Tag: CD4

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)

Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome

Abstract:

A substantial number of patients recovering from acute SARS-CoV-2 infection present serious lingering symptoms, often referred to as long COVID (LC). However, a subset of these patients exhibits the most debilitating symptoms characterized by ongoing myalgic encephalomyelitis or chronic fatigue syndrome (ME/CFS).

We specifically identified and studied ME/CFS patients from two independent LC cohorts, at least 12 months post the onset of acute disease, and compared them to the recovered group (R). ME/CFS patients had relatively increased neutrophils and monocytes but reduced lymphocytes. Selective T cell exhaustion with reduced naïve but increased terminal effector T cells was observed in these patients. LC was associated with elevated levels of plasma pro-inflammatory cytokines, chemokines, Galectin-9 (Gal-9), and artemin (ARTN). A defined threshold of Gal-9 and ARTN concentrations had a strong association with LC.

The expansion of immunosuppressive CD71+ erythroid cells (CECs) was noted. These cells may modulate the immune response and contribute to increased ARTN concentration, which correlated with pain and cognitive impairment. Serology revealed an elevation in a variety of autoantibodies in LC. Intriguingly, we found that the frequency of 2B4+CD160+ and TIM3+CD160+ CD8+ T cells completely separated LC patients from the R group.

Our further analyses using a multiple regression model revealed that the elevated frequency/levels of CD4 terminal effector, ARTN, CEC, Gal-9, CD8 terminal effector, and MCP1 but lower frequency/levels of TGF-β and MAIT cells can distinguish LC from the R group. Our findings provide a new paradigm in the pathogenesis of ME/CFS to identify strategies for its prevention and treatment.

Source: Saito S, Shahbaz S, Osman M, Redmond D, Bozorgmehr N, Rosychuk RJ, Lam G, Sligl W, Cohen Tervaert JW, Elahi S. Diverse immunological dysregulation, chronic inflammation, and impaired erythropoiesis in long COVID patients with chronic fatigue syndrome. J Autoimmun. 2024 May 25;147:103267. doi: 10.1016/j.jaut.2024.103267. Epub ahead of print. PMID: 38797051. https://www.sciencedirect.com/science/article/pii/S089684112400101X (Full text)

Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection

Abstract:

Crimean-Congo hemorrhagic fever (CCHF) caused by CCHF virus (CCHFV) is one of the epidemic-prone diseases prioritized by the World Health Organisation as public health emergency with an urgent need for accelerated research. The trajectory of host response against CCHFV is multifarious and remains unknown. Here, we reported the temporal spectrum of pathogenesis following the CCHFV infection using genome-wide blood transcriptomics analysis followed by advanced systems biology analysis, temporal immune-pathogenic alterations, and context-specific progressive and postinfection genome-scale metabolic models (GSMM) on samples collected during the acute (T0), early convalescent (T1), and convalescent-phase (T2).

The interplay between the retinoic acid-inducible gene-I-like/nucleotide-binding oligomerization domain-like receptor and tumor necrosis factor signaling governed the trajectory of antiviral immune responses. The rearrangement of intracellular metabolic fluxes toward the amino acid metabolism and metabolic shift toward oxidative phosphorylation and fatty acid oxidation during acute CCHFV infection determine the pathogenicity. The upregulation of the tricarboxylic acid cycle during CCHFV infection, compared to the noninfected healthy control and between the severity groups, indicated an increased energy demand and cellular stress. The upregulation of glycolysis and pyruvate metabolism potentiated energy generation through alternative pathways associated with the severity of the infection.

The downregulation of metabolic processes at the convalescent phase identified by blood cell transcriptomics and single-cell type proteomics of five immune cells (CD4+ and CD8+ T cells, CD14+ monocytes, B cells, and NK cells) potentially leads to metabolic rewiring through the recovery due to hyperactivity during the acute phase leading to post-viral fatigue syndrome.

