Impaired Immunity Research Articles

Booster COVID-19 mRNA vaccination ameliorates impaired B-cell but not T-cell responses in older adults

Age-associated differences in the effect of repetitive vaccination, particularly on memory T-cell and B-cell responses, remain unclear. While older adults (aged ≥65 years) exhibited enhanced IgG responses following COVID-19 mRNA booster vaccination, they produced fewer spike-specific circulating follicular helper T cells-1 than younger adults. Similarly, the cytotoxic CD8+ T-cell response remained diminished with reduced PD-1 expression even after booster vaccination compared with that in younger adults, suggesting impaired memory T-cell activation in older adults. In contrast, although B-cell responses in older adults were weaker than those in younger adults in the primary response, the responses were significantly enhanced upon booster vaccination, reaching levels comparable with that observed in younger adults. Therefore, while booster vaccination ameliorates impaired humoral immunity in older adults by efficiently stimulating memory B-cell responses, it may less effectively enhance T-cell-mediated cellular immunity. Our study provides insights for the development of effective therapeutic and vaccine strategies for the most vulnerable older population.

Berberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling

BackgroundInflammatory bowel disease (IBD), a persistent gastrointestinal disease, is featured with impaired gut immunity. Previous studies have demonstrated that tuft cells can regulate the intestinal type 2 immune response by activating downstream ILC2 and Th2 cells and repair gut barrier upon invasion of parasitic helminths, bacteria, protozoans, and enteritis through different chemo-sensing receptors, such as bitter taste receptors. Berberine is a widely used in the treatment of diarrhea in clinic, however the mechanism underlying this effect is not clear. In this study, we aim to explore the relationship between berberine and tuft cells in dextran sulfate sodium (DSS) -induced colitis.ResultsOur data showed that berberine significantly ameliorated DSS-induced colitis and regulating type 2 innate immune lymphocytes (ILC2) and Th2 immune cells via tuft cells in the gut. Furthermore, the effect of berberine on colitis was partially abolished by U73122, a bitter taste receptor inhibitor, suggesting that bitter taste signalling pathway played an important role in the effect of berberine on relieving colitis.ConclusionsBerberine ameliorates dextran sulfate sodium -induced colitis through tuft cells and bitter taste signalling. Our study reveals the unique pharmacological mechanisms of berberine in the context of colitis, laying the foundation for further clinical applications of this compound.

Infections in sickle cell disease.

Sickle cell disease (SCD) is one of the commonest severe inherited disorders in the world. Infection accounts for a significant amount of the morbidity and mortality, particularly in sub- Saharan Africa, but is relatively poorly studied and characterized. Patients with SCD have significant immunodeficiency and are more likely to suffer severe and life-threatening complications of infection, and additionally infections can trigger complications of SCD itself. Those with more severe forms of SCD have functional asplenia from a very early age, which accounts for much of the morbidity in young children, particularly invasive infections from encapsulated bacteria including Streptococcus Pneumoniae, Haemophilus Influenzae, Salmonella Typhi and meningococcal disease. Additionally, there are other defects in immune function in SCD, associated with anemia, tissue infarction and impaired adaptive immunity. Complications of infections in SCD include acute chest syndrome (ACS), acute painful episodes, osteomyelitis, meningitis, urinary tract infections, overwhelming sepsis and death. Viral infections cause significant morbidity, particularly severe anemia associated with Parvovirus, and to a lesser extent other infections such as influenza and COVID19. The relationship between malaria and SCD is complicated and discussed in this review. Unlike many of the genetic risk factors for poor outcomes in SCD, it is theoretically possible to modify the risks associated with infections with established public health measures. These include the provision of vaccinations, prophylactic antibiotics and access to clean water and mosquito avoidance, although current financial restraints and political priorities have made this difficult.

Impaired anti-viral immunity in frequent exacerbators of chronic obstructive pulmonary disease.

