pathogenesis – Page 3 – American ME and CFS Society

No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a disease with a variety of symptoms such as post-exertional malaise, fatigue, and pain, but where aetiology and pathogenesis are unknown. An increasing number of studies have implicated the involvement of the immune system in ME/CFS. Furthermore, a hereditary component is suggested by the reported increased risk for disease in relatives, and genetic association studies are being performed to identify potential risk variants.

We recently reported an association with the immunologically important human leucocyte antigen (HLA) genes HLA-C and HLA-DQB1 in ME/CFS. Furthermore, a genome-wide genetic association study in 42 ME/CFS patients reported significant association signals with two variants in the T cell receptor alpha (TRA) locus (P value <5 × 10^-8). As the T cell receptors interact with the HLA molecules, we aimed to replicate the previously reported findings in the TRA locus using a large Norwegian ME/CFS cohort (409 cases and 810 controls) and data from the UK biobank (2105 cases and 4786 controls).

We investigated numerous SNPs in the TRA locus, including the two previously ME/CFS-associated variants, rs11157573 and rs17255510. No associations were observed in the Norwegian cohort, and there was no significant association with the two previously reported SNPs in any of the cohorts. However, other SNPs showed signs of association (P value <0.05) in the UK Biobank cohort and meta-analyses of Norwegian and UK biobank cohorts, but none survived correction for multiple testing. Hence, our research did not identify any reliable associations with variants in the TRA locus.

Source: Ueland M, Hajdarevic R, Mella O, Strand EB, Sosa DD, Saugstad OD, Fluge Ø, Lie BA, Viken MK. No replication of previously reported association with genetic variants in the T cell receptor alpha (TRA) locus for myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Transl Psychiatry. 2022 Jul 11;12(1):277. doi: 10.1038/s41398-022-02046-1. PMID: 35821115. https://www.nature.com/articles/s41398-022-02046-1 (Full text)

Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Infectious pathogens are implicated in the etiology of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) because of the occurrence of outbreaks of the disease. While a number of different infectious agents have been associated with the onset of ME/CFS, the identity of a specific organism has been difficult to determine in individual cases. The aim of our study is to survey ME/CFS subjects for evidence of an infectious trigger and/or evidence of immune dysregulation via serological testing of plasma samples for antibodies to 122 different pathogen antigens.

Immune profiles were compared to age-, sex-, and BMI-matched controls to provide a basis for comparison. Antibody levels to individual antigens surveyed in this study do not implicate any one of the pathogens in ME/CFS, nor do they rule out common pathogens that frequently infect the US population. However, our results revealed sex-based differences in steady-state humoral immunity, both within the ME/CFS cohort and when compared to trends seen in the healthy control cohort.

Source: O’Neal AJ, Glass KA, Emig CJ, Vitug AA, Henry SJ, Shungu DC, Mao X, Levine SM, Hanson MR. Survey of Anti-Pathogen Antibody Levels in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Proteomes. 2022; 10(2):21. https://doi.org/10.3390/proteomes10020021 https://www.mdpi.com/2227-7382/10/2/21/htm (Full text)

Unexplained post-acute infection syndromes

Abstract:

SARS-CoV-2 is not unique in its ability to cause post-acute sequelae; certain acute infections have long been associated with an unexplained chronic disability in a minority of patients. These post-acute infection syndromes (PAISs) represent a substantial healthcare burden, but there is a lack of understanding of the underlying mechanisms, representing a significant blind spot in the field of medicine.

The relatively similar symptom profiles of individual PAISs, irrespective of the infectious agent, as well as the overlap of clinical features with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggest the potential involvement of a common etiopathogenesis.

In this Review, we summarize what is known about unexplained PAISs, provide context for post-acute sequelae of SARS-CoV-2 infection (PASC), and delineate the need for basic biomedical research into the underlying mechanisms behind this group of enigmatic chronic illnesses.

Source: Choutka J, Jansari V, Hornig M, Iwasaki A. Unexplained post-acute infection syndromes. Nat Med. 2022 May;28(5):911-923. doi: 10.1038/s41591-022-01810-6. Epub 2022 May 18. PMID: 35585196. https://www.nature.com/articles/s41591-022-01810-6 (Full text)

Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

We propose an initial explanation for how myalgic encephalomyelitis / chronic fatigue syndrome (ME/CFS) could originate and perpetuate by drawing on findings from critical illness research. Specifically, we combine emerging findings regarding (a) hypoperfusion and endotheliopathy, and (b) intestinal injury in these illnesses with our previously published hypothesis about the role of (c) pituitary suppression, and (d) low thyroid hormone function associated with redox imbalance in ME/CFS.

