Category: Immune System

Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/anti-pathogen agent in a retrospective case series

Highlights:

• Both Long COVID and ME/CFS are characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα.

• In a small Long COVID and ME/CFS case series, patients’ immune deficiency and health improve during treatment period with a nebulized antioxidant, anti-pathogen and immune-modulatory pharmacological agent.

• This work provides evidence of a useful biomarker, CD8 T-cell dysfunction reminiscent of T cell exhaustion, that may assist diagnosis and have utility for tracking disease outcome during therapy, including response to a potential new treatment.

Abstract:

Background: Patients with post-acute sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection (PASC, i.e., Long COVID) have a symptom complex highly analogous to many features of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS), suggesting they may share some aspects of pathogenesis in these similar disorders. ME/CFS is a complex disease affecting numerous organ systems and biological processes and is often preceded by an infection-like episode. It is postulated that the chronic manifestations of illness may result from an altered host response to infection or inability to resolve inflammation, as is being reported in Long COVID. The immunopathogenesis of both disorders is still poorly understood. Here, we show data that suggest Long COVID and ME/CFS may be due to an aberrant response to an immunological trigger-like infection, resulting in a dysregulated immune system with CD8 T-cell dysfunction reminiscent of some aspects of T-cell clonal exhaustion, a phenomenon associated with oxidative stress. As there is an urgent need for diagnostic tools and treatment strategies for these two related disabling disorders, here, in a retrospective case series, we have also identified a potential nebulized antioxidant/anti-pathogen treatment that has evidence of a good safety profile. This nebulized agent is comprised of five ingredients previously reported individually to relieve oxidative stress, attenuate NF-κB signaling, and/or to act directly to inhibit pathogens, including viruses. Administration of this treatment by nebulizer results in rapid access of small doses of well-studied antioxidants and agents with anti-pathogen potential to the lungs; components of this nebulized agent are also likely to be distributed systemically, with potential to enter the central nervous system.

Methods and Findings: We conducted an analysis of CD8 T-cell function and severity of symptoms by self-report questionnaires in ME/CFS, Long COVID and healthy controls. We developed a CD8 T-cell functional assay, assessing CD8 T-cell dysfunction by intracellular cytokine staining (ICS) in a group of ME/CFS (n = 12) and Long COVID patients (n = 8), comparing to healthy controls (HC) with similar age and sex (n = 10). Magnet-enriched fresh CD8 T-cells in both patient groups had a significantly diminished capacity to produce both cytokines, IFNγ or TNFα, after PMA stimulation when compared to HC. The symptom severity questionnaire showed similar symptom profiles for the two disorders. Fortuitously, through a retrospective case series, we were able to examine the ICS and questionnaire data of 4 ME/CFS and 4 Long COVID patients in conjunction with their treatment (3–15 months). In parallel with the treatment pursued electively by participants in this retrospective case series, there was an increase in CD8 T-cell IFNγ and TNFα production and a decrease in overall self-reported symptom severity score by 54%. No serious treatment-associated side effects or laboratory anomalies were noted in these patients.

Conclusions: Here, in this small study, we present two observations that appear potentially fundamental to the pathogenesis and treatment of Long COVID and ME/CFS. The first is that both disorders appear to be characterized by dysfunctional CD8 T-cells with severe deficiencies in their abilities to produce IFNγ and TNFα. The second is that in a small retrospective Long COVID and ME/CFS case series, this immune dysfunction and patient health improved in parallel with treatment with an immunomodulatory, antioxidant pharmacological treatment with anticipated anti-pathogen activity. This work provides evidence of the potential utility of a biomarker, CD8 T-cell dysfunction, and suggests the potential for benefit from a new nebulized antioxidant/anti-pathogen treatment. These immune biomarker data may help build capacity for improved diagnosis and tracking of treatment outcomes during clinical trials for both Long COVID and ME/CFS while providing clues to new treatment avenues that suggest potential efficacy for both conditions.

