Category: Immune System

Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic, complex multi-organ illness characterized by unexplained debilitating fatigue and post-exertional malaise (PEM), which is defined as a worsening of symptoms following even minor physical or mental exertion. Our study aimed to evaluate transcriptomic changes in ME/CFS female patients undergoing an exercise challenge intended to precipitate PEM.
Our time points (baseline before exercise challenge, the point of maximal exertion, and after an exercise challenge) allowed for the exploration of the transcriptomic response to exercise and recovery in female patients with ME/CFS, as compared to healthy controls (HCs). Under maximal exertion, ME/CFS patients did not show significant changes in gene expression, while HCs demonstrated altered functional gene networks related to signaling and integral functions of their immune cells.
During the recovery period (commonly during onset of PEM), female ME/CFS patients showed dysregulated immune signaling pathways and dysfunctional cellular responses to stress. The unique functional pathways identified provide a foundation for future research efforts into the disease, as well as for potential targeted treatment options.
Source: Van Booven DJ, Gamer J, Joseph A, Perez M, Zarnowski O, Pandya M, Collado F, Klimas N, Oltra E, Nathanson L. Stress-Induced Transcriptomic Changes in Females with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome Reveal Disrupted Immune Signatures. International Journal of Molecular Sciences. 2023; 24(3):2698. https://doi.org/10.3390/ijms24032698 https://www.mdpi.com/1422-0067/24/3/2698 (Full text)

The Role of Immunity and Inflammation in ME/ CFS and Post-COVID Syndrome: Implications for Treatment

Abstract:

Probably one in seven patients who have experienced acute COVID-19 continue having long-lasting complaints, called post-COVID syndrome or long-COVID, that are similar to those observed in patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS).

There are good reasons to believe that common immunological, epigenetic and inflammatory mechanisms are involved in the pathogenesis both diseases.

To date, various therapeutic approaches have been recommended, but with moderate success. In the present opinion paper, the author weights his clinical experience against data from the literature, and suggests novel approaches.

In addition to general measures and paramedical approaches, food supplementation with a specific nutraceutical can be completed by oral administration of sodium dichloroacetate and Meldonium to optimize glucose metabolism and mitochondrial energy generation.

Alternatively, intravenous infusions with magnesium salt and multivitamins can be completed with glutathione, m-tranexamic acid, and cultured stem cells.

Preliminary results of an open-label, prospective, two-centre trial suggest more than four in five patients benefit from combined oral and infusion therapy with significantly diminished fatigue and improved well-being.

Monoclonal antibodies in “biologicals”, blocking the effects of cytokines, and “small molecules” with Janus kinase inhibiting activity may offer novel opportunities by focusing on both immunologic and inflammation targets. A pilot trial with, in particular, one of the Janus kinase inhibitors could be considered.

Source: Comhaire F. The Role of Immunity and Inflammation in ME/CFS and Post-COVID Syndrome: Implications for Treatment. MedLife Clinics 2022, Volume 4 (2), Article 1043 http://www.medtextpublications.com/open-access/the-role-of-immunity-and-inflammation-in-me-cfs-and-1254.pdf (Full text)

The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Purpose: Leptin is a member of the cytokine family; its receptor (LEPR-b) is the longest form receptor expressed in cells of the immune system; wherein LEPR-b deficiency causes a decrease in CD4+ cells. LEPR-b is located in hypothalamic and brain stem nuclei, and it primarily regulates energy status. As well, leptin indirectly regulates widespread pain and exercise tolerance by decreasing circulating cortisol.

Hyperinsulinemia increases leptin production in adipocytes on a diurnal rhythm; however, the precise relationship between insulin, leptin and pro-inflammatory markers remains uncertain. In clinical settings, high-sensitivity C-reactive protein (hsCRP) has been widely used, as an inflammatory predictor for leptin-related cardiometabolic outcomes and chronic inflammatory symptoms.

Leptin-related metabolic and inflammation dysregulations have been clinically reported in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), but not fully elucidated. We examined the association of plasma insulin, leptin, and hsCRP levels with ME/CFS self-reported symptom severity.

Methods: Prospective analyses were conducted on ME/CFS patients who met Fukuda/CDC criteria at Birmingham hospital, Alabama, U.S.A. The independent variables were hyperinsulinemia (>174 μIU/mL), hyperleptinemia/hypoleptinemia (>18.3/<3.3 ng/mL), residual inflammation risk (hsCRP ≥2 and ≠26.2 mg/L) and within-individual-variability (WIV) for each biomarker.

WIV was defined for each individual as standard deviation/sample residuals adjusting for time and calculated from once-daily random plasma samples over 10–12 weeks.

