Immunocompetent Research Articles

Review of the potential value of serum interleukin levels as prognostic biomarkers of liver failure.

Liver failure (LF) is prevalent in China and is characterized by complex pathogenesis, challenging clinical management, poor prognosis, and rising incidence and mortality rates. The immune status is an important factor affecting LF prognosis. Interleukins (Ils) are a type of cytokine that act and interact with multiple cells, including immune cells. These signaling molecules play important roles in intercellular information transmission, including the regulation of immune cells; mediation of the activation, proliferation, and differentiation of T and B cells; and orchestration of the inflammatory response. To date, many studies have explored the correlation between IL expression and liver disease prognosis, but few studies have evaluated Ils as the prognostic biomarkers of LF. This article reviews the potential use of Ils as the prognostic biomarkers of LF. Particularly, it evaluates the predictive values of IL-21, IL-22, and IL-31, the three often overlooked yet promising prognostic biomarkers, in predicting susceptibility to LF. Harnessing biomarkers for early prognostic insights can facilitate tailored treatment strategies and enhance patient survival. Thus, this article focuses on the identification of IL-21, IL-22, and IL-33 as biomarkers in preclinical and clinical studies on LF and reviews their role as biomarkers in the pathogenesis and diagnosis of LF.

Tuft cells in the intestine, immunity and beyond.

Tuft cells have gained substantial attention over the past 10 years due to numerous reports linking them with type 2 immunity and microorganism-sensing capacity in many mucosal tissues. This heightened interest is fuelled by their unique ability to produce an array of biological effector molecules, including IL-25, allergy-related eicosanoids, and the neurotransmitter acetylcholine, enabling downstream responses in diverse cell types. Operating through G protein-coupled receptor-mediated signalling pathways reminiscent of type II taste cells in oral taste buds, tuft cells emerge as chemosensory sentinels that integrate luminal conditions, eliciting appropriate responses in immune, epithelial and neuronal populations. How tuft cells promote tissue alterations and adaptation to the variety of stimuli at mucosal surfaces has been explored in multiple studies in the past few years. Since the initial recognition of the role of tuft cells, the discovery of diverse tuft cell effector functions and associated feedback loops have also revealed the complexity of tuft cell biology. Although earlier work largely focused on extraintestinal tissues, novel genetic tools and recent mechanistic studies on intestinal tuft cells established fundamental concepts of tuft cell activation and functions. This Review is an overview of intestinal tuft cells, providing insights into their development, signalling and interaction modules in immunity and other states.

Identifying genetic variants that influence the abundance of cell states in single-cell data.

Disease risk alleles influence the composition of cells present in the body, but modeling genetic effects on the cell states revealed by single-cell profiling is difficult because variant-associated states may reflect diverse combinations of the profiled cell features that are challenging to predefine. We introduce Genotype-Neighborhood Associations (GeNA), a statistical tool to identify cell-state abundance quantitative trait loci (csaQTLs) in high-dimensional single-cell datasets. Instead of testing associations to predefined cell states, GeNA flexibly identifies the cell states whose abundance is most associated with genetic variants. In a genome-wide survey of single-cell RNA sequencing peripheral blood profiling from 969 individuals, GeNA identifies five independent loci associated with shifts in the relative abundance of immune cell states. For example, rs3003-T (P = 1.96 × 10-11) associates with increased abundance of natural killer cells expressing tumor necrosis factor response programs. This csaQTL colocalizes with increased risk for psoriasis, an autoimmune disease that responds to anti-tumor necrosis factor treatments. Flexibly characterizing csaQTLs for granular cell states may help illuminate how genetic background alters cellular composition to confer disease risk.

