Immune System Interactions Research Articles

Immune system activation and cognitive impairment in arterial hypertension.

Chronic arterial hypertension disrupts the integrity of the cerebral microvasculature, doubling the risk of age-related dementia. Despite sufficient antihypertensive therapy, in still a significant proportion of individuals blood pressure lowering alone does not preserve cognitive health. Accumulating evidence highlights the role of inflammatory mechanisms in the pathogenesis of hypertension. In this review, we introduce a temporal framework to explore how early immune system activation and interactions at neurovascular-immune interfaces pave the way to cognitive impairment. The overall paradigm suggests that pro-hypertensive stimuli induce mechanical stress and systemic inflammatory responses that shift peripheral and meningeal immune effector mechanisms towards a pro-inflammatory state. Neurovascular-immune interfaces in the brain include a dysfunctional blood-brain barrier, crossed by peripheral immune cells; the perivascular space, in which macrophages respond to cerebrospinal fluid- and blood-derived immune regulators; and the meningeal immune reservoir, particularly T cells. Immune responses at these interfaces bridge peripheral and neurovascular unit inflammation, directly contributing to impaired brain perfusion, clearance of toxic metabolites and synaptic function. We propose that deep immunophenotyping in biofluids together with advanced neuroimaging could aid in the translational determination of sequential immune and brain endotypes specific to arterial hypertension. This could close knowledge gaps on how and when immune system activation transits into neurovascular dysfunction and cognitive impairment. In the future, targeting specific immune mechanisms could prevent and halt hypertension disease progression before clinical symptoms arise, addressing the need for new interventions against one of the leading threats to cognitive health.

Gestational diabetes exacerbates intrauterine microbial exposure induced intestinal microbiota change in offspring contributing to increased immune response.

maternal health during pregnancy can affect the intestinal microbial community of offspring, but currently the impact of intrauterine environmental changes resulting from gestational diabetes mellitus (GDM) on the microbiota of offspring as well as its interaction with the immune system remains unclear. to explore the impact of intrauterine microbial exposure during pregnancy of gestational diabetes mellitus on the development of neonate's intestinal microbiota and activation of immune responses. Levels of lipopolysaccharides in cord blood from GDM and expression of microbial recognition-related proteins in the placenta were measured. To evaluate embryonic intestinal colonization, pregnant mice with GDM were administered with labeled Escherichia coli or Lactobacillus. The intestinal colonization of pups was analyzed through 16S rRNA gene sequencing and labeled microbial culture. Additionally, memory T lymphocyte and dendritic cell co-culture experiments were conducted to elucidate the immune memory of intestinal microbes during the embryonic stages. Gestational diabetes mellitus led to elevated umbilical cord blood LPS level and increased GFP labeled Escherichia coli in the offspring's intestine after gestational microbial exposure. The mouse model of GDM exhibited increased immune markers including TLR4, TLR5, IL-22 and IL-23 in the placenta and a recall response from memory T cells in offspring's intestines, with similar observations found in human experiments. Furthermore, reduced intestinal microbiome diversity and an increased ratio of Firmicutes/Bacteroidetes was found in GDM progeny, with the stability of bacterial colonization been interfered. Our investigation has revealed a noteworthy correlation between gestational diabetes and intrauterine microbial exposure, as well as alterations in the neonatal microbiota and activation of immune responses. These findings highlight the gestational diabetes's role on offspring's gut microbiota and immune system interactions with early-life pathogen exposure.

MEF2C is a Potential Prognostic Biomarker and is Correlated with Immune Infiltrates in Lung Adenocarcinoma.