Moreover, we describe interlinkages between these pathophysiological mechanisms as well as “vicious cycles” involving cytokines and inflammation that may contribute to explain the chronic nature of these illnesses. This paper summarizes and expands on our previous publications about the relevance of findings from critical illness for ME/CFS. New knowledge on diagnostics, prognostics and treatment strategies could be gained through active collaboration between critical illness and ME/CFS researchers, which could lead to improved outcomes for both conditions.

Source: Stanculescu Dominic, Bergquist Jonas. Perspective: Drawing on Findings From Critical Illness to Explain Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Frontiers in Medicine, 9, 2022. DOI: 10.3389/fmed.2022.818728 https://www.frontiersin.org/articles/10.3389/fmed.2022.818728/full#h1 (Full text)

Prevalence of Aspergillus-Derived Mycotoxins (Ochratoxin, Aflatoxin, and Gliotoxin) and Their Distribution in the Urinalysis of ME/CFS Patients

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a known complex, multi-organ system disorder with a sudden or subacute onset. ME/CFS occurs most commonly among women between 30 and 50 years of age. The current diagnostic criteria of ME/CFS, as defined by the Centers for Disease Control and Prevention, includes: profound fatigue and post-exertional malaise (>6 mo) unrelieved by rest, persistent cognitive impairment or orthostatic intolerance, and chronic unrefreshing sleep.

Despite reported associations between ME/CFS onset and exposure to infectious agents (viral, bacterial, or fungal), the pathophysiology of ME/CFS remains unknown. In this prevalence study, we investigated the rates of Aspergillus-derived toxin levels, Aflatoxin (AF), Ochratoxin A (OTA), and Gliotoxin (GT), in the urinalysis of 236 ME/CFS patients with a history of chronic exposure to mold (i.e., from water-damaged buildings).

Among ME/CFS patients reporting chronic exposure to mold, we found evidence of exposure in 92.4 percent of patients, with OTA being the most prevalent mycotoxin. Mold distributions (OTA, AF, and GT) in the urinalysis all demonstrated right skewness, while the distribution of age of ME/CFS patients diagnosed showed no deviation from normality.

This study aims to provide preliminary, epidemiological evidence among ME/CFS patients who were diagnosed in South Florida with a history of exposure to mycotoxins. Based on these findings, we proposed how future control studies should approach investigating the association between chronic mold exposure and the diagnosis of ME/CFS.

Source: Wu TY, Khorramshahi T, Taylor LA, Bansal NS, Rodriguez B, Rey IR. Prevalence of Aspergillus-Derived Mycotoxins (Ochratoxin, Aflatoxin, and Gliotoxin) and Their Distribution in the Urinalysis of ME/CFS Patients. Int J Environ Res Public Health. 2022 Feb 12;19(4):2052. doi: 10.3390/ijerph19042052. PMID: 35206241. https://www.mdpi.com/1660-4601/19/4/2052 (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic systemic disease that manifests via various symptoms such as chronic fatigue, post-exertional malaise, and cognitive impairment described as “brain fog”. These symptoms often prevent patients from keeping up their pre-disease onset lifestyle, as extended periods of physical or mental activity become almost impossible. However, the disease presents heterogeneously with varying severity across patients. Therefore, consensus criteria have been designed to provide a diagnosis based on symptoms. To date, no biomarker-based tests or diagnoses are available, since the molecular changes observed also largely differ from patient to patient.

In this review, we discuss the infectious, genetic, and hormonal components that may be involved in CFS pathogenesis, we scrutinize the role of gut microbiota in disease progression, we highlight the potential of non-coding RNA (ncRNA) for the development of diagnostic tools and briefly mention the possibility of SARS-CoV-2 infection causing CFS.

Source: Deumer US, Varesi A, Floris V, Savioli G, Mantovani E, López-Carrasco P, Rosati GM, Prasad S, Ricevuti G. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS): An Overview. J Clin Med. 2021 Oct 19;10(20):4786. doi: 10.3390/jcm10204786. PMID: 34682909; PMCID: PMC8538807. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8538807/ (Full text)

HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract:

BACKGROUND: Chronic fatigue syndrome/myalgic encephalomyelitis (CFS/MS) is an incapacitating chronic disease that dramatically compromise the life quality. The CFS/ME pathogenesis is multifactorial, and it is believed that immunological, metabolic and environmental factors play a role. It is well documented an increased activity of Human endogenous retroviruses (HERVs) from different families in autoimmune and neurological diseases, making these elements good candidates for biomarkers or even triggers for such diseases.

METHODS: Here the expression of Endogenous retroviruses K and W (HERV-K and HERV-W) was determined in blood from moderately and severely affected ME/CFS patients through real time PCR.

RESULTS: HERV-K was overexpressed only in moderately affected individuals but HERV-W showed no difference.

