Immune Lymphocytes Research Articles

Immune Impairment Associated with Vitamin A Deficiency: Insights from Clinical Studies and Animal Model Research.

Vitamin A (VA) is critical for many biological processes, including embryonic development, hormone production and function, the maintenance and modulation of immunity, and the homeostasis of epithelium and mucosa. Specifically, VA affects cell integrity, cytokine production, innate immune cell activation, antigen presentation, and lymphocyte trafficking to mucosal surfaces. VA also has been reported to influence the gut microbiota composition and diversity. Consequently, VA deficiency (VAD) results in the imbalanced production of inflammatory and immunomodulatory cytokines, intestinal inflammation, weakened mucosal barrier functions, reduced reactive oxygen species (ROS) and disruption of the gut microbiome. Although VAD is primarily known to cause xerophthalmia, its role in the impairment of anti-infectious defense mechanisms is less defined. Infectious diseases lead to temporary anorexia and lower dietary intake; furthermore, they adversely affect VA status by interfering with VA absorption, utilization and excretion. Thus, there is a tri-directional relationship between VAD, immune response and infections, as VAD affects immune response and predisposes the host to infection, and infection decreases the intestinal absorption of the VA, thereby contributing to secondary VAD development. This has been demonstrated using nutritional and clinical studies, radiotracer studies and knockout animal models. An in-depth understanding of the relationship between VAD, immune response, gut microbiota and infections is critical for optimizing vaccine efficacy and the development of effective immunization programs for countries with high prevalence of VAD. Therefore, in this review, we have comprehensively summarized the existing knowledge regarding VAD impacts on immune responses to infections and post vaccination. We have detailed pathological conditions associated with clinical and subclinical VAD, gut microbiome adaptation to VAD and VAD effects on the immune responses to infection and vaccines.

Characteristics of lymphocyte subset alterations in COVID-19 patients with different levels of disease severity

BackgroundCoronavirus disease 2019 (COVID-19) is a respiratory disorder caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which had rapidly spread all over the world and caused public health emergencies in the past two years. Although the diagnosis and treatment for COVID-19 have been well defined, the immune cell characteristics and the key lymphocytes subset alterations in COVID-19 patients have not been thoroughly investigated.MethodsThe levels of immune cells including T cells, B cells, and natural killer (NK) cells in 548 hospitalized COVID-19 patients, and 30 types of lymphocyte subsets in 125 hospitalized COVID-19 patients admitted to Wuhan Huoshenshan Hospital of China were measured using flow cytometry. The relationship between lymphocytes subsets with the cytokine interleukin-6 (IL-6) and the characteristics of lymphocyte subsets in single-cell RNA sequencing (scRNA-seq) data obtained from peripheral blood mononuclear cells (PBMCs) were also analysed in COVID-19 patients.ResultsIn this study, we found that patients with critical COVID-19 infection exhibited an overall decline in lymphocytes including CD4+ T cells, CD8+ T cells, total T cells, B cells, and NK cells compared to mild and severe patients. However, the number of lymphocyte subsets, such as CD21low CD38low B cells, effector T4 cells, and PD1+ depleted T8 cells, was moderately increased in critical COVID-19 patients compared to mild cases. Notably, except for effector memory T4 cells, plasma blasts and Tregs, the number of all lymphocyte subsets was markedly decreased in COVID-19 patients with IL-6 levels over 30-fold higher than those in healthy cases. Moreover, scRNA-seq data showed obvious differences in the distribution and numbers of lymphocyte subsets between COVID-19 patients and healthy persons, and subsets-specific marker genes of lymphocyte subsets including CD4, CD19, CCR7, and IL7R, were markedly decreased in COVID-19 patients compared with those in healthy cases.ConclusionA comprehensive decrease in immune cell and lymphocyte subsets in critical COVID-19 patients, and peripheral lymphocyte subset alterations showed a clear association with clinical characteristics.

Role of lymphocyte immunization therapy (LIT) in repeated miscarriages - A review.