Source: Gil, A., Hoag, G.E., Salerno, J.P., Hornig, M., Klimas, N., Selin, L.K. Identification of CD8 T-cell dysfunction associated with symptoms in myalgic encephalomyelitis/ chronic fatigue syndrome (ME/CFS) and Long COVID and treatment with a nebulized antioxidant/antipathogen agent in a retrospective case series. Brain, Behavior, & Immunity – Health (2024), doi: https://doi.org/10.1016/j.bbih.2023.100720 https://www.sciencedirect.com/science/article/pii/S2666354623001345 (Full text)

Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis

Abstract:

Myalgic Encephalomyelitis / Chronic Fatigue Syndrome is a debilitating, multisystem disease of unknown mechanism, with a currently ongoing search for its endocrine mediators. Circulating microRNAs (miRNA) are a promising candidate for such a mediator and have been reported as significantly different in the patient population versus healthy controls by multiple studies. None of these studies, however, agree with each other on which specific miRNA are under- or over-expressed.

This discrepancy is the subject of the computational study presented here, in which a deep dive into the predicted gene targets and their functional interactions is conducted, revealing that the aberrant circulating miRNAs in ME/CFS, although different between patients, seem to mainly target the same specific set of genes (p ≈ 0.0018), which are very functionally related to each other (p ≲ 0.0001).

Further analysis of these functional relations, based on directional pathway information, points to impairments in exercise hyperemia, angiogenic adaptations to hypoxia, antioxidant defenses, and TGF-β signaling, as well as a shift towards mitochondrial fission, corroborating and explaining previous direct observations in ME/CFS. Many transcription factors and epigenetic modulators are implicated as well, with currently uncertain downstream combinatory effects.

As the results show significant similarity to previous research on latent herpesvirus involvement in ME/CFS, the possibility of a herpesvirus origin of these miRNA changes is also explored through further computational analysis and literature review, showing that 8 out of the 10 most central miRNAs analyzed are known to be upregulated by various herpesviruses. In total, the results establish an appreciable and possibly central role for circulating microRNAs in ME/CFS etiology that merits further experimental research.

Source: Kaczmarek MP. Heterogenous circulating miRNA changes in ME/CFS converge on a unified cluster of target genes: A computational analysis. PLoS One. 2023 Dec 29;18(12):e0296060. doi: 10.1371/journal.pone.0296060. PMID: 38157384; PMCID: PMC10756525. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10756525/ (Full text)

Role of pharmacological activity of autoantibodies in ME/CFS

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a condition characterised by extreme fatigue, memory impairment, pain and other symptoms that vary from patient to patient. It affects about 0.9% of the population and is often triggered by an acute viral or bacterial infection, such as Epstein-Barr virus. The underlying physiological and molecular basis of ME/CFS is unknown, and no effective treatments exist.

One proposed mechanism is that the blood flow is altered by autoantibodies against receptors involved in blood flow regulation. Antibodies are generated by the immune system to recognise intruders and under normal conditions, our immune system is trained not to attack our own tissues. However, during a severe infection, the immune system adopts an “all hands on deck” approach, which results in some of the newly-produced antibodies escaping quality control and targeting our own tissues, autoantibodies. Receptors regulation blood flow are located in walls of blood vessels and cause a blood vessel to dilate or contract as the demand for oxygen and nutrients to tissues such as the brain or muscles changes. Research has found increased levels of these autoantibodies in ME/CFS patients and initial trials removing these autoantibodies from the blood using a technique called immunoadsorption have shown improvement in symptoms.

In this project, we will test the hypothesis that autoantibodies can activate or inhibit the receptors responsible for the blood flow regulation, in a similar way medical drugs are used to regulate blood pressure.
We aim to profile serum samples from 325 ME/CFS patients and 130 healthy individuals to determine the presence of autoantibodies against all thirty receptors involved in blood pressure regulation. Importantly, we will study the ability of autoantibodies detected in each sample to activate or inhibit these receptors in order to test the hypothesis that the activity of these autoantibodies is a decisive factor in the disease.
If our hypothesis is correct, we will be able to develop an accurate blood test that may be able to detect ME/CFS earlier or to independently confirm the diagnosis. Ultimately, we hope that these results may also indicate a possible route for therapeutic intervention to counteract the effects of autoantibodies and alleviate the ME/CFS symptoms using a combination of already existing drugs, specific for each individual case.

