Tag: autoimmunity

Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis

Abstract:

Myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS), long COVID (LC) and post-COVID-19 vaccine syndrome show similarities in their pathophysiology and clinical manifestations. These disorders are related to viral or adjuvant persistence, immunological alterations, autoimmune diseases and hormonal imbalances.

A developmental model is postulated that involves the interaction between immune hyperactivation, autoimmune hypophysitis or pituitary hypophysitis, and immune depletion. This process might begin with a deficient CD4 T-cell response to viral infections in genetically predisposed individuals (HLA-DRB1), followed by an uncontrolled immune response with CD8 T-cell hyperactivation and elevated antibody production, some of which may be directed against autoantigens, which can trigger autoimmune hypophysitis or direct damage to the pituitary, resulting in decreased production of pituitary hormones, such as ACTH. As the disease progresses, prolonged exposure to viral antigens can lead to exhaustion of the immune system, exacerbating symptoms and pathology.

It is suggested that these disorders could be included in the autoimmune/adjuvant-induced inflammatory syndrome (ASIA) because of their similar clinical manifestations and possible relationship to genetic factors, such as polymorphisms in the HLA-DRB1 gene. In addition, it is proposed that treatment with antivirals, corticosteroids/ginseng, antioxidants, and metabolic precursors could improve symptoms by modulating the immune response, pituitary function, inflammation and oxidative stress.

Therefore, the purpose of this review is to suggest a possible autoimmune origin against the adenohypophysis and a possible improvement of symptoms after treatment with corticosteroid replacement therapy.

Source: Manuel Ruiz-Pablos, Bruno Paiva, Aintzane Zabaleta. Hypocortisolemic ASIA: a vaccine- and chronic infection-induced syndrome behind the origin of long COVID and myalgic encephalomyelitis. Front. Immunol., 08 July 2024, Sec. Viral Immunology, Volume 15 – 2024 | https://doi.org/10.3389/fimmu.2024.1422940 https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1422940/full (Full text)

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease

Abstract:

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic, debilitating disease characterised by a wide range of symptoms that severely impact all aspects of life. Despite its significant prevalence, ME/CFS remains one of the most understudied and misunderstood conditions in modern medicine. ME/CFS lacks standardised diagnostic criteria owing to variations in both inclusion and exclusion criteria across different diagnostic guidelines, and furthermore, there are currently no effective treatments available.

Moving beyond the traditional fragmented perspectives that have limited our understanding and management of the disease, our analysis of current information on ME/CFS represents a significant paradigm shift by synthesising the disease’s multifactorial origins into a cohesive model. We discuss how ME/CFS emerges from an intricate web of genetic vulnerabilities and environmental triggers, notably viral infections, leading to a complex series of pathological responses including immune dysregulation, chronic inflammation, gut dysbiosis, and metabolic disturbances.

This comprehensive model not only advances our understanding of ME/CFS’s pathophysiology but also opens new avenues for research and potential therapeutic strategies. By integrating these disparate elements, our work emphasises the necessity of a holistic approach to diagnosing, researching, and treating ME/CFS, urging the scientific community to reconsider the disease’s complexity and the multifaceted approach required for its study and management.

Source: Arron HE, Marsh BD, Kell DB, Khan MA, Jaeger BR, Pretorius E. Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: the biology of a neglected disease. Front Immunol. 2024 Jun 3;15:1386607. doi: 10.3389/fimmu.2024.1386607. PMID: 38887284; PMCID: PMC11180809. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11180809/ (Full text)

The risks of autoimmune- and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the US, and Korea

ABSTRACT

Objectives We aimed to assess the risk of autoimmune- and inflammatory post-acute COVID-19 conditions.

Design Descriptive network cohort study.

Setting Electronic health records from UK and Dutch primary care, Norwegian linked health registry, hospital records of specialist centres in Spain, France, and Korea, and healthcare claims from Estonia and the US.

Participants We followed individuals between September 2020 and the latest available data from the day they fulfilled at least 365 days of prior observation (general population), additionally from day 91 after a SARS-Cov-2 negative test (comparator) or a COVID-19 record (exposed patients).

Main outcome measures We assessed postural orthostatic tachycardia syndrome (POTS) diagnoses/symptoms, myalgic encephalomyelitis / chronic fatigues syndrome (ME/CFS) diagnoses/symptoms, multi-inflammatory syndrome (MIS), and several autoimmune diseases. For contextualisation, we assessed any diabetes mellitus (DM).

Meta-analysed crude incidence rate ratios (IRR) of outcomes measures after COVID-19 versus negative testing yield the ratios of absolute risks. Furthermore, incidence rates (IR) of the outcomes in the general population describe the total disease burden.