Head of state immunity, order, justice and the international criminal court: limits of international criminal justice in international society

Head of state immunity, order, justice and the international criminal court: limits of international criminal justice in international society

Assessment of immune status markers during occupational lead exposure

The immune system is sensitive to the effects of environmental factors, and according to numerous studies, lead has an immunotoxic effect. At the same time, there is evidence of the multidirectional nature of the impact of lead on the immune system, determined by the degree of exposure to this heavy metal, which makes it current to study changes in immunological markers in workers of a modern lead recycling plant, taking into account levels and complexity of exposure. In the era of personalized medicine, monitoring the potential influence of occupational factors exposure on the immune system can facilitate a personalized approach to the prevention of work-related health conditions. The aim of the study: to evaluate changes in immune status markers among employees of lead recycling plant. The main group – 62 men working at a lead recycling plant, the control group – 47 men not exposed to occupational factors. Laboratory examination included a determination of the lead blood level, a clinical blood test, the serum levels of IL- 1â, IL- 10, IL- 8, MCP-1, C3 and C4 complement components, IgA, IgM, IgG. In the main group, compared to the control group, a higher number of neutrophils, lymphocytes, monocytes, higher levels of IL-8, C3 and C4 components of the complement system, and lower levels of IgM were detected. In the main group, the following changes in markers were significantly more often detected in comparison with reference values: an increase in the C3 component of complement (51.6% in the main group compared to 12.5% in the control group), decreased IgG (24.2% compared to 6.2%) and increased IgA (22.6% compared to 6.2%). Associations were identified between the lead blood level and the number of lymphocytes, the level of IgG, between work experience in contact with lead and the level of MCP-1 and C3 complement components. The results of the studies revealed the presence of changes in the immune status markers of workers at a lead recycling plant, which demonstrate a proinflammatory effect of lead and an influence on the humoral immune status. The identified changes in immunological parameters may underlie the mechanisms of formation of pathological conditions associated with lead exposure, which determines the relevance of continuing research to assess dynamic changes in immunological parameters and develop a system for monitoring the immune status of workers exposed to lead and its compounds to optimize preventive measures.

Torque Teno Virus Loads as a Marker of Immunosuppression in Pediatric Kidney Transplant Recipients.

Long-term renal function and survival after kidney transplantation rely on appropriate immunosuppressive treatment to prevent the risk of rejection. New biomarkers are needed to accurately assess the degree of immunosuppression in renal transplant recipients in order to avoid organ rejection and the development of opportunistic infections. Highly prevalent in humans, torque teno virus (TTV), which belongs to the family Anelloviridae, is a small, nonenveloped, single-stranded DNA virus which has not been linked with any specific human illness, but which constitutes a major component of the human virome. Host antiviral responses allow TTV levels to be controlled; however, viral persistence remains, explaining the high prevalence in human populations, including healthy individuals. Important confounders of TTV load include time since transplantation, age, gender, obesity, and smoking status. TTV-based guidance of immunosuppressive drug dosing could help with risk stratification, reducing the risk of infection, graft rejection and oncologic disease on an individual level, enabling long-term patient and graft survival. Original studies were accessed by a systematic search from electronic databases including PubMed, ScienceDirect and Wiley Online Library. The presented data mainly derive from adult transplant recipients showing an association between TTV plasma levels and the immune status of the host: High-TTV load and high immunosuppression are associated with a risk of infection, and low-TTV load and low immunosuppression indicate a risk of rejection. However, there is minimal information on pediatric transplant recipients with further research required in this cohort. To date, it has been demonstrated that longer posttransplant times are significantly associated with lower TTV levels in children with renal transplant. Meanwhile, an association between lower TTV loads and increased risk of graft reject during the first year of transplantation was also reported. More recently, Eibensteiner etal. revealed a robust, independent association between TTV plasma load and the onset of Cytomegalovirus and BK virus infections. Data from randomized controlled trials are still missing, even in adults, but a multicenter randomized controlled trial for TTV-guided immunosuppression in adult kidney recipients (TTVguideIT) began in 2022. There is, therefore, great promise for TTV levels to be used as a biomarker that could potentially improve both graft and patient survival in transplantation.

