Immunological Profile Research Articles

Individual Genomic Loci, Transcript Level and Serum Profile of Immune, Antioxidant and Hormonal Markers Associated with Sheep Arthritis

Arthritis is a leading cause of economic loss in livestock farming including sheep. This study examined the changes in gene expression, antioxidants, pro-inflammatory cytokines, acute-phase proteins (APPs), hormonal assays and iron profiles linked to sheep arthritis, as well as the diagnostic utility of these markers. Blood samples were obtained from 30 apparently healthy rams and 30 rams with arthritis for gene expression and biochemical analyses. Gene expression intensities were much higher in the arthritis-affected rams than in the healthy ones for the genes IL-1α, IL-1β, IL-6, IL-10, TNFα, NCF4, NFKB, TMED, FCAMR, iNOS and COX18. The SOD3, CAT, GPX and ATOX1 genes were expressed at substantially lower levels in arthritis-affected rams. Disparities in the nucleotide sequence variants for the amplified DNA bases linked to arthritis for the studied genes were found in the PCR-DNA sequence verdicts of the affected and healthy rams. Immunological, acute-phase protein (APP), antioxidant, hormonal and iron profiles were estimated in both groups and statistically analyzed. The arthritic group in relation to the healthy one showed a significant (p < 0.05) increase in pro-inflammatory cytokines, APPs, free radicals, immunoglobulins, cortisol, GH, TSH, ferritin, TIBC and UIBC and a significant (p ˂ 0.05) decrease in anti-inflammatory cytokines, antioxidants, complements, insulin, T3, T4, SI, and Tf and Tf sat.% serum levels. The estimated pro-inflammatory cytokines and APPs achieved high values of sensitivity and specificity, positive predictive values (PPVs), negative predictive values (NPVs), a high accuracy rate and a moderate likelihood ratio (LR). The study concluded that ovine arthritis stimulates innate and humeral immunity, resulting in prominent alterations in gene expression, pro-inflammatory cytokines, APP assays and antioxidant profiles, which could be valuable indicators of sheep arthritis.

Abstract TP346: Investigating Transcriptomic Profiles of Peripheral Blood Mononuclear Cells in Moyamoya Disease Using Single-Cell RNAseq

Objectives: Moyamoya Disease (MMD) is a complex cerebrovascular disease marked by progressive narrowing in the cerebral arteries. Previous studies have suggested that dysregulated genes in the peripheral blood of MMD patients are involved in extracellular matrix organization and immune responses. However, the mechanism by which the immune response contributes to MMD progression is unclear. In this study we investigated the immune landscape in the peripheral blood mononuclear cells (PBMCs) of MMD patients using single-cell RNA sequencing (scRNA-seq). Methods: Blood samples were collected from 3 bilateral MMD patients and 2 healthy controls. PBMCs were isolated and processed for 10x single-cell RNA sequencing. Immune cell heterogeneity and differentially expressed genes (DEGs) in each cell type were identified. Top biological pathways were determined using Ingenuity Pathway Analysis (IPA). Flow cytometry with an 11-fluorochrome panel was use to validate key immune populations and fluorescence-activated cell sorting (FACS) was used to isolate specific immune populations for transcriptome analysis. Results: Preliminary analysis revealed notable increase of cell percentages in certain cell types in MMD, such as CD8+T (9.21% vs 7.11%), B cells (6.94% vs 3.45%) and CD4+NKT (5.78% vs 3.22%), and decrease in CD8+NKT (9.59% vs 15.74%), compared to controls. Higher transcriptome dynamics were observed in certain cell type in MMD, with 2402 DEGs in classical monocytes, 1379 DEGs in CD4+T, 1312 DEGs in CD8+NKT and 997 DEGs in B cells. Interestingly, many cell types, except for classical and non-classical monocytes, displayed a higher number of downregulated DEGs in MMD, particularly in T cells, B cells, and NKT cells. Pathway analysis indicated that CD4+T, CD8+NKT, and B cells show predicted inhibition in several pathways, including T cell receptor and mTOR signaling, interleukins and CXCR4 signaling, as well as cell surface interactions at the vascular wall. Conclusion: These preliminary findings point to a distinct immunological profile in MMD, suggesting significant alterations in both immune cell activity and interaction within the vascular environment. Ongoing studies utilize FACS to validate specific immune populations and their transcriptomes in a larger cohort. These findings reveal unique transcriptomic signatures of peripheral blood immune cells in MMD and highlight key immune cell types that may contribute to its pathogenesis.