 

Technical Summary:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a condition of extreme tiredness and brain fog, often triggered by an acute infection. Its prevalence is ca 0.9% and here is no effective treatment. Competing theories for the root cause of ME/CFS include metabolic or redox homeostasis disruption, and presence of autoantibodies (AABs) against G protein coupled receptors (GPCRs) involved in regulation of blood flow.
Triggered by acute infection, autoimmunity is a result of reduced immuno-vigilance during severe infections, when an “all hands on deck” approach confers survival advantage. About 30% of ME/CFS patients show increased titre of autoantibodies against beta2-adrenoceptor and M3/4 muscarinic receptors controlling vasodilation/vasoconstriction, but this could become higher if all 30 receptors controlling blood flow would be taken into account.
In this project, we will test a hypothesis that the pharmacological activity of AABs against GPCRs is the key to their involvement in ME/CFS. Similar to medical drugs, AABs can be stimulatory (agonistic) or inhibitory (antagonistic) and induce a therapeutic or an undesired side effect.
We will profile 325 patient samples and 130 control plasma samples for AABs and their pharmacological activity using a state-of-the art GPCR drug screening pipeline we have established, against all 30 GPCRs involved in blood pressure regulation. We also have machine learning expertise that would allow us to interpret this extensive dataset, extract the most salient features. This will advance the understanding of the molecular basis of ME/CFS and could form the basis of a robust diagnostic blood test for ME/CFS. Ultimately, our findings may point in the direction of developing combination therapy using repurposed drugs to counteract the effects of autoantibodies and mitigate ME/CFS symptoms and stimulate the development of specific B-cell elimination strategy to cure ME/CFS.
Source: Lead Research Organisation: University of Nottingham, Department Name: School of Life Sciences. https://gtr.ukri.org/projects?ref=MR%2FY003667%2F1&pn=0&fetchSize=25&selectedSortableField=date&selectedSortOrder=ASC

Characterization of subgroups of myalgic encephalomyelitis/chronic fatigue syndrome based on disease onset, symptoms and biomarkers

Abstract:

Myalgic encephalomyelitis, also called chronic fatigue syndrome (ME/CFS), is an acquired multisystem disease. The core symptoms include fatigue, exercise intolerance and pain as well as cognitive, autonomic and immunological manifestations. The diagnosis of ME/CFS is based on clinical criteria. Specific biomarkers do not currently exist, but studies suggest a role for soluble cluster of differentiation 26 (sCD26) and autoantibodies (AAK) against G protein-coupled receptors (GPCR). In many cases, the disease begins as a result of infections. 

The aim of this work was to determine the pathophysiological significance of potential biomarkers, assuming different development mechanisms in patients with infection-associated disease onset compared to those with other triggers. In a first study, sCD26, also called dipeptidyl peptidase-4 (DPP-4) due to its enzymatic activity, was analyzed and compared in the serum of 205 ME/CFS patients and 98 controls. This was followed by a comprehensive correlation analysis between sCD26 and clinical and laboratory parameters for ME/CFS patients, separated by type of disease onset. In addition, CD26 expression on lymphocyte subpopulations was determined for 12 patients and 12 controls. 

In another study, a correlation analysis was carried out between AAK against vasoregulatory GPCR and symptoms in 116 ME/CFS patients, separated by type of disease onset. It was shown that in ME/CFS patients with infection-associated disease onset, sCD26 correlated with numerous immunological and metabolic parameters, the changes of which have also been described in connection with DPP-4 inhibitors. In addition, there were inverse correlations with AAK against alpha1-adrenergic and M3-acetylcholine receptors. 

In this subgroup, the second study found correlations between numerous GPCR-AAK and the severity of fatigue, muscle pain and cognitive symptoms as well as greater functional impairment relevant to everyday life. None of these correlations were found in patients without infection-associated disease onset. 

Here, sCD26 correlated inversely with orthostatically induced heart rate increases and AAK against alpha- and beta-adrenergic receptors with the severity of orthostatic symptoms. Different correlation patterns between AAK against GPCR and symptoms allow us to assume that in patients with ME/CFS, an altered function of the AAK or its receptors or signaling pathways has occurred as a result of an infection. The association of sCD26 and GPCR-AAK also indicates the dysregulation of other parts of the immune system with potentially pathological consequences. The differences presented compared to patients with non-infectious genesis suggest two definable subgroups.