Recurrent Miscarriages are seen in 2%-5% of women and 50% of these are labelled as unexplained as no underlying cause is found in them. Various studies have explained possible alloimmune basis in these couples. Lymphocyte Immunization Therapy (LIT) was the earliest immunomodulatory method suggested in these cases. The efficacy of LIT was questioned by REMIS study in 1999 and subsequent Cochrane reviews. However, recent meta-analyses have shown that LIT is not only effective in the treatment of repeated miscarriages but it is also safe. Review of the odds ratio for live birth of various meta-analyses of studies in recurrent miscarriages has also shown that newer meta-analyses have shown higher odds ratios. The purpose of this paper is to put forward the current perspective of LIT in reproductive failure and bring forth the recent evidence. In addition, we share our experience with the use of LIT in women with recurrent pregnancy losses. However, large multicentric RCTs are required to further prove efficacy of LIT.

Longitudinal Profiling of the T Cell Compartment in Patients with Chronic Lymphocytic Leukemia Treated with Venetoclax

Venetoclax (ven), an inhibitor of the BCL2 anti-apoptotic protein, has been proven remarkably effective in the treatment of patients with chronic lymphocytic leukemia (CLL), where the malignant B cells typically overexpress BCL2. BCL2 is also expressed by various bystander cells in the CLL microenvironment, including T cells. Hence, investigating the effects of ven treatment on T cells is highly relevant, especially considering that distinct T cell subpopulations exhibit different sensitivity to anti-apoptotic signaling blockade. Herein we interrogated the molecular and phenotypic profiles of the T cell compartment in 1 treatment-naïve and 15 relapsed/refractory CLL patients who received ven either as monotherapy (n=12) or in combination with an anti-CD20 antibody (obinutuzumab, n=1; rituximab, n=3). We studied peripheral blood samples collected prior to ven initiation and after 5 months of treatment, from which we isolated T cell subpopulations (CD3+ T cells n=8; CD4+ and CD8+ T cells, n=8). Longitudinal analysis of pre/post-treatment samples by flow cytometry (n=7) revealed a significant (p=0.01) decrease in the numbers of central memory (CD45RO+/CCR7+) CD4+ (21.8% vs 8.8%) and CD8+ cells (21.4% vs 9.7%) under ven; in contrast, a significant (p=0.01) increase of CD8+ effector memory cells (CD45RO+/CCR7-) was observed (27.8% vs 32.9%). Profiling of the T cell receptor beta (TRB) chain gene repertoire overtime (n=15) was performed by next generation sequencing (NGS). Clonotypes (i.e. TRBV-TRBD-TRBJ gene rearrangements with unique pairs of TRBV genes and identical CDR3 amino acid sequences) were calculated and clonality was estimated as the average cumulative frequency of the 10 most frequent clonotypes per sample (ACF-10). A significantly (p=0.01) more diverse repertoire was identified in CD4+ vs CD8+ cells at both pre- and post-treatment timepoints (average numbers of clonotypes pre-/post-treatment: CD4+ cells, 16,908/13,768; CD8+ cells, 4,437/3,633). Expanded clonotypes corresponding to oligoclonal expansions were documented in all examined subpopulations at both timepoints. However, significantly (p=0.01) more pronounced skewing was observed in CD8+ vs CD4+ cells (pre-/post-treatment ACF-10 values: 64.4%/70.6% vs 31.4%/42.2%, respectively). Repertoire comparisons overtime highlighted a fraction of T clonotypes that were retained after treatment in all examined subpopulations. Of note, repertoire conservation was significantly (p=0.01) greater in CD8+ vs CD4+ T cells [retained pre-treatment clonotypes: 7,102/31,063 (28%) vs 11,525/118,359 (12%), respectively]. Transcriptome profiling of CD4+ and CD8+ cells pre-/post-treatment was performed using the Oncomine Immune Response Research Assay (395 genes) in 5 cases attaining a complete response after treatment. While the transcriptomes of CD4+ cells remained essentially unaltered, significant differences were identified in CD8+ cells, where 19 genes were found to be downregulated (adj.p<0.05, fold change>2). These genes are implicated in functions such as immune response (e.g. TLR7, TLR9, CD40), regulation of immune system (e.g. HLA genes, CIITA, TNFAIP8) and lymphocyte activation pathways (e.g. ICOSLG, CEACAM1, CXCR5), with at least some of these having immunosuppressive functions (e.g. BTLA and CTLA4 encoding inhibitory receptors associated with T cell exhaustion). In conclusion, ven treatment led to increased numbers of CD8+ effector subpopulations along with prominent clonal expansions and transcriptional rewiring that could conceivably contribute to clinical response. Downregulation of immune-related genes implicated in core regulatory/activation pathways supports immune recovery by ven, offering a rationale for future combination strategies aiming to increase the depth of clinical response.

