Tag: autoimmunity

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)

Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study

Summary:

Background: Case reports suggest that SARS-CoV-2 infection could lead to immune dysregulation and trigger autoimmunity while COVID-19 vaccination is effective against severe COVID-19 outcomes. We aim to examine the association between COVID-19 and development of autoimmune diseases (ADs), and the potential protective effect of COVID-19 vaccination on such an association.

Methods: A retrospective cohort study was conducted in Hong Kong between 1 April 2020 and 15 November 2022. COVID-19 was confirmed by positive polymerase chain reaction or rapid antigen test. Cox proportional hazard regression with inverse probability of treatment weighting was applied to estimate the risk of incident ADs following COVID-19. COVID-19 vaccinated population was compared against COVID-19 unvaccinated population to examine the protective effect of COVID-19 vaccination on new ADs.

Findings: The study included 1,028,721 COVID-19 and 3,168,467 non-COVID individuals. Compared with non-COVID controls, patients with COVID-19 presented an increased risk of developing pernicious anaemia [adjusted Hazard Ratio (aHR): 1.72; 95% Confidence Interval (CI): 1.12–2.64]; spondyloarthritis [aHR: 1.32 (95% CI: 1.03–1.69)]; rheumatoid arthritis [aHR: 1.29 (95% CI: 1.09–1.54)]; other autoimmune arthritis [aHR: 1.43 (95% CI: 1.33–1.54)]; psoriasis [aHR: 1.42 (95% CI: 1.13–1.78)]; pemphigoid [aHR: 2.39 (95% CI: 1.83–3.11)]; Graves’ disease [aHR: 1.30 (95% CI: 1.10–1.54)]; anti-phospholipid antibody syndrome [aHR: 2.12 (95% CI: 1.47–3.05)]; immune mediated thrombocytopenia [aHR: 2.1 (95% CI: 1.82–2.43)]; multiple sclerosis [aHR: 2.66 (95% CI: 1.17–6.05)]; vasculitis [aHR: 1.46 (95% CI: 1.04–2.04)]. Among COVID-19 patients, completion of two doses of COVID-19 vaccine shows a decreased risk of pemphigoid, Graves’ disease, anti-phospholipid antibody syndrome, immune-mediated thrombocytopenia, systemic lupus erythematosus and other autoimmune arthritis.

Interpretation: Our findings suggested that COVID-19 is associated with an increased risk of developing various ADs and the risk could be attenuated by COVID-19 vaccination. Future studies investigating pathology and mechanisms would be valuable to interpreting our findings.

Source: Kuan Peng, Xue Li, Deliang Yang, Shirley C.W. Chan, Jiayi Zhou, Eric Y.F. Wan, et al. Risk of autoimmune diseases following COVID-19 and the potential protective effect from vaccination: a population-based cohort study. The Lancet, VOLUME 63, 102154, SEPTEMBER 2023 https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370(23)00331-0/fulltext (Full text)

Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases?

Abstract:

It is now well established that the blood-clotting protein fibrinogen can polymerise into an anomalous form of fibrin that is amyloid in character; the resultant clots and microclots entrap many other molecules, stain with fluorogenic amyloid stains, are rather resistant to fibrinolysis, can block up microcapillaries, are implicated in a variety of diseases including Long COVID, and have been referred to as fibrinaloids. A necessary corollary of this anomalous polymerisation is the generation of novel epitopes in proteins that would normally be seen as ‘self’, and otherwise immunologically silent.

The precise conformation of the resulting fibrinaloid clots (that, as with prions and classical amyloid proteins, can adopt multiple, stable conformations) must depend on the existing small molecules and metal ions that the fibrinogen may (and is some cases is known to) have bound before polymerisation. Any such novel epitopes, however, are likely to lead to the generation of autoantibodies.

A convergent phenomenology, including distinct conformations and seeding of the anomalous form for initiation and propagation, is emerging to link knowledge in prions, prionoids, amyloids and now fibrinaloids. We here summarise the evidence for the above reasoning, which has substantial implications for our understanding of the genesis of autoimmunity (and the possible prevention thereof) based on the primary process of fibrinaloid formation.

Source: Kell DB, Pretorius E. Are fibrinaloid microclots a cause of autoimmunity in Long Covid and other post-infection diseases? Biochem J. 2023 Aug 16;480(15):1217-1240. doi: 10.1042/BCJ20230241. PMID: 37584410. https://portlandpress.com/biochemj/article/480/15/1217/233389/Are-fibrinaloid-microclots-a-cause-of-autoimmunity (Full text)

Pediatric de novo movement disorders and ataxia in the context of SARS-CoV-2

Abstract:

Objective: In the fourth year of the COVID-19 pandemic, mortality rates decreased, but the risk of neuropsychiatric disorders remained the same, with a prevalence of 3.8% of pediatric cases, including movement disorders (MD) and ataxia.