Results We included 34’549’575 individuals of whom 2’521’812 had COVID-19, and 4’233’145 a first negative test. After COVID-19 compared to test negative patients, we observed IRRs of 1.24 (1.23-1.25), 1.22 (1.21-1.23), and 1.12 (1.04-1.21) for POTS symptoms, ME/CFS symptoms and diagnoses, respectively. In contrast, autoimmune diseases and DM did not yield higher rates after COVID-19. In individual general database populations, IRs of POTS and ME/CFS diagnoses were 17-1’477/100’000 person-years (pys) and 2-473/100’000 pys, respectively. IRs of MIS were lowest with IRs 0.4-16/100’000 pys, those of DM as a benchmark 8-86/100’000 pys. IRs largely depended on the care setting.

Conclusion In our unmatched comparison, we observed that, following COVID-19, POTS and ME/CFS yielded higher rates than after negative testing. In absolute terms, we observed POTS and ME/CFS diagnoses to have a similar disease burden as DM.

WHAT IS ALREADY KNOWN ON THIS TOPIC

  • Observational research suggested positive associations between COVID-19 and so called post-acute COVID-19 conditions, whose spectrum is yet to be established

  • Basic research suggested pathways that link COVID-19 with autoimmune- and inflammatory diseases such as postural orthostatic tachycardia syndrome (POTS), myalgic encephalomyelitis / chronic fatigues syndrome (ME/CFS), multiple inflammatory syndrome (MIS), and autoimmune diseases

WHAT THIS STUDY ADDS

  • After COVID-19, the rates of POTS symptoms and ME/CFS symptoms/diagnoses was higher than those after negative testing

  • After COVID-19 versus negative testing, rates of ME/CFS diagnoses were increased in the working age group and rates of symptoms of POTS and ME/CFS were increased in children and elderly

  • Disease burdens of POTS and ME/CFS diagnoses in the general population were higher among women than among men and overall similar to that of diabetes mellitus

Source: Theresa Burkard, Kim López-Güell, Martí Català, Edward Burn, Antonella Delmestri, Sara Khalid, Annika M Joedicke, Daniel Dedman, Jessie O Oyinlola, Alicia Abellan, Laura Pérez-Crespo, Núria Mercadé-Besora, Talita Duarte-Salles, Daniel Prieto-Alhambra, Johnmary T Arinze, Mees Mosseveld, Raivo Kolde, Jaime Meléndez-Cardiel, Raúl López-Blasco, Álvaro Martínez, Bernardo Valdivieso, Dominique Delseny, Gregoire Mercier, Chungsoo Kim, Ji-woo Kim, Kristin Kostka, Juan Manuel Ramírez-Anguita, Miguel A Mayer, Nhung TH Trinh, Hedvig ME Nordeng, Roger Paredes, Anneli Uusküla, Akihiko Nishimura, Cora Loste, Lourdes Mateu, Junqing Xie. The risks of autoimmune- and inflammatory post-acute COVID-19 conditions: a network cohort study in six European countries, the US, and Korea. medRxiv 2024.05.15.24307344; doi: https://doi.org/10.1101/2024.05.15.24307344 https://www.medrxiv.org/content/10.1101/2024.05.15.24307344v1.full-text (Full text)

Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α

Abstract:

The cGAS-STING pathway appears to contribute to dysregulated inflammation during coronavirus disease 2019 (COVID-19); however, inflammatory factors related to long COVID are still being investigated.

In the present study, we evaluated the association of cGAS and STING gene expression levels and plasma IFN-α, TNF-α and IL-6 levels with COVID-19 severity in acute infection and long COVID, based on analysis of blood samples from 148 individuals, 87 with acute COVID-19 and 61 in the post-COVID-19 period.

Quantification of gene expression was performed by real-time PCR, and cytokine levels were quantified by ELISA and flow cytometry. In acute COVID-19, cGAS, STING, IFN-α, TNF-α, and IL-6 levels were higher in patients with severe disease than in those with nonsevere manifestations (p < 0.05). Long COVID was associated with elevated cGAS, STING and IFN-α levels (p < 0.05).

Activation of the cGAS-STING pathway may contribute to an intense systemic inflammatory state in severe COVID-19 and, after infection resolution, induce an autoinflammatory disease in some tissues, resulting in long COVID.

Source: Queiroz, M.A.F., Brito, W.R.S., Pereira, K.A.S. et al. Severe COVID-19 and long COVID are associated with high expression of STING, cGAS and IFN-α. Sci Rep 14, 4974 (2024). https://doi.org/10.1038/s41598-024-55696-0 https://www.nature.com/articles/s41598-024-55696-0 (Full text)

Analysis and clinical determinants of post-COVID-19 syndrome in the Lombardy region: evidence from a longitudinal cohort study

Abstract:

Objective: To define macro symptoms of long COVID and to identify predictive factors, with the aim of preventing the development of the long COVID syndrome.