CONCLUSIONS: This is the first report about HERV-K differential expression in moderate ME/CFS. Although the relationship between HERVs and ME/CFS has yet to be proven, the observation of this phenomenon deserves further attention.

Source: Rodrigues LS, da Silva Nali LH, Leal COD, Sabino EC, Lacerda EM, Kingdon CC, Nacul L, Romano CM. HERV-K and HERV-W transcriptional activity in myalgic encephalomyelitis/chronic fatigue syndrome. Auto Immun Highlights. 2019 Nov 15;10(1):12. doi: 10.1186/s13317-019-0122-8. eCollection 2019 Dec. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065355/ (Full text)

Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS)

Abstract:

A recent study on the pathogenesis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) has revealed an elevation of inflammatory and anti-inflammatory cytokines in the sera and cerebrospinal fluids of the patients and presence of autoantibodies in subgroups of ME/CFS patients. Furthermore, investigator-initiated clinical trials have proved the efficacy of anti-CD20 antibody (rituximab), that eliminate B cells, in the treatment of ME/CFS. Based on these findings, we hypothesize that immune abnormalities, such as enhanced autoimmune responses, may play an essential role in the neuroinflammatory pathogenesis of ME/CFS.

Source: Yamamura T, Ono H, Sato W. Immunopathogenesis of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Brain Nerve. 2018 Jan;70(1):35-40. doi: 10.11477/mf.1416200947 [Article in Japanese] https://www.ncbi.nlm.nih.gov/pubmed/29348373

The aetiopathogenesis of fatigue: unpredictable, complex and persistent

Abstract:

BACKGROUND: Chronic fatigue syndrome is a common condition characterized by severe fatigue with post-exertional malaise, impaired cognitive ability, poor sleep quality, muscle pain, multi-joint pain, tender lymph nodes, sore throat or headache. Its defining symptom, fatigue is common to several diseases.

AREAS OF AGREEMENT: Research has established a broad picture of impairment across autonomic, endocrine and inflammatory systems though progress seems to have reached an impasse.

AREAS OF CONTROVERSY: The absence of a clear consensus view of the pathophysiology of fatigue suggests the need to switch from a focus on abnormalities in one system to an experimental and clinical approach which integrates findings across multiple systems and their constituent parts and to consider multiple environmental factors.

GROWING POINTS: We discuss this with reference to three key factors, non-determinism, non-reductionism and self-organization and suggest that an approach based on these principles may afford a coherent explanatory framework for much of the observed phenomena in fatigue and offers promising avenues for future research.

AREAS TIMELY FOR DEVELOPING RESEARCH: By adopting this approach, the field can examine issues regarding aetiopathogenesis and treatment, with relevance for future research and clinical practice.

Source: Clark JE, Fai Ng W, Watson S, Newton JL. The aetiopathogenesis of fatigue: unpredictable, complex and persistent. Br Med Bull. 2016 Mar;117(1):139-48. doi: 10.1093/bmb/ldv057. Epub 2016 Feb 12. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4782751/ (Full article)

Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome

CFS a complex disorder characterized by unexplained severe fatigue for over 6 months with a broad range of additional symptoms involving the nervous, endocrine and immune systems, and an estimated prevalence of 1%1. Tricyclic antidepressants (TCAs) are prescribed off label for a number of painful diseases that are often comorbid, such as chronic fatigue syndrome (CFS), fibromyalgia, interstitial cystitis, and irritable bowel syndrome, the symptoms of which are worsened by stress2. However, there is no known mechanism to explain the apparent beneficial action of TCAs3.

Mast cells and their mediators have been implicated in inflammatory diseases4, including CFS5. Mast cells are located perivascularly in close proximity to neurons in the thalamus and hypothalamus, especially the median eminence6, where they are juxtaposed to corticotropin-releasing hormone (CRH)-positive nerve processes7. CRH activates mast cells to release vascular endothelial growth factor (VEGF)8, which could participate in neurogenic inflammation and contribute to the pathogenesis of CFS. Such mediators may be released locally in the brain or may cross the blood-brain-barrier (BBB), which can be disrupted by stress, subsequent to mast cell activation9. Given the above, we hypothesized that TCAs may be helpful through inhibition of mast cell release of pro-inflammatory mediators.

You can read the rest of this letter here: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498825/

Source: Clemons A, Vasiadi M, Kempuraj D, Kourelis T, Vandoros G, Theoharides TC. Amitriptyline and prochlorperazine inhibit proinflammatory mediator release from human mast cells: possible relevance to chronic fatigue syndrome. J Clin Psychopharmacol. 2011 Jun;31(3):385-7. doi: 10.1097/JCP.0b013e3182196e50. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3498825/ (Full article)