Methods: In this study, we report on a 10-year-old girl with hemichorea after SARS-CoV-2 infection and immunostained murine brain with patient CSF to identify intrathecal antibodies. Additionally, we conducted a scoping review of children with MD and ataxia after SARS-CoV-2 infection.

Results: We detected antibodies in the patient’s CSF binding unknown antigens in murine basal ganglia. The child received immunosuppression and recovered completely. In a scoping review, we identified further 32 children with de novo MD or ataxia after COVID-19. While in a minority of cases, MD or ataxia were a symptom of known clinical entities (e.g. ADEM, Sydenham’s chorea), in most children, the etiology was suspected to be of autoimmune origin without further assigned diagnosis. (i) Children either presented with ataxia (79%), but different from the well-known postinfectious acute cerebellar ataxia (older age, less favorable outcome, or (ii) had hypo-/hyperkinetic MD (21%), which were choreatic in most cases. Besides 14% of spontaneous recovery, immunosuppression was necessary in 79%. Approximately one third of children only partially recovered.

Conclusions: Infection with SARS-CoV-2 can trigger de novo MD in children. Most patients showed COVID-19-associated-ataxia and fewer-chorea. Our data suggest that patients benefit from immunosuppression, especially steroids. Despite treatment, one third of patients recovered only partially, which makes up an increasing cohort with neurological sequelae.

Source: Wilpert NM, de Almeida Marcelino AL, Knierim E, Incoronato P, Sanchez-Sendin E, Staudacher O, Drenckhahn A, Bittigau P, Kreye J, Prüss H, Schuelke M, Kühn AA, Kaindl AM, Nikolaus M. Pediatric de novo movement disorders and ataxia in the context of SARS-CoV-2. J Neurol. 2023 Jul 29. doi: 10.1007/s00415-023-11853-5. Epub ahead of print. PMID: 37515734. https://link.springer.com/article/10.1007/s00415-023-11853-5 (Full text)

Long COVID-19 and Insulin Autoimmune Syndrome: A Case Report

Abstract:

Purpose: To describe a case report of a patient with symptoms associated with metabolic alterations 1 month after having COVID-19.

Methods: Laboratory tests, clinical evaluations, and body composition assessments were performed by specialists.

Findings: The patient presented excessive sweating, hot flashes, dizziness, blurred vision, and seizure. Laboratory tests indicated low glucose levels after convulsions (50, 42.7, and 55 mg/dL), high insulin levels (basal, 638 µIU/mL; 2-hour, >1000 µU/mL), and positivity for anti-insulin antibodies. The patient was diagnosed with insulin autoimmune syndrome. Treatment with azathioprine and nutritional recommendations improved remission.

Implications: SARS-CoV-2 infection or vaccination might induce insulin tolerance failure.

Source: Corona-Meraz FI, Quintero-Castillo BP, Hernández-Palma LA, Machado-Sulbaran AC. Long COVID-19 and Insulin Autoimmune Syndrome: A Case Report. Clin Ther. 2023 Jul 29:S0149-2918(23)00250-3. doi: 10.1016/j.clinthera.2023.06.026. Epub ahead of print. PMID: 37524570. https://pubmed.ncbi.nlm.nih.gov/37524570/

Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID

Abstract:

While immunologic correlates of COVID-19 have been widely reported, their associations with post-acute sequelae of COVID-19 (PASC) remain less clear. Due to the wide array of PASC presentations, understanding if specific disease features associate with discrete immune processes and therapeutic opportunities is important.

Here we profile patients in the recovery phase of COVID-19 via proteomics screening and machine learning to find signatures of ongoing antiviral B cell development, immune-mediated fibrosis, and markers of cell death in PASC patients but not in controls with uncomplicated recovery. Plasma and immune cell profiling further allow the stratification of PASC into inflammatory and non-inflammatory types.

Inflammatory PASC, identifiable through a refined set of 12 blood markers, displays evidence of ongoing neutrophil activity, B cell memory alterations, and building autoreactivity more than a year post COVID-19. Our work thus helps refine PASC categorization to aid in both therapeutic targeting and epidemiological investigation of PASC.

Source: Woodruff MC, Bonham KS, Anam FA, Walker TA, Faliti CE, Ishii Y, Kaminski CY, Ruunstrom MC, Cooper KR, Truong AD, Dixit AN, Han JE, Ramonell RP, Haddad NS, Rudolph ME, Yalavarthi S, Betin V, Natoli T, Navaz S, Jenks SA, Zuo Y, Knight JS, Khosroshahi A, Lee FE, Sanz I. Chronic inflammation, neutrophil activity, and autoreactivity splits long COVID. Nat Commun. 2023 Jul 14;14(1):4201. doi: 10.1038/s41467-023-40012-7. PMID: 37452024; PMCID: PMC10349085. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10349085/ (Full text)

A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms

Abstract:

Approximately 30% of COVID-19 cases may experience chronic symptoms, known as post-COVID-19 syndrome (PCS). Common PCS symptoms can include fatigue, cognitive impairment, and persistent physical, neurological, and neuropsychiatric complaints.