The primary outcomes were:

(1) ME/CFS symptom score trends [generalized pain, persistent fatigue, sleep disturbance, impairment of concentration and memory (brain fog), and post-exertional malaise (PEM)] calculated from the MFI-20 questionnaire with anchors from 0 to 100 and recorded once daily over a matching 12–14 weeks, and

(2) dichotomized symptom severity, with severe symptoms defined as scores > 60/100. After adjusting for age and time, we reported: (1) standard errors (SEM) and p-values for symptom trends using multivariable mixed-effect linear regression models, and (2) odds ratios for severe symptoms using multivariable alternating logistic regression models.

Results: We included 29 ME/CFS patients. All were females and >18 years old. Hyperinsulinemia, hyperleptinemia/hypoleptinemia, and residual inflammation risk were 7%, 80%/7%, and 74%, respectively.

The medians of insulin-WIV, leptin-WIV and hsCRP-WIV were [(0.24; IQR 0.15–0.38), (0.25; IQR 0.15–0.40), (0.33; IQR 0.18–0.51)] respectively. On average, hyperleptinemic patients had the highest leptin-WIV and 50% of them had residual inflammation risk.

Severe (fatigue, pain, brain fog, sleep disturbance, and PEM) were reported in 50%, 29%, 41%, 30%, and 57% of patients, respectively. In the adjusted analysis, worse fatigue scores (7.49; SEM, 2.23; p = 0.002) were associated with higher insulin-WIV.

Hyperleptinemia (OR 1.54; 95% CI 1.13–2.09) compared to hypoleptinemia, and residual inflammation risk (OR 1.65; 95% CI 1.21–2.25) were associated with higher odds of severe fatigue. Worse pain scores (7.17; SEM, 2.30; p = 0.005) were associated with higher leptin-WIV, and (8.45; SEM, 2.25; p = 0.0009) higher hsCRP-WIV, and residual inflammation risk (OR 1.75; 95% CI 1.34–2.29) was associated with higher odds of severe pain.

Severe brain fog scores (9.20; SEM, 2.44; p = 0.0008) were associated with higher insulin-WIV, higher leptin-WIV (4.73; SEM, 2.12; p = 0.03). Residual inflammation risk (OR 1.40; 95% CI 1.16–1.77) was associated with higher odds of severe brain fog.

Hyperleptinemia (OR 0.60; 95% CI 0.43–1.19) was associated with lower odds of severe PEM compared to hypoleptinemia, and better sleep quality was associated (6.07; SEM, 1.70; p = 0.001) with higher insulin-WIV, and (3.37; SEM, 1.47; p = 0.03) higher leptin-WIV.

Conclusions: In patients with ME/CFS, symptoms severity was associated with hyperleptinemia, inflammation and within-individual-variability of these biomarkers. Leptin and hsCRP may be clinically useful in predicting symptom severity.

Larger clinical trials are needed to further examine the prediction and causality of these biomarkers in the development of ME/CFS diagnosis. The efficacy and safety of anti-inflammatory therapies may be evaluated in sub-clusters of ME/CFS with metabolic responses and inflammation dysregulations to improve patient-reported symptoms.

Source: Rahaf Al Assil and Jarred W Younger. “The Role of Leptin and Inflammatory Related Biomarkers in Individuals with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome” in Karandrea S, Agarwal N, Organizing Committee of Cardiometabolic Health Congress. Report from the Scientific Poster Session at the 16th Annual Cardiometabolic Health Congress in National Harbor, USA, 14–17 October 2021. Proceedings. 2022; 80(1):6. https://doi.org/10.3390/proceedings2022080006 (Full text)

Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity

Abstract:

Background: Recent studies provide some evidence for the contribution of antibody-mediated autoimmune mechanisms to the nature of fibromyalgia (FM) and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). Much attention was paid to the autoantibodies (AAb) targeting G protein-coupled receptors as natural components of the immune system. However, natural AAb network is much more extensive, and has not been previously investigated in these disorders;

Methods: The enzyme immunoassays ELI-Viscero-Test and ELI-Neuro-Test were used to determine changes in serum content of a 33 natural AAb to neural, organ-specific and non-tissue-specific autoantigens a) in 11 FM patients with comorbid ME/CFS; b) in 11 ME/CFS patients without FM; c) in 11 healthy controls. Individual autoantibody profiles and their correlation with some clinical symptoms were analyzed.

Results: Both patients with ME/CFS and ME/CFS+FM were characterized by more frequent and pronounced deviations in the immunoreactivity to GABA-receptors than healthy controls. Although the level of other natural AAb did not differ between study groups, AAb correlation signatures were changing in patients compared to healthy controls. Both in patients and healthy controls the level of natural AAb to various neural and tissue-specific antigens correlated with the severity of fatigue, bodily pain, depression, anxiety, physical and mental-health related quality of life. Notably, that widely different correlation patterns were observed between study groups.