P-994. Cellular and humoral immunological profile of Human T-Lymphotropic Virus type I (HTLV-1) in a pediatric case series

Abstract Background Human T- lymphotropic Virus type 1 (HTLV-1) is a powerful oncovirus. In South America there is a high incidence of cases in countries such as Brazil, Peru and Colombia, mainly affecting the indigenous and Afro-descendant population. In children, the main clinical findings are dermatological manifestations followed by lung disease, opportunistic coinfections, and autoinflammatory disorders. The main target of HTLV-1 is CD4+ T lymphocytes, which are the regulators of the acquired immune response, but It’s also capable of infecting CD8+ T lymphocytes, B cells, dendritic cells and synovial cells. The purpose of this study is to describe the humoral and cellular immunological profile in pediatric patients diagnosed with HTLV-1 in a reference center in Cali, Colombia.Table 1.Characterization of cellular immunity in pediatric patients diagnosed with HTLV1 (n = 6)BL: B lymphocyte, TL: T lymphocyte Source: Self elaboration Methods This is an observational, descriptive, retrospective cross-sectional study carried out between January 2017 and March 2021.Table 2.Characterization of humoral immunity in pediatric patients diagnosed with HTLV1 (n = 16) Results Nineteen patients were included in this study with a median age at diagnosis of 94 months, most of them were schoolchildren (52.6%), 50% of patients had elevated B lymphocytes (CD19), and 50% of them had normal range cytotoxic T lymphocytes (CD8+) and helper T lymphocytes (CD4) (Table 1 and graph 1). None of the patients had decreases in serum immunoglobulins (IgM, IgG, IgE and IgA) (Table 2 and graph 2)Graph 1.Cellular immunological profile (n=6) Conclusion HTLV-1 immunosuppression is not mediated by low levels of lymphocyte subpopulations in the pediatric population.Graph 2.Humoral immunological profile (n=16) Disclosures All Authors: No reported disclosures

P-2064. COVID-19 Vaccination-infection Status and Immunological Profile: Identification of High-Risk Population for Targeted Booster Immunization In India

Abstract Background The immunological profiles and predictors of immune response in people with hybrid immunity, resulting from a combination of natural infection and vaccination, particularly in regions where non-mRNA vaccines were administered, remain less understood. Methods This was a cross-sectional study done at AIG Hospitals, Hyderabad, India. Consecutive participants were enrolled, and sampled for immunological testing. The study population was divided into six cohorts based on their infection and vaccination status. Immunological assays were performed to measure anti-spike protein and interferon-γ release assay. Hospitalization rates were compared in all groups. Chi-square test was used to compare categorical variables, and the Mann-Whitney U test was used for comparing medians. Post-hoc Dunn test was used for pairwise comparison. Bonferroni adjustment for p-value was performed for multiple pairwise comparisons. Linear regression model was used appropriately to find predictors of antibody titres. Results A total of 1040 patients were enrolled in the study. The population was divided into six cohorts: Unvaccinated, Primary, Booster, Hybrid (Pre-Omicron only), Hybrid (Omicron only), and Hybrid (Both). Antibody titres and IGRA levels were found to be statistically higher in the Hybrid (both infection) group (Table 1 and Figures 1a & 1b). The linear regression model showed factors predicting antibody response (Table 2). Age and hypertension were independent (negative) predictors of antibody levels. During the follow-up (median 30.7 [26.6 – 34.4 months]) of 1008 patients, 770 (76.4%) had a documented COVID infection with Omicron. Hospitalization was evaluated in three groups: Hybrid, vaccination only and unvaccinated. The incidence was significantly lower in the Hybrid group; log-rank test: p < 0.001. (Figure 2) Conclusion The prevalence of hybrid immunity was high in the study population. Individuals above 60 years old and with comorbidities are more likely to have lower antibody titers. Immunized patients were protected against hospitalization. There is a need for prioritized immune-boosting efforts in high-risk individuals. Disclosures All Authors: No reported disclosures

