Pathogenesis and clinical features of severe hepatitis E virus infection.

The hepatitis E virus (HEV), a member of the Hepeviridae family, is a small, non-enveloped icosahedral virus divided into eight distinct genotypes (HEV-1 to HEV-8). Only genotypes 1 to 4 are known to cause diseases in humans. Genotypes 1 and 2 commonly spread via fecal-oral transmission, often through the consumption of contaminated water. Genotypes 3 and 4 are known to infect pigs, deer, and wild boars, often transferring to humans through inadequately cooked meat. Acute hepatitis caused by HEV in healthy individuals is mostly asymptomatic or associated with minor symptoms, such as jaundice. However, in immunosuppressed individuals, the disease can progress to chronic hepatitis and even escalate to cirrhosis. For pregnant women, an HEV infection can cause fulminant liver failure, with a potential mortality rate of 25%. Mortality rates also rise amongst cirrhotic patients when they contract an acute HEV infection, which can even trigger acute-on-chronic liver failure if layered onto pre-existing chronic liver disease. As the prevalence of HEV infection continues to rise worldwide, highlighting the particular risks associated with severe HEV infection is of major medical interest. This text offers a brief summary of the characteristics of hepatitis developed by patient groups at an elevated risk of severe HEV infection.

Immune Dysfunction in Schizophrenia Spectrum Disorders.

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

Exposure to Trimethyltin Chloride Induces Pyroptosis and Immune Dysfunction in Grass Carp CIK Cells by Activating the NF-κB Pathway Through Oxidative Stress.

Trimethyltin chloride (TMT) is a highly toxic organotin pollutant frequently found in aquatic environments, posing a significant threat to the ecological system. The kidney plays a vital role in the body's detoxification processes, and TMT present in the environment tends to accumulate in the kidneys. However, it remained unclear whether exposure to different doses of TMT could induce pyroptosis and immune dysfunction in grass carp kidney cells (CIK cells). For this purpose, after assessing the half-maximal inhibitory concentration (IC50) of TMT on CIK cells, we established a model for exposure of CIK cells at varying concentrations of TMT. CIK cells were treated with various doses of TMT (2.5, 5, 10 µM) for 24 h. Oxidative stress levels were measured using kits and fluorescence methods, whereas the expression of related genes was verified through western blot and quantitative real-time PCR (qRT-PCR). The results indicated that TMT exposure led to oxidative stress, with increased levels of ROS, H2O2, MDA, and GSH, and inhibited activities of T-AOC, SOD, and CAT. It activated the NF-κB pathway, leading to the upregulation of NF-κB p65, NF-κB p50, GSDMD, NLRP3, ASC, and Caspase-1. Furthermore, TMT exposure also resulted in increased expression of cytokines (IL-18, IL-6, IL-2, IL-1ß, and TNF-α) and decreased expression of antimicrobial peptides (LEAP2, HEPC, and ß-defensin). In summary, exposure to TMT induces dose-dependent oxidative stress that activates the NF-κB pathway, leading to pyroptosis and immune dysfunction in grass carp CIK cells.

Pathology of Diabetes-Induced Immune Dysfunction.

Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.

Single-cell landscape of immunological responses in elderly patients with sepsis.

Sepsis is a dysregulated host response to severe infections, and immune dysfunction plays a crucial role in its pathogenesis. Elderly patients, a special population influenced by immunosenescence, are more susceptible to sepsis and have a worse prognosis. However, the immunopathogenic mechanisms underlying sepsis in elderly patients remain unclear. Here, we performed single-cell RNA sequencing of peripheral blood samples from young and old subjects and patients with sepsis. By exploring the transcriptional profiles of immune cells, we analyzed immune cell compositions, phenotype shifts, expression heterogeneities, and intercellular communication. In elderly patients with sepsis, innate immune cells (e.g., monocytes and DCs) exhibit decreased antigen presentation, presenting an overactive inflammatory and senescent phenotype. However, the immunophenotype of T cells shifted to characterize effector, memory, and exhaustion. Moreover, we identified strong interferon-γ responses of T cells in both aging and sepsis groups and a deranged inflammaging status in elderly sepsis patients. Tregs in elderly patients with sepsis showed increased abundance and enhanced immunosuppressive effects. In addition, metabolism-associated pathways were upregulated in T cells in elderly patients with sepsis, and the lysine metabolism pathway was enriched in Tregs. Cell-cell interaction analysis showed that the expression profile of ligand-receptor pairs was probably associated with aggravated immune dysfunction in elderly patients with sepsis. A novel HLA-KIR interaction was observed between Tregs and CD8 + T cells. These findings illustrate the immunological hallmarks of sepsis in elderly patients, and highlight that immunosuppressive and metabolic regulatory pathways may undergo important alterations in elderly patients with sepsis.