Source: Szklarski, Marvin. Characterization of subgroups of myalgic encephalomyelitis/chronic fatigue syndrome based on disease onset, symptoms and biomarkers. Charité – University Medicine Berlin, dissertation. https://refubium.fu-berlin.de/handle/fub188/40276

Immunosuppression in ME may underlie energy deficits that drive ME symptomology

Interview of Dr. Armin Alaedini by Bronc

In October of 2023 the UK the Department of Health and Social Care held a public consultation to improve the care/life outcomes for people with ME. It included an acknowledgement that there has been a lack of biomedical research into ME but failed to accept the very negative impact this has had on the lives of people living with the illness. It also failed to point the finger at those responsible for this which includes the National Institute of Clinical Excellence and the Medical Research Council amongst others.

Despite calling for more research into ME there is acknowledgement that this will need substantial sums of money for this to happen. The DHSC consultation also asked for views about its plans which included a section about disability benefits and how the Department of Work and Pensions wants to improve the service it provides to those people who claim disability benefits. This laughable comment ignores the war on people claiming disability benefits which has been waged by the DWP since 2010. To compound matters the British government recently announced that it wants to make it harder for people to claim disability benefits and snoop on their bank accounts.

The DWP has consistently failed to acknowledge the debilitating nature of ME and instead focuses on the fluctuating nature of the illness to deny many people with ME disability benefits such as ESA and PIP.

Thankfully, there is plenty of evidence revealing how people with ME suffer from a suppressed immune response which accounts for many of the debilitating symptoms of the illness.

I recently talked with Dr. Armin Alaedini about his recent research into this issue. Dr Alaedini is an assistant professor at Columbia University and principal investigator at the Alaedini Lab. Its research is aimed at identifying ‘novel biomarkers, understanding disease mechanism, and finding therapeutic targets in gastrointestinal and neuropsychiatric disease.’ He is chair of ME/CFS Biospecimen Resource Access Committee at the National Institute of Neurological Disorders and Stroke and a member of the Neurobiology of Pain Study Section at NIH.

Dr Alaedini took time out of his busy schedule to talk to me about his research into ME.

How did you get involved in the field of ME research?

I have always been interested in the study of complex medical conditions, especially those that are poorly understood and understudied. I became specifically involved in ME research because of my acquaintance with Dr. Suzanne Vernon, who at that time was the chief scientific officer at The Solve ME/CFS Initiative. I was fortunate to have her support for a NIH-funded project, which resulted in our recent publication that demonstrates how microbial translocation links gastrointestinal, immunologic, and metabolic defects in ME/CFS.

In the paper you co-authored, Suppressed immune and metabolic responses to intestinal damage-associated microbial translocation in myalgic encephalomyelitis/chronic fatigue syndrome, it notes that the relationship between immunologic, metabolic and gastrointestinal abnormalities remains unclear. In your study you examined two groups of people with ME: one at rest and one undergoing an exercise challenge. They were compared to a group of healthy people. Can you explain what differences you noted between the healthy control group and the people with ME and between the two groups of people with ME? What may have caused this elevated antibody response to microbial agents in people with ME?

I had been particularly intrigued by the fact that gastrointestinal complaints are common in ME/CFS. Data from the patients in our study clearly confirmed this, showing that gastrointestinal symptoms were indeed much more common and more severe in ME/CFS study participants than in the non-ME/CFS controls. Along with this, we found a specific marker of injury or damage to the intestinal lining, called FABP2, to be higher in the blood of ME/CFS participants than in controls, providing a potential biological link to least some of the associated gastrointestinal symptoms. Increased intestinal permeability due to damage can lead to greater translocation of dietary and microbial antigens, which are typically constrained within the gut lumen, across the intestinal barrier. This, in turn, may result in an immune response to those translocated dietary and microbial products to counter and remove the potentially inflammatory antigens from systemic circulation.

Indeed, our data pointed to a significant increase in antibody responses to microbial and dietary antigens in ME/CFS patients in comparison to controls. What especially surprised us, however, was the fact that we did not observe an expected rise in the more immediate, or what we call “acute-phase”, innate immune responses. Specifically, we found that despite the increased markers of intestinal damage and higher antibody responses, ME/CFS patients did not exhibit a significant acute-phase immune response to counter circulating microbial products. This was suggestive of a suppressed systemic immune response that could possibly explain some of the ME/CFS symptoms.