Background Respiratory viruses cause chronic obstructive pulmonary disease (COPD) exacerbations. Rhinoviruses (RVs) are the most frequently detected. Some COPD patients experience frequent exacerbations ({greater than or equal to}2 exacerbations/ year). The relationship between exacerbation frequency and anti-viral immunity remains poorly understood. Objectives To investigate the relationship between exacerbation frequency and anti-viral immunity in COPD Methods Alveolar macrophages and bronchial epithelial cells (BECs) were obtained from COPD patients and healthy participants. Alveolar macrophages were infected with RV-A16 multiplicity of infection 5 (MOI 5) and BECs infected with RV-A16 MOI 1 for 24 hours. Interferons (IFN) and pro-inflammatory cytokines IL-1β, IL-6, CXCL8 and TNF were measured in cell supernatants using mesoscale discovery platform. Viral load and interferon stimulated genes were measured in cell lysates using qPCR. Results Spontaneous and RV induced IFN-β, IFN-γ and CXCL-11 release were significantly reduced in alveolar macrophages from COPD patients compared to healthy subjects. IFN-β was further impaired in uninfected alveolar macrophages from COPD patients with frequent exacerbations 82.0 pg/mL vs infrequent exacerbators 234.7 pg/mL P=0.008 and RV-infected alveolar macrophages from frequent exacerbators 158.1 pg/mL vs infrequent exacerbators 279.5 pg/mL P=0.022. Release of proinflammatory cytokines CXCL8, IL-6, TNF and IL-1β was higher in uninfected BECs from COPD patients compared to healthy subjects but there was no difference in pro-inflammatory response to RV between groups. Conclusions IFN responses to RV was impaired in alveolar macrophages from COPD patients and further reduced in patients with frequent exacerbations.

Palmitoylation of TIM-3 promotes immune exhaustion and restrains antitumor immunity.

T cell immunoglobulin and mucin domain-containing protein 3 (TIM-3) is an immune checkpoint that has critical roles in immune exhaustion. However, little is known about the mechanisms that regulate TIM-3 surface expression and turnover. Here, we report that human TIM-3 is palmitoylated by the palmitoyltransferase DHHC9 at residue cysteine 296 (Cys296). Palmitoylation stabilized TIM-3 by preventing binding to E3 ubiquitin ligase HRD1, thereby suppressing its polyubiquitination and degradation. DHHC9 knockdown attenuated chimeric antigen receptor T (CAR-T) cell exhaustion, and a peptidic inhibitor of TIM-3 palmitoylation accelerated TIM-3 degradation and enhanced antitumor immunity mediated by CAR-T cells and natural killer (NK) cells. In hepatocellular carcinoma, DHHC9 expression correlated with TIM-3 expression in CD8+ T cells and NK cells, and high DHHC9 expression was associated with shorter survival in patients with high TIM-3. These findings demonstrate that palmitoylation of TIM-3 catalyzed by DHHC9 promotes its stability, resulting in immune exhaustion and impaired antitumor immunity.

Cytomegalovirus Infection After Solid Organ Transplantation: How I Use Cell-Mediated Immune Assays for Management.

The pathogenesis and outcome of cytomegalovirus (CMV) infection after solid organ transplantation (SOT) reflects the interplay between viral replication and CMV-specific immunity. Despite advances in its diagnosis and treatment, CMV continues to cause significant morbidity after SOT. Since CMV is an opportunistic pathogen that occurs as a result of impaired pathogen-specific immunity, laboratory assays that measure CMV-specific immune responses may be useful in assisting clinicians in its management. The author summarizes the evolving and emerging data on the clinical utility of assays that quantify cell-mediated immune responses to CMV in SOT recipients. The majority of publications are observational studies that demonstrate that a lack or deficiency in CMV-specific cell-mediated immunity is correlated with a heightened risk of primary, reactivation, or recurrent CMV after transplantation. A few prospective interventional studies have utilized CMV-specific cell-mediated immune assays in guiding the duration of antiviral prophylaxis among CMV-seropositive SOT recipients. Likewise, CMV-specific cell-mediated immunity assays have been suggested to inform the need for secondary antiviral prophylaxis and immunologic optimization to prevent CMV relapse after treatment. CMV-specific cell-mediated immune assays are emerging to assist transplant clinicians in predicting a patient's risk of CMV after transplantation, and these assays have been utilized to individualize the approach to CMV prevention and treatment. The author suggests the conduct of more interventional studies to further solidify the role of CMV-specific cell-mediated immune assays in routine clinical practice.