P-556. Efficacy and Safety of Bictegravir/Emtricitabine/TenofovirAlafenamide in Females Living With HIV: 96 Weeks Real Life Analysis

Abstract Background Females with HIV (FWH) are underrepresented in HIV trials. Pooled data from 5 trials at 48 weeks demonstrated the virological efficacy and safety of bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF). We evaluated the safety and efficacy of B/F/TAF in a cohort of 99 FWH, in a real-life setting, at 48 and 96 weeks from the switch. Methods We conducted a multicentric cohort study that included all experienced FWH starting B/F/TAF treatment in the Shine&Shic cohort across six Infectious Disease Centers in Italy. We collected demographic, epidemiological, clinical, and laboratory data at the time of the switch and at 48 and 96 weeks. Informed consent was obtained from all participants. Data were reported as numbers (%), or using median and interquartile range (IQR), as appropriate. We assessed differences between baseline, 48 weeks, and 96 weeks using the Mann-Whitney test. A p-value of less than 0.05 was considered significant. Results We included 99 females with HIV (FWH) in the study, with a median age of 51.9 years (IQR 43.1-57.8) and a duration of HIV infection of 15.1 years (IQR 5.1-24.7). During follow-up, we observed an increase in the percentage of FWH with an undetectable viral load (Figure 1). We noted a significant increase in CD4 cells/mL and in CD4/CD8 ratio at 48 and 96 weeks and no differences in CD8 cell counts (Table 2). Of importance, we observed a significant reductions in total cholesterol and low-density lipoprotein (LDL) at both 48 and 96 weeks. No significant changes were observed in transaminase levels, glucose levels, high-density lipoprotein (HDL), or triglycerides (Table 2). Regarding safety, there was a significant increase in creatinine at 48 and 96 weeks. We registered 9 interruptions of B/F/TAF: 3 due to loss to follow-up, 1 death, 1 switch to long-acting treatment, 1 due to adverse events, and in 3 cases, due to patient’s choice. Conclusion The number of FWH on B/F/TAF under virological suppression increased at 48 and 96 weeks. Furthermore, CD4 T-cell and CD4/CD8 ratio also augmented, underlining an amelioration of the immunological and inflammatory profile. Of note, LDL cholesterol levels significantly decreased overtime. B/F/TAF is virologically and immunologically effective in FWH, in a real-life setting, at 96 weeks from the switch. Disclosures All Authors: No reported disclosures

P-2011. Blood Transcriptomic Stratification for Acute Encephalitis/encephalopathy and Croup in Children with Omicron Infection