The role of Myocyte Enhancer Factor 2 C (MEF2C) in lung adenocarcinoma (LUAD) is unclear. To address this gap in knowledge, we employed bioinformatics analysis and experimental validation in this study. This study investigated MEF2C expression across a spectrum of cancers, with a specific focus on lung adenocarcinoma (LUAD), utilizing Cancer Genome Atlas (TCGA) data to assess its potential as a diagnostic marker. The study also investigated correlations between MEF2C expression and clinical traits and prognostic indicators of LUAD. Additionally, this study also delved into the regulatory mechanisms of MEF2C, examining its connections to immune system interactions, immune checkpoint genes, tumor mutational burden (TMB), and the sensitivity of LUAD to various drugs. Through single-cell sequencing of LUAD cells and genetic variation of MEF2C in LUAD, we explored the expression of MEF2C in cell lines and verified it by quantitative real-time PCR (qRT-PCR). MEF2C exhibited aberrant expression in both pan-cancer and LUAD. In individuals with LUAD, diminished levels of MEF2C expression were notably linked to the effectiveness of primary therapy outcome (p = 0.025), gender (p < 0.001), and the subdivision of anatomic neoplasms 2 (p = 0.011). A decline in MEF2C levels was also found to be significantly related to reduced overall survival (OS) in LUAD patients (p = 0.026). The presence of MEF2C was recognized as a standalone factor predictive of prognosis in LUAD (p = 0.029). MEF2C was found to be involved in multiple biological pathways, such as those involving cell adhesion molecules. Additionally, its expression was correlated with the extent of immune cell presence, the activity of immune checkpoint genes, and TMB in LUAD. Notably, an inverse relationship was observed between MEF2C expression and the sensitivity to several agents, including Topotecan, Irinotecan, Panobinostat, Nilotinib, and Tp38-279, within the context of LUAD. Furthermore, MEF2C was found to be significantly negatively regulated in LUAD cell lines. The results imply that MEF2C could be a valuable indicator for predicting outcomes and a possible target for immunotherapy for LUAD patients.

Association between blood total mercury and psoriasis: The NHANES 2005-2006 and 2013-2014: A cross-sectional study.

An inflammatory skin condition called psoriasis results from immune system interactions that are out of balance. Reactive oxygen species are produced as a general mechanism of mercury toxicity. This study aimed to determine whether there was an association between blood total mercury and psoriasis in US adults. Utilizing data from the National Health and Nutrition Examination Survey (NHANES) 2005-2006 and 2013-2014. NHANES is a national research survey program every two years to assess the population's nutritional and physical health. The relationship between blood total mercury and psoriasis was studied using multivariable logistic regression models and smooth curve fitting. Subgroup analysis and interaction tests were used to investigate if this association was stable across populations. After adjusting for several factors, we found a positive association between blood total mercury and psoriasis in 6086 participants. According to the fully adjusted model, each 1-unit increase in blood total mercury was associated with an 8% increase in the prevalence of psoriasis [1.08 (1.03, 1.14)]. The favorable association seems to be more pronounced in non-diabetes. Our research shows a positive association between psoriasis and blood total mercury in US adults. The results of this study need to be supported by additional prospective research.

Unraveling molecular and clinical aspects of ALKBH5 as dual role in colorectal cancer.

This study investigates the dual role of ALKBH5, an eraser enzyme, in colorectal cancer (CRC), focusing on how N6-methyladenosine (m6A) mutations influence CRC development and progression. We reviewed various studies that highlighted the role of ALKBH5 in colorectal cancer (CRC). This includes the impact of ALKBH5 on tumor cell behavior including immune system interactions, invasion, and proliferation in CRC. We also looked into how ALKBH5 acts as a tumor suppressor under different conditions analyzed clinical data to assess the impact of ALKBH5 expression on outcomes in colorectal cancer patients. In CRC, ALKBH5 plays a dual role. In certain situations, it inhibits the progression of the tumor, but in other circumstances, it promotes tumor growth and immunosuppression. The interaction with RABA5 plays a role in the development of CRC. Having elevated levels of ALKBH5 has been associated with unfavorable patient outcomes, such as reduced survival rates and more advanced cancer stages. Various factors, including tumor differentiation, TNM stages, and carcinoembryonic antigen (CEA) levels, be linked to ALKBH5 expression. ALKBH5 plays a complicated and situation-specific role in colorectal cancer (CRC). Targeting ALKBH5 could result in novel therapy options that balance its tumor-promoting and tumor-fighting properties in CRC. Further research into m6A alterations and ALKBH5 could enhance CRC treatment approaches and patient outcomes.