Parkin-TLR4-NLRP3 Axis Directs Melatonin to Alleviate Atrazine-Induced Immune Impairment in Splenic Macrophages.

Atrazine (ATR) is a widespread environmental herbicide that seriously affects agricultural work and human safety. Melatonin (MLT) as an endogenous neuroendocrine hormone is widely found in animals and plants, which have antioxidant and anti-inflammatory effects. Pink1/Parkin-mediated mitophagy keeps normal physiological processes by degrading damaged mitochondria in cells. Therefore, we investigated the potential role and mechanism of MLT in ATR-induced toxic injury of the spleen. The results showed that MLT alleviated ATR-induced unclear boundary between the white pulp and the red pulp of the spleen. It is also shown that ATR resulted in swollen mitochondria, partial extinction of mitochondrial membranes and cristae, and increased mitophagy under the action of MLT. ATR-induced reactive oxygen species (ROS) activates the Pink1/Parkin pathway, which guides mitophagy development and then causes the activation of TLR4/NF-κB inflammatory pathway. Meanwhile, these damages further exacerbated the production of NLRP3 inflammasomes, leading to spleen necrosis. Interestingly, these changes were improved after MLT treatment. Collectively, we found that MLT alleviates ATR-induced immune impairment in splenic macrophages via regulating Parkin-TLR4-NLRP3 axis which elucidates the effect of melatonin on the spleen and provides a novel perspective on melatonin in splenic inflammatory injury treatment.

Are HFPO-TA and HFPO-DA safe substitutes for PFOA? A comprehensive toxicity study using zebrafish (Danio rerio) embryos and adults

Due to the multiple biotoxicity caused by perfluorooctanoic acid (PFOA), the application and production of PFOA is regulated globally. PFOA substitutes including hexafluoropropylene oxide trimer acid (HFPO-TA) and hexafluoropropylene oxide dimer acid (HFPO-DA) have been applied to industrial processes and subsequently detected in surface and groundwater, yet there is a lack of comprehensive assessment of their toxicity to aquatic organisms. Therefore, under the same time and same experimental conditions, the toxic effects and differences of PFOA, HFPO-TA, and HFPO-DA on zebrafish adults and embryos were assessed from oxidative damage, apoptosis, immune function impairment, and protein interactions. The HFPO-TA and HFPO-DA caused more severe oxidative damage than PFOA. While PFOA only disrupted immune function in adults, HFPO-TA and HFPO-DA affected immune homeostasis in both adults and embryos. Integrated biomarker response results showed that superoxide dismutase (SOD) activity and reactive oxygen species content could be used as early warning indicators of toxicity in adults and embryos, respectively. Molecular docking simulations identified HFPO-TA as having the lowest binding energy with SOD proteins, thereby exerting the greatest effect on SOD activity. Compared to PFOA, HFPO-TA and HFPO-DA exhibited a greater toxicological response and, therefore, may not be suitable substitutes for PFOA.