Are Infants and Children at Risk of Adverse Health Effects from Dietary Deoxynivalenol Exposure? An Integrative Review.

Deoxynivalenol (DON) is a foodborne mycotoxin produced by Fusarium molds that commonly infect cereal grains. It is a potent protein synthesis inhibitor that can significantly impact humans' gastrointestinal, immune, and nervous systems and can alter the microbiome landscape. Low-dose, chronic exposure to DON has been found to stimulate the immune system, inhibit protein synthesis, and cause appetite suppression, potentially leading to growth failure in children. At higher doses, DON has been shown to cause immune suppression, nausea, vomiting, abdominal pain, headache, diarrhea, gastroenteritis, the malabsorption of nutrients, intestinal hemorrhaging, dizziness, and fever. A provisional maximum tolerable daily intake (PMTDI) limit of 1 µg/kg/body weight has been established to protect humans, underscoring the potential health risks associated with DON intake. While the adverse effects of dietary DON exposure have been established, healthcare communities have not adequately investigated or addressed this threat to child health, possibly due to the assumption that current regulatory exposure limits protect the public appropriately. This integrative review investigated whether current dietary DON exposure rates in infants and children regularly exceed PMTDI limits, placing them at risk of negative health effects. On a global scale, the routine contamination of cereal grains, bakery products, pasta, and human milk with DON could lead to intake levels above PMTDI limits. Furthermore, evidence suggests that other food commodities, such as soy, coffee, tea, dried spices, nuts, certain seed oils, animal milk, and various water reservoirs, can be intermittently contaminated, further amplifying the scope of the issue. Better mitigation strategies and global measures are needed to safeguard vulnerable youth from this harmful toxicant.

Low density granulocytes and neutrophil extracellular trap formation are increased in incomplete systemic lupus erythematosus.

OBJECTIVE: To investigate the proportion of low-density granulocytes (LDGs), circulating plasma neutrophil extracellular traps (NETs), and serum-induced NET formation in patients with incomplete systemic lupus erythematosus (iSLE) and systemic lupus erythematosus (SLE). METHODS: LDGs were measured cross-sectionally in 18 iSLE patients, 11 SLE patients and 14 healthy controls (HCs), whereas circulating NETs and serum-induced NET formation were assessed in 35 iSLE patients, 41 SLE patients and 16 HCs. LDGs (CD14lowCD15+) were measured in PBMCs using flow cytometry and circulating plasma NETs were measured using anti-myeloperoxidase-DNA, anti-citrullinated histone H3 and anti-elastase-DNA complex ELISAs. Serum-induced NET formation was assessed by incubating healthy neutrophils with serum from iSLE patients, SLE patients or HCs and visualizing NETs with fluorescence microscopy. RESULTS: Proportions of LDGs and circulating plasma NETs were similarly elevated in iSLE and SLE patients compared with those in HCs. Furthermore, patients under hydroxychloroquine (HCQ) treatment had lower proportions of LDGs than those without. Serum from iSLE and SLE patients similarly induced NET formation in healthy neutrophils. In iSLE patients, myeloperoxidase-DNA complexes were correlated with proportions of age-associated B-cells, memory B-cells and negatively with naïve B-cells, while we did not find associations between measures of NETs or serum-induced NET formation and interferon score or clinical parameters. CONCLUSION: These results show that neutrophil dysfunction, including higher proportions of LDGs, and increased NET formation, already occur in iSLE, similar to SLE, despite differences in disease manifestations. Thereby, neutrophil dysfunction may contribute to sustained exposure to autoantigens and autoreactivity in early stages of SLE.

mTOR signaling is required for phagocyte free radical production, GLUT1 expression, and control of Staphylococcus aureus infection.