Source: Ambikan AT, Elaldi N, Svensson-Akusjärvi S, Bagci B, Pektas AN, Hewson R, Bagci G, Arasli M, Appelberg S, Mardinoglu A, Sood V, Végvári Á, Benfeitas R, Gupta S, Cetin I, Mirazimi A, Neogi U. Systems-level temporal immune-metabolic profile in Crimean-Congo hemorrhagic fever virus infection. Proc Natl Acad Sci U S A. 2023 Sep 12;120(37):e2304722120. doi: 10.1073/pnas.2304722120. Epub 2023 Sep 5. PMID: 37669378; PMCID: PMC10500270. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10500270/ (Full text)

Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome

Abstract;
Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a chronic and incapacitating multisystem condition with unknown etiology, no cure, and no FDA- approved treatments, all of which can be attributed to historical underfunding, widespread misinformation, and the complexity of the disease. Many patients encounter several immune-related symptoms, extreme fatigue, post-exertional malaise, and a flu-like onset. Studies have documented changes in ME/CFS immune cell populations and decreased natural killer (NK) cell performance, along with aberrant cytokine production, reduced glycolysis in T cells, and altered metabolites relevant to fatty acid oxidation, implicating potential intracellular metabolic dysregulation.
This knowledge prompted me to investigate fatty acid oxidation and immune cell functional states in isolated ME/CFS lymphocytes. Using extracellular flux analysis and flow cytometry, I observed elevated fatty acid oxidation levels in ME/CFS immune cells, including NK cells, CD4+ memory cells, CD4+ effector cells, CD8+ naïve cells, and CD8+ memory cells compared to healthy controls, particularly during high energy demands and activation. My findings suggest a metabolic dysfunction in ME/CFS immune cells, consistent with T cell exhaustion – a state that hinders immune cell proliferation, survival, and cytokine production following persistent antigen stimulation.
Building upon these results, I further investigated immune cell exhaustion and dysfunction in isolated CD8+ and CD4+ T cells from ME/CFS and healthy samples. I analyzed T cell sub-populations, including naïve, effector, memory, regulatory, and helper T cells, for frequencies of inhibitory receptors and transcription factors associated with dysfunctional immune cell states.
I detected distinct transcription factor dynamics and elevated exhausted T cell phenotype proportions in ME/CFS CD8+ T cell populations compared to healthy controls. In ME/CFS CD4+ T cells, I also observed altered inhibitory receptor population frequencies compared to healthy control samples. Moreover, dysfunctional T cell features correlated with ME/CFS health status and symptom presentation.
Overall, my findings detect dysfunctional T cell states in specific ME/CFS cell populations, which can lead to reduced effector function that may contribute to ME/CFS symptom presentation. This work highlights the significance of assessing both metabolic components and immune cell dysfunction-associated targets in the development of potential therapeutic interventions for individuals with ME/CFS.
Source: Maya, Jessica. Immune cell exhaustion, dysfunction, and metabolism in myalgic encephalomyelitis/chronic fatigue syndrome. Cornell Theses and Dissertations. 2024. https://ecommons.cornell.edu/items/242f8723-6f87-47cc-b36d-bf51a21f4255

Blood T cell phenotypes correlate with fatigue severity in post-acute sequelae of COVID-19

Abstract:

Purpose: Post-acute sequelae of COVID-19 (PASC) affect approximately 10% of convalescent patients. The spectrum of symptoms is broad and heterogeneous with fatigue being the most often reported sequela. Easily accessible blood biomarkers to determine PASC severity are lacking. Thus, our study aimed to correlate immune phenotypes with PASC across the severity spectrum of COVID-19.

Methods: A total of 176 originally immunonaïve, convalescent COVID-19 patients from a prospective cohort during the first pandemic phase were stratified by initial disease severity and underwent clinical, psychosocial, and immune phenotyping around 10 weeks after first COVID-19 symptoms. COVID-19-associated fatigue dynamics were assessed and related to clinical and immune phenotypes.

Results: Fatigue and severe fatigue were commonly reported irrespective of initial COVID-19 severity or organ-specific PASC. A clinically relevant increase in fatigue severity after COVID-19 was detected in all groups. Neutralizing antibody titers were higher in patients with severe acute disease, but no association was found between antibody titers and PASC. While absolute peripheral blood immune cell counts in originally immunonaïve PASC patients did not differ from unexposed controls, peripheral CD3+CD4+ T cell counts were independently correlated with fatigue severity across all strata in multivariable analysis.