Roles of transducin-like enhancer of split (TLE) family proteins in tumorigenesis and immune regulation.

Mammalian transducin-like enhancer of split family proteins (TLEs) are homologous to Drosophila Groucho (Gro) and are essential transcriptional repressors. Seven TLE family members, TLE1-7, have been identified to date. These proteins do not bind DNA directly; instead, they bind a set of transcription factors and thereby inhibit target gene expression. Loss of TLEs in mice usually leads to defective early development; however, TLE functions in developmentally mature cells are unclear. Recent studies have revealed that TLEs are dysregulated in certain human cancer types and may function as oncogenes or tumor suppressors in different contexts. TLE levels also affect the efficacy of cancer treatments and the development of drug resistance. In addition, TLEs play critical roles in the development and function of immune cells, including macrophages and lymphocytes. In this review, we provide updates on the expression, function, and mechanism of TLEs; discuss the roles played by TLEs in tumorigenesis and the inflammatory response; and elaborate on several TLE-associated signaling pathways, including the Notch, Wnt, and MAPK pathways. Finally, we discuss potential strategies for targeting TLEs in cancer therapy.

α-MSH is partially involved in the immunomodulation of Nile tilapia (Oreochromis niloticus) antibacterial immunity

α-Melanocyte-stimulating hormone (α-MSH) is a well-studied neuropeptide controlling skin and hair color. Besides, numerous immunomodulation roles of α-MSH were recorded in humans and mice. However, the regulatory effects of α-MSH in teleost immunity haven't been well elucidated. In this study, several precursor molecules of α-MSH (POMCs) and its receptors (MCRs) in Nile tilapia (Oreochromis niloticus) were characterized, and their expression characteristics and specific functions on antibacterial immunity were determined. Overall, POMCs and MCRs were principally detected in the brain, skin, and liver, and were remarkably promoted post Streptococcus agalactiae infection. However, tiny POMCs and MCRs were observed in tilapia immune organs (head kidney and spleen) or lymphocytes, and no evident immunomodulation effect was detected in vitro. Moreover, the in vivo challenge experiments revealed that α-MSH protects tilapia from bacterial infection by regulating responses in the brain and intestine. This study lays theoretical data for a deeper comprehension of the immunomodulation mechanisms of teleost α-MSH and the evolutional process of the vertebrate melanocortin system.

A Case Series Exploration of Multi-Regional Expression Heterogeneity in Triple-Negative Breast Cancer Patients.

Extensive intratumoral heterogeneity (ITH) is believed to contribute to therapeutic failure and tumor recurrence, as treatment-resistant cell clones can survive and expand. However, little is known about ITH in triple-negative breast cancer (TNBC) because of the limited number of single-cell sequencing studies on TNBC. In this study, we explored ITH in TNBC by evaluating gene expression-derived and imaging-derived multi-region differences within the same tumor. We obtained tissue specimens from 10 TNBC patients and conducted RNA sequencing analysis of 2-4 regions per tumor. We developed a novel analysis framework to dissect and characterize different types of variability: between-patients (inter-tumoral heterogeneity), between-patients across regions (inter-tumoral and region heterogeneity), and within-patient, between-regions (regional intratumoral heterogeneity). We performed a Bayesian changepoint analysis to assess and classify regional variability as low (convergent) versus high (divergent) within each patient feature (TNBC and PAM50 subtypes, immune, stroma, tumor counts and tumor infiltrating lymphocytes). Gene expression signatures were categorized into three types of variability: between-patients (108 genes), between-patients across regions (183 genes), and within-patients, between-regions (778 genes). Based on the between-patient gene signature, we identified two distinct patient clusters that differed in menopausal status. Significant intratumoral divergence was observed for PAM50 classification, tumor cell counts, and tumor-infiltrating T cell abundance. Other features examined showed a representation of both divergent and convergent results. Lymph node stage was significantly associated with divergent tumors. Our results show extensive intertumoral heterogeneity and regional ITH in gene expression and image-derived features in TNBC. Our findings also raise concerns regarding gene expression based TNBC subtyping. Future studies are warranted to elucidate the role of regional heterogeneity in TNBC as a driver of treatment resistance.