Abstract Background Omicron poses significant concerns, leading to two severe complications, encephalitis and croup in children. Neutrophil predominance and lymphopenia were observed in severe cases. We propose a distinctive blood RNA signature to characterize COVID-19's immune landscape, potentially aiding in differentiating severe from mild cases in pediatric patients, with implications for clinical management. Volcano plot of differentially expressed genes between encephalitis and mild disease Fold change was the ratio of the average expression of genes in the encephalitis/encephalopathy group to those in the mild disease group. DEGs were determined using cutoff values: |log2 (fold change) | > 1 and adjusted p value < 0.05. Genes with log2(fold change) > 1 and adjusted p value < 0.05 were deemed upregulated, while those with log2(fold change) < -1 and adjusted p value < 0.05 were considered downregulated. Methods The case-control cohort spanned two medical centers, Chang Gung Memorial Hospital, Linkou/Kaohsiung branches. Enrolled patients, with confirmed acute SARS-CoV-2 infection, were categorized into mild febrile disease, croup, or encephalitis/encephalopathy. A total of 61 children participated, with 29 mild febrile illness, 14 croup, and 18 encephalitis/encephalopathy cases. Samples collected a median of 2 (1-2) days post-symptom onset underwent RNA sequencing. Differences in gene expression and functional pathways were analyzed. The prediction model for COVID-19-associated encephalitis was developed using random forest analysis. Encephalitis/encephalopathy vs. mild disease DEGs heatmap The warmer color indicates a higher expression level of DEGs, whereas cooler colors signify a lower expression level of DEGs. Results A total of 1780 and 136 DEGs were identified in mild disease vs. encephalitis/encephalopathy and mild disease vs. croup, respectively. The heatmap from top DEGs indicates clustering into granulocyte activation, response to IFN-γ, and myeloid cell differentiation. GOBP and KEGG enrichment analyses revealed up-regulation of neutrophil function, TNF-alpha signaling pathway, NF-kappa B complex, and down-regulation of T cell activation in COVID-19 encephalitis group. CIBERSORT analysis showed distinct immunological profiles in the encephalitis group: elevated neutrophils, activated dendritic cells, follicular helper T cells; diminished CD4, CD8 T cells, monocytes, naïve B cells. Overexpression of systemic inflammation in severe COVID-19 may result from impaired bridge between innate immunity and adaptive immunity. The top 10-DEG prediction model for COVID-19 associated encephalitis yielded an AUC of 0.938. Encephalitis/encephalopathy vs. mild disease upregulated DEG GO_BP dot plot. GO is an abbriviation for Gene Ontology, with Biological Process (BP) constituting a pivotal component of GO. Generation refers to the ratio of genes enriched in this biological process to all upregulated DEGs. The shading intensity of the circle indicates the quantity of enriched genes. Conclusion In this study, we delineated the immune landscape and functional pathways linked to COVID-19 encephalitis in the pediatric population. Our findings hold potential for enhancing the precision of diagnosing encephalitis/encephalopathy in pediatric COVID-19 patients. Cibersortx analysis between the encephalitis/encephalopathy group and mild disease group Average percentage of immune cells of the innate immune response and adaptive immune response in the encephalitis/encephalopathy group and mild disease group. Disclosures All Authors: No reported disclosures

Tofacitinib Treatment for Active Dermatomyositis and Anti-synthetase Syndrome: A Prospective Cohort Pilot Study.

The objective of this study was to evaluate the efficacy and safety of tofacitinib in the treatment of active dermatomyositis (DM) and anti-synthetase syndrome (ASS). Tofacitinib was administered at a dose of 5 mg twice daily to patients who exhibited inadequate response to conventional treatments. The primary end point was the reduction of T follicular helper (Tfh) cells at week 24. Key secondary endpoints included clinical scores. Moreover, we analyzed the immunological profiles and conducted RNA sequencing (RNAseq) on peripheral blood samples from four patients. A total of twenty-six patients were enrolled, with twenty-one completing the study. Both DM and ASS patients demonstrated significant improvements in disease activity. Among these, the percentage of Tfh cells in peripheral blood decreased by 81.0% (17/21) of patients (p = 0.003). Significant reductions in Th17 cells were observed in vivo in the PBMCs of these patients (p = 0.017). In vitro, Tfh cells (2.88 ± 1.13 vs 2.28 ± 0.92, p < 0.001), Th17 cells (1.42 ± 0.92 vs 1.01 ± 0.74, p = 0.016), Treg cells (2.06 ± 1.26 vs 0.98 ± 0.65, p = 0.019) and Tfh17 cells (33.38 ± 15.14 vs 30.28 ± 4.89, p = 0.014) were inhibited. RNAseq analysis revealed significant downregulation of genes associated with the 'herpes simplex virus 1 infection' and 'IL-17 signalling' pathway. MDAAT scores improved in 21 out of 24 patients. Fifteen (62.5%) patients met the criteria for IMACS DOI. Importantly, no severe adverse events necessitated treatment discontinuation. Tofacitinib demonstrated significant immunologic and clinical effectiveness in DM and ASS patients, reducing key immune cell populations and downregulating immune activation pathways.

Combination adjuvant improves influenza virus immunity by downregulation of immune homeostasis genes in lymphocytes.