Clinical and immunological characteristics of post-covid patients with infectious immunopathology syndrome

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has caused global morbidity and high mortality worldwide. Today it is known that, despite recovery from COVID-19, confirmed by both laboratory and instrumental diagnostic methods, many patients, regardless of the severity of the disease, suffer from a significant deterioration in health and increased exacerbations of chronic diseases. During examinations by attending physicians, they note fatigue, an increase in cases of acute respiratory viral infections per year, an increase in relapses of skin diseases such as furunculosis, pyoderma, exacerbation of pulmonary pathologies, pathologies of the urinary tract of inflammatory origin, as well as chronic infectious diseases such as herpesvirus and human papillomavirus infections, which occur for the first time or are characterized by frequent relapses no less than six months after recovery from acute COVID-19. Such persistent post-infectious consequences are known as post-COVID syndrome. SARS-CoV-2 infection is accompanied by damage to both the acquired and innate immune systems. In previous work, we determined the role of B cells, cytotoxic T lymphocytes, natural killer cells and the regulatory properties of CD46, as well as its involvement in the processes of viral entry into the cell. In this study, we studied the relationship of immune disorders of these factors of innate and acquired immunity with the clinical manifestations of post-COVID infectious syndrome in this category of patients and the severity of lung damage in these patients during the acute period of COVID-19. The results of the study showed that in some patients more than six months after suffering from COVID-19, the following was revealed: in patients who had a coronavirus infection without lung damage, no violations of the innate and acquired parts of the immune system were detected. In addition, significant differences were identified between clinical manifestations of diseases with increasing cases of relapses or newly identified after clinical recovery from an acute COVID-19 infection, depending on the phenotype of immune status disorders.

Meningococcal Carriage in Children with Atypical Hemolytic Uremic Syndrome Receiving Eculizumab Therapy.

Eculizumab is a first-line treatment for atypical hemolytic uremic syndrome (aHUS), and patients undergoing eculizumab therapy may become more susceptible to infection caused by Neisseria meningitidis (Nm). While meningococcal vaccination is required for patients undergoing eculizumab therapy, there is limited knowledge about meningococcal carriage in children with aHUS. We aimed to evaluate (1) the prevalence of Nm carriage, (2) serogroup distribution, and (3) the immunization status of children undergoing eculizumab treatment for aHUS. The Meningo-aHUS study is a prospective, multi-center study evaluating meningococcal carriage in children and adolescents in Türkiye receiving eculizumab for aHUS. We noted the age, gender, daycare, school, or university attendance, passive smoking status, previous infection and antibiotic use, and previous immunization history, including meningococcal vaccines, from the medical records of those children with aHUS. We collected nasopharyngeal samples, tested them for Nm using real-time polymerase chain reaction, and performed a serogroup analysis on the positive samples. We collected nasopharyngeal samples from 62 children with aHUS. Out of 62 children, 61 (98.4%) had received at least one dose of the meningococcal vaccine. The median time since the last meningococcal vaccine dose was 15 months (1-59 months). We detected meningococcal carriage in three (4.8%, 95% CI 1.0-13.5) children, and all three strains were non-groupable (NG). No other serogroups were detected. Almost all the children received their risk-group meningococcal immunization, including booster doses. A 4.8% of children with aHUS carried NG meningococci and, no vaccine serogroups were detected. Patients treated with eculizumab remain profoundly susceptible to IMD due to these NG meningococcal strains. The occurrence of breakthrough cases and carriage of Nm, especially NG strains, highlights the significance of maintaining a state of constant alertness, promptly seeking medical attention, and swiftly treating any symptoms that align with IMD, regardless of their vaccination status or antibiotic prophylaxis.