Airway epithelium damage in acute respiratory distress syndrome

BackgroundThe airway epithelium (AE) fulfils multiple functions to maintain pulmonary homeostasis, among which ensuring adequate barrier function, cell differentiation and polarization, and actively transporting immunoglobulin A (IgA), the predominant mucosal immunoglobulin in the airway lumen, via the polymeric immunoglobulin receptor (pIgR). Morphological changes of the airways have been reported in ARDS, while their detailed features, impact for mucosal immunity, and causative mechanisms remain unclear. Therefore, this study aimed to assess epithelial alterations in the distal airways of patients with ARDS.MethodsWe retrospectively analyzed lung tissue samples from ARDS patients and controls to investigate and quantify structural and functional changes in the small airways, using multiplex fluorescence immunostaining and computer-assisted quantification on whole tissue sections. Additionally, we measured markers of mucosal immunity, IgA and pIgR, alongside with other epithelial markers, in the serum and the broncho-alveolar lavage fluid (BALF) prospectively collected from ARDS patients and controls.ResultsCompared to controls, airways of ARDS were characterized by increased epithelial denudation (p = 0.0003) and diffuse epithelial infiltration by neutrophils (p = 0.0005). Quantitative evaluation of multiplex fluorescence immunostaining revealed a loss of ciliated cells (p = 0.0317) a trend towards decreased goblet cells (p = 0.056), and no change regarding cell progenitors (basal and club cells), indicating altered mucociliary differentiation. Increased epithelial permeability was also shown in ARDS with a significant decrease of tight (p < 0.0001) and adherens (p = 0.025) junctional proteins. Additionally, we observed a significant decrease of the expression of pIgR, (p < 0.0001), indicating impaired mucosal IgA immunity. Serum concentrations of secretory component (SC) and S-IgA were increased in ARDS (both p < 0.0001), along other lung-derived proteins (CC16, SP-D, sRAGE). However, their BALF concentrations remained unchanged, suggesting a spillover of airway and alveolar proteins through a damaged AE.ConclusionThe airway epithelium from patients with ARDS exhibits multifaceted alterations leading to altered mucociliary differentiation, compromised defense functions and increased permeability with pneumoproteinemia.

Stability and bifurcation of an HIV-1 infection model with latent reservoir, cell-to-cell transmission and immune impairment

Stability and bifurcation of an HIV-1 infection model with latent reservoir, cell-to-cell transmission and immune impairment

Serum Immunoglobulin G Levels Are Associated with Risk for Exacerbations: An Analysis of SPIROMICS.

Serum Immunoglobulin G (IgG) deficiency is associated with morbidity in chronic obstructive pulmonary disease (COPD) but it is unclear whether concentrations in the lower end of the normal range still confer risk. To determine if levels above traditional cutoffs for serum IgG deficiency are associated with exacerbations among current and former smokers with or at risk for COPD. Former and current smokers in SPIROMICS (n=1,497) were studied, n=1,026 with and n=471 at risk for COPD. In a subset (n=1,031), IgG subclasses were measured. Associations between total IgG or subclasses and prospective exacerbations were evaluated with multivariable models adjusting for demographics, current smoking, smoking history, FEV1% predicted, inhaled corticosteroids, and serum IgA. The 35th percentile (1225 mg/dL in this cohort) of IgG was the best cutoff by Akaike Information Criterion (AIC). Below this, there was increased exacerbation risk (IRR 1.28, 95% CI 1.08-1.51). Among subclasses, IgG1 and IgG2 below 35th percentile (354 and 105 mg/dL, respectively) were both associated with increased risk of severe exacerbation (IgG1: IRR 1.39, 95% CI 1.06-1.84; IgG2: IRR 1.50, 95% CI 1.14-1.1.97). These associations remained significant when additionally adjusting for history of exacerbations. Lower serum IgG is prospectively associated with exacerbations in individuals with or at risk for COPD. Among subclasses, lower IgG1 and IgG2 are prospectively associated with severe exacerbations. The optimal IgG cutoff was substantially higher than traditional cutoffs for deficiency, suggesting subtle impairment of humoral immunity may be associated with exacerbations.

Anti-Bacterial Action of Silver Nanoparticles Against MDR Bacteria Isolated from Hospital

Hospital-associated infections (HAIs) are considered to be a major source of infections in patients, especially in patients with permanently impaired immunity. There is alarming increase of multi drug resistant (MDR) bacteria and Antibacterial medication resistance has been deemed a serious hazard to public health by the World Health Organisation (WHO). The study aimed to isolate and identify main bacteria caused nosocomial infection, and trying to treatments by using nanoparticles. By measuring the antibacterial activity of the synthesised AgNPs using the agar disc diffusion technique, AgNPs demonstrated antibacterial properties against the Pseudomonas aeruginosa and Staphylococcus aureus MDR.

Clinical features of chronic tibial osteomyelitis: a single-center retrospective study of 282 cases in Xinjiang, China.