Your study also noted ‘Enhanced antibody response to dietary antigens in ME/CFS’. What might be causing this?

The antibody response to dietary antigens is likely part of the same process resulting from a dysfunctional intestinal barrier that results in an enhanced immune response to the contents of the gut lumen. These would include both microbial and dietary antigens that the immune system is generally tolerant to and does not mount a significant antibody response against under normal conditions.

People with ME suffer from post exertion malaise which means that exercise will exacerbate their symptoms. What differences did you note between the healthy participants and people with ME who took the exercise challenge? What might be causing the differences in their response to exercise?

Intense exercise is known to cause increased intestinal permeability. Therefore, a maximal exercise challenge can be a particularly useful tool to better understand the effect of gut barrier function on the dysfunctional immune responses we were seeing in the ME/CFS cohort. The data from the exercise challenge confirmed our earlier data, suggesting that ME/CFS patients have a dysfunctional immune response, characterized by a suppressed innate/acute-phase response that is ineffective at countering microbial translocation from the intestinal tract into systemic circulation.

At the same time, another part of the immune response, the adaptive immune system, tries to compensate for this dysfunction by producing antibodies against those microbial antigens. However, the antibody response appears to be inadequate, as the ME/CFS patients continued to have increased circulating microbial antigens. We hypothesize that these microbial antigens can trigger downstream inflammatory responses that impact the central nervous system and may contribute to some of the hallmark symptoms of ME/CFS, such as fatigue.

We also compared metabolic responses in response to exercise between ME/CFS and control study participants. Of particular significance, we found a suppression of glucose and citrate metabolic responses in ME/CFS that to some extent correlated with the suppressed innate immune responses in these patients. This dysfunctional metabolic response is not only conceivably capable of contributing to the observed immunosuppression in ME/CFS, but it may also further underlie energy deficits that drive ME/CFS symptomology.

In your study you observed an increase in antibody responses to both microbial and dietary antigens, reflecting greater epithelial cell damage, which point to enhanced translocation of gut luminal antigens across a compromised intestinal barrier in ME/CFS. Did your findings point to a possible treatment for this damage to the intestinal barrier?

Indeed, the data point to a number of potential targets to consider for therapy in the context of ME/CFS. These include reducing or repairing the intestinal damage in order to decrease the microbial translocation; blocking or sequestering the already translocated microbial antigens; reversing the identified defects in the acute-phase immune responses towards the microbial antigens, and targeting the suppressed metabolic pathways.

What further research is needed to address the issues highlighted in your study?

More research is needed to better understand the relevance and level of contribution of the identified defects in the intestinal barrier, immune response, and metabolic pathways to ME/CFS symptomology, as well as to further characterize the molecular pathways involved, in order to move this research closer to development of effective treatments for ME/CFS.

In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS

Abstract:

Disturbances of energy metabolism contribute to clinical manifestations of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Previously we found that B cells from ME/CFS patients have increased expression of CD24, a modulator of many cellular functions including those of cell stress.

The relative ability of B cells from ME/CFS patients and healthy controls (HC) to respond to rapid changes in energy demand were compared. CD24, the ectonucleotidases CD39, CD73, the NAD-degrading enzyme CD38 and mitochondrial mass (MM) were measured following cross-linking of the B cell receptor (BCR) and co-stimulation with either T cell dependent or Toll-like receptor-9 dependent agonists. Levels of metabolites consumed/produced were measured using 1H-NMR spectroscopy and analysed in relation to cell growth and immunophenotype.

Proliferating B cells from patients with ME/CFS showed lower mitochondrial mass and a significantly increased usage of essential amino acids compared those from HC, with a significantly delayed loss of CD24 and increased expression of CD38 following stimulation. Immunophenotype results suggested the triggering of a stress response in ME/CFS B cells associated with increased usage of additional substrates to maintain necessary ATP levels. Disturbances in energy metabolism in ME/CFS B cells were thus confirmed in a dynamic in vitro model, providing the basis for further mechanistic investigations.