Pseudorabies Virus Glycoproteins E and B Application in Vaccine and Diagnosis Kit Development.

Background: Pseudorabies virus (PRV) is a highly infectious pathogen that affects a wide range of mammals and imposes a significant economic burden on the global pig industry. The viral envelope of PRV contains several glycoproteins, including glycoprotein E (gE) and glycoprotein B (gB), which play critical roles in immune recognition, vaccine development, and diagnostic procedures. Mutations in these glycoproteins may enhance virulence, highlighting the need for updated vaccines. Method: This review examines the functions of PRV gE and gB in vaccine development and diagnostics, focusing on their roles in viral replication, immune system interaction, and pathogenicity. Additionally, we explore recent findings on the importance of gE deletion in attenuated vaccines and the potential of gB to induce immunity. Results: Glycoprotein E (gE) is crucial for the virus's axonal transport and nerve invasion, facilitating transmission to the central nervous system. Deletion of gE is a successful strategy in vaccine development, enhancing the immune response. Glycoprotein B (gB) plays a central role in viral replication and membrane fusion, aiding viral spread. Mutations in these glycoproteins may increase PRV virulence, complicating vaccine efficacy. Conclusion: With PRV glycoproteins being essential to both vaccine development and diagnostic approaches, future research should focus on enhancing these components to address emerging PRV variants. Updated vaccines and diagnostic tools are critical for combating new, more virulent strains of PRV.

Gene expression changes in Brodmann’s Area 46 differentiate epidermal growth factor and immune system interactions in schizophrenia and mood disorders

How early in life stress-immune related environmental factors increase risk predisposition to schizophrenia remains unknown. We examined if pro-inflammatory changes perturb the brain epidermal growth factor (EGF) system, a system critical for neurodevelopment and mature CNS functions including synaptic plasticity. We quantified genes from key EGF and immune system pathways for mRNA levels and eight immune proteins in post-mortem dorsolateral prefrontal (DLPFC; Brodmann’s Area (BA) 46) and orbitofrontal (OFC; BA11) cortices from people with schizophrenia, mood disorders and neurotypical controls. In BA46, 64 genes were differentially expressed, predominantly in schizophrenia, where attenuated expression of the MAPK-ERK, NRG1-PI3K-AKT and mTOR cascades indicated reduced EGF system signalling, and similarly diminished immune molecular expression, notably in TLR, TNF and complement pathways, along with low NF-κB1 and elevated IL12RB2 protein levels were noted. There was nominal evidence for altered convergence between ErbB-PI3K-AKT-mTOR and TLR pathways in BA46 in schizophrenia. Comparatively minimal changes were noted in BA11. Overall, distinct pathway gene expression changes may reflect variant pathological processes involving immune and EGF system signalling between schizophrenia and mood disorder, particularly in DLPFC. Further, the abnormal convergence between innate immune signalling and candidate EGF signalling pathways may indicate a pathologically important interaction in the developing brain in response to environmental stressors.

Rational Design of a Multi-epitope Vaccine Using Neoantigen Against Colorectal Cancer Through Structural Immunoinformatics and ML-Enabled Simulation Approach.

Colorectal cancer poses a substantial global health burden. Regarding WHO, the global burden of colorectal cancer will be about 3.2 million new cases by the year 2040. Simultaneously, it indicated that this cancer will cause 6 million deaths per year. Despite advancements in chemotherapy and monoclonal antibody therapy, the disease remains a significant challenge due to the resistance of cancer stem cells. This study endeavors to design a multi-epitopic peptide (9-mer epitopes) neoantigen-based vaccine targeting the TLR4/MD2 complex as a potential vaccine candidate. These tumor-specific neoantigens (TSA) are considered novel antigens that can be used for vaccine development against cancer. To develop the neoantigen vaccine candidate, we used the SPENCER database, and 140 lncRNA-derived epitopes were retrieved. From 140 epitopes, we selected seven neoantigens with high antigenic properties for the vaccine construct. A novel vaccine containing epitopes, linkers(EAAAK and CPCPG), and adjuvants(ribosomal [50S]protein L7L12) was formulated utilizing immunoinformatics tools. The vaccine's biophysical properties were evaluated, revealing its antigenicity(0.6469), stability(instability index:37.05), and potential for immune system interaction. In-depth structural analyses, molecular docking studies, and ML-enabled immune simulation profiling underscored the vaccine's structural integrity, binding affinity with TLR4, and ability to elicit robust immune responses against colorectal cancer antigens. These findings suggest that the multi-epitopic vaccine holds promise as a next-generation approach to combat colorectal cancer. Our in silico studies exhibit potentiality of the vaccine candidate; however, further in vivo and in vitro investigations are crucial to validate immunogenicity, safety, and efficacy before clinical implementation. Our study developed a first-time lncRNA-derived neoantigen-based cancer vaccine.