Chronic osteomyelitis is a highly prevalent and severe orthopaedic complication, representing a critical unresolved issue. The clinical symptoms of osteomyelitis are influenced by various factors, including geography, lifestyle, and pre-existing medical conditions.This study aims to provide theoretical basis for treatment and prevention of osteomyelitis by investigating and analyzing clinical features and pathogen distribution among 282 patients with chronic tibial osteomyelitis in xinjiang. A total of 282 patients with chronic tibial osteomyelitis from January 1, 2012 to January 1, 2022 in the First Affiliated Hospital of Xinjiang Medical University were retrospectively analyzed. All data were collected from electronic medical record (EMR) system including demographics, etiology, risk factors, osteomyelitis location and clinical classification. Farmers, students, unemployed and retirees accounted for a relatively large proportion of the 282 patients. There were 233 males and 49 females with a gender ratio of 4.75:1. The average age was 40.21 ± 15.68 years and was mainly concentrated in 41-50 years, specifically, the mean age of females was slightly older than that of males. Education level was mostly primary and secondary school education, and illiteracy. Risk factors of chronic tibial osteomyelitis included history of smoking and drinking, history of multiple repeated surgeries, and impaired immunity. Frequent clinical symptoms were in the order of pain, local swelling, pus discharge and skin ulceration. Among all inflammatory markers, proportion of positive results were 30.85%, 59.93% and 53.90% for white blood cell (WBC), erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), respectively. Positive rate of pathogenic microorganism culture was low and the three most common bacteria were Staphylococcus aureus (S. aureus), Pseudomonas aeruginosa (P. aeruginosa) and Escherichia coli (E. coli). The most frequent site of infection was middle tibia. According to Cierny-Mader osteomyelitis classification, the most common types were type IIIA, IVA and IIA. Number of visits due to chronic osteomyelitis increased year by year, with young and middle-aged male farmers and low education level as the main groups. Smoking and drinking were two considerable risk factors that should be attached to a great importance. No significant increase was found in inflammatory markers and lower positive rate of pathogenic microorganism culture was observed. Multi-drug resistant bacteria were common and S. aureus remained the most frequent pathogen. Elevated ESR had certain diagnostic value for osteomyelitis. Type III and type IV osteomyelitis accounted for a large proportion which posed great challenges for clinical diagnosis and treatment.

In Vivo Dynamics of HIV-1 Infection With Impaired Antibody Immunity and Three General Infection Mechanisms

In this paper we investigate two generalized human immunodeficiency virus type-1 (HIV-1) dynamics models with impaired antibody immunity. The models include both latently and actively infected cells. Three infection mechanisms are incorporated into the models, viral infection mechanism (VIM), latent cellular infection mechanism (CIM) and active CIM. The three infection rates are provided by generic nonlinear functions. The second model includes three types of distributed time delays. We find that our models are biologically feasible. The global stability analysis of equilibria are performed and found the basic reproduction ratio (R0) as a threshold parameter. Using Lyapunov method we show that, the virus-free equilibrium is globally asymptotically stable when R0≤1 and the virus-persistence equilibrium is globally asymptotically stable when R0&gt;1. Sensitivity analysis on R0 is studied. To support our theoretical results we provide some numerical simulations. We have demonstrated that R0 is influenced by all three of the infection types, and that if one of them were ignored, R0 would be underestimated. This might lead to inadequate medication effectiveness that aims to remove HIV-1 from the body. The effects of time delay and impaired antibody immunity on HIV-1 progression are examined. According to our research, lowered immunity is a significant factor in the infection's growth. Furthermore, time delays might drastically reduce R0, which would prevent HIV-1 from replicating. The information provided by our research in this work can improve our comprehension of HIV-1 dynamics within-host and provide guidance for the creation of novel pharmacological treatments.