Immune status of students with different levels of physical activity

The nature of changes in the immune system during physical work is a complex process involving many different mechanisms. Research in this direction is an urgent problem. The purpose of the research was to study the indicators of cellular and humoral immunity in students with different levels of physical activity. A total of 77 male students were examined, consisting of 3 groups: 1) with a low level of physical activity (n = 32) – students who were not involved in sports activities on a regular basis; 2) students with an average level of physical activity (n = 22) – beginner sambo wrestlers without sports categories; and 3) students with a high level of physical activity (n = 23) – highly qualified sambo wrestlers – first-class athletes, candidates for masters and masters of sports. In students of all groups, the quantitative content of various phenotypes of lymphocytes in the blood was studied by flow cytometry; serum immunoglobulin levels by laser nephelometry; phagocytic parameters by traditional methods; and oxygen-dependent metabolism of neutrophils by chemiluminescence. In students with a high level of physical activity, the content of T and B lymphocytes in the blood was significantly increased compared to similar indicators of the group with a low level of physical activity and the group of students who did not participate in sports. The concentration of class G immunoglobulin in the blood serum of students with a high level of physical activity significantly exceeded the corresponding values in students with an average level and students not engaged in sports. The highest concentration of class M immunoglobulin was observed in students with high levels of physical activity. Phagocytic activity and phagocytic count in individuals with high levels of physical activity and neutrophils were significantly higher than those of students with medium and low levels of physical activity. The rates of spontaneous and induced chemiluminescence in the groups with high and medium levels of physical activity were significantly higher than in students with low levels. The studies carried out indicate the positive effect of regular training physical activity on the factors of humoral and cellular links of immunity in students in the conditions of the educational environment of a higher educational institution.

Phylogenetic position of the pigeon mite, Ornithonyssus sylviarum, with amplification of its immunogenetic biomarkers in Egypt

Ornithonyssus sylviarum (O. sylviarum) is an obligatory, blood-sucking ectoparasite widely distributed among poultry and other mammals, causing significant economic losses. This study represented the first report of molecular genotypic identification of O. sylviarum from pigeons, Columba livia domestica, in Egypt. PCR and sequencing of the 28S rRNA gene were conducted. The resulting mite sequences were subjected to BLAST analysis, revealing 90–100% similarity to O. sylviarum in all tested samples. The sequences were deposited in GenBank under the accession numbers PP049086 and PP033720. A phylogenetic tree was constructed to compare the obtained species with related species worldwide. Additionally, infected pigeons showed increased expression of IL-1, IL-10, IFN-γ, and TGF-β3 genes and elevated serum levels of stress biomarkers. The increased level of these cytokines indicates there was a disturbance in the immune status of the infected host with parasite compared with control healthy ones. This increases the susceptibility to infection with other pathogens.

Construction of an endoplasmic reticulum stress and cuproptosis -related lncRNAs signature in chemosensitivity in hepatocellular carcinoma by comprehensive bioinformatics analysis

Endoplasmic reticulum stress (ERS) and cuproptosis have remarkable effects on hepatocellular carcinoma (HCC) leading to a poor prognosis. The current study aimed to explore credible signature for predicting the prognosis of HCC based on ERS and cuproptosis-related lncRNAs. In our study, clinical and transcriptomic profiles of HCC patients were obtained from the Cancer Genome Atlas (TCGA) database. An ERS and cuproptosis-related lncRNA prognostic signature, including NRAV, SNHG3, LINC00839 and AC004687.1, was determined by correlation tests, Cox regression analysis, least absolute shrinkage, and selection operator (LASSO) methods. Survival and predictive value were evaluated using Kaplan–Meier and receiver operating characteristic (ROC) curves, while calibration and nomograms curves were developed. Besides the enrichment analyses for ERS and cuproptosis-related lncRNAs, mutational status and immune status were assessed with TMB and ESTIMATE. Additionally, consensus cluster analysis was employed to compare cancer subtype differences, while drug sensitivity and immunologic efficacy were evaluated for further exploration. qRT-PCR and CCK-8 were utilized to verify the alteration of the prognostic lncRNAs expression and proliferation in vitro. High-risk groups exhibited poorer prognosis. The signature exhibited robust predictive value as an independent prognostic indicator and showed significant correlation with clinicopathological features. In the enriched analysis, biological membrane pathways were enriched. Low-risk patients had lower TMB and higher immune status. A cluster analysis revealed that cluster 2 had the best clinical immunological efficacy and most active immune function. In brief, our constructed signature with ERS and cuproptosis-related lncRNAs was associated survival outcomes of HCC, and can be used to predict the clinical classification and curative effect.