Microbiota-Derived Extracellular Vesicle as Emerging Actors in Host Interactions.

The human microbiota is an intricate micro-ecosystem comprising a diverse range of dynamic microbial populations mainly consisting of bacteria, whose interactions with hosts strongly affect several physiological and pathological processes. The gut microbiota is being increasingly recognized as a critical player in maintaining homeostasis, contributing to the main functions of the intestine and distal organs such as the brain. However, gut dysbiosis, characterized by composition and function alterations of microbiota with intestinal barrier dysfunction has been linked to the development and progression of several pathologies, including intestinal inflammatory diseases, systemic autoimmune diseases, such as rheumatic arthritis, and neurodegenerative diseases, such as Alzheimer's disease. Moreover, oral microbiota research has gained significant interest in recent years due to its potential impact on overall health. Emerging evidence on the role of microbiota-host interactions in health and disease has triggered a marked interest on the functional role of bacterial extracellular vesicles (BEVs) as mediators of inter-kingdom communication. Accumulating evidence reveals that BEVs mediate host interactions by transporting and delivering into host cells effector molecules that modulate host signaling pathways and cell processes, influencing health and disease. This review discusses the critical role of BEVs from the gut, lung, skin and oral cavity in the epithelium, immune system, and CNS interactions.

Breast cancer diagnostics by the intelligent analysis of white blood cells’ interaction with target cancer cells using convolutional neural networks

Interaction of immune system and cancer cells plays a crucial role in defining the physical and chemical characteristics of the tumor microenvironment. Consequently, monitoring and analyzing these interactions may prove essential for cancer diagnosis and prognosis. While standard techniques assessing cellular interaction are technically complicated and usually expensive, engineering solutions can be employed to introduce novel methods and effective techniques. In this paper, we presented a new blood-based breast cancer hallmark for people suspected of breast tumor disease (BTD) by time-lapse microscopy imaging from the interaction between the patient’s blood and MDA-MB-231 breast cancer cell lines. The detection protocol is based on the quantifying invasion of the WBCs to the breast cancer cell line. Many cytological, molecular, and immunofluorescent assays were carried out to approve the hypothesis. Blood immune cells showed meaningful invasion patterns to breast cancer cell lines in reverse correlation by the cancerous stage of the patients. Hence, we believe that the immune system is cognizant of the neoplastic nature of breast tumor disease. To eliminate all the human-related limitations, a convolutional neural network (CNN) architecture was used for invasion recognition. The proposed CNN architecture showed an accuracy of approximately 86%, making it a reliable, fast, and easy way for intelligent detection of invasion patterns to decide on the tumor stage. Results made us present the hypothesis that people with more aggressive breast cancer tumors have less strong immune cells to invade cancer cells which could be a start in the clinical use of the cellular-based immune system for cancer investigation. As WBCs were isolated from the blood with no pre-processing, this method would shed new light as a simple complementary method for better clarification of tumor nature.

Dietary fibre optimisation in support of global health.

