Systemic Adaptive Immune Responses Research Articles

Enhancing CAR-T cell therapy against solid tumor by drug-free triboelectric immunotherapy

Chimeric antigen receptor (CAR) T cell therapy is a highly effective immunotherapy for hematological tumors, but its efficacy against most solid tumors remains challenging. Herein, a novel synergistic combination therapy of drug-free triboelectric immunotherapy and CAR-T cell therapy against solid tumor was proposed. A triboelectric nanogenerator (TENG) that can generate pulsed direct-current by coupling triboelectrification effect and electrostatic breakdown effect was fabricated. The TENG can generate up to 30 pulse direct-current peaks with peak current output ≈35 μA in a single sliding to power the triboelectric immunotherapy. The pulsed direct-current stimulation induced immunogenic cell death of tumor cells (survival rate of 35.9 %), which promoted dendritic cells maturation, accelerated the process of antigen presentation to CAR-T cells and enhanced the systemic adaptive immune response. Furthermore, triboelectric immunotherapy promoted M1-like macrophage polarization, reduced regulatory T cells differentiation and reprogrammed the tumor immunosuppressive microenvironment, which ultimately enhanced the efficacy of CAR-T cells to eradicate nearly 60 % of NALM6 solid tumor mass. Notably, considering that triboelectric immunotherapy is a safe and effective drug-free antitumor strategy, the combined therapy did not increase the burden of double-medication on patients.

TG6050, an oncolytic vaccinia virus encoding interleukin-12 and anti-CTLA-4 antibody, favors tumor regression via profound immune remodeling of the tumor microenvironment

BackgroundTG6050 was designed as an improved oncolytic vector, combining the intrinsic properties of vaccinia virus to selectively replicate in tumors with the tumor-restricted expression of recombinant immune effectors to modify...

Mycobacterium tuberculosis-Human Immunodeficiency Virus Infection and the Role of T Cells in Protection.

Tuberculosis (TB), primarily caused by Mycobacterium tuberculosis (M. tb), remains a widespread fatal health issue that becomes significantly detrimental when coupled with HIV. This study explores the host's innate and adaptive immune system response to TB in HIV immunocompromised patients, highlighting the significant role of CD8+ T cells. While the crucial role of macrophages and cytokines, like TNF-α and IFN-γ, in managing the host's immune response to M. tb is examined, the emphasis is on the changes that occur as a result of HIV coinfection. With the progression of HIV infection, the primary source of IFN-γ changes from CD4+ to CD8+ T cells, especially when latent TB advances to an active state. This study sheds light on the necessity of developing new preventative measures such as vaccines and new treatment approaches to TB, especially for immunocompromised patients, who are at a higher risk of life-threatening complications due to TB-HIV coinfection.

Do domain-specific protein language models outperform general models on immunology-related tasks?

Deciphering the antigen recognition capabilities by T-cell and B-cell receptors (antibodies) is essential for advancing our understanding of adaptive immune system responses. In recent years, the development of protein language models (PLMs) has facilitated the development of bioinformatic pipelines where complex amino acid sequences are transformed into vectorized embeddings, which are then applied to a range of downstream analytical tasks. With their success, we have witnessed the emergence of domain-specific PLMs tailored to specific proteins, such as immune receptors. Domain-specific models are often assumed to possess enhanced representation capabilities for targeted applications, however, this assumption has not been thoroughly evaluated. In this manuscript, we assess the efficacy of both generalist and domain-specific transformer-based embeddings in characterizing B and T-cell receptors. Specifically, we assess the accuracy of models that leverage these embeddings to predict antigen specificity and elucidate the evolutionary changes that B cells undergo during an immune response. We demonstrate that the prevailing notion of domain-specific models outperforming general models requires a more nuanced examination. We also observe remarkable differences between generalist and domain-specific PLMs, not only in terms of performance but also in the manner they encode information. Finally, we observe that the choice of the size and the embedding layer in PLMs are essential model hyperparameters in different tasks. Overall, our analyzes reveal the promising potential of PLMs in modeling protein function while providing insights into their information-handling capabilities. We also discuss the crucial factors that should be taken into account when selecting a PLM tailored to a particular task.