Source: Christopher Armstrong, Fane F. Mensah, Maria Leandro, Venkat Reddy, Paul R. Gooley, Saul Berkovitz, Geraldine Cambridge. In vitro B cell experiments explore the role of CD24, CD38 and energy metabolism in ME/CFS. Front. Immunol. Sec. B Cell Biology, Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1178882 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1178882/abstract

Exploring the Joint Potential of Inflammation, Immunity, and Receptor-Based Biomarkers for Evaluating ME/CFS Progression

Abstract:

Background: Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating chronic condition with no identified diagnostic biomarkers to date. Its prevalence is as high as 0.89% according to metastudies, with a quarter of patients bed-or home-bound, which presents a serious public health challenge. Investigations into the inflammation-immunity axis is encouraged by links to outbreaks and disease waves. Recently, research of our group revealed that antibodies to beta2adrenergic (anti-β2AdR) and muscarinic acetylcholine (anti-M4) receptors demonstrate sensitivity to the progression of ME/CFS.

The purpose of this study is to investigate the joint potential of inflammatome -characterized by interferon (IFN)-γ, tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-21, Il-23, IL-6, IL-17A, Activin-B, immunome (IgG1, IgG2, IgG3, IgG4, IgM, IgA) and receptor-based biomarkers (anti-M3, anti-M4, anti-β2AdR) determined for evaluating ME/CFS progression, and to identify an optimal selection for future validation in prospective clinical studies.

Methods: A dataset was used originating from 188 persons, including 54 healthy controls, 30 patients classified as “mild” by severity, 73 as “moderate,” and 31 as “severe,” clinically assessed by Fukuda/CDC 1994 and International consensus criteria. Markers characterizing inflammatome, immunome, and receptor-based biomarkers were determined in blood plasma via ELISA and multiplex methods.

Statistical analysis was done via correlation analysis, principal component, and linear discriminant analysis, and random forest classification; inter-group differences tested via nonparametric Kruskal-Wallis H test followed by the two-stage linear step-up procedure of Benjamini, Krieger, and Yekutieli, and via Mann-Whitney U test.

The association between inflammatome and immunome markers is broader and stronger (coupling) in severe group. Principal component factoring separate components affiliated with inflammatome, immunome, and receptor biomarkers. Random forest modeling demonstrates an out-of-box accuracy for splitting healthy/with condition groups of over 90%, and of 45% for healthy/severity groups. Classifiers with the highest potential are anti-β2AdR, anti-M4, IgG4, IL-2, and IL-6.

Discussion: Association between inflammatome and immunome markers is a candidate for controlled clinical study of ME/CFS progression markers that could be used for treatment individualization. Thus, coupling effects between inflammation and immunity have a potential for the identification of prognostic factors in the context of ME/CFS progression mechanism studies.

Source: Uldis Berkis, Simons Svirskis, Angelika Krumina, Sabine Gravelsina, Anda Vilmane, Diana Araja, Zaiga Nora-Krukle, Modra Murovska. Exploring the Joint Potential of Inflammation, Immunity, and Receptor-Based Biomarkers for Evaluating ME/CFS Progression. Frontiers in Immunology. Sec. Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders. Volume 14- 2023.  https://www.frontiersin.org/articles/10.3389/fimmu.2023.1294758/abstract

Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex disease characterized by profound fatigue, post-exertional malaise (PEM), and neurocognitive dysfunction. Immune dysregulation and gastrointestinal symptoms are commonly observed in ME/CFS patients. Despite affecting approximately 0.89% of the general population, the underlying pathophysiological mechanisms remain poorly understood. This study aimed to elucidate the relationship between immunological characteristics and intestinal barrier function in ME/CFS patients.

ME/CFS patients were stratified into two groups based on their immune competence. After documentation of detailed medical records, serum and plasma samples were collected for assessment of inflammatory immune mediators and biomarkers for intestinal barrier integrity by ELISA. We found reduced complement protein C4a levels in immunodeficient ME/CFS patients suggesting a sub-group specific innate immune dysregulation. ME/CFS patients without immunodeficiencies exhibit a mucosal barrier leakage, as indicated by elevated levels of Lipopolysaccharide-binding protein (LBP).

Stratifying ME/CFS patients based on immune competence enabled the distinction of two subgroups with different pathophysiological patterns. The study highlights the importance of emphasizing precise patient stratification in ME/CFS, particularly in the context of defining suitable treatment strategies. Given the substantial health and socioeconomic burden associated with ME/CFS, urgent attention and research efforts are needed to define causative treatment approaches.