Editorial: Regulatory T lymphocytes in cancer immunity

Editorial: Regulatory T lymphocytes in cancer immunity

Treatment Induced Changes in Systemic Immune Environment in Patients with Unresectable Hepatocellular Carcinoma

<h3>Purpose/Objective(s)</h3> Host immune status plays an essential role in cancer patients. However, it is unknown whether therapy can change or remodel this environment which can influence treatment response to the remaining treatment. It is unknown however whether such change varies with treatment modality. This study aimed to exam the systemic immune status, explore the changes after arterial chemotherapy embolization (TACE), stereotactic body radiation therapy (SBRT) and immunotherapy (IO) as well as their correlation with treatment responses in patients with hepatocellular carcinoma (HCC). <h3>Materials/Methods</h3> This is a pilot study of correlative research for a prospective phase II trial. Patients with unresectable HCC were eligible. The protocol treatment included sequential TACE, SBRT (27.5–40 Gy/5 fractions) and IO. TACE and SBRT were per standard of care. Treatment response was assessed according to mRECIST by CT or MRI around 6 months from treatment commencement. Peripheral blood samples were collected at baseline and after TACE, SBRT and IO for lymphocyte subtypes of our interest by flow cytometry, including NKT cell, T, CD4+T, CD8+T, CD25+CD8+T, CD127+CD8+T, Th1, Th2, Th17, Treg, CD4/CD8 T cell, Th2/Th1, Th1/Th17 and Th17/Treg. Generalized estimation equation was employed for longitudinal analyses, and Bonferroni adjustment for multiple testing was performed for statistical significance at a p < 0.0083 (0.05/6) level. <h3>Results</h3> A pilot of 12 patients were enrolled between July 2020 and February 2021, with Child Pugh score of A, mean tumor greatest dimension of 8.4 ± 3.7 cm, and lesion number of less than 4. The circulating immune cells and lymphocyte subtypes were quite heterogeneous among patients at baseline, e.g., the median percent of CD8+T cell was 27% (95% CI, 19% - 43%). The treatment induced changes of circulating immune components were heterogeneous from patient to patient but most significant after SBRT. On average, CD8+T cell (27% to 51%, p = 0.01) increased after sequential treatment, while its non-effector component CD127+CD8+T cell (51% to 18%, p < 0.001) decreased significantly. SBRT reduced the counts of lymphocyte (1.3 to 0.7, p < 0.001) and platelet (226 to 156, p=0.001), while T cell increased significantly (45% to 54%, p = 0.031). Our pilot study of 12 patients demonstrated 58.3% tumor control (7 complete response, 5 progression disease). After grouping by treatment response, the baseline CD4+T (65% vs. 53%, p = 0.01), Th1 cells (21% vs. 10%, p = 0.007) and Th1/Th17 (10% vs. 1%, p = 0.001) were significantly higher in responders, while CD25+CD8+T (4% vs. 12%, p < 0.001), CD127+CD8+T (42% vs. 60%, p = 0.003), Th17 (2% vs. 8%, p = 0.047) and Treg cells (p = 0.002) and ratio of Th2/Th1 (3% vs. 9%, p = 0.028) were significantly higher in non-responders. <h3>Conclusion</h3> This pilot study revealed heterogeneous components of systemic immunities at baseline and changes after different treatments, with most significant changes from SBRT. Future scale verification trials are warranted.

The thin red line between the immune system and cancer evolution

The cancer immunoediting theory describes the dual ability of endogenous antitumor immunity to inhibit or promote progressing cancers. Tumor-specific neoantigens arising from somatic mutations serve as targets for the endogenous T-cell-mediated antitumor immunity and therefore possess a crucial role for tumor development. Additionally, targeting these molecules is conceptually appealing because neoantigens are not expressed in healthy tissue and therefore confer less toxicity and greater specificity when used in therapeutic interventions. Moreover, intratumor neo-antigenic heterogeneity is believed to play a pivotal role in the activation of adaptive immunity and in the efficacy of immunotherapies that are based on immune checkpoint inhibition. In this respect, mutual interactions between tumor cells and immune lymphocytes regulate the levels of antitumor immunity, but also shape tumor heterogeneity through the selective outgrowth of tumor subclones. Therefore, the exploration of the mechanistic pathways and the identification of the genomic aberrations underlying the clonal evolution of tumors is considered mandatory for improving the clinical outcomes of therapies, as it will assist in the selection of the appropriate therapeutic decisions so as to delay, avoid, or overcome resistance through the identification of the most effective therapeutic strategies.

C10orf55, CASC2, and SFTA1P lncRNAs Are Potential Biomarkers to Assess Radiation Therapy Response in Head and Neck Cancers.