Conclusions: Findings from this pilot study provide some evidence that the homeostasis of autoimmune relationships, which are possibly a physiological part of our immune system, may break down in FM and ME/CFS. The correlation of disease-induced perturbations in individual AAb profiles with some clinical symptoms may arise from the immune system’s ability to reflect qualitative and quantitative changes in antigenic composition of the body.

Source: Ryabkova, V.A.; Gavrilova, N.Y.; Poletaeva, A.A.; Pukhalenko, A.I.; Koshkina, I.A.; Churilov, L.P.; Shoenfeld, Y. Autoantibody Correlation Signatures in Fibromyalgia and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Association with Symptom Severity . Preprints 2022, 2022120224 (doi: 10.20944/preprints202212.0224.v1). https://www.preprints.org/manuscript/202212.0224/v1 (Full text available as PDF file)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back!

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) or Systemic Exertion Intolerance Disease (SEID) is a chronic multisystem illness of unconfirmed etiology. There are currently no biomarkers and/or signatures available to assist in the diagnosis of the syndrome and while numerous mechanisms have been hypothesized to explain the pathology of ME/CFS, the triggers and/or drivers remain unknown.

Initial studies suggested a potential role of the human herpesviruses especially Epstein-Barr virus (EBV) in the disease process but inconsistent and conflicting data led to the erroneous suggestion that these viruses had no role in the syndrome. New studies using more advanced approaches have now demonstrated that specific proteins encoded by EBV could contribute to the immune and neurological abnormalities exhibited by a subgroup of patients with ME/CFS. Elucidating the role of these herpesvirus proteins in ME/CFS may lead to the identification of specific biomarkers and the development of novel therapeutics.

Source: Ariza ME. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: The Human Herpesviruses Are Back! Biomolecules. 2021 Jan 29;11(2):185. doi: 10.3390/biom11020185. PMID: 33572802; PMCID: PMC7912523. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912523/ (Full text)

What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) remains an enigmatic highly disabling and complex long-term condition with a wide range of aetiologies and symptoms.

A viral onset is commonly mentioned by patients and several bodily systems are ultimately disturbed. The parallel with long-covid is clear.

However, immune dysregulation with impaired NK cell dysfunction and tendency to novel autoimmunity have been frequently reported. These may contribute to reactivation of previous acquired viruses/retroviruses accompanied by impaired endocrine regulation and mitochondrial energy generation.

The unpredictable nature of seemingly unconnected and diverse symptoms that are poorly responsive to several allopathic and alternative therapies then contributes to an escalation of the illness with secondary dysfunction of multiple other systems. Treatment of established ME/CFS is therefore difficult and requires multi-specialty input addressing each of the areas affected by the illness.

Source: Amolak S Bansal, Aletta D Kraneveld, Elisa Oltra and Simon Carding. What Causes ME/CFS: The Role of the Dysfunctional Immune System and Viral Infections. Journal of Immunology and Allergy 2022;3(2):1-15. https://maplespub.co.in/assets/images/files/doc_1663924267.pdf (Full text)

Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants

Abstract:

Chronic fatigue syndrome (CFS), fibromyalgia, silicone breast implants syndrome (SBIs), COVID and post-COVID syndrome (PCS), sick building syndrome (SBS), post-orthostatic tachycardia syndrome (POTS), autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants (ASIA) are frequently accompanied by clinical symptoms characteristic for dysautonomia: severe fatigue, dizziness, fogginess, memory loss, dry mouth and eyes, hearing dysfunction, tachycardia etc.

The recent discovery of an imbalance of autoantibodies against G protein-coupled receptors (GPCR) in some autoimmune diseases, post-COVID syndrome, SBIs allowed researchers to assume the novel mechanism in these conditions – autoimmune autonomic nervous system imbalance.

In this review, all data published on an imbalance of autoantibodies against GPCR, clinical symptoms and pathogenic mechanisms in CFS, Fibromyalgia, SBIs, COVID and PCS, SBS, POTS, and some autoimmune diseases were analyzed. Possible criteria to diagnose the autoimmune autonomic nervous system imbalance were created.