Ascaris suum infection in juvenile pigs elicits a local Th2 response in a setting of ongoing Th1 expansion.

Ascaris spp. undergo extensive migration within the body before establishing patent infections in the small intestinal tract of humans and pigs. However, whether larval migration is critical for inducing efficient type 2 responses remains poorly understood. Therefore, we investigated systemic versus local adaptive immune responses along the hepato-tracheal migration of Ascaris suum during primary, single infections in conventionally raised pigs. Neither the initial invasion of gut tissue nor migration through the liver resulted in discernable Th2 cell responses. In contrast, lung-stage larvae elicited a Th2-biased pulmonary response, which declined after the larvae had left the lungs. In the small intestine, we observed an accumulation of Th2 cells upon the arrival of fourth-stage larvae (L4) to the small intestinal lumen. In parallel, we noticed robust and increasing Th1 responses in circulation, migration-affected organs, and draining lymph nodes. Phenotypic analysis of CD4+ T cells specifically recognizing A. suum antigens in the circulation and lung tissue of infected pigs confirmed that the majority of Ascaris-specific T cells produced IL-4 (Th2) and, to a much lesser extent, IL-4/IFN-g (Th2/1 hybrids) or IFN-g alone (Th1). These data demonstrate that lung-stage but not the early liver-stage larvae lead to a locally restricted Th2 response. Significant Th2 cell accumulation in the small intestine occurs only when L4 complete the body migration. In addition, Th2 immunity seems to be hampered by the concurrent, nonspecific Th1 bias in growing pigs. Together, the late onset of Th2 immunity at the site of infection and the Th1-biased systemic immunity likely enable the establishment of intestinal infections by sufficientlylarge L4 stages and pre-adult worms, some of which resist expulsion mechanisms.

Abstract 184: M1-like macrophage infiltration, CD8+ T cell activation, and increased cancer cell apoptosis in immunologically cold Lewis lung carcinoma treated with tumor-trophic Salmonella Typhimurium expressing anticancer proteins in immunocompetent C57BL/6 mice

Abstract Immunotherapy has revolutionized cancer treatment with Immune checkpoint inhibitors (ICIs) and genetically engineered T-Cells expressing chimeric antigen receptors (CARs). CAR-T treatment of hematologic malignancies has achieved outstanding patient response rate. CAR T therapy, however, is thwarted in solid tumor treatment due to two major factors: the immune-suppressive tumor microenvironment that Inhibits T-cell infiltration and T-cell function. In addition, cancer resistance to ICIs treatment also limits the solid tumor response rate. This research aims to activate proinflammatory anticancer immune responses in immunologically cold solid tumors using the genetically engineered Salmonella typhimurium VNP20009 strains that express anticancer proteins. Previously, we have shown that the Salmonella Typhimurium VNP20009 strain expressing methioninase (METase) and/or Tumor Necrosis Factor (TNFα) caused rapid tumor destruction of cold Lewis Lung Carcinoma (LLC) grown on immunocompetent C57BL/6 mice. In this investigation, several mechanisms of this tumor tropic anti-cancer bacteria were studied including the innate and adaptive immune system responses and cancer cell apoptosis. In a pilot study, we selected eight tumor tissues treated with several different bacteria strains and performed histological analysis to observe the effectiveness of each. We found that in the tumor tissues treated with VNP20009_rMETase_TNFα, there was infiltration and activation of CD8+ T cells coupled with reduced amounts of T regulatory cells, as well as an increased ratio of M1-like to M2-like macrophages. We also observed increased tumor apoptosis associated with an elevated detection of an apoptosis biomarker and a suppressed amount of the Ki67 tumor growth signal. These findings indicate that VNP20009_rMETase_TNFα anticancer bacteria can disrupt the tumor microenvironment in the cold LLC tumors and active innate and adaptive anti-cancer immune response in immunocompetent mice. Further, we are investigating additional cold solid mouse tumor models to validate our findings and how this can apply to bacteria-based immunotherapy. Citation Format: Qiuhong He, Lindsay R. Brncick, Boxi Gong, Julia L. Flowers. M1-like macrophage infiltration, CD8+ T cell activation, and increased cancer cell apoptosis in immunologically cold Lewis lung carcinoma treated with tumor-trophic Salmonella Typhimurium expressing anticancer proteins in immunocompetent C57BL/6 mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 184.