Long non-coding RNAs have proven to be important molecules in carcinogenesis. Due to little knowledge about them, the molecular mechanisms of tumorigenesis are still being explored. The aim of this work was to study the effect of ionizing radiation on the expression of lncRNAs in head and neck squamous cell carcinoma (HNSCC) in patients responding and non-responding to radiotherapy. The experimental model was created using a group of patients with response (RG, n = 75) and no response (NRG, n = 75) to radiotherapy based on the cancer genome atlas (TCGA) data. Using the in silico model, statistically significant lncRNAs were defined and further validated on six HNSCC cell lines irradiated at three different doses. Based on the TCGA model, C10orf55, C3orf35, C5orf38, CASC2, MEG3, MYCNOS, SFTA1P, SNHG3, and TMEM105, with the altered expression between the RG and NRG were observed. Analysis of pathways and immune profile indicated that these lncRNAs were associated with changes in processes, such as epithelial-to-mesenchymal transition, regulation of spindle division, and the p53 pathway, and differences in immune cells score and lymphocyte infiltration signature score. However, only C10orf55, CASC2, and SFTA1P presented statistically altered expression after irradiation in the in vitro model. In conclusion, the expression of lncRNAs is affected by ionization radiation in HNSCC, and these lncRNAs are associated with pathways, which are important for radiation response and immune response. Potentially presented lncRNAs could be used as biomarkers for personalized radiotherapy in the future. However, these results need to be verified based on an in vitro experimental model to show a direct net of interactions.

HIV Dynamics with a Trilinear Antibody Growth Function and Saturated Infection Rate

The objective of this paper is to study a new mathematical model describing the human immunodeficiency virus (HIV). The model incorporates the impacts of cytotoxic T lymphocyte (CTL) immunity and antibodies with trilinear growth functions. The boundedness and positivity of solutions for non-negative initial data are proved, which is consistent with biological studies. The local stability of the equilibrium is established. Finally, numerical simulations are presented to support our theoretical findings.

Colorectal Cancer and Purinergic Signalling: An Overview.

Highlights What are the main findings? CD39-CD73 axis in tumor-associated immune cells promotes immune exhaustion, impairment of antitumor immune activity, and increased CRC progression.CD73 overexpression in cancer cells is associated with tumor growth, chemoresistance, and decreased patient survival.Extracellular ATP exhibits dual effects, either reducing tumor cell proliferation or favoring chemoresistance in a concentration-dependent fashion.Purinergic signaling components exhibit prognostic value and have the potential to be utilized as therapeutic targets. What is the implication of the main finding? CD73 induces colorectal cancer progression.CD39 contributes to immunosuppressive activity of T cells and poor prognosis.P2 and P1 purinoceptors were mainly associated with poor prognosis for patients.Ectonucleotidases and purinoceptors have potential as therapeutic targets in CRC. Simple SummaryColorectal cancer is a leading cause of cancer-related death. Activated immune cells have the potential to eliminate tumor cells, but cancers gain the ability to suppress immune cell functions and escape immune attack. We explored one mechanism that cancers use to evade immune cells in colorectal cancer. This mechanism alters levels of molecules known as purines. Purines are key players in cellular energetics and many cellular processes and can also lead to immune suppression in cancer. In this study, we reviewed the literature that identified specific enzymes (ectonucleoetidases) and receptors (purinoceptors) which alter the levels of purines and contribute to immunosuppression in colorectal cancer. We hope that targeting these enzymes and receptors can activate the immune response against colorectal cancer and halt cancer growth and progression.Colorectal cancer (CRC) is among the most common cancers and exhibits a high fatality rate. Gut inflammation is related to CRC, with loss of homeostasis in immune cell activities. The cells of the innate and adaptive immune system, including macrophages, neutrophils, mast cells, and lymphocytes, are present in most solid tumors. Purinergic signaling allows for communication between immune cells within the tumor microenvironment (TME) and can alter the TME to promote tumor progression. This system is regulated by the availability of extracellular purines to activate purinoceptors (P1 and P2) and is tightly controlled by ectonucleotidases (E-NPP, CD73/CD39, ADA) and kinases, which interact with and modify nucleotides and nucleosides availability. In this review, we compiled articles detailing the relationship of the purinergic system with CRC progression. We found that increased expression of CD73 leads to the suppression of effector immune cell functions and tumor progression in CRC. The P1 family purinoceptors A1, A2A, and A2B were positively associated with tumor progression, but A2B resulted in increased cancer cell apoptosis. The P2 family purinoceptors P2X5, P2X7, P2Y2, P2Y6, and P2Y12 were factors primarily associated with promoting CRC progression. In summary, CD39/CD73 axis and the purinergic receptors exhibit diagnostic and prognostic value and have potential as therapeutic targets in CRC.