Mammalian target of rapamycin (mTOR) is a key regulator of metabolism in the mammalian cell. Here, we show the essential role for mTOR signaling in the immune response to bacterial infection. Inhibition of mTOR during infection with Staphylococcus aureus revealed that mTOR signaling is required for bactericidal free radical production by phagocytes. Mechanistically, mTOR supported glucose transporter GLUT1 expression, potentially through hypoxia-inducible factor 1α, upon phagocyte activation. Cytokine and chemokine signaling, inducible nitric oxide synthase, and p65 nuclear translocation were present at similar levels during mTOR suppression, suggesting an NF-κB-independent role for mTOR signaling in the immune response during bacterial infection. We propose that mTOR signaling primarily mediates the metabolic requirements necessary for phagocyte bactericidal free radical production. This study has important implications for the metabolic requirements of innate immune cells during bacterial infection as well as the clinical use of mTOR inhibitors.IMPORTANCESirolimus, everolimus, temsirolimus, and similar are a class of pharmaceutics commonly used in the clinical treatment of cancer and the anti-rejection of transplanted organs. Each of these agents suppresses the activity of the mammalian target of rapamycin (mTOR), a master regulator of metabolism in human cells. Activation of mTOR is also involved in the immune response to bacterial infection, and treatments that inhibit mTOR are associated with increased susceptibility to bacterial infections in the skin and soft tissue. Infections caused by Staphylococcus aureus are among the most common and severe. Our study shows that this susceptibility to S. aureus infection during mTOR suppression is due to an impaired function of phagocytic immune cells responsible for controlling bacterial infections. Specifically, we observed that mTOR activity is required for phagocytes to produce antimicrobial free radicals. These results have important implications for immune responses during clinical treatments and in disease states where mTOR is suppressed.

B7-H4 reduces the infiltration of CD8+T cells and induces their anti-tumor dysfunction in gliomas.

B7-H4 is a promising immune checkpoint molecule in tumor immunotherapy. Our previous study showed that high B7-H4 expression was strongly correlated with deficiency in tumor infiltrated lymphocytes (TILs) in glioma patients. On this basis, we investigated the impact of B7-H4 on CD8+TILs in gliomas and the associated molecular mechanism here. B7-H4-positive tumor samples (n=129) from our glioma cohort were used to assess B7-H4 expression and CD8+TIL quantification by immunohistochemistry. CD8+TILs from five glioma patients cultured with B7-H4 protein were used to evaluate anti-tumor dysfunction by flow cytometry and ELISpot. An orthotopic murine glioma model was used to investigate the role of B7-H4 in glioma CD8+TILs by immunohisto- chemistry and flow cytometry. CD8+TILs from glioma patients cultured with B7-H4 protein were used to explore the potential molecular mechanism by RNA sequencing and western blot. Our results showed that glioma CD8+TIL density was negatively correlated with B7-H4 expression both in glioma patient cohort (P < 0.05) and orthotopic glioma murine model (P < 0.01). B7-H4 also lowered the expression of CD137 and CD103 (P < 0.05 for both) in glioma CD8+TILs and reduced their secretion of the anti-tumor cytokines IFN-γ and TNF-α (P < 0.01 for both) in a dose-dependent manner. Furthermore, B7-H4 was found to induce early dysfunction of glioma CD8+TILs by downregulating the phosphorylation of AKT and eNOS (P < 0.05 for both). In conclusion, B7-H4 reduced the infiltration of glioma CD8+TILs and induced an anti-tumor dysfunction phenotype. B7-H4 may also impair the anti-tumor function of glioma CD8+TILs via the AKT-eNOS pathway. These results indicated that B7-H4 may serve as a potential target in future glioma immunotherapy.

Herpes virus entry mediator signaling blockade produces mortality in neonatal sepsis through induced cardiac dysfunction.

