aranda, Antoni Rozadilla-Sacanell, Belén Arranz, Jesús Montero-Marin, Javier García-Campayo, Natalia Angarita-Osorio, Michael Maes and Juan V. Luciano

Int. J. Mol. Sci. 2019, 20(17), 4231; https://doi.org/10.3390/ijms20174231 - 29 Aug 2019

Cited by 23 | Viewed by 5290

Abstract

Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain, and physical and emotional symptoms. Although its pathophysiology is largely unknown, immune-inflammatory pathways may be involved. We examined serum interleukin (IL)-6, high sensitivity C-reactive protein (hs-CRP), CXCL-8, and IL-10 in 67 female [...] Read more.

Fibromyalgia (FM) is a chronic syndrome characterized by widespread musculoskeletal pain, and physical and emotional symptoms. Although its pathophysiology is largely unknown, immune-inflammatory pathways may be involved. We examined serum interleukin (IL)-6, high sensitivity C-reactive protein (hs-CRP), CXCL-8, and IL-10 in 67 female FM patients and 35 healthy women while adjusting for age, body mass index (BMI), and comorbid disorders. We scored the Fibromyalgia Severity Score, Widespread Pain Index (WPI), Symptom Severity Scale (SSS), Hospital Anxiety (HADS-A), and Depression Scale and the Perceived Stress Scale (PSS-10). Clinical rating scales were significantly higher in FM patients than in controls. After adjusting for covariates, IL-6, IL-10, and CXCL-8 were lower in FM than in HC, whereas hs-CRP did not show any difference. Binary regression analyses showed that the diagnosis FM was associated with lowered IL-10, quality of sleep, aerobic activities, and increased HADS-A and comorbidities. Neural networks showed that WPI was best predicted by quality of sleep, PSS-10, HADS-A, and the cytokines, while SSS was best predicted by PSS-10, HADS-A, and IL-10. Lowered levels of cytokines are associated with FM independently from confounders. Lowered IL-6 and IL-10 signaling may play a role in the pathophysiology of FM. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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Review

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20 pages, 3871 KiB

Open AccessReview

Electrohypersensitivity as a Newly Identified and Characterized Neurologic Pathological Disorder: How to Diagnose, Treat, and Prevent It

by Dominique Belpomme and Philippe Irigaray

Int. J. Mol. Sci. 2020, 21(6), 1915; https://doi.org/10.3390/ijms21061915 - 11 Mar 2020

Cited by 31 | Viewed by 38822

Abstract

Since 2009, we built up a database which presently includes more than 2000 electrohypersensitivity (EHS) and/or multiple chemical sensitivity (MCS) self-reported cases. This database shows that EHS is associated in 30% of the cases with MCS, and that MCS precedes the occurrence of [...] Read more.

Since 2009, we built up a database which presently includes more than 2000 electrohypersensitivity (EHS) and/or multiple chemical sensitivity (MCS) self-reported cases. This database shows that EHS is associated in 30% of the cases with MCS, and that MCS precedes the occurrence of EHS in 37% of these EHS/MCS-associated cases. EHS and MCS can be characterized clinically by a similar symptomatic picture, and biologically by low-grade inflammation and an autoimmune response involving autoantibodies against O-myelin. Moreover, 80% of the patients with EHS present with one, two, or three detectable oxidative stress biomarkers in their peripheral blood, meaning that overall these patients present with a true objective somatic disorder. Moreover, by using ultrasonic cerebral tomosphygmography and transcranial Doppler ultrasonography, we showed that cases have a defect in the middle cerebral artery hemodynamics, and we localized a tissue pulsometric index deficiency in the capsulo-thalamic area of the temporal lobes, suggesting the involvement of the limbic system and the thalamus. Altogether, these data strongly suggest that EHS is a neurologic pathological disorder which can be diagnosed, treated, and prevented. Because EHS is becoming a new insidious worldwide plague involving millions of people, we ask the World Health Organization (WHO) to include EHS as a neurologic disorder in the international classification of diseases. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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13 pages, 279 KiB

Open AccessReview

T Cell Subpopulations in the Physiopathology of Fibromyalgia: Evidence and Perspectives

by Giuseppe Banfi, Marco Diani, Paolo D. Pigatto and Eva Reali

Int. J. Mol. Sci. 2020, 21(4), 1186; https://doi.org/10.3390/ijms21041186 - 11 Feb 2020

Cited by 33 | Viewed by 6010

Abstract

Fibromyalgia is one of the most important “rheumatic” disorders, after osteoarthritis. The etiology of the disease is still not clear. At the moment, the most defined pathological mechanism is the alteration of central pain pathways, and emotional conditions can trigger or worsen symptoms. [...] Read more.