CD4+ Cytotoxic T Lymphocytes in Cancer Immunity and Immunotherapy.

CD4+ T cells have the ability to differentiate into relatively specialized effector subsets after exposure to innate immune signals. The remarkable plasticity of CD4+ T cells is required to achieve immune responses in different tissues and against various pathogens. Numerous studies have shown that CD4+ T cells can play direct and indispensable roles in protective immunity by killing infected or transformed cells. Although the lineage decision of commitment to the CD4+ or CD8+ cell lineage is once thought to be inflexible, the identification of antigen-experienced CD4+ T cells with cytotoxic activity suggests the existence of unexpected plasticity for these cells. The recognition of CD4+ cytotoxic T lymphocytes (CTLs) and the mechanisms driving the differentiation of this particular cell subset create opportunities to explore the roles of these effector cells in protective immunity and immune-related pathology. CD4+ CTLs are proven to play a protective role in antiviral immunity. Here, the latest investigations on the phenotypic and functional features of CD4+ CTLs and their roles in antitumor immunity and immunotherapy are briefly reviewed.

Strategies targeting hemagglutinin cocktail as a potential universal influenza vaccine.

Vaccination is the most effective means of protecting people from influenza virus infection. The effectiveness of existing vaccines is very limited due to antigenic drift of the influenza virus. Therefore, there is a requirement to develop a universal vaccine that provides broad and long-lasting protection against influenza. CD8+ T-cell response played a vital role in controlling influenza virus infection, reducing viral load, and less clinical syndrome. In this study, we optimized the HA sequences of human seasonal influenza viruses (H1N1, H3N2, Victoria, and Yamagata) by designing multivalent vaccine antigen sets using a mosaic vaccine design strategy and genetic algorithms, and designed an HA mosaic cocktail containing the most potential CTL epitopes of seasonal influenza viruses. We then tested the recombinant mosaic antigen, which has a significant number of potential T-cell epitopes. Results from genetic evolutionary analyses and 3D structural simulations demonstrated its potential to be an effective immunogen. In addition, we have modified an existing neutralizing antibody-based seasonal influenza virus vaccine to include a component that activates cross-protective T cells, which would provide an attractive strategy for improving human protection against seasonal influenza virus drift and mutation and provide an idea for the development of a rationally designed influenza vaccine targeting T lymphocyte immunity.

Immunomodulatory effects of vinegar-egg juice: Potential pharmacological effects of a traditional Chinese food remedy?

Thousands of years of historical practice have proven that the ancient Chinese food, vinegar-egg juice, has immune-boosting effects with the presence of many nutritional factors. However, its mechanism of action in the body remains unclear. In this research project, vinegar-egg juice was chosen to analyze its immune-enhancing effects on mice. The immune enhancing effects of egg, vinegar and vinegar egg juice on lymphocytes of mouse spleen were compared. The effects on immune function of mice were analyzed by studying the organ index, natural killer(NK) cell activity, lymphocyte transformation function and cytokine changes in immune organs after treatment with vinegar-egg juice. The mechanism of immune enhancement was speculated by analyzing the changes of total IKKα/β/IκBα/NF-κB and its phosphorylated protein kinase by Western blot. Experiments have shown that vinegar and eggs have less immune regulation than vinegar-egg juice. Vinegar-egg juice can regulate the cellular and humoral immunity of spleen lymphocytes, increase the phosphorylated kinases of IKKα/β, reduce the total protein expression of IκBα, and activate the signaling pathway of IKK/IκB/NF-κB. In addition, compared with the control group, vinegar-egg juice reduced the Firmicutes/Bacteroidetes ratio and increased the relative abundance of beneficial bacteria. Furthermore, vinegar-egg juice can raise phosphatidylserine (PS) and serotonin (5-HT) levels in the body. The results showed that the vinegar-egg juice had obvious immunomodulatory activity. It was speculated that the intake of vinegar-egg juice can increase the activity of NK cells, T lymphocytes and B lymphocytes by increasing 5-HT levels, ultimately enhancing the body's immune function. PRACTICAL APPLICATIONS: In this work, we evaluated the immune regulation of vinegar, egg and vinegar-egg juice in mice. In addition, we investigated the effects of vinegar-egg juice on gut microbiota. And combined with the composition of the vinegar-egg juice, it was found that the intake of vinegar-egg juice could increase the activity of NK cells, T lymphocytes and B lymphocytes by increasing 5-HT levels, ultimately enhancing the body's immune function. On the basis of the results of this study, we recommend vinegar-egg juice can be a potential health food to resist the epidemic and improve autoimmunity in special times of the novel coronavirus outbreak.