To improve healthcare and management of the current and future pandemics, we highlight the need for establishing interdisciplinary post-viral outpatient clinics comprised of specialists in fields such as psychiatry, psychotherapy, neurology, cardiology, pneumology, and immunology. In this way, PCS patients with a high health burden can receive modern diagnostics and targeted therapeutic recommendations. A key objective is to distinguish the “sick recovered” from the “healthy recovered.”

Our hypothesis is that there is a PCS subgroup with autoimmune-mediated systemic and brain-vascular dysregulation, which may lead to circulatory disorders, fatigue, cognitive impairment, depression, and anxiety. This can be clarified using a combination of specific antibody diagnostics and precise clinical, psychological, and apparative testing.

Source: Guest PC, Neyazi A, Braun-Dullaeus RC, Müller P, Schreiber J, Haghikia A, Vasilevska V, Steiner J. A Molecular Biomarker-Based Triage Approach for Targeted Treatment of Post-COVID-19 Syndrome Patients with Persistent Neurological or Neuropsychiatric Symptoms. Adv Exp Med Biol. 2023;1412:97-115. doi: 10.1007/978-3-031-28012-2_5. PMID: 37378763. https://pubmed.ncbi.nlm.nih.gov/37378763/

Autoantibody production is enhanced after mild SARS-CoV-2 infection despite vaccination in individuals with and without long COVID

Abstract:

Long COVID patients who experienced severe acute SARS-CoV-2 infection can present with humoral autoimmunity. However, whether mild SARS-CoV-2 infection increases autoantibody responses and whether vaccination can decrease autoimmunity in long COVID patients is unknown.

Here, we demonstrate that mild SARS-CoV-2 infection increases autoantibodies associated with systemic lupus erythematosus (SLE) and inflammatory myopathies in long COVID patients with persistent neurologic symptoms to a greater extent than COVID convalescent controls at 8 months post-infection. Furthermore, high titers of SLE-associated autoantibodies in long COVID patients are associated with impaired cognitive performance and greater symptom severity, and subsequent vaccination/booster does not decrease autoantibody titers.

In summary, we found that mild SARS-CoV-2 infection can induce persistent humoral autoimmunity in both long COVID patients and healthy COVID convalescents, suggesting that a reappraisal of vaccination and mitigation strategies is warranted.

Source: Visvabharathy L, Zhu C, Orban ZS, Yarnoff K, Palacio N, Jimenez M, Lim PH, Penaloza-MacMaster P, Koralnik IJ. Autoantibody production is enhanced after mild SARS-CoV-2 infection despite vaccination in individuals with and without long COVID. medRxiv [Preprint]. 2023 Apr 12:2023.04.07.23288243. doi: 10.1101/2023.04.07.23288243. PMID: 37090595; PMCID: PMC10120795. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120795/ (Full text)

Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS)

Abstract:

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a multisystemic disease of unknown aetiology that is characterised by disabling chronic fatigue and involves both the immune and gastrointestinal (GI) systems. Patients display alterations in GI microbiome with a significant proportion experiencing GI discomfort and pain and elevated blood biomarkers for altered intestinal permeability compared with healthy individuals.

To investigate a possible GI origin of ME/CFS we designed a feasibility study to test the hypothesis that ME/CFS pathogenesis is a consequence of increased intestinal permeability that results in microbial translocation and a breakdown in immune tolerance leading to generation of antibodies reactive to indigenous intestinal microbes. Secretory IgA and serum IgG levels and reactivity to intestinal microbes were assessed in five pairs of severe ME/CFS patients and matched same-household healthy controls. For profiling serum IgG we developed IgG-Seq which combines flow-cytometry based bacterial cell sorting and metagenomics to detect mucosal IgG reactivity to the microbiome.

We uncovered evidence for immune dysfunction in severe ME/CFS patients that was characterised by reduced capacity and reactivity of serum IgG to stool microbes, irrespective of their source. This study provides the rationale for additional studies in larger cohorts of ME/CFS patients to further explore immune-microbiome interactions.

Source: Katharine A. Seton, Marianne Defernez, Andrea Telatin, Sumeet K. Tiwari, George M. Savva, Antonietta Hayhoe, Alistair Noble, Ana Carvalho, Steve James, Amolak Bansal, Thomas Wileman, Simon R. Carding. Investigating antibody reactivity to the intestinal microbiome in severe myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). medRxiv 2023.05.21.23290299; doi: https://doi.org/10.1101/2023.05.21.23290299 https://www.medrxiv.org/content/10.1101/2023.05.21.23290299v1.full-text (Full text)