Design: A single-centre longitudinal prospective cohort study conducted from May 2020 to October 2022.

Setting: The study was conducted at Luigi Sacco University Hospital in Milan (Italy). In May 2020, we activated the ARCOVID (Ambulatorio Rivalutazione COVID) outpatient service for the follow-up of long COVID.

Participants: Hospitalised and non-hospitalised patients previously affected by COVID-19 were either referred by specialists or general practitioners or self-referred.

Intervention: During the first visit, a set of questions investigated the presence and the duration of 11 symptoms (palpitations, amnesia, headache, anxiety/panic, insomnia, loss of smell, loss of taste, dyspnoea, asthenia, myalgia and telogen effluvium). The follow-up has continued until the present time, by sending email questionnaires every 3 months to monitor symptoms and health-related quality of life.

Primary and secondary outcome measures: Measurement of synthetic scores (aggregation of symptoms based on occurrence and duration) that may reveal the presence of long COVID in different clinical macro symptoms. To this end, a mixed supervised and empirical strategy was adopted. Moreover, we aimed to identify predictive factors for post-COVID-19 macro symptoms.

Results: In the first and second waves of COVID-19, 575 and 793 patients (respectively) were enrolled. Three different post-COVID-19 macro symptoms (neurological, sensorial and physical) were identified. We found significant associations between post-COVID-19 symptoms and (1) the patients’ comorbidities, and (2) the medications used during the COVID-19 acute phase. ACE inhibitors (OR=2.039, 95% CI: 1.095 to 3.892), inhaled steroids (OR=4.08, 95% CI: 1.17 to 19.19) and COVID therapies were associated with increased incidence of the neurological macro symptoms. Age (OR=1.02, 95% CI: 1.01 to 1.04), COVID-19 severity (OR=0.42, 95% CI: 0.21 to 0.82), number of comorbidities (OR=1.22, 95% CI: 1.01 to 1.5), metabolic (OR=2.52, 95% CI: 1.25 to 5.27), pulmonary (OR=1.87, 95% CI: 1.10 to 3.32) and autoimmune diseases (OR=4.57, 95% CI: 1.57 to 19.41) increased the risk of the physical macro symptoms.

Conclusions: Being male was the unique protective factor in both waves. Other factors reflected different medical behaviours and the impact of comorbidities. Evidence of the effect of therapies adds valuable information that may drive future medical choices.

Source: Borgonovo F, Lovaglio PG, Mariani C, Berta P, Cossu MV, Rizzardini G, Vittadini G, Capetti AF. Analysis and clinical determinants of post-COVID-19 syndrome in the Lombardy region: evidence from a longitudinal cohort study. BMJ Open. 2024 Feb 6;14(2):e075185. doi: 10.1136/bmjopen-2023-075185. PMID: 38320835; PMCID: PMC10860093. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10860093/ (Full text)

From Viral Infection to Autoimmune Reaction: Exploring the Link between Human Herpesvirus 6 and Autoimmune Diseases

Abstract:

The complexity of autoimmunity initiation has been the subject of many studies. Both genetic and environmental factors are essential in autoimmunity development. Among others, environmental factors include infectious agents. HHV-6 is a ubiquitous human pathogen with a high global prevalence. It has several properties suggestive of its contribution to autoimmunity development.
HHV-6 has a broad cell tropism, the ability to establish latency with subsequent reactivation and persistence, and a range of immunomodulation capabilities. Studies have implicated HHV-6 in a plethora of autoimmune diseases—endocrine, neurological, connective tissue, and others—with some studies even proposing possible autoimmunity induction mechanisms. HHV-6 can be frequently found in autoimmunity-affected tissues and lesions; it has been found to infect autoimmune-pathology-relevant cells and influence immune responses and signaling.
This review highlights some of the most well-known autoimmune conditions to which HHV-6 has been linked, like multiple sclerosis and autoimmune thyroiditis, and summarizes the data on HHV-6 involvement in autoimmunity development.
Source: Sokolovska L, Cistjakovs M, Matroze A, Murovska M, Sultanova A. From Viral Infection to Autoimmune Reaction: Exploring the Link between Human Herpesvirus 6 and Autoimmune Diseases. Microorganisms. 2024; 12(2):362. https://doi.org/10.3390/microorganisms12020362 https://www.mdpi.com/2076-2607/12/2/362 (Full text)

Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach

Abstract:

The dermatological manifestations of Long Covid (LC) have languished in the shadows of chronic fatigue and brain fog. Yet they are all linked by gut dysbiosis and the cytokine triad of TNF-α, IL-1β, and IL-6. The gut microbiome common not only to LC, psoriasis, AA, and vitiligo but also to neurodegenerative disease has been recently described. This gut microbiome induces an altered tryptophan metabolism linked to autoimmune disease. SARS CoV2 invades enterochromaffin cells rich in ACE2 receptors and curtails absorption of the essential amino acid tryptophan and subsequent synthesis of serotonin and melatonin.