Adjuvants play a central role in enhancing the immunogenicity of otherwise poorly immunogenic vaccine antigens. Combining adjuvants has the potential to enhance vaccine immunogenicity compared with single adjuvants, although the cellular and molecular mechanisms of combination adjuvants are not well understood. Using the influenza virus hemagglutinin H5 antigen, we define the immunological landscape of combining CpG and MPLA (TLR-9 and TLR-4 agonists, respectively) with a squalene nanoemulsion (AddaVax) using immunologic and transcriptomic profiling. Mice immunized and boosted with recombinant H5 in AddaVax, CpG+MPLA, or AddaVax plus CpG+MPLA (IVAX-1) produced comparable levels of neutralizing antibodies and were equally well protected against the H5N1 challenge. However, after challenge with H5N1 virus, H5/IVAX-1-immunized mice had 100- to 300-fold lower virus lung titers than mice receiving H5 in AddaVax or CpG+MPLA separately. Consistent with enhanced viral clearance, unsupervised expression analysis of draining lymph node cells revealed the combination adjuvant IVAX-1 significantly downregulated immune homeostasis genes, and induced higher numbers of antibody-producing plasmablasts than either AddaVax or CpG+MPLA. IVAX-1 was also more effective after single-dose administration than either AddaVax or CpG+MPLA. These data reveal a novel molecular framework for understanding the mechanisms of combination adjuvants, such as IVAX-1, and highlight their potential for the development of more effective vaccines against respiratory viruses.

Comprehensive single-cell pan-cancer atlas unveils IFI30+ macrophages as key modulators of intra-tumoral immune dynamics

BackgroundThe convergence of macrophage-targeted strategies with immune checkpoint blockade therapies defines a pivotal avenue in contemporary tumor therapy. Identifying robust genetic regulators in this context is imperative.MethodsThis study elucidates IFI30's role in enhancing Major Histocompatibility Complex II (MHC-II) restriction antigen processing. Despite its recognition in cancer immunotherapy, IFI30 remains a nascent focus. Our approach involves a multi-omics analysis of IFI30 tumor immunological profile in the macrophage-mediated Tumor Microenvironment (TME), spanning various cancers and bolstered by rigorous co-culture laboratory work.ResultsIFI30 predominantly localizes in monocyte/macrophage populations, correlating strongly with immune cell infiltration. Substantiated by single-cell analysis, IFI30 exhibits significant functional enrichment in immune-related pathways. Co-expression with immune-related genes, including MHC elements and immune checkpoints, further validates its relevance.ConclusionOur study positions IFI30 as a promising immunotherapeutic target. Pan-cancer analyses and glioblastoma multiforme (GBM) investigations collectively underscore IFI30's potential as a TME modulator, particularly in its interaction with M2-macrophages. IFI30 emerges as a prospective intervention point in the immunotherapeutic landscape.

Antioxidant Synergy in a Mixture of Powder Plant Leaves and Effects on Metabolic Profile, Oxidative Status and Intestinal Morpho-Histochemical Features of Laying Hens

Phenolic antioxidant intake is encouraged to prevent oxidative damage, and antioxidant synergy is considered an advantage in adding polyphenols from varied plants. This study investigated the antioxidant and synergistic interactions among olive leaf (OL), bay laurel (BL), and rosemary (RL) leaf powder mixture (LPM: OL + BL + RL), using in vitro chemical tests [TPC, ORAC, TEAC-ABTS, FRAP; combination index (CI)], and in vivo validation on blood oxidative status, metabolic profile, and intestinal histomorphology in laying hens. The in vitro study indicated a whole higher antioxidant capacity for the LPM than respective single/double-leave combinations. The LPM CI value (IC50, 0.60) indicated a synergistic effect compared to the binary combinations. Thus, the LPM was validated in vivo through dietary supplementation on sixty Lohmann Brown hens (30 weeks old), reared in an indoor–outdoor rearing system divided. The hens were allocated into two experimental groups (n. 30): basal control diet group; and diet supplemented group with 6 g/kg feed of LPM) containing OL, BL, and RL (respectively, at 65.7%:18.9%:15.4%), for 60 days. The LPM improved (p &lt; 0.05) the oxidative status (TAS, FRAP; ROMs, TBARs) and vitamin E level, metabolic and immunological profiles, and it induced region-specific changes in the morphology and carbohydrate composition of mucins along intestinal tracts of the animals. These findings could provide a valuable strategy for identifying synergistic combinations in functional feed formulations for laying hens.

Clinical utility of the lymphocyte proliferation assay, an in vitro functional readout of the adaptive immune response.