Introduction: Sepsis remains a major source of morbidity and mortality in neonates, and characterization of immune regulation in the neonatal septic response remains limited. HVEM is a checkpoint regulator which can both stimulate or inhibit immune responses and demonstrates altered expression after sepsis. We hypothesized that signaling via HVEM would be essential for the neonatal response to sepsis, and that therefore blockade of this pathway would improve survival to septic challenge. Methods: To explore this, neonatal mice were treated with cecal slurry (CS), CS with Anti-HVEM antibody (CS-Ab) or CS with isotype (CS-IT) and followed for 7-day survival. Mice from all treatment groups had thymus, lung, kidney and peritoneal fluid harvested, weighed, and stained for histologic evaluation, and changes in cardiac function were assessed with echocardiography. Results: Mortality was significantly higher for CS-Ab mice (72.2%) than for CS-IT mice (22.2%). CS resulted in dysregulated alveolar remodeling, but CS-Ab lungs demonstrated significantly less dysfunctional alveolar remodeling than CS alone (MCL 121.0 CS vs. 87.6 CS-Ab), as well as increased renal tubular vacuolization. No morphologic differences in alveolar septation or thymic karyorrhexis were found between CS-Ab and CS-IT. CS-Ab pups exhibited a marked decrease in heart rate (390.3 Sh vs. 342.1 CS-Ab), stroke volume (13.08 CS-IT vs. 8.83 CS-Ab) and ultimately cardiac output (4.90 Sh vs. 3.02 CS-Ab) as well as a significant increase in ejection fraction (73.74 Sh vs. 83.75 CS-Ab) and cardiac strain (40.74 Sh vs. 51.16 CS-Ab) as compared to CS-IT or Sham animals. Discussion: While receptor ligation of aspects of HVEM signaling, via antibody blockade, appears to mitigate aspects of lung injury and thymic involution, stimulatory signaling via HVEM still seems to be necessary for vascular and hemodynamic resilience and overall neonatal mouse survival in response to this experimental polymicrobial septic insult. This dissonance in the activity of anti-HVEM neutralizing antibody in neonatal animals speaks to the differences in how septic cardiac dysfunction should be considered and approached in the neonatal population.

Coexistence of Parkinson's disease and myasthenia gravis: A case report and literature review.

The coexistence of Parkinson's disease (PD) and myasthenia gravis (MG) is rare. When similar symptoms of both diseases overlap, it is challenging to make a concomitant diagnosis of PD and MG. The present study describes the case of a patient with concomitant PD and MG. In addition, a systematic literature review was conducted by searching PubMed and Embase for reports on all patients with concomitant PD and MG, which were then grouped and compared according to different preexisting diseases. Finally, a total of 47 cases of concomitant PD and MG (35 men; 12 women), including the present case, were analyzed. The median age of the patients at first diagnosis was 66.59±9.91 years. The interval between the two diseases varied from 2 months to 22 years. Based on the sequential occurrence of these two diseases, the patients were categorized into three groups: The prePD-MG (30 cases), preMG-PD (12 cases), and coPD-MG (5 cases) groups. In the prePD-MG group, the onset age of MG was older and head drop was more common. In the preMG-PD group, the patients were more likely to have comorbid immune diseases.

Prediction of Prognostic Features Based on Neutrophil-Related Genes for Lung Squamous Cell Carcinoma Reveals Immune Landscape and Drug Candidates.

UNASSIGNED: Background: Since to the prognosis of lung squamous cell carcinoma is generally poor, there is an urgent need to innovate new prognostic biomarkers and therapeutic targets to improve patient outcomes. Objectives: Our goal was to develop a novel multi-gene prognostic model linked to neutrophils for predicting lung squamous cell carcinoma prognosis. Methods: We utilized messenger RNA expression profiles and relevant clinical data of lung squamous cell carcinoma patients from the Cancer Genome Atlas database. Through K-means clustering, least absolute shrinkage and selection operator regression, and univariate/multivariate Cox regression analyses, we identified 12 neutrophil-related genes strongly related to patient survival and constructed a prognostic model. We verified the stability of the model in the Cancer Genome Atlas database and gene expression omnibus validation set, demonstrating the robust predictive performance of the model. Results: Immunoinfiltration analysis revealed remarkably elevated levels of infiltration for natural killer cells resting and monocytes in the high-risk group compared to the low-risk group, while macrophages had considerably lower infiltration in the high risk group. Most immune checkpoint genes, including programmed cell death protein 1 and cytotoxic T-lymphocyte-associated antigen 4, exhibited high expression levels in the high risk group. Tumor immune dysfunction and exclusion scores and immunophenoscore results suggested a potential inclination toward immunotherapy in the "RIC" version V2 revised high risk group. Moreover, prediction results from the CellMiner database revealed great correlations between drug sensitivity (e.g., Vinorelbine and PKI-587) and prognostic genes. Conclusion: Overall, our study established a reliable prognostic risk model that possessed significant value in predicting the overall survival of lung squamous cell carcinoma patients and may guide personalized treatment strategies. (Rev Invest Clin. 2024;76(2):116-31).