Fibromyalgia is one of the most important “rheumatic” disorders, after osteoarthritis. The etiology of the disease is still not clear. At the moment, the most defined pathological mechanism is the alteration of central pain pathways, and emotional conditions can trigger or worsen symptoms. Increasing evidence supports the role of mast cells in maintaining pain conditions such as musculoskeletal pain and central sensitization. Importantly, mast cells can mediate microglia activation through the production of proinflammatory cytokines such as IL-1β, IL-6, and TNFα. In addition, levels of chemokines and proinflammatory cytokines are enhanced in serum and could contribute to inflammation at systemic level. Despite the well-characterized relationship between the nervous system and inflammation, the mechanism that links the different pathological features of fibromyalgia, including stress-related manifestations, central sensitization, and dysregulation of the innate and adaptive immune responses is largely unknown. This review aims to provide an overview of the current understanding of the role of adaptive immune cells, in particular T cells, in the physiopathology of fibromyalgia. It also aims at linking the latest advances emerging from basic science to envisage new perspectives to explain the role of T cells in interconnecting the psychological, neurological, and inflammatory symptoms of fibromyalgia. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

21 pages, 834 KiB

Open AccessReview

An Association of Serotonin with Pain Disorders and Its Modulation by Estrogens

by Stephania Paredes, Santiago Cantillo, Kenneth D. Candido and Nebojsa Nick Knezevic

Int. J. Mol. Sci. 2019, 20(22), 5729; https://doi.org/10.3390/ijms20225729 - 15 Nov 2019

Cited by 82 | Viewed by 17427

Abstract

Ovarian hormones play an important role in pain perception, and are responsible, at least in part, for the pain threshold differences between the sexes. Modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and [...] Read more.

Ovarian hormones play an important role in pain perception, and are responsible, at least in part, for the pain threshold differences between the sexes. Modulation of pain and its perception are mediated by neurochemical changes in several pathways, affecting both the central and peripheral nervous systems. One of the most studied neurotransmitters related to pain disorders is serotonin. Estrogen can modify serotonin synthesis and metabolism, promoting a general increase in its tonic effects. Studies evaluating the relationship between serotonin and disorders such as irritable bowel syndrome, fibromyalgia, migraine, and other types of headache suggest a clear impact of this neurotransmitter, thereby increasing the interest in serotonin as a possible future therapeutic target. This literature review describes the importance of substances such as serotonin and ovarian hormones in pain perception and illustrates the relationship between those two, and their direct influence on the presentation of the aforementioned pain-related conditions. Additionally, we review the pathways and receptors implicated in each disorder. Finally, the objective was to stimulate future pharmacological research to experimentally evaluate the potential of serotonin modulators and ovarian hormones as therapeutic agents to regulate pain in specific subpopulations. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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14 pages, 1260 KiB

Open AccessReview

Neuroimmunology: What Role for Autoimmunity, Neuroinflammation, and Small Fiber Neuropathy in Fibromyalgia, Chronic Fatigue Syndrome, and Adverse Events after Human Papillomavirus Vaccination?

by Varvara A. Ryabkova, Leonid P. Churilov and Yehuda Shoenfeld

Int. J. Mol. Sci. 2019, 20(20), 5164; https://doi.org/10.3390/ijms20205164 - 18 Oct 2019

Cited by 46 | Viewed by 15108

Abstract

Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate. We highlight the role of three mechanisms—autoimmunity, neuroinflammation, and small fiber [...] Read more.

Fibromyalgia is a disorder characterized by chronic widespread pain and non-pain symptoms, such as fatigue, dysautonomia, and cognitive and sleep disturbances. Its pathogenesis and treatment continue to be the subject of debate. We highlight the role of three mechanisms—autoimmunity, neuroinflammation, and small fiber neuropathy—in the pathogenesis of the disease. These mechanisms are shown to be closely interlinked (also on a molecular level), and the review considers the implementation of this relationship in the search for therapeutic options. We also pay attention to chronic fatigue syndrome, which overlaps with fibromyalgia, and propose a concept of “autoimmune hypothalamopathy” for its pathogenesis. Finally, we analyze the molecular mechanisms underlying the neuroinflammatory background in the development of adverse events following HPV vaccination and suggesting neuroinflammation, which could exacerbate the development of symptoms following HPV vaccination (though this is hotly debated), as a model for fibromyalgia pathogenesis. Full article

(This article belongs to the Special Issue Environmental Sensitivity Illnesses: Mechanisms and Molecular Signatures)

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