The human gut microbiota influences its host via multiple molecular pathways, including immune system interactions, the provision of nutrients and regulation of host physiology. Dietary fibre plays a crucial role in maintaining a healthy microbiota as its primary nutrient and energy source. Industrialisation has led to a massive decrease of habitual fibre intake in recent times, and fibre intakes across the world are below the national recommendations. This goes hand in hand with other factors in industrialised societies that may negatively affect the gut microbiota, such as medication and increased hygiene. Non-communicable diseases are on the rise in urbanised societies and the optimisation of dietary fibre intake can help to improve global health and prevent disease. Early life interventions shape the developing microbiota to counteract malnutrition, both in the context of industrialised nations with an overabundance of cheap, highly processed foods, as well as in Low- and Middle-Income Countries (LMICs). Adequate fibre intake should, however, be maintained across the life course to promote health. Here we will discuss the current state of dietary fibre research in the global context and consider different intervention approaches.

Crosstalk between gut microbiota and host immune system and its response to traumatic injury.

Millions of microorganisms make up the complex microbial ecosystem found in the human gut. The immune system's interaction with the gut microbiota is essential for preventing inflammation and maintaining intestinal homeostasis. Numerous metabolic products that can cross-talk between immune cells and the gut epithelium are metabolized by the gut microbiota. Traumatic injury elicits a great and multifaceted immune response in the minutes after the initial offense, containing simultaneous pro- and anti-inflammatory responses. The development of innovative therapies that improve patient outcomes depends on the gut microbiota and immunological responses to trauma. The altered makeup of gut microbes, or gut dysbiosis, can also dysregulate immunological responses, resulting in inflammation. Major human diseases may become more common as a result of chronic dysbiosis and the translocation of bacteria and the products of their metabolism beyond the mucosal barrier. In this review, we briefly summarize the interactions between the gut microbiota and the immune system and human disease and their therapeutic probiotic formulations. We also discuss the immune response to traumatic injury.

TGFβ2 Promotes the Construction of Fibrotic and Immunosuppressive Tumor Microenvironment in Pancreatic Adenocarcinoma: A Comprehensive Analysis.

Pancreatic adenocarcinoma (PAAD) was characterized by dense fibrotic stroma and immunosuppressive tumor microenvironment (TME). TGFβ signaling pathways are highly activated in human cancers. However, the role of TGFβ2 in TME of PAAD remains to be elucidated. In this study, we showed that TGFβ2 was expressed at a relatively high level in PAAD tissues or cancer cells. Moreover, its high expression predicted unfavorable prognosis. In PAAD, gene set enrichment analysis showed that TGFβ2 correlated positively with leukocyte transendothelial migration, but negatively with aerobic metabolism, including oxidative phosphorylation. Results in Tumor and Immune System Interaction Database showed that TGFβ2 correlated with the infiltration of tumor-associated macrophages (TAMs), which could be attributed to that TGFβ2 promote CCL2 expression in PAAD. Moreover, correlation analysis showed that TGFβ2 could trigger cancer-associated fibroblasts (CAFs) activation in PAAD. The drug sensitivity analysis may indicate that patients with TGFβ2 high expression have higher sensitivity to chemotherapeutics, but the sensitivity to targeted drugs is still controversial. TGFβ2 could promote expansion of CAFs and infiltration of TAMs, thus participating in the construction of a fibrotic and immunosuppressive TME in PAAD. Targeting TGFβ2 could be a promising therapeutic approach, which needs to be elucidated by clinical and experimental evidences.

The prognostic value and its relationship with immune infiltration of ACLY in clear cell renal cell carcinoma

ATP citrate lyase (ACLY) is activated in various cancers, but its role in clear cell renal cell carcinoma (ccRCC) remains poorly understood. Herein, we investigated the prognostic role and potential mechanism of ACLY in ccRCC. The expression profile of ACLY in ccRCC was explored using Gene Expression Profiling Interactive Analysis 2 (GEPIA2), Gene Expression Omnibus (GEO), UALCAN and western blotting assays. The prognosis was investigated using immunohistochemistry (IHC) and Kaplan–Meier plotter assays. The relationship with immune infiltration was further evaluated using Tumor Immune Estimation Resource 2 (TIMER2) and Tumor Immune System Interactions and DrugBank (TISIDB) databases, respectively. Further biological function of ACLY in ccRCC pathogenesis was explored using in vitro experiments. ACLY level was higher in ccRCC than adjacent kidney tissues, and Kaplan–Meier survival analysis showed ACLY mRNA or protein were predictors of poor prognosis in ccRCC patients. Importantly, we reported for the first time that ACLY gene expression was significantly correlated with numerous immune cells and immune inhibitors in ccRCC. ACLY inhibition significantly impaired cell proliferation, induced cell apoptosis, attenuated cell migration, decreased lipid droplets formation, and suppressed epithelial-mesenchymal transition (EMT) of ccRCC. Moreover, these effects might be acted through mammalian target of rapamycin complex 1 (mTORC1) pathway. Collectively, ACLY was not only implicated in ccRCC tumorigenesis and progression, but also potentially interacted with immune infiltration and mTORC1 pathway. Our findings may provide a novel therapeutic strategy by targeting ACLY for ccRCC treatment.