Immunophenotypes of anti-SARS-CoV-2 responses associated with fatal COVID-19.

BackgroundThe relationship between anti-SARS-CoV-2 humoral immune response, pathogenic inflammation, lymphocytes and fatal COVID-19 is poorly understood.MethodsLongitudinal prospective cohort of hospitalized patients with COVID-19 (N=254) was followed up to 35 d after admission (median, 8 d). We measured early anti-SARS-CoV-2 S1 antibody IgG levels and dynamic (698 samples) of quantitative circulating T, B, NK lymphocyte subsets and serum interleukin-6 response. We used machine learning to identify patterns of the immune response, and related these patterns to the primary outcome of 28-day mortality in analyses adjusted for clinical severity factors.ResultsOverall, 45 (18%) patients died within 28 days after hospitalization. We identified six clusters representing discrete anti-SARS-CoV-2 immunophenotypes. Clusters differed considerably in COVID-19 survival. Two clusters, the anti-S1-IgGlowestTlowestBlowestNKmodIL-6mod, and the anti-S1-IgGhighTlowBmodNKmodIL-6highest had a high risk of fatal COVID-19 (HR, 3.36–21.69; 95% CI, 1.51–163.61 and HR, 8.39–10.79; 95% CI, 1.20–82.67; P≤0.03, respectively). The anti-S1-IgGhighestTlowestBmodNKmodIL-6mod and anti-S1-IgGlowThighestBhighestNKhighestIL-6low cluster were associated with moderate risk of mortality. In contrast, two clusters the anti-S1- anti-S1-IgGhighThighBmodNKmodIL-6low and anti-S1-IgGhighestThighestBhighNKhighIL-6lowest clusters were characterized by a very low risk of mortality.ConclusionsBy employing unsupervised machine learning we identified multiple anti-SARS-CoV-2 immune response clusters and observed major differences in COVID-19 mortality between these clusters. Two discrete immune pathways may lead to fatal COVID-19. One is driven by impaired or delayed antiviral humoral immunity, independently of hyper-inflammation, and the other may arise through excessive IL-6 mediated host inflammation response, independently of the protective humoral response. Those observations could be explored further for application in clinical practice.

Assessment of lymphocyte populations and their subsets in the patients with acute coronary syndrome

We examined 23 patients aged 40 to 65 years (mean age 54.526.72) with a diagnosis of acute coronary syndrome (ACS) at admission, who underwent emergency or delayed coronary stenting a day later. All patients had arterial hypertension as a concomitant disease. Upon additional examination, blood troponin levels were determined, ECG was performed in the time dynamics. Acute myocardial infarction with ST elevation was diagnosed in 7 patients, infarction without ST elevation, in 6 patients, the unstable angina rest, in the rest of this group (Grace risk from 75 to 150 points, on average, 107.727.16 points). To assess the immune status, especially, lymphocyte populations and subsets we used standardized techniques, i.e., flow cytometric assays with Navios cytofluorimeter (Beckman Coulter, USA). The following subpopulations were determined: CD45+ (panleukocyte marker for gating lymphocytes), CD45+, CD3+ (T cells), CD45+, CD3+, CD4+ (helper inducers), CD45+, CD3+, CD8+ (cytotoxic T cells), CD45+, CD3+CD16+, CD56+ (TNK cells) CD45+, CD3-, CD16+, CD56+ (natural killer cells), CD45+, CD3-, CD19+CD5+ (B cells), CD45+, CD3+, CD4+, CD25+ (activated helpers, early activation phase), CD45+, CD3+, HLA-DR (activated T lymphocytes late activation phase). The data obtained indicate that the relative indices of T helper subpopulations, T cells at early and late activation step, and B lymphocytes were increased in the patients with acute coronary syndrome, compared with control group. At the same time, there is a trend for increasing absolute values of these indexes. The subpopulation of TNK lymphocytes proved to be significantly increased both in relative and absolute values, whereas percentages of CD45+CD3+CD19- (p 0.01) and T cytotoxic lymphocytes (p 0.001) were decreased and showed the same trend in absolute terms. The ratio of CD4/CD8 lymphocytes was almost doubled (p 0.001), due to increased content of T-helpers and decrease in cytotoxic T lymphocytes. In clinical blood analyses of ACS patients a tendency for leukocytosis was shown, (10.155.22), with a shift to the band forms.