Prevalence of human herpesvirus in plasma and saliva of cirrhotic patients: A pilot study.

AIMS: The objective of this study was to identify the presence of human herpesvirus (HHV) in the plasma and saliva of hepatic-cirrhosis patients and correlate it with clinical data and laboratory tests. This is a pilot, observational, and cross-sectional study. METHODS AND RESULTS: Specimens of plasma and saliva from 72 cirrhotic individuals were analyzed by means of polymerase chain reaction. The patient population had a mean age of 54.84 years old (SD ± 10) and was 70% males (51/72). Approximately 47% (n = 34) of the patients had leukopenia and HHV was not identified in the plasma specimens. The main species of HHV identified in the saliva were HHV-7 (n = 42, 62%) and Epstein-Barr virus (EBV) (n = 30, 41%). Moreover, there was a significant decrease in the total number of leukocytes and lymphocytes in saliva containing EBV (P = .038 and P = .047, respectively). CONCLUSION: The results show that the presence of EBV in the saliva of cirrhotic patients was correlated with their circulating immune status. It may be possible that the immune dysfunction displayed by the cirrhotic patients plays a role in the shedding of EBV into saliva.

Immune Dysfunction-Associated Elevated RDW, APACHE-II, and SOFA Scores Were a Possible Cause of 28-Day Mortality in Sepsis Patients.

Objective: To explore the early predictors and their predicting value of 28-day mortality in sepsis patients and to investigate the possible causes of death. Methods: 127 sepsis patients were included, including 79 cases in the survival group and 48 cases in the death group. The results of all patients on admission were recorded. After screening the risk factors of 28-day mortality, the receiver operating characteristic curve (ROC) was used to determine their predictive value for the 28-day mortality rate on admission, and the Kaplan-Meier curve was drawn to compare the 28-day mortality rate between groups. Finally, patients with cytokine and lymphocyte subsets results were included for investigating the possible causes of death through correlation analysis. Results: APACHE II (acute physiology and chronic health evaluation II), SOFA (Sequential Organ Failure Assessment) and red blood cell distribution width (RDW) were the risk factors for 28-day mortality in sepsis patients (OR: 1.130 vs.1.160 vs.1.530, P < 0.05). The area under the curve (AUC), sensitivity and specificity of APACHE II, SOFA and RDW in predicting the mortality rate at 28 days after admission in sepsis patients were 0.763 vs 0.806 vs 0.723, 79.2% vs 68.8% vs 75.0%, 65.8% vs 89.9% vs 68.4%. The combined predicted AUC was 0.873, the sensitivity was 89.6%, and the specificity was 82.3%. The Kaplan-Meier survival curve showed that the 28-day mortality rates of sepsis patients with APACHE II≥18.5, SOFA≥11.5 and RDW≥13.8 were 58.5%, 80.5% and 59.0%, respectively. In the death group, APACHE II was positively correlated with SOFA, IL-2, and IL-10, and RDW was positively correlated with PLT, TNF-α, CD3+ lymphocyte count, and CD8+ lymphocyte count. Conclusion: Sepsis patients with high APACHE II, SOFA and RDW levels at admission have an increased 28-day mortality rate. The elevation of these indicators in dead patients are related to immune dysfunction.

Tumor immune dysfunction and exclusion subtypes in bladder cancer and pan-cancer: a novel molecular subtyping strategy and immunotherapeutic prediction model.