Dendritic Cell-Related Immune Marker CD1C for Predicting Prognosis and Immunotherapy Opportunities of Lung Adenocarcinoma Patients.

Lung adenocarcinoma (LUAD) is the most frequent type of lung cancer with a high mortality rate. Here, we aim to explore novel immune-related biomarkers for LUAD patients. Datasets, mRNA expression profiles, and clinical data concerned with LUAD were obtained from Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA), respectively. Differential expression analysis was performed to obtain differentially expressed genes (DEGs). Based on DEGs, we conducted functional enrichment analyses. Subsequently, Kaplan‑Meier (KM) was performed to analyze survival differences among different groups. Furthermore, immune cell infiltration proportion was calculated by CIBERSORT and TIMER. The relationship between gene and immune response was analyzed using Tumor Immune System Interactions (TISIDB) database. Finally, Pearson correlation analysis was performed between CD1C and six immune checkpoints. We identified dendritic cells (DCs)-related expression profiles from four LUAD samples. DCs' immune marker CD1C in LUAD was selected by univariate Cox regression analysis. Low CD1C expression patients had a poor prognosis. A total of 332 DEGs were identified in high and low CD1C expression groups, which primarily enriched in 348 GO terms and 30 KEGG pathways. There were significant differences in the infiltration proportion of 17 immune cells between high and low CD1C expression groups. Most immunomodulators, chemokines, and chemokine receptors were positively associated with CD1C expression. Six immune checkpoints were also positively correlated with CD1C expression. DCs related immunomarker CD1C probably plays a pivotal part in prognosis and immunotherapy of LUAD via a joint analysis of single-cell and bulk sequencing data.

Association of bioimpedance analysis parameters trajectories with clinical outcomes in neurocritical patients

Background and objectiveNeurocritical patients often experience uncontrolled high catabolic metabolism state during the acuta phase of the disease. The complex interactions of neuroendocrine, inflammation, and immune system lead to massive protein breakdown and changes in body composition. Bioelectrical impedance analysis (BIA) evaluates the content and proportions of body components based on the principles of bioelectricity. Its parameters reflect the overall health status of the body and the integrity of cellular structure and function, playing an important role in assessing the disease status and predicting prognosis of such patients. This study explored the association of BIA parameters trajectories with clinical outcomes in neurocritical patients. MethodsThis study prospectively collected BIA parameters of 127 neurocritical patients in the Department of Neurology admitted to the NICU for the first 1–7 days. All these patients were adults (≥18 years old) experiencing their first onset of illness and were in the acute phase of the disease. The group-based trajectory modeling (GBTM), which aims to identify individuals following similar developmental trajectories, was used to identify potential subgroups of individuals based on BIA parameters. The short-term prognosis of patients in each trajectory group with variations in phase angle (PA) and extracellular water/total body water (ECW/TBW) over time was differentially analyzed, and the logistic regression model was used to analyze the relationship between potential trajectory groups of PA and ECW/TBW and the short-term prognosis of neurocritical patients. The outcome was Glasgow Outcome Scale (GOS) score at discharge. ResultsFour PA trajectories and four ECW/TBW trajectories were detected respectively in neurocritical patients. Among them, compared with the other latent subgroups, the “Low PA rapidly decreasing subgroup” and the “High ECW/TBW slowly rising subgroup” had higher incidences of adverse outcomes at discharge (GOS:1–3), in-hospital mortality, and length of neurology intensive care unit stay (all P < 0.05). After correcting for potential confounders, compared with the “Low PA rapidly decreasing subgroup”, the risk of adverse outcome (GOS:1–3) was lower in the other three PA trajectories, with OR values of 0.0003, 0.0004, and 0.003 respectively (all P < 0.05). Compared with the “High ECW/TBW slowly rising subgroup”, the risk of adverse outcome (GOS:1–3) was lower in the other three ECW/TBW trajectories, with OR values of 0.013, 0.035 and 0.038 respectively (all P < 0.05). ConclusionLatent PA trajectories and latent ECW/TBW trajectories during 1–7 days after admission were associated with the clinical outcomes of neurocritical patients. The risk of adverse outcomes was highest in the “Low PA rapidly decreasing subgroup” and the “High ECW/TBW slowly rising subgroup”. These results reflected the overall health status and nutritional condition of neurocritical patients at the onset of the disease, and demonstrated the dynamic change process in body composition caused by the inflammatory response during the acute phase of the disease. This provided a reference basis for the observation and prognostic evaluation of such patients.