Conclusions: Patients were at similar risk of self-reported PASC irrespective of initial disease severity. The independent correlation between fatigue severity and blood T cell phenotypes indicates a possible role of CD4+ T cells in the pathogenesis of post-COVID-19 fatigue, which might serve as a blood biomarker.

Source: Pink, I., Hennigs, J.K., Ruhl, L. et al. Blood T cell phenotypes correlate with fatigue severity in post-acute sequelae of COVID-19. Infection (2023). https://doi.org/10.1007/s15010-023-02114-8 https://link.springer.com/article/10.1007/s15010-023-02114-8 (Full text)

Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments

Abstract:

Introduction: Q fever, caused by the intracellular bacterium Coxiella burnetii, is considered an occupational and biodefense hazard and can result in debilitating long-term complications. While natural infection and vaccination induce humoral and cellular immune responses, the exact nature of cellular immune responses to C. burnetii is incompletely understood. The current study seeks to investigate more deeply the nature of long-term cellular recall responses in naturally exposed individuals by both cytokine release assessment and cytometry profiling.

Methods: Individuals exposed during the 2007-2010 Dutch Q fever outbreak were grouped in 2015, based on a C. burnetii-specific IFNγ release assay (IGRA), serological status, and self-reported clinical symptoms during initial infection, into asymptomatic IGRA-negative/seronegative controls, and three IGRA-positive groups (seronegative/asymptomatic; seropositive/asymptomatic and seropositive/symptomatic). Recall responses following in vitro re-stimulation with heat-inactivated C. burnetii in whole blood, were assessed in 2016/2017 by cytokine release assays (n=55) and flow cytometry (n=36), and in blood mononuclear cells by mass cytometry (n=36).

Results: Cytokine release analysis showed significantly elevated IL-2 responses in all seropositive individuals and elevated IL-1β responses in those recovered from symptomatic infection. Comparative flow cytometry analysis revealed significantly increased IFNγ, TNFα and IL-2 recall responses by CD4 T cells and higher IL-6 production by monocytes from symptomatic, IGRA-positive/seropositive individuals compared to controls. Mass cytometry profiling and unsupervised clustering analysis confirmed recall responses in seropositive individuals by two activated CD4 T cell subsets, one characterized by a strong Th1 cytokine profile (IFNγ+IL-2+TNFα+), and identified C. burnetii-specific activation of CD8 T cells in all IGRA-positive groups. Remarkably, increased C. burnetii-specific responses in IGRA-positive individuals were also observed in three innate cell subpopulations: one characterized by an IFNγ+IL-2+TNFα+ Th1 cytokine profile and lack of canonical marker expression, and two IL-1β-, IL-6- and IL-8-producing CD14+ monocyte subsets that could be the drivers of elevated secretion of innate cytokines in pre-exposed individuals.

Discussion: These data highlight that there are long-term increased responses to C. burnetii in both adaptive and innate cellular compartments, the latter being indicative of trained immunity. These findings warrant future studies into the protective role of these innate responses and may inform future Q fever vaccine design.

Source: Raju Paul S, Scholzen A, Reeves PM, Shepard R, Hess JM, Dzeng RK, Korek S, Garritsen A, Poznansky MC, Sluder AE. Cytometry profiling of ex vivo recall responses to Coxiella burnetii in previously naturally exposed individuals reveals long-term changes in both adaptive and innate immune cellular compartments. Front Immunol. 2023 Oct 11;14:1249581. doi: 10.3389/fimmu.2023.1249581. PMID: 37885896; PMCID: PMC10598782. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10598782/ (Full text)

Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC)

Abstract:

Background: A proportion of the convalescent SARS-CoV-2 pediatric population presents nonspecific symptoms, mental health problems and a reduction in quality of life similar to myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) and long COVID-19 symptomatic. However, data regarding its clinical manifestation and immune mechanisms are currently scarce.