Source: A.M.Malkova, Y.Shoenfeld. Autoimmune autonomic nervous system imbalance and conditions: Chronic fatigue syndrome, fibromyalgia, silicone breast implants, COVID and post-COVID syndrome, sick building syndrome, post-orthostatic tachycardia syndrome, autoimmune diseases and autoimmune/inflammatory syndrome induced by adjuvants. Autoimmunity Reviews, 5 November 2022, 103230. https://www.sciencedirect.com/science/article/abs/pii/S1568997222002002 (Full text)

Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation

Summary:

ME/CFS is a serious and poorly understood disease. To understand immune dysregulation in ME/CFS, we used single-cell RNA-seq (scRNA-seq) to examine immune cells in cohorts of patients and controls. Post-exertional malaise (PEM), an exacerbation of symptoms following strenuous exercise, is a characteristic symptom of ME/CFS. Thus, to detect changes coincident with PEM, we also performed scRNA-seq on the same cohorts following exercise. At baseline, ME/CFS patients displayed dysregulation of classical monocytes suggestive of inappropriate differentiation and migration to tissue. We were able to identify both diseased and more normal monocytes within patients, and the fraction of diseased cells correlated with metrics of disease severity. Comparing the transcriptome at baseline and post-exercise challenge, we discovered patterns indicative of improper platelet activation in patients, with minimal changes elsewhere in the immune system. Taken together, these data identify immunological defects present at baseline in patients and an additional layer of dysregulation following exercise.

Highlights ME/CFS is a debilitating disease with unknown causes. Here, we provide, for the first time, an extensive single cell resolution dataset detailing the gene expression programs of circulating immune cells of ME/CFS cases at baseline and after symptom provocation. We were able to detect robust dysregulation in certain immune cells from patients, with dysregulation of classical monocytes manifesting the strongest signal. Indeed, the fraction of aberrant monocytes in ME/CFS patients correlated with the degree of disease severity. Surprisingly, platelet transcriptomes were also altered in ME/CFS, and they were the only component of the immune system that showed large-scale changes following symptom provocation.

Source: Faraz Ahmed, Luyen Tien Vu, Hongya Zhu, David Shing Huk Iu, Elizabeth A. Fogarty, Yeonui Kwak, Weizhong Chen, Carl J. Franconi, Paul R. Munn, Susan M. Levine, Jared Stevens, Xiangling Mao, Dikoma C. Shungu, Geoffrey E. Moore, Betsy A. Keller, Maureen R. Hanson, Jennifer K. Grenier, Andrew Grimson. Single-cell transcriptomics of the immune system in ME/CFS at baseline and following symptom provocation. bioRxiv 2022.10.13.512091; doi: https://doi.org/10.1101/2022.10.13.512091 https://www.cell.com/cell-reports-medicine/fulltext/S2666-3791(23)00602-X (Full text)

Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a chronic disease considered to be triggered by viral infections in a majority of cases. Symptoms overlap largely with those of post-acute sequelae of COVID-19/long-COVID implying common pathogenetic mechanisms. SARS-CoV-2 infection is risk factor for sustained latent virus reactivation that may account for the symptoms of post-viral fatigue syndromes. The aim of this study was first to investigate whether patients with ME/CFS and healthy donors (HDs) differed in their antibody response to mild/asymptomatic SARS-CoV-2 infection. Secondly, to analyze whether COVID-19 imposes latent virus reactivation in the cohorts.

Methods: Anti-SARS-CoV-2 antibodies were analyzed in plasma and saliva from non-vaccinated ME/CFS (n=95) and HDs (n=110) using soluble multiplex immunoassay. Reactivation of human herpesviruses 1-6 (HSV1, HSV2, VZV, EBV, CMV, HHV6), and human endogenous retrovirus K (HERV-K) was detected by anti-viral antibody fingerprints in saliva.

Results: At 3-6 months after mild/asymptomatic SARS-CoV-2 infection, virus-specific antibodies in saliva were substantially induced signifying a strong reactivation of latent viruses (EBV, HHV6 and HERV-K) in both cohorts. In patients with ME/CFS, antibody responses were significantly stronger, in particular EBV-encoded nuclear antigen-1 (EBNA1) IgG were elevated in patients with ME/CFS, but not in HDs. EBV-VCA IgG was also elevated at baseline prior to SARS-infection in patients compared to HDs.

Conclusion: Our results denote an altered and chronically aroused anti-viral profile against latent viruses in ME/CFS. SARS-CoV-2 infection even in its mild/asymptomatic form is a potent trigger for reactivation of latent herpesviruses (EBV, HHV6) and endogenous retroviruses (HERV-K), as detected by antibody fingerprints locally in the oral mucosa (saliva samples). This has not been shown before because the antibody elevation is not detected systemically in the circulation/plasma.

Source: Apostolou Eirini, Rizwan Muhammad, Moustardas Petros, Sjögren Per, Bertilson Bo Christer, Bragée Björn, Polo Olli, Rosén Anders. Saliva antibody-fingerprint of reactivated latent viruses after mild/asymptomatic COVID-19 is unique in patients with myalgic-encephalomyelitis/chronic fatigue syndrome. Frontiers in Immunology, Vol 13, 2022. https://www.frontiersin.org/articles/10.3389/fimmu.2022.949787/full (Full text)