Refined polysaccharide from Dendrobium devonianum resists H1N1 influenza viral infection in mice by activating immunity through the TLR4/MyD88/NF-κB pathway.

Dendrobium polysaccharide exhibits multiple biological activities, such as immune regulation, antioxidation, and antitumor. However, its resistance to viral infection by stimulating immunity is rarely reported. In this study, we explored the effect and mechanism of DVP-1, a novel polysaccharide from Dendrobium devonianum, in the activation of immunity. After being activated by DVP-1, the ability of mice to prevent H1N1 influenza virus infection was investigated. Results of immune regulation showed that DVP-1 significantly improved the immune organ index, lymphocyte proliferation, and mRNA expression level of cytokines, such as IL-1β, IL-4, IL-6, and TNF-α in the spleen. Immunohistochemical results showed that DVP-1 obviously promoted the mucosal immunity in the jejunum tissue. In addition, the expression levels of TLR4, MyD88, and TRAF6 and the phosphorylation levels of TAK1, Erk, JNK, and NF-κB in the spleen were upregulated by DVP-1. The virus infection results showed that the weight loss of mice slowed down, the survival rate increased, the organ index of the lung reduced, and the virus content in the lung decreased after DVP-1 activated immunity. By activating immunity with DVP-1, the production of inflammatory cells and inflammatory factors in BALF, and alveolar as well as peribronchiolar inflammation could be prevented. The results manifested that DVP-1 could resist H1N1 influenza virus infection by activating immunity through the TLR4/MyD88/NF-κB pathway.

The regulation of ISG20 expression on SARS-CoV-2 infection in cancer patients and healthy individuals.

ISG20 inhibits viruses such as SARS-CoV-2 invasion; however, details of its expression and regulation with viral susceptibility remain to be elucidated. The present study analyzed ISG20 expression, isoform information, survival rate, methylation patterns, immune cell infiltration, and COVID-19 outcomes in healthy and cancerous individuals. Cordycepin (CD) and N6, N6-dimethyladenosine (m6 2A) were used to treat cancer cells for ISG20 expression. We revealed that ISG20 mRNA expression was primarily located in the bone marrow and lymphoid tissues. Interestingly, its expression was significantly increased in 11 different types of cancer, indicating that cancer patients may be less vulnerable to SARS-CoV-2 infection. Among them, higher expression of ISG20 was associated with a long OS in CESC and SKCM, suggesting that ISG20 may be a good marker for both viral prevention and cancer progress. ISG20 promoter methylation was significantly lower in BLCA, READ, and THCA tumor tissues than in the matched normal tissues, while higher in BRCA, LUSC, KIRC, and PAAD. Hypermethylation of ISG20 in KIRC and PAAD tumor tissues was correlated with higher expression of ISG20, suggesting that methylation of ISG20 may not underlie its overexpression. Furthermore, ISG20 expression was significantly correlated with immune infiltration levels, including immune lymphocytes, chemokine, receptors, immunoinhibitors, immunostimulators, and MHC molecules in pan-cancer. STAD exhibited the highest degree of ISG20 mutations; the median progression-free survival time in months for the unaltered group was 61.84, while it was 81.01 in the mutant group. Isoforms ISG20-001 and ISG20−009 showed the same RNase_T domain structure, demonstrating the functional roles in tumorigenesis and SARS-CoV-2 invasion inhibition in cancer patients. Moreover, CD and m6 2A increase ISG20 expression in various cancer cell lines, implying the antiviral/anti-SARS-CoV-2 therapeutic potential. Altogether, this study highlighted the value of combating cancer by targeting ISG20 during the COVID-19 pandemic, and small molecules extracted from traditional Chinese medicines, such as CD, may have potential as anti-SARS-CoV-2 and anticancer agents by promoting ISG20 expression.