Methods: In this study, we perform a comprehensive clinical and immunological profiling of 17 convalescent COVID-19 children with post-acute COVID-19 sequelae (PASC) manifestation and 13 convalescent children without PASC manifestation. A detailed medical history, blood and instrumental tests and physical examination were obtained from all patients. SARSCoV-2 reactive T cell response was analyzed via multiparametric flowcytometry and the humoral immunity was addressed via pseudovirus neutralization and ELISA assay.

Results: The most common PASC symptoms were shortness of breath/exercise intolerance, paresthesia, smell/taste disturbance, chest pain, dyspnea, headache and lack of concentration. Blood count and clinical chemistry showed no statistical differences among the study groups. We detected higher frequencies of spike (S) reactive CD4+ and CD8+ T cells among the PASC study group, characterized by TNFα and IFNγ production and low functional avidity. CRP levels are positively correlated with IFNγ producing reactive CD8+ T cells.

Conclusions: Our data might indicate a possible involvement of a persistent cellular inflammatory response triggered by SARS-CoV-2 in the development of the observed sequelae in pediatric PASC. These results may have implications on future therapeutic and prevention strategies.

Source: Krystallenia Paniskaki, et al. Increased SARS-CoV-2 reactive low avidity T cells producing inflammatory cytokines in pediatric post-acute COVID-19 sequelae (PASC) https://d197for5662m48.cloudfront.net/documents/publicationstatus/144335/preprint_pdf/a855de5e766f9457795050e56413075a.pdf (Full text)

Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome

Abstract:

Millions globally suffer from myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). The inflammatory symptoms, illness onset, recorded outbreak events, and physiological variations provide strong indications that ME/CFS, at least sometimes, has an infectious origin, possibly resulting in a chronic unidentified viral infection.
Meanwhile, studies exposing generalized metabolic disruptions in ME/CFS have stimulated interest in isolated immune cells with an altered metabolic state. As the metabolism dictates the cellular function, dissecting the biomechanics of dysfunctional immune cells in ME/CFS can uncover states such as exhaustion, senescence, or anergy, providing insights into the consequences of these phenotypes in this disease. Despite the similarities that are seen metabolically between ME/CFS and other chronic viral infections that result in an exhausted immune cell state, immune cell exhaustion has not yet been verified in ME/CFS.
This review explores the evidence for immunometabolic dysfunction in ME/CFS T cell and natural killer (NK) cell populations, comparing ME/CFS metabolic and functional features to dysfunctional immune cell states, and positing whether anergy, exhaustion, or senescence could be occurring in distinct immune cell populations in ME/CFS, which is consistent with the hypothesis that ME/CFS is a chronic viral disease.
This comprehensive review of the ME/CFS immunometabolic literature identifies CD8+ T cell exhaustion as a probable contender, underscores the need for further investigation into the dysfunctional state of CD4+ T cells and NK cells, and explores the functional implications of molecular findings in these immune-cell types. Comprehending the cause and impact of ME/CFS immune cell dysfunction is critical to understanding the physiological mechanisms of ME/CFS, and developing effective treatments to alleviate the burden of this disabling condition.
Source: Maya J. Surveying the Metabolic and Dysfunctional Profiles of T Cells and NK Cells in Myalgic Encephalomyelitis/Chronic Fatigue Syndrome. International Journal of Molecular Sciences. 2023; 24(15):11937. https://doi.org/10.3390/ijms241511937 https://www.mdpi.com/1422-0067/24/15/11937 (Full text)

Divergent Adaptive Immune Responses Define Two Types Of Long Covid

The role of adaptive immune responses in long COVID remains poorly understood, with contrasting hypotheses suggesting either an insufficient antiviral response or an excessive immune response associated with inflammatory damage. To address this issue, we set to characterize humoral and CD4+ T cell responses in long COVID patients prior to SARS-CoV-2 vaccination.