Source: Rohrhofer, J.; Hauser, L.; Lettenmaier, L.; Lutz, L.; Koidl, L.; Gentile, S.A.; Ret, D.; Stingl, M.; Untersmayr, E. Immunological Patient Stratification in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. Preprints 2023, 2023112007. https://doi.org/10.20944/preprints202311.2007.v1 https://www.preprints.org/manuscript/202311.2007/v1 (Full text available as PDF file)

Sex differences in vascular endothelial function related to acute and long COVID-19

Abstract:

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been at the forefront of health sciences research since its emergence in China in 2019 that quickly led to a global pandemic. As a result of this research, and the large numbers of infected patients globally, there were rapid enhancements made in our understanding of Coronavirus disease 2019 (COVID-19) pathology, including its role in the development of uncontrolled immune responses and its link to the development of endotheliitis and endothelial dysfunction.

There were also some noted differences in the rate and severity of infection between males and females with acute COVID. Some individuals infected with SARS-CoV-2 also experience long-COVID, an important hallmark symptom of this being Myalgic Encephalomyelitis-Chronic Fatigue Syndrome (ME-CFS), also experienced differently between males and females.

The purpose of this review is to discuss the impact of sex on the vasculature during acute and long COVID-19, present any link between ME-CFS and endothelial dysfunction, and provide evidence for the relationship between ME-CFS and the immune system. We also will delineate biological sex differences observed in other post viral infections and, assess if sex differences exist in how the immune system responds to viral infection causing ME-CFS.

Source: Kayla KA, Bédard-Matteau J, Rousseau S, Tabrizchi R, Noriko D. Sex differences in vascular endothelial function related to acute and long COVID-19. Vascul Pharmacol. 2023 Dec 1:107250. doi: 10.1016/j.vph.2023.107250. Epub ahead of print. PMID: 38043758. https://www.sciencedirect.com/science/article/abs/pii/S1537189123001106 (Full text)

Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms

Abstract:

Background Autoimmune responses contribute to the pathophysiology of Long COVID, affective symptoms and myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).

Objectives To examine whether Long COVID, and its accompanying affective symptoms and CFS are associated with immunoglobulin (Ig)A/IgM/IgG directed at neuronal proteins including myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), synapsin, α+β-tubulin, neurofilament protein (NFP), cerebellar protein-2 (CP2), and the blood-brain-barrier-brain-damage (BBD) proteins claudin-5 and S100B.

Methods IgA/IgM/IgG to the above neuronal proteins, human herpes virus-6 (HHV-6) and Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) were measured in 90 Long COVID patients and 90 healthy controls, while C-reactive protein (CRP), and advanced oxidation protein products (AOPP) in association with affective and CFS ratings were additionally assessed in a subgroup thereof.

Results Long COVID is associated with significant increases in IgG directed at tubulin (IgG-tubulin), MBP, MOG and synapsin; IgM-MBP, MOG, CP2, synapsin and BBD; and IgA-CP2 and synapsin. IgM-SARS-CoV-2 and IgM-HHV-6 antibody titers were significantly correlated with IgA/IgG/IgM-tubulin and -CP2, IgG/IgM-BBD, IgM-MOG, IgA/IgM-NFP, and IgG/IgM-synapsin. Binary logistic regression analysis shows that IgM-MBP and IgG-MBP are the best predictors of Long COVID. Multiple regression analysis shows that IgG-MOG, CRP and AOPP explain together 41.7% of the variance in the severity of CFS. Neural network analysis shows that IgM-synapsin, IgA-MBP, IgG-MOG, IgA-synapsin, IgA-CP2, IgG-MBP and CRP are the most important predictors of affective symptoms due to Long COVID with a predictive accuracy of r=0.801.

Conclusion Brain-targeted autoimmunity contributes significantly to the pathogenesis of Long COVID and the severity of its physio-affective phenome.

Source: Abbas F. Almulla, Michael Maes, Bo Zhou, Hussein K. Al-Hakeim, Aristo Vojdani. Brain-targeted autoimmunity is strongly associated with Long COVID and its chronic fatigue syndrome as well as its affective symptoms. medRxiv [Preprint] https://www.medrxiv.org/content/10.1101/2023.10.04.23296554v1 (Full text available as PDF file)