BACKGROUND: Molecular subtyping is expected to enable precise treatment. However, reliable subtyping strategies for clinical application remains defective and controversial. Given the significance of tumor immune dysfunction and exclusion (TIDE), we aimed to develop a novel TIDE-based subtyping strategy to guide personalized immunotherapy in the bladder cancer (BC). METHODS: Transcriptome data of BC was used to evaluate the heterogeneity and the status of TIDE patterns. Subsequently, consensus clustering was applied to classify BC patients based on TIDE marker-genes. Patients' clinicopathological, molecular features and signaling pathways of the different TIDE subtypes were well characterized. We also utilize the deconvolution algorithms to analyze the tumor microenvironment, and further explore the sensitivity and mechanisms of each subtype to immunotherapy. Furthermore, BC patient clinical information, real-world BC samples and urine samples were collected for the validation of our findings, which were used for RNA-seq analysis, H&E staining, immunohistochemistry and immunofluorescence staining, and enzyme-linked immunosorbent assay. Finally, we also explored the conservation of our novel TIDE subtypes in pan-cancers. RESULTS: We identified 69 TIDE biomarker genes and classified BC samples into three subtypes using consensus clustering. Subtype I showed the lowest TIDE status and malignancy with the best prognosis and highest sensitivity to immune checkpoint blockade (ICB) treatment, which was enriched of metabolic related signaling pathways. Subtype III represented the highest TIDE status and malignancy with the poorest prognosis and resistance to ICB treatment, resulting from its inhibitory immune microenvironment and T cell terminal exhaustion. Subtype II was in a transitional state with intermediate TIDE level, malignancy, and prognosis. We further confirmed the existence and characteristics of our novel TIDE subtypes using real-world BC samples and collected patient clinical data. This subtyping method was proved to be more efficient than previous known methods in identifying non-responders to immunotherapy. We also propose that combining our TIDE subtypes with known biomarkers can potentially improve the sensitivity and specificity of these biomarkers. Moreover, besides guiding ICB treatment, this classification approach can assist in selecting the frontline or recommended drugs. Finally, we confirmed that the TIDE subtypes are conserved across the pan-tumors. CONCLUSIONS: Our novel TIDE-based subtyping method can serve as a powerful clinical tool for BC and pan-cancer patients, and potentially guiding personalized therapy decisions for selecting potential beneficiaries and excluding resistant patients of ICB therapy.

Decreased Treg cells induced by bisphenol A is associated with up-regulation of PI3K/Akt/mTOR signaling pathway and Foxp3 DNA methylation in spleen of adolescent mice.

The current study aimed to explore whether bisphenol A (BPA) exposure aggravated the decrease in Tregs induced by ovalbumin (OVA) in adolescent female mouse models of asthma, and whether the process was associated with mTOR-mediated signaling pathways and DNA methylation levels. A total of 40 female C57BL/6 mice at the age of four weeks were used and divided into five groups after 1 week of domestication. Each group consisted of eight mice: the control group, OVA group, OVA + BPA (0.1 µg mL-1) group, OVA + BPA (0.2 µg mL-1) group, and OVA + BPA (0.4 µg mL-1) group. Results revealed that Foxp3 protein levels decreased in the spleens of mice exposed to BPA compared to those in the OVA group. After an elevation in BPA dose, the mRNAs of methyltransferases (Dnmt1, Dnmt3a, and Dnmt3b) were gradually upregulated. The mechanism was related to the activity of TLR4/NF-κB and PI3K/Akt/mTOR signaling pathways and the enhancement of Foxp3 DNA methylation. Our results, collectively, provided a new view for studying the mechanisms underlying BPA exposure-induced immune dysfunction. Investigation of the regulatory mechanisms of DNA methylation in the abnormal Th immune response caused by BPA exposure could help reveal the causes and molecular mechanisms underlying the high incidence of allergic diseases in children in recent years.

Oxidative stress, defective proteostasis and immunometabolic complications in critically ill patients.