Long COVID patients who were seropositive (LC+, n=28) or seronegative (LC-, n=23) by spike ELISA assay were recruited based on (i) an initial SARS-CoV-2 infection documented by PCR or the conjunction of three major signs of COVID-19 and (ii) the persistence or resurgence of at least 3 symptoms for over 3 months. They were compared to COVID patients with resolved symptoms (RE, n=29) and uninfected control individuals (HD, n=29).

The spectrum of persistent symptoms proved similar in both long COVID groups, with a trend for a higher number of symptoms in the seronegative group (median=6 vs 4.5; P=0.01). The use a highly sensitive S-flow assay enabled the detection of low levels of SARS-CoV-2 spike-specific IgG in 22.7% of ELISA-seronegative long COVID (LC-) patients. In contrast, spike-specific IgG levels were uniformly high in the LC+ and RE groups.

Multiplexed antibody analyses to 30 different viral antigens showed that LC-patients had defective antibody responses to all SARS-CoV-2 proteins tested but had in most cases preserved responses to other viruses. A sensitive primary T cell line assay revealed low but detectable SARS-CoV-2-specific CD4 responses in 39.1% of LC-patients, while response frequencies were high in the LC+ and RE groups. Correlation analyses showed overall strong associations between humoral and cellular responses, with exceptions in the LC-group.

These findings provide evidence for two major types of antiviral immune responses in long COVID. Seropositive patients showed coordinated cellular and humoral responses at least as high as those of recovered patients. In contrast, ELISA-seronegative long COVID patients showed overall low antiviral responses, with detectable specific CD4+ T cells and/or antibodies in close to half of patients (52.2%). These divergent findings in patients sharing a comparable spectrum of persistent symptoms raise the possibility of multiple etiologies in long COVID.

Source: Jérôme Kervevan, Isabelle Staropoli, Dorsaf Slama, Raphaël Jeger-Madiot, Françoise Donnadieu, Delphine Planas, Marie-Pierre Pietri, Wiem Loghmari-Bouchneb, Motolete A. Tanah, Rémy Robinot, Faroudy Boufassa, Michael White, Dominique SALMON and Lisa A. Chakrabarti. Front. Immunol. Sec. Viral Immunology. Volume 14 – 2023 | doi: 10.3389/fimmu.2023.1221961 https://www.frontiersin.org/articles/10.3389/fimmu.2023.1221961/abstract

Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months

Abstract:

COVID-19 causes immune perturbations which may persist long-term, and patients frequently report ongoing symptoms for months after recovery. We assessed immune activation at 3-12 months post hospital admission in 187 samples from 63 patients with mild, moderate or severe disease and investigated whether it associates with long COVID.

At 3 months, patients with severe disease displayed persistent activation of CD4+ and CD8+ T-cells, based on expression of HLA-DR, CD38, Ki67 and granzyme B, and elevated plasma levels of IL-4, IL-7, IL-17 and TNF-α compared to mild and/or moderate patients. Plasma from severe patients at 3 months caused T-cells from healthy donors to upregulate IL-15Rα, suggesting that plasma factors in severe patients may increase T-cell responsiveness to IL-15-driven bystander activation.

Patients with severe disease reported a higher number of long COVID symptoms which did not however, correlate with cellular immune activation/pro-inflammatory cytokines after adjusting for age, sex and disease severity. Our data suggests that long COVID and persistent immune activation may correlate independently with severe disease.

Source: Marianna Santopaolo, Michaela Gregorova, Fergus Hamilton, David Arnold, Anna Long, Aurora Lacey, Alice Halliday, Holly Baum, Kristy Hamilton, Rachel Milligan, Elizabeth Oliver, Olivia Pearce, Lea Knezevic, Begonia Morales Aza, Alice Milne, Emily Milodowski, Eben Jones, Rajeka Lazarus, Anu Goenka, Adam Finn, Nicholas Maskell, Andrew D Davidson, Kathleen Gillespie, Linda Wooldridge, Laura Rivino (2023) Prolonged T-cell activation and long COVID symptoms independently associate with severe COVID-19 at 3 months eLife 12:e85009 https://doi.org/10.7554/eLife.85009 https://elifesciences.org/articles/85009