A comprehensive review on the role of Vitamin A on human health and nutrition

Vitamin A is a crucial nutrient that protects the body from oxidative stress caused by free radicals, which are unstable molecules that can damage cellular components. Its antioxidant properties helps maintaining various physiological functions that depend on its presence, including vision, immune function and skin health. The human body can convert natural forms of vitamin A (retinol, retinal and retinoic acid) and provitamin A (β-carotene) into active forms, which interact with specific molecular targets, influencing gene expression, cell differentiation and cellular processes. This comprehensive review provides an in-depth examination of vitamin A, covering its dietary sources, physiological roles and consequences of deficiency. In this research review explored the metabolic pathways of vitamin A, including absorption, transport and storage, as well as its potential applications, offering a thorough understanding of this essential nutrient. Furthermore, we have decreased the latest research on vitamin A's role in, maintaining healthy vision, immune function, and skin health, treating various diseases and conditions, such as retinal disorders, infectious diseases and cancer, mechanisms of action, including gene regulation, cell signaling, and antioxidant activity, relationships with other nutrients and health outcomes, including vitamin D, iron, and zinc, impact of deficiency on human health, including night blindness, impaired immunity, and skin disorders and emerging research on potential benefits and risks, including its role in chronic diseases and interactions with medications. Key words: Nutrition, retinyl ester, Nyctalopia, Rhodopsin, Vitamin A, β-carotene

Tumor-colonized Streptococcus mutans metabolically reprograms tumor microenvironment and promotes oral squamous cell carcinoma

BackgroundOral squamous cell carcinoma (OSCC) remains a major death cause in head and neck cancers, but the exact pathogenesis mechanisms of OSCC are largely unclear.ResultsSaliva derived from OSCC patients but not healthy controls (HCs) significantly promotes OSCC development and progression in rat models, and metabolomic analyses reveal saliva of OSCC patients but not HCs and OSCC tissues but not adjacent non-tumor tissues contain higher levels of kynurenic acid (KYNA). Furthermore, large amounts of Streptococcus mutans (S. mutans) colonize in OSCC tumor tissues, and such intratumoral S. mutans mediates KYNA overproductions via utilizing its protein antigen c (PAc). KYNA shifts the cellular types in the tumor microenvironment (TME) of OSCC and predominantly expedites the expansions of S100a8highS100a9high neutrophils to produce more interleukin 1β (IL-1β), which further expands neutrophils and induces CD8 + T cell exhaustion in TME and therefore promotes OSCC. Also, KYNA compromises the therapeutic effects of programmed cell death ligand 1 (PD-L1) and IL-1β blockades in oral carcinogenesis model. Moreover, KYNA-mediated immunosuppressive program and aryl hydrocarbon receptor (AHR) expression correlate with impaired anti-tumor immunity and poorer survival of OSCC patients.ConclusionsThus, aberration of oral microbiota and intratumoral colonization of specific oral bacterium such as S. mutans may increase the production of onco-metabolites, exacerbate the oral mucosal carcinogenesis, reprogram a highly immunosuppressive TME, and promote OSCC, highlighting the potential of interfering with oral microbiota and microbial metabolism for OSCC preventions and therapeutics.5ViVJ5sCbraGF_6Zi1UXojVideo

Transcriptome signature of juvenile Litopenaeus vannamei cultured under different salinity levels in response to Vibrio harveyi infection

Although the widely cultured Litopenaeus vannamei is highly tolerant to varying salinity levels, the rapid fluctuation of abiotic and biotic factors due to climatic changes may become stressors to the shrimp's physiology, resulting in impaired immunity and increased disease susceptibility. This study aimed to investigate the combined effects of both factors towards L. vannamei at transcriptomic level. L. vannamei were cultured at three different salinity levels (5 ppt, 20 ppt and 30 ppt) for 60 days and were challenged with Vibrio harveyi. RNA-seq analysis was conducted on the hepatopancreas to assess the differential expressed genes (DEGs) in both control and V. harveyi infected groups. Our results revealed 5,725 DEGs was observed in shrimp reared at 5 ppt, 3,643 DEGs at 20 ppt and 1,560 DEGs at 30 ppt. Most DEGs were identified to be associated with osmoregulation and transport activities, immune and stress regulation, nutrient metabolism, growth, chitin binding, gonadal development, and metal ion binding and toxicity. We identified that shrimp cultured at intermediate salinity of 20 ppt exhibits the greatest immunity level after infection by V. harveyi, given that low salinity (5 ppt) may augment the free ion metal toxicity, resulting in higher disease susceptibility. Both V. harveyi and salinity stress function together or separately to activate a wide range of immune and stress regulatory genes, which could be potential candidate markers for future RNAi and knockdown research in developing efficient prophylactic management strategies for L. vannamei.