Despite great advancements in the discovery of genetic variants underlying inborn errors of immunity, functional assessment of the immunological profile of patients in routine clinical practice remains challenging. The lymphocyte proliferation assay using 3H-thymidine incorporation has been the gold standard for decades for functional evaluation of T cells in the clinical laboratory, however, recently developed flow cytometry methods allowing for single cell analysis provide non-radioactive alternatives. Understanding the technical and analytical challenges of test development, validation and maintenance is essential for correct interpretation and test utilization, to assure appropriate and timely patient care. This review will discuss the technological aspects, validation and clinical utilization of in vitro lymphocyte proliferation assays performed in the clinical immunology laboratory, providing a diagnostic readout for T lymphocyte function, an essential hallmark of a functional cellular immune response, and allowing for the detection of impaired responses such as in patients with functional T cell defects.

Immunomodulatory Effects of Mesenchymal Stem Cell Secretome in Systemic Lupus Erythematosus: A Meta-Analysis

Background: Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by immune system dysregulation and multi-organ damage. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option due to their immunomodulatory properties, primarily mediated through their secretome (MSCS). This meta-analysis aimed to evaluate the efficacy and safety of MSCS in SLE patients. Methods: A systematic search of PubMed, Embase, and Web of Science was conducted for studies published between 2013 and 2024 investigating the effects of MSCS in SLE. Randomized controlled trials (RCTs) comparing MSCS with placebo or standard care were included. The primary outcome was SLE disease activity, assessed using the SLE Disease Activity Index (SLEDAI). Secondary outcomes included immunological markers (e.g., anti-dsDNA antibodies, complement levels), quality of life, and adverse events. Data were pooled using a random-effects model. Results: Nine RCTs (n=485 patients) met the inclusion criteria. MSCS therapy significantly reduced SLEDAI scores compared to controls (standardized mean difference [SMD] -0.78, 95% CI -1.25 to -0.31, p=0.001). Significant improvements were also observed in anti-dsDNA antibody levels (SMD -0.62, 95% CI -1.01 to -0.23, p=0.002) and complement C3 levels (SMD 0.55, 95% CI 0.21 to 0.89, p=0.002). MSCS was generally well-tolerated, with no serious adverse events reported. Conclusion: This meta-analysis demonstrates that MSCS therapy has significant immunomodulatory effects in SLE, leading to improved disease activity and immunological profiles. Larger, well-designed RCTs with longer follow-up periods are needed to confirm these findings and assess the long-term efficacy and safety of MSCS in SLE.

RNA modification writer-based immunological profile and genomic landscape of tumor microenvironment in lung adenocarcinoma

BackgroundRecent studies have highlighted the role of RNA modification, that is, the dysregulation of epitranscriptomics, in tumorigenesis and progression. The potential for undoing epigenetic changes may develop novel therapeutic and prognostic approaches. However, the roles of these RNA modifications in the tumor microenvironment (TME) are still unknown.MethodsWe assessed the expression properties and genetic alterations of 26 RNA modification writers, including adenosine-to-inosine RNA editing, alternative polyadenylation, m1A, and m6A in 502 lung adenocarcinoma (LUAD) samples from the Cancer Genome Atlas (TCGA) datasets. Then, we used differentially expressed gene (DEGs) to develop a signature for predicting patient outcomes, which was dubbed the “writer score” for RNA-modified writers. In addition, we analyzed the association between TME features, molecular subtypes, treatment sensitivity, and immunotherapy efficacy.ResultsWe comprehensively evaluated the changes in multilayer RNA modification writers and identified the role of RNA modification writer expression imbalances in LUAD emergence and progression. Additionally, we constructed a risk-score model based on six LUAD prognosis-associated differentially expressed RNA modification writer genes. Kaplan–Meier (K–M) analyses revealed that the low risk-score signature had high overall patient survival. The predictive significance of the risk-score model was demonstrated using both univariate and multivariate Cox analyses. The risk-score model was positively correlated with the immune- and proliferation-related pathways. In response to anti-cancer treatment, high-risk score is related with high TMB, which has been discovered to correlate with immunotherapy effectiveness.ConclusionThis study showed a strong correlation between the TME variety, level of complexity, and the four types of RNA modification writers. In addition, this scoring system could potentially predict effective immunotherapy and deepens our understanding of TME characteristics.