Oxidative stress (OS) develops in critically ill patients as a metabolic consequence of the immunoinflammatory and degenerative processes of the tissues. These induce increased and/or dysregulated fluxes of reactive species enhancing their pro-oxidant activity and toxicity. At the same time, OS sustains its own inflammatory and immunometabolic pathogenesis, leading to a pervasive and vitious cycle of events that contribute to defective immunity, organ dysfunction and poor prognosis. Protein damage is a key player of these OS effects; it generates increased levels of protein oxidation products and misfolded proteins in both the cellular and extracellular environment, and contributes to forms DAMPs and other proteinaceous material to be removed by endocytosis and proteostasis processes of different cell types, as endothelial cells, tissue resident monocytes-macrophages and peripheral immune cells. An excess of OS and protein damage in critical illness can overwhelm such cellular processes ultimately interfering with systemic proteostasis, and consequently with innate immunity and cell death pathways of the tissues thus sustaining organ dysfunction mechanisms. Extracorporeal therapies based on biocompatible/bioactive membranes and new adsorption techniques may hold some potential in reducing the impact of OS on the defective proteostasis of patients with critical illness. These can help neutralizing reactive and toxic species, also removing solutes in a wide spectrum of molecular weights thus improving proteostasis and its immunometabolic corelates. Pharmacological therapy is also moving steps forward which could help to enhance the efficacy of extracorporeal treatments. This narrative review article explores the aspects behind the origin and pathogenic role of OS in intensive care and critically ill patients, with a focus on protein damage as a cause of impaired systemic proteostasis and immune dysfunction in critical illness.

Circulating immune cell landscape and T-cell abnormalities in patients with moyamoya disease.

BACKGROUND: Moyamoya disease (MMD) stands as a prominent cause of stroke among children and adolescents in East Asian populations. Although a growing body of evidence suggests that dysregulated inflammation and autoimmune responses might contribute to the development of MMD, a comprehensive and detailed understanding of the alterations in circulating immune cells associated with MMD remains elusive. METHODS: In this study, we employed a combination of single-cell RNA sequencing (scRNA-seq), mass cytometry and RNA-sequencing techniques to compare immune cell profiles in peripheral blood samples obtained from patients with MMD and age-matched healthy controls. RESULTS: Our investigation unveiled immune dysfunction in MMD patients, primarily characterized by perturbations in T-cell (TC) subpopulations, including a reduction in effector TCs and an increase in regulatory TCs (Tregs). Additionally, we observed diminished natural killer cells and dendritic cells alongside heightened B cells and monocytes in MMD patients. Notably, within the MMD group, there was an augmented proportion of fragile Tregs, whereas the stable Treg fraction decreased. MMD was also linked to heightened immune activation, as evidenced by elevated expression levels of HLA-DR and p-STAT3. CONCLUSIONS: Our findings offer a comprehensive view of the circulating immune cell landscape in MMD patients. Immune dysregulation in patients with MMD was characterized by alterations in T-cell populations, including a decrease in effector T-cells and an increase in regulatory T-cells (Tregs), suggest a potential role for disrupted circulating immunity in the aetiology of MMD.

Exploring Ribosomal Genes as Potential Biomarkers of the Immune Microenvironment in Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is the most common pathogen causing acute lower respiratory tract infection in infants and children. Due to limited knowledge of the pathological and molecular mechanisms of immunodeficiency underlying RSV disease, there is currently a lack of an approved and effective RSV vaccine to combat RSV infections. This study aimed to identify genes associated with immune dysfunction using bioinformatics methods to gain insights into the role of dysregulated immune genes in RSV disease progression, and to predict potential therapeutic drugs by targeting dysregulated immune-related genes. 423 immune-related differential genes (DEIRGs) were filtered from the blood samples of 87 healthy individuals and 170 RSV patients. According to CIBERSORT analysis, the blood of RSV patients showed increased infiltration of various immune cells. Subsequently, ten immune-related hub genes were screened via Protein-Protein Interaction Networks. Six signature immune-related genes (RPS2, RPS5, RPS13, RPS14, RPS18, and RPS4X) as candidate characteristic genes for the diagnostic model were identified by Lasso regression. The AUC value of the ROC curve of the six signature genes was 0.884. This result, intriguingly, suggested that all six immune-related genes with a good internal validation effect were ribosome family genes. Finally, through molecular docking analyses targeting these differential immune genes, ADO and fluperlapine were found to have high stable binding to major proteins of important immune-related genes in nine drug-protein interactions. Overall, the present study screened immune-related genes that are dysregulated in the development of RSV disease to investigate the pathogenesis of RSV infection from the standpoint of immune disorders. Unexpectedly, bioinformatics analysis revealed that ribosome family genes may be involved in the immune dysregulation of RSV disease, and these genes as targets formed the basis for potential drug modification candidates in RSV disease.