Study of extended homozygous chromosome regions in Italian partridge breed of chickens

Selection and accompanying inbreeding are the basis for breeding chicken breeds. With the advent of modern molecular methods for assessing inbreeding, it has become possible to identify genes and their functions in the homozygous regions (ROH) of chicken chromosomes. In this study, a genome-wide analysis of homozygous regions of chromosomes in Italian partridge chickens was carried out using an SNP chip Illumina Chicken 60KSNPiSelectBeadChipchip. An average of 177 ± 5 ROH-sequences per chicken were identified in the chicken chromosomes, and the average inbreeding coefficient was 0.30 ± 0.01. It was determined that the chicken genome is dominated by short ROH-sequences of 0.25–2 Mbp. ROH-sequences longer than 8 Mbp indicating recent inbreeding account for no more than 2.2%. It was found that, in general, ROH-sequences are more densely distributed in chicken microchromosomes, with the exception of chromosome 16, which does not have ROH-sequences. This fact is due to the heterozygosity of the alleles of the genes responsible for immunity, located in microchromosome 16. ROH-islands were found in the chicken chromosomes 1, 5, and 14. The genes in ROH-islands are responsible for feather pecking in chickens (DMD gene), immune status (TAB3, EIF2S3 genes), body weight (IL1RAPL1 gene), pH of meat (EIF2S3, APOO, KLHL15 genes), egg production (APOO gene), feed uptake (SAT1 gene), aggressiveness of roosters (SLITRK6 gene), transport of intracellular components in developing neurons and protection of heterochromatin in the cell nuclei of neurons (NDE1 gene), adaptation of chickens to tropical living conditions (CDIN1 gene). Thus, ROH analysis allowed us to identify genes potentially selectable as a result of breeding Italian partridge breed chickens.

Evaluation of prognostic efficacy of liver immune status index in predicting postoperative outcomes in hepatocellular carcinoma patients: A multi-institutional retrospective study.

Hepatocellular carcinoma (HCC) ranks third in cancer-related deaths globally. Despite treatment advances, high post-hepatectomy recurrence rates (RR), especially with liver fibrosis and hepatitis C virus infection, remain challenging. Key prognostic factors include vascular invasion and perioperative blood loss, impacting extrahepatic recurrence. Natural killer (NK) cells are crucial in countering circulating tumor cells through TRAIL-mediated pathways. The aim of this study was to validate the liver immune status index (LISI) as a predictive tool for liver NK cell antitumor efficiency, particularly in HCC patients with vascular invasion. A retrospective analysis of 1337 primary HCC hepatectomies was conducted by the Hiroshima Surgical Study Group of Clinical Oncology (HiSCO). Clinicodemographic data were extracted from electronic medical records. Prognostic indices (FIB-4, ALBI, ALICE, GNRI, APRI, and LISI) were evaluated using area under the receiver operating characteristic curve values. Survival analyses employed Kaplan-Meier estimations and log-rank tests. LISI significantly correlated with other prognostic markers and stratified patients into risk groups with distinct overall survival (OS) and RR. It showed superior predictive performance for 2-year OS and RR, especially in patients with vascular invasion. Over longer periods, APRI and FIB-4 index reliabilities improved. The HISCO-HCC score, combining LISI, tumor burden score, and alpha-fetoprotein levels, enhanced prognostic accuracy. LISI outperformed existing models, particularly in HCC with vascular invasion. The HISCO-HCC score offers improved prognostic precision, guiding immunotherapeutic strategies and individualized patient care in HCC.

IL15/IL15Rα complex induces an anti-tumor immune response following radiation therapy only in the absence of Tregs and fails to induce expansion of progenitor TCF1+ CD8 T cells.