Single-cell transcriptomics unveils multifaceted immune heterogeneity in early-onset versus late-onset cervical cancer

Early-onset (EOCC) and late-onset cervical cancers (LOCC) represent two clinically distinct subtypes, each defined by unique clinical manifestations and therapeutic responses. However, their immunological profiles remain poorly explored. Herein, we analyzed single-cell transcriptomic data from 4 EOCC and 4 LOCC samples to compare their immune architectures. Epithelial cells in EOCC exhibited a notable dual immunological phenotype, characterized by immune-suppressive properties driven by elevated CXCL production, alongside immune-stimulatory features linked to heightened HLA molecule expression. CD4 + and CD8 + T cells in LOCC demonstrated a heightened activation state, while NK cells exhibited diminished cytotoxicity. Macrophages in LOCC displayed enhanced polarization towards both M1 and M2 phenotypes, along with dendritic cells showing augmented antigen-presenting capacity. Regarding cancer-associated fibroblasts (CAFs), EOCC was enriched with inflammatory CAFs, whereas LOCC harbored a higher proportion of antigen-presenting CAFs. These findings reveal the multifaceted immune heterogeneity between EOCC and LOCC, underscoring the imperative for age-tailored immunotherapeutic strategies.

Immunotherapy in Recurrent Ovarian Cancer.

It remains challenging to treat recurrent ovarian cancer effectively as traditional interventions like chemotherapy and surgery have limited long-term efficacy, highlighting an urgent need for innovative approaches. Immunotherapy offers potential advantages in modulating the immune response against tumor cells and has emerged as a promising strategy in ovarian cancer management. This review discusses various immunotherapy modalities, including active and passive immune strategies, for recurrent ovarian cancer. We systematically reviewed recent immunotherapy advances for recurrent ovarian cancer, including the efficacy and mechanisms of single and dual immune checkpoint inhibitors, checkpoint inhibitor combinations with chemotherapy or radiotherapy, anti-angiogenic agents, PARP inhibitors, antibody-drug conjugates (ADC), tumor vaccines, and adoptive cell therapies (ACT). Additionally, we assessed emerging research on biomarkers predictive of immunotherapy responsiveness in ovarian cancer. The findings indicate that immunotherapy, particularly combinations involving immune checkpoint inhibitors and other agents, demonstrates promising efficacy in recurrent ovarian cancer, with some therapies showing enhanced benefits in specific subtypes. The immune microenvironment in platinum-sensitive and -resistant cases exhibits distinct immunological profiles, influencing therapy outcomes. Several potential biomarkers have been identified, potentially aiding in patient stratification and treatment optimization. Immunotherapy significantly advances recurrent ovarian cancer treatment, with various combinations potentially improving outcomes. Further research on predictive biomarkers and immune microenvironment characteristics is crucial for personalizing immunotherapy approaches and enhancing their efficacy in managing recurrent ovarian cancer.

Immunological and autonomic profile of ischemic stroke in lowlands

Immunological and autonomic profile of ischemic stroke in lowlands

The therapeutic potential of circular RNAs.

Over the past decade, research into circular RNA (circRNA) has increased rapidly, and over the past few years, circRNA has emerged as a promising therapeutic platform. The regulatory functions of circRNAs, including their roles in templating protein translation and regulating protein and RNA functions, as well as their unique characteristics, such as increased stability and a favourable immunological profile compared with mRNAs, make them attractive candidates for RNA-based therapies. Here, we describe the properties of circRNAs, their therapeutic potential and technologies for their synthesis. We also discuss the prospects and challenges to be overcome to unlock the full potential of circRNAs as drugs.