Modeling the Nonmonotonic Immune Response in a Tumor–Immune System Interaction

Tumor–immune system interactions are very complicated, being highly nonlinear and not well understood. A large number of tumors can potentially weaken the immune system through various mechanisms such as secreting cytokines that suppress the immune response. In this paper, we propose a tumor–immune system interaction model with a nonmonotonic immune response function and adoptive cellular immunotherapy (ACI). The model has a tumor-free equilibrium and at most three tumor-presence equilibria (low, moderate and high ones). The stability of all equilibria is studied by analyzing their characteristic equations. The consideration of nonmonotonic immune response results in a series of bifurcations such as the saddle-node bifurcation, transcritical bifurcation, Hopf bifurcation and Bogdanov–Takens bifurcation. In addition, numerical simulation results show the coexistence of periodic orbits and homoclinic orbits. Interestingly, along with various bifurcations, we also found two bistable scenarios: the coexistence of a stable tumor-free as well as a high-tumor-presence equilibrium and the coexistence of a stable-low as well as a high-tumor-presence equilibrium, which can show symmetric and antisymmetric properties in a range of model parameters and initial cell concentrations. The new findings indicate that under ACI, patients can possibly reach either a stable tumor-free state or a low-tumor-presence state in the presence of nonmonotonic immune response once the immune system is activated.

#1550 Incident hypertension: immune biomarkers and vascular phenotypes

Abstract Background and Aims Blood pressure (BP) regulation is mediated by cardiac, vascular, endocrine, renal, and immune system interactions. Hence, hypertension may exist as different phenotypic variants, with different clinical features and susceptibility to target organ damage. We aimed to analyse the circulating protein biomarker ‘signature’ of: 1) untreated hypertension; 2) hypertensive phenotypes identified by arterial and blood pressure parameters. Method 61 patients with hypertension, and 61 controls were assessed using 24hr ambulatory BP monitoring; endothelial function, arterial stiffness, carotid intima-media thickness (CIMT), and cardiovascular variability [1]. Circulating protein biomarkers analysed using Olink® Inflammation plasma biomarker panel, reported as NPX (Normalized Protein eXpression), in Log2 scale. Results 34 biomarkers dominated by cytokines and chemokines differed between normotensive and hypertensive subjects (Fig. 1), though failed to meet Bonferroni-adjusted threshold. Inflammatory biomarkers correlated with BP and arterial stiffness, BP variability, and CIMT, but not endothelial function. Associations were concordant across systolic and diastolic BP; TPP1, CCL7, CCL11, and CCL21 positively correlating; IL18R1, and KYNU negatively. These relationships were more pronounced in hypertensive subgroup, 85 biomarkers correlating including CD molecules (CD200R1, CD22, CD58, CD6, CD70) and cytokines (IL-5, IL-11, IL-15, IL-18, IL-32, IL-1RL2, IL-22RA1, IL-5RA). HGF, AGE, and CCL21 showed greatest between group differences and correlated with multiple BP or vascular parameters. Systolic nocturnal dipping demonstrated negative correlation with biomarkers relating to immune cell interactions and cellular adhesion (CTRC, EPHA1, LGALS4, SIT1, SMOC, IL-18 and TNFSF11). Machine learning techniques identified three phenotypes of hypertension, ‘arterially stiffened’, ‘vaso-protected’, and ‘non-dipper’ [1]. Sixteen of the 85 correlating biomarkers also differed between these phenotypic groups: Conclusion Hypertension is linked to alterations in circulating immune biomarkers. Multiple biomarkers correlated with both arterial stiffness and BP parameters. Some biomarkers are only correlated in the hypertensive group. Many also relate to nocturnal dipping, and differed across the hypertension endotypes. HGF is a promising biomarker for BP and arterial function; warranting further validation.