This work seeks to understand whether IL15-incorporating treatments improve response to radiotherapy and uncover mechanistic rationale for overcoming resistance to IL15 agonism using novel therapeutic combinations. Orthotopic tumor models of PDAC were used to determine response to treatment. IL15-/- and Rag1-/- mouse models were employed to determine dependence on IL15 and CTLs, respectively. Flow cytometry was used to assess immune cell frequency and activation state. Phospho-proteomic analyses were used to characterize intracellular signaling pathways. We show that the combination of radiation therapy (RT) and an IL15/IL15Ra fusion complex (denoted IL15c) fails to confer anti-tumor efficacy; however, a CD8-driven anti-tumor immune response is elicited with the concurrent administration of an aCD25 Treg-depleting antibody. Using IL15-/- and Rag1-/- mice, we demonstrate that response to RT + IL15c + aCD25 is dependent on both IL15 and CTLs. Furthermore, despite an equivalent survival benefit following treatment with RT + IL15c + aCD25 and combination RT + PD1-IL2v, a novel immunocytokine with PD-1 and IL2Rβγ binding domains, CTL immunophenotyping and phospho-proteomic analysis of intracellular metabolites showed significant upregulation of activation and functionality in CD8 T cells treated with RT + PD1-IL2v. Finally, we show the immunostimulatory response to RT + PD1-IL2v is significantly diminished with a concurrent lack of TCF+ CD8 T cell generation in the absence of functional IL15 signaling. Our results are illustrative of a mechanism wherein unimpeded effector T cell activation through IL2Rβ signaling and Treg inhibition are necessary in mediating an anti-tumor immune response.

Oncolytic adenovirus encoding decorin and CD40 ligand inhibits tumor growth and liver metastasis via immune activation in murine colorectal tumor model

Colorectal cancer (CRC) is the second common cause of cancer mortality worldwide, and it still lacks effective approaches for relapsed and metastatic CRC. Recently, oncolytic virus has been emerged as a promising immune therapeutic strategy. In this study, we develop a novel oncolytic adenovirus, rAd.mDCN.mCD40L, which drive oncolytic activity by telomerase reverse transcriptase promoter (TERTp). rAd.mDCN.mCD40L expressed both mouse genes of decorin (mDCN) and CD40 ligand (mCD40L), and produced effective cytotoxicity in both human and mouse CRC cells. Moreover, oncolytic adenovirus mediated mDCN over-expression inhibited Met expression in vitro. In CT26 subcutaneous tumor model, intratumorally delivery of oncolytic adenoviruses could inhibit tumor growth and liver metastasis, while mDCN and/or mCD40L armed oncolytic adenoviruses produced much more impressive responses. No obvious toxicity was detected in lung, liver and spleen. Moreover, mDCN and/or mCD40L armed oncolytic adenoviruses altered the immune state to activate anti-tumor responses, including increasing CD8+ T effector cells and CD4+ memory T cells, reducing MDSCs and Tregs in peripheral blood. Furthermore, mDCN and/or mCD40L armed oncolytic adenoviruses mediated mDCN and/or mCD40L expression in tumors, and up-regulated Th1 cytokines and reduced Th2 cytokines in tumors, which will be benefit for remodeling tumor microenvironment. Importantly, rAd.mDCN.mCD40L and rAd.mCD40L prevented tumor liver metastasis much more effectively than rAd.Null and rAd.mDCN. Therefore, rAd.mDCN.mCD40L and rAd.mCD40L are promising approaches for CRC therapy.

A Retrospective Study of the Profiles of Outpatients Attending the State Adolescent Friendly Health Resource Center, Andhra Pradesh, South India.

Adolescents compose a significantly large age group, and attention to their health needs is lacking due to insufficient data and policy implementation globally and in India. India, having 268 million adolescents, faces the world's largest adolescent population, which highlights the importance of addressing their health requirements. The aim of this study was to describe the morbidity profiles of adolescent patients attending the State Adolescent Friendly Health Resource Centre at a tertiary-level healthcare institution in South India. A retrospective secondary data analysis was conducted at the State Adolescent Friendly Health Resource Center from 2022 to 2023. Data on adolescent health were collected from this center's OPD using a structured questionnaire, which included information on demographics, immunization status, chief complaints, and dietary intake. Diagnosis coding was done using the International Classification of Diseases, Tenth Revision (ICD-10), with estimated energy and protein intake. The study analyzed 4,000 adolescent patients, with a nearly equal gender distribution across physical OPD and telemedicine services. Adolescent females between 15 and 16 years had more visits for consultation. Most patients were within the normal BMI range, and telemedicine was popular among females with normal BMI. Obesity was more common in males, while overweight was prevalent in females. Energy and protein intake varied across BMI categories, with obese individuals having the highest intake. The morbidity profiles revealed significant gender differences in healthcare utilization and disease patterns. Gender differences in adolescent morbidity and the underutilization of telemedicine highlight the need for tailored healthcare interventions and further research based on socioeconomic factors.