Novel Gain-of-Function Mutation in STAT-1 Protein with ALPS-like presentation

Background: Germline mutations in STAT1 lead to primary immunodeficiency affecting both intrinsic and innate immunity. These immunodeficiencies can manifest as either loss-of-function (LOF) mutations or gain-of-function (GOF) mutations. LOF mutations result in a significant reduction in STAT1 protein functionality and are associated with Mendelian susceptibility to mycobacterial disease. Conversely, GOF mutations occur when a gene undergoes a change that enhances its normal function, resulting in an overactive form of the protein. Heterozygous STAT1 GOF mutations are the predominant cause of Chronic Mucocutaneous Candidiasis (CMC) in individuals with inborn errors of immunity. Aim: The study aims to report the clinical features, immune profile, and unique characteristics of a 9-year-old female patient with GOF mutations in STAT-1. Results: We present a case of an 8-year-old female who has been genetically diagnosed with a GOF mutation in the STAT 1 gene. The patient's clinical presentation includes lymphadenopathy, splenomegaly, the presence of non-caseating granulomas, and cytopenia. Notably, there is no evidence of mycobacterial infection typically associated with LOF mutation, nor any indication of fungal, viral, or malignant conditions. Furthermore, there are no signs of endocrine abnormalities such as thyroiditis or diabetes mellitus. The patient's immunological profile reveals evidence of autoimmunity, including symptoms of arthralgia and oral ulcers. Manual calculations of DN T cells showed no increase in their numbers. The patient did not exhibit typical signs of chronic mucocutaneous candidiasis (CMC) but presented with Autoimmune Lymphoproliferative Syndrome (ALPS)-like features, expanding the clinical spectrum of STAT1 GOF mutations. Discussion: The clinical and immunological characteristics of GOF mutations in STAT-1 vary considerably among case reports. The current case had no evidence of CMC, thus raising the possibility of ALPS-like syndrome as an extension of the commonly addressed features of GOF mutations. Statement of novelty: The absence of CMC in a patient with GOF mutations in STAT-1 is a rare presentation that should be considered when evaluating patients with inborn errors of immunity.

Abnormal T-Cell Activation And Cytotoxic T-Cell Frequency Discriminates Symptom Severity In Myalgic Encephalomyelitis/Chronic Fatigue Syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating but poorly-understood disease. ME/CFS symptoms can range from mild to severe, and include immune system effects alongside incapacitating fatigue and post-exertional disease exacerbation. In this study, we examined immunological profiles of people living with ME/CFS by flow cytometry, focusing on cytotoxic cells, to determine whether people with mild/moderate (n= 43) or severe ME/CFS (n=53) expressed different immunological markers. We found that people with mild/moderate ME/CFS had increased expression of cytotoxic effector molecules alongside enhanced proportions of early-immunosenescence cells, determined by the CD28 - CD57 - phenotype, indicative of persistent viral infection. In contrast, people with severe ME/CFS had higher proportions of activated circulating lymphocytes, determined by CD69 + and CD38 + expression, and expressed more pro-inflammatory cytokines, including IFNγ, TNF and IL-17, following stimulation in vitro , indicative of prolonged non-specific inflammation. These changes were consistent across different cell types including CD8 + T cells, mucosal associated invariant T cells and Natural Killer cells, indicating generalised altered cytotoxic responses across the innate and adaptive immune system. These immunological differences likely reflect different disease pathogenesis mechanisms occurring in the two clinical groups, opening up opportunities for the development of prognostic markers and stratified treatments.

Pathophysiology and Treatment of Psoriasis: From Clinical Practice to Basic Research.

Psoriasis, a chronic inflammatory dermatosis, represents a significant clinical challenge due to its complex pathogenesis and the limitations of existing therapeutic strategies. Current psoriasis diagnoses are primarily clinician-dependent, with instrumental diagnostics serving as adjuncts. Ongoing research is progressively deciphering its molecular underpinnings; the future of psoriasis diagnostics may involve genetic and immunological profiling to pinpoint biomarkers, enabling more accurate and timely interventions. The administration of psoriasis medications, whether oral, injectable, or topical, is associated with a range of side effects and compliance issues. Topical medications, despite their advantages in patient compliance and reduced systemic side effects, are hindered by the altered skin barrier in psoriasis, which impedes effective drug penetration and retention. In recent years, the development of novel transdermal drug delivery systems represents a promising frontier in psoriasis management. Nanotechnology-, microneedle- and dressing-based systems have demonstrated the potential for improved skin penetration, enhanced bioavailability, or extended retention time. Here, we will focus on the latest insights into the etiology, diagnostic methodologies, and therapeutic approaches for psoriasis, with a particular emphasis on the evolution and challenges of novel transdermal drug delivery systems.