Role of B Cells beyond Antibodies in HBV-Induced Oncogenesis: Fulminant Cancer in Common Variable Immunodeficiency-Clinical and Immunotransplant Implications with a Review of the Literature.

Although lymphoma is the most frequent malignancy in common variable immunodeficiency (CVID), solid tumors, especially affected by oncogenic viruses, are not considered. Furthermore, in vitro genetic studies and cell cultures are not adequate for immune system and HBV interaction. We adopted a previously introduced clinical model of host-virus interaction (i.e., infectious process in immunodeficiency) for analysis of B cells and the specific IgG role (an observational study of a CVID patient who received intravenous immunoglobulin (IVIG). Suddenly, the patient deteriorated and a positive results of for HBs and HBV-DNA (369 × 106 copies) were detected. Despite lamivudine therapy and IVIG escalation (from 0.3 to 0.4 g/kg), CT showed an 11 cm intrahepatic tumor (hepatocellular carcinoma). Anti-HBs were positive in time-lapse analysis (range 111-220 IU/mL). Replacement therapy intensification was complicated by an immune complex disease with renal failure. Fulminant HCC in CVID and the development of a tumor as the first sign is of interest. Unfortunately, treatment with hepatitis B immune globulins (HBIG) plays a major role in posttransplant maintenance therapy. Anti-HB substitution has not been proven to be effective, oncoprotective, nor safe. Therefore, immunosuppression in HBV-infected recipients should be carefully minimized, and patient selection more precise with the exclusion of HBV-positive donors. Our clinical model showed an HCC pathway with important humoral host factors, contrary to epidemiological/cohort studies highlighting risk factors only (e.g., chronic hepatitis). The lack of cell cooperation as well as B cell deficiency observed in CVID play a crucial role in high HBV replication, especially in carcinogenesis.

Prognostic value and immunological role of MMRN1: a rising star in cancer

Background Multimerin 1 (MMRN1) is a factor V binding protein, which can support platelet adhesion and thrombus formation. In recent years, the role of MMRN1 in cancer has begun to attract attention. But systematic studies in this area are lacking. Therefore, we used bioinformatics methods to analyze MMRN1 in tumors to reveal the possible role of MMRN1. Methods Using the Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) database, we obtained relevant data for analyzing MMRN1. Using Gene Expression Profiling Interactive Analysis (GEPIA), Human Protein Atlas (HPA), TCGA, GeneMANIA, and cBioPortal, we explored the potential role of MMRN1 in different types of tumors. Tumor Immune System Interactions and Drug Bank (TISIDB) and Sangerbox were used to analyze the correlation between MMRN1 and tumor immunity. Gene set cancer analysis (GSCA) and UALCAN were used to analyze the methylation of MMRN1. GSCA was also used to analyze the drug sensitivity of MMRN1. Results MMRN1 is down-regulated in most cancer types and is closely related to the prognosis of cancer patients. Interestingly, in most tumors, MMRN1 is positively correlated with immune -related genes. In addition, we observed different levels of methylation and mutations in different types of tumors. Drug sensitivity analysis found that MMRN1 was negatively correlated with several drugs, including GW-2580 and TL-1-85, suggesting that it can be used to develop potential anticancer therapies. Conclusion Our analysis demonstrated a significant relationship between MMRN1 and prognosis, tumor immunity, and drug sensitivity of several tumors. As a rising star in cancer, it needs further research.