Integrated GMPS and RAMP3 as a signature to predict prognosis and immune heterogeneity in hepatocellular carcinoma

BackgroundHepatocellular carcinoma (HCC) is a highly fatal malignant worldwide. As different expression levels of specific genes can lead to different HCC outcomes, we aimed to develop a gene signature capable of predicting HCC prognosis. MethodsIn this study, transcriptomic sequencing and relevant clinical data were extracted from public platforms. The guanine monophosphate synthase (GMPS)|receptor activity-modifying protein 3 (RAMP3) gene pair was developed based on the relative values of gene expression levels. Nomograms were developed using R software. Immune status was assessed through single‐sample gene set enrichment analysis. GMPS knockdown was achieved through siRNA transfection. Quantitative reverse transcription PCR, apoptosis assays, and cell proliferation were performed to verify the function of GMPS|RAMP3 in HCC cells. ResultsHere, a gene pair containing GMPS and RAMP3 was successfully constructed. We demonstrated that the GMPS|RAMP3 gene pair was an independent predictor with strong prognostic prediction power, based on which a nomogram was established. Functional analysis revealed that the enrichment of cell cycle-related pathways and immune status differed considerably between the two groups, with cell cycle-related genes highly expressed in the high GMPS|RAMP3 value group. Finally, cell experiments indicated that GMPS knockdown significantly repressed proliferation, promoted apoptosis, and enhanced the sensitivity of HCC cells to gemcitabine. ConclusionsThe gene pair GMPS|RAMP3 is a novel prognostic predictor of HCC, providing a promising approach to the treatment and assessment of immune heterogeneity in HCC.

Expression of immune checkpoint markers in peripheral blood lymphocytes of women with fibroadenoma of the breast

Changes of the immune state in patients with fibroadenoma (FA) or other benign lesions of the breast, as well as the involvement of immune checkpoints in pathogenesis of these lesions, remain underexplored. The aim of this study was to compare the expression level of the key immune checkpoint markers CD279/PD-1, CD274/PD-L1, CD366/TIM3, and CD223/LAG3 in total circulating lymphocytes, T cell population as well as in its CD4 and CD8 subsets in peripheral blood from women with breast FA and healthy controls. Blood samples were taken from 12 women diagnosed with FA of the breast (aged 23-54 years, FA group) and 15 healthy women (aged 22-52 years, control group). Sample uptake was performed immediately before surgery, and samples were further analyzed by multicolor flow cytometry using monoclonal antibodies CD3-VioBlue, CD4/CD8-FITC, PD1-PE, PD-L1-PerCP-Cy.5.5, and TIM3/LAG3-APC. Each sample was incubated with 4 antibody combinations: CD3/CD4/PD1/PD-L1/TIM3, CD3/CD4/PD1/PD-L1/LAG3, CD3/CD8/PD1/PD-L1/TIM3, and CD3/CD8/PD1/PD-L1/LAG3. First, mono-expression of each of the 4 immune checkpoint markers was evaluated in the lymphocyte gate from both investigated groups. In FA samples, a significant increase in PD-L1 expression (assessed as percent of positive cells and fluorescence intensity change) was observed. Regarding expression of immune checkpoints in CD3+ T cells, along with significantly increased %PD-L1+, elevated numbers of PD1+T cells were detected. As for the differences in immune checkpoint expression changes between CD4+ and CD8+ T cell subsets, FA patient group demonstrated a more prominent increase in the amount of CD8+PD1+T cells relative to CD4 subset. The profiles of PD-L1 changes in CD4 and CD8 subpopulations were comparable showing, in both cases, a significant increase in FA sample group. We also analyzed changes in co-expression of any two immune checkpoint markers in CD4+ and CD8+ T cell subsets. The most noticeable was as increase in the prevalence of PD1+PD-L1+ phenotype in both T cell subpopulations from FA patients compared to the controls. With respect to co-expression of 3 checkpoint markers in CD4+ and CD8+ T cells, a significant increase in the percentage of PD1+PD-L1+TIM3+ cells among CD4 T helpers was found in FA. Thus, specific changes of T cell phenotype related to (co-)expression of immune checkpoint regulators may occur in systemic circulation of women with breast FA.