This review suggests that an etiologic prebiotic (d-mannose)/probiotic (lactobacilli, bifidobacteria)/postbiotic (butyrate) approach to autoimmune skin disease that improves intestinal barrier integrity and that suppresses the triad of TNF-α, IL-6, and IL-1β may enhance or even eliminate the traditional immunotherapy of targeted monoclonal antibodies, Janus kinase inhibitors, and steroids. Health benefits of this approach extend well beyond suppression of autoimmune skin disease.

Source: Chambers, P.W.; Chambers, S.E. Long Covid, the Gut, and Autoimmune Skin Diseases: A Novel Therapeutic Approach. Preprints 2023, 2023121881. https://doi.org/10.20944/preprints202312.1881.v2 https://www.preprints.org/manuscript/202312.1881/v2 (Full text available as PDF file)

IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry

Abstract:

The diagnosis and the pathology of Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) remain under debate. However, there is a growing body of evidence for an autoimmune component in ME/CFS caused by the Epstein-Barr virus (EBV) and other viral infections.
In this work, we took advantage of a large public dataset on the IgG antibodies to 3,054 EBV peptides to understand whether these immune responses could be used as putative biomarkers for disease diagnosis and triggers of pathological autoimmunity in ME/CFS patients using healthy controls (HCs) as a comparator cohort. We then aimed at predicting disease status of study participants using a Super Learner algorithm targeting an accuracy of 85% when splitting data into train and test datasets.
When we compared data of all ME/CFS patients or data of a subgroup of these patients with non-infectious or unknown disease trigger to the dataset of HC, we could not find an antibody-based classifier that would meet the desired accuracy in the test dataset. In contrast, we could identify a 26-antibody classifier that could distinguish ME/CFS patients with an infectious disease trigger from HCs with 100% and 90% accuracies on the train and test sets, respectively.
We finally performed a bioinformatic analysis of the EBV peptides associated with these 26 antibodies. We found no correlation between the importance metric of the selected antibodies in the classifier and the maximal sequence homology between human proteins and each EBV peptide recognized by these antibodies.
In conclusion, these 26 antibodies against EBV have an effective potential for disease diagnosis of a subset of patients, but they are less likely to trigger pathological autoimmune responses that could explain the pathogenesis of ME/CFS.
Source: Fonseca, A.; Szysz, M.; Ly, H.T.; Cordeiro, C.; Sepúlveda, N. IgG Antibody Responses to Epstein-Barr Virus in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome: Their Effective Potential for Disease Diagnosis and Pathological Antigenic Mimicry. Preprints 2023, 2023111523. https://doi.org/10.20944/preprints202311.1523.v1 https://www.preprints.org/manuscript/202311.1523/v1 (Full text available as PDF file)

From aging to long COVID: exploring the convergence of immunosenescence, inflammaging, and autoimmunity

Abstract:

The process of aging is accompanied by a dynamic restructuring of the immune response, a phenomenon known as immunosenescence. This mini-review navigates through the complex landscape of age-associated immune changes, chronic inflammation, age-related autoimmune tendencies, and their potential links with immunopathology of Long COVID. Immunosenescence serves as an introductory departure point, elucidating alterations in immune cell profiles and their functional dynamics, changes in T-cell receptor signaling, cytokine network dysregulation, and compromised regulatory T-cell function.

Subsequent scrutiny of chronic inflammation, or “inflammaging,” highlights its roles in age-related autoimmune susceptibilities and its potential as a mediator of the immune perturbations observed in Long COVID patients. The introduction of epigenetic facets further amplifies the potential interconnections.

In this compact review, we consider the dynamic interactions between immunosenescence, inflammation, and autoimmunity. We aim to explore the multifaceted relationships that link these processes and shed light on the underlying mechanisms that drive their interconnectedness. With a focus on understanding the immunological changes in the context of aging, we seek to provide insights into how immunosenescence and inflammation contribute to the emergence and progression of autoimmune disorders in the elderly and may serve as potential mediator for Long COVID disturbances.

Source: Müller L, Di Benedetto S. From aging to long COVID: exploring the convergence of immunosenescence, inflammaging, and autoimmunity. Front Immunol. 2023 Oct 24;14:1298004. doi: 10.3389/fimmu.2023.1298004. PMID: 37942323; PMCID: PMC10628127. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10628127/ (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)