Downregulating LKB1 in bone marrow mesenchymal stem cells could inhibit CD4+ T cell proliferation via the PD-1/PD-L1 signaling pathway

BackgroundOur previous research has shown that LKB1 in amniotic mesenchymal stem cells (MSCs) serves as a vital regulator of regulatory T cell differentiation and T cell proliferation, which may have a similar role in bone marrow MSCs (BMMSCs). Therefore, we investigated the role of LKB1 in BMMSCs for regulating CD4+ T cell proliferation in the bone micro-environment of AML. MethodsRT-PCR was used to assessed LKB1 expression in BMMSCs derived from AML patients and healthy controls. Subsequently, LKB1 was knocked down in the BMMSCs line HS-5 (HS-5-LKB1KD). Co-cultures in vitro were established to analyze the effect of HS-5-LKB1KD on CD4+ T cell. Flow cytometry was employed to measure PD-L1 and CD4+ T cell proliferation levels. Western blot was utilized to detect related proteins. ResultsThe expression of LKB1 in BMMSCs derived from AML patients was decreased. Knockdown of LKB1 in HS-5 resulted in upregulation of PD-L1 expression. Co-culture of peripheral blood CD4+ T cell with HS-5-LKB1KD exhibited reduced CD4+ T cell proliferation compared to co-culture with HS-5-LKB1con. Furthermore, blocking PD-L1 in the co-culture conditions could restore the reduced CD4+ T cell proliferation. Additionally, it was found that upregulation of the Wnt signaling pathway-related proteins following LKB1 knockdown in HS-5, indicating that downregulating LKB1 could promote PD-L1 expression through activation of the Wnt signaling pathway. ConclusionsThe decreased expression of LKB1 in BMMSCs may activate the Wnt signaling pathway, leading to increased PD-L1 expression. This inhibited CD4+ T cell proliferation, which might lead to impaired anti-tumor immunity in AML patients and promote AML progression.

The Human Neural Cell Atlas of Zika Infection in developing human brain tissue: viral pathogenesis, innate immunity, and lineage reprogramming.

Zika virus (ZIKV) infection during pregnancy can lead to fetal brain infection and developmental anomalies collectively known as congenital Zika syndrome (CZS). To define the molecular features underlying CZS in a relevant human cell model, we evaluated ZIKV infection and neurodevelopment in primary fetal brain explants and induced pluripotent stem cell-derived mixed neural cultures at single cell resolution. We identified astrocytes as key innate immune sentinel cells detecting ZIKV and producing IFN-β. In contrast, neural progenitor cells displayed impaired innate immunity and supported high levels of viral replication. ZIKV infection of neurons suppressed differentiation and synaptic signaling networks and programmed a molecular switch from neurogenesis to astrogliogenesis. We identified a universal ZIKV-driven cellular stress response linked to intrinsic apoptosis and regulated by IFN-β. These findings reveal how innate immune signaling intersects with ZIKV-driven perturbations in cellular function to influence CZS outcomes including neuron developmental dysfunction and apoptotic cell death.

Immunomodulatory Therapy for Ischemic Heart Disease.

Ischemic heart disease is a leading cause of death worldwide, manifested clinically as myocardial infarction (and ischemic cardiomyopathy. Presently, there exists a notable scarcity of efficient interventions to restore cardiac function after myocardial infarction. Cumulative evidence suggests that impaired tissue immunity within the ischemic microenvironment aggravates cardiac dysfunction, contributing to progressive heart failure. Recent research breakthroughs propose immunotherapy as a potential approach by leveraging immune and stroma cells to recalibrate the immune microenvironment, holding significant promise for the treatment of ischemic heart disease. In this Primer, we highlight three emerging strategies for immunomodulatory therapy in managing ischemic cardiomyopathy: targeting vascular endothelial cells to rewire tissue immunity, reprogramming myeloid cells to bolster their reparative function, and utilizing adoptive T cell therapy to ameliorate fibrosis. We anticipate that immunomodulatory therapy will offer exciting opportunities for ischemic heart disease treatment.