The impact of plant cryoextract on productivity and factors of innate immunity of pond fish against the background of stress in the experiment

The search for effective and environmentally friendly means to increase the productivity and natural resistance of animals, especially in aquaculture, remains an urgent socio-economic task. This article presents the results of the study of the effect of the cryobiological supplement ‘Immunolife-Fish’, based on medicinal plants, on the weight gain of juvenile common carp (Cyprinus carpio) and indicators of innate immunity of two-year-old common carp (Cyprinus carpio) and silver carp (Hypophthalmichthys molitrix) under the influence of thermal stress factor in aquarium conditions. It was found that the weight gain of juvenile carp treated with the cryobiological supplement ‘Immunolife-Fish’ was higher than that of the control group at all stages of the study. The increase was most pronounced during the first 42 days of feeding. A significant increase in the number of leukocytes was found in the blood of fish (common carp and silver carp) exposed to a heat stressor compared to control values. In fish that received a supplement of the herbal preparation during stress, this indicator only tended to increase. The effect of the stressor in fish of both species is manifested by a significant increase in the leukocyte content, a decrease in the indicators characterizing the functional state of cellular immunity — phagocytic activity and number of phagocytes, as well as a tendency to decrease the phagocytic index of neutrophils in the blood. The use of the cryobiological supplement ‘Immunolife-Fish’ in fish exposed to stress not only prevented the decrease in the phagocytic activity of neutrophils but also contributed to a slight increase in their activity in comparison with the control. A significant decrease in the activity of lysozyme and the level of circulating immune complexes, as well as an increase in the content of seromucoids, was found in the blood serum of common and silver carp under the influence of the stress factor. The use of the drug against the background of stress leveled the negative changes in the above indicators characterizing the state of the humoral link of innate immunity. In addition, a mild immune stimulating effect of the cryobiological supplement on fish of both species, which were kept in optimal conditions, was noted. The research is aimed at the development and testing of organic, environmentally friendly anti-stress and immunostimulant agents in commercial fish farming

Repeated LPS induces training and tolerance of microglial responses across brain regions

BackgroundNeuroinflammation is involved in the pathogenesis of almost every central nervous system disorder. As the brain’s innate immune cells, microglia fine tune their activity to a dynamic brain environment. Previous studies have shown that repeated bouts of peripheral inflammation can trigger long-term changes in microglial gene expression and function, a form of innate immune memory.Methods and resultsIn this study, we used multiple low-dose lipopolysaccharide (LPS) injections in adult mice to study the acute cytokine, transcriptomic, and microglia morphological changes that contribute to the formation of immune memory in the frontal cortex, hippocampus, and striatum, as well as the long-term effects of these changes on behavior. Training and tolerance of gene expression was shared across regions, and we identified 3 unique clusters of DEGs (2xLPS-sensitive, 4xLPS-sensitive, LPS-decreased) enriched for different biological functions. 2xLPS-sensitive DEG promoters were enriched for binding sites for IRF and NFkB family transcription factors, two key regulators of innate immune memory. We quantified shifts in microglia morphological populations and found that while the proportion of ramified and rod-like microglia mostly remained consistent within brain regions and sexes with LPS treatment, there was a shift from ameboid towards hypertrophic morphological states across immune memory states and a dynamic emergence and resolution of events of microglia aligning end-to-end with repeated LPS.ConclusionsTogether, findings support the dynamic regulation of microglia during the formation of immune memories in the brain and support future work to exploit this model in brain disease contexts.