Photodynamic Therapy and Adaptive Immunity Induced by Reactive Oxygen Species: Recent Reports.

Cancer is one of the most significant causes of death worldwide. Despite the rapid development of modern forms of therapy, results are still unsatisfactory. The prognosis is further worsened by the ability of cancer cells to metastasize. Thus, more effective forms of therapy, such as photodynamic therapy, are constantly being developed. The photodynamic therapeutic regimen involves administering a photosensitizer that selectively accumulates in tumor cells or is present in tumor vasculature prior to irradiation with light at a wavelength corresponding to the photosensitizer absorbance, leading to the generation of reactive oxygen species. Reactive oxygen species are responsible for the direct and indirect destruction of cancer cells. Photodynamically induced local inflammation has been shown to have the ability to activate an adaptive immune system response resulting in the destruction of tumor lesions and the creation of an immune memory. This paper focuses on presenting the latest scientific reports on the specific immune response activated by photodynamic therapy. We present newly discovered mechanisms for the induction of the adaptive response by analyzing its various stages, and the possible difficulties in generating it. We also present the results of research over the past 10 years that have focused on improving the immunological efficacy of photodynamic therapy for improved cancer therapy.

CTIM-20. SYSTEMIC IMMUNE CORRELATES ASSOCIATED WITH LONG-TERM SURVIVAL AFTER THERAPEUTIC ADENOVIRUS (DNX2401) PLUS INTERFERON GAMMA FOR RECURRENT GLIOBLASTOMA EFFECT TRIAL (TARGET): A RANDOMIZED PHASE 1 TRIAL

Abstract Anti-tumor immune response following oncolytic virus treatment of glioblastoma may be enhanced by immune activating therapies. Here, in this Phase Ib, multicenter, randomized, open-label study we evaluated the combination of intra-tumoral delivery of oncolytic virus DNX-2401 with subcutaneous interferon gamma (IFN-γ) a T-helper 1 response activator in 37 patients with recurrent glioblastoma. In part 1, 27 patients were randomized 2:1 into DNX-2401 with IFN-γ and DNX-2401 alone with intra-tumoral DNX-2401 administered via a standard biopsy needle. In part 2, 10 patients received intra-tumoral DNX-2401 via an FDA-approved Alcyone MEMS Cannula designed to prevent backflow at high infusion flowrates. DNX-2401 was well tolerated but the addition of IFN- γ was not well tolerated. The primary efficacy endpoint, objective clinical response, was not met. The secondary endpoint of 12-month overall survival for DNX-2401 with IFN-γ, DNX-2401 alone and DNX-2401 via Cannula were 33%, 22%, 0% respectively. The 18-month OS for DNX-2401 with IFN-γ, DNX-2401 alone and DNX-2401 via Cannula were 25%, 9%, 0% respectively. The DNX-2401 with IFN- γ cohort had the most long-term survivors (44.2, 23.7, 20.6 and 20.1 months). Systemic antibody and immune cell profiling following DNX-2401 treatment showed that long term survivors had significantly higher anti-adenovirus specific antibody reactivity and a higher activated CD8+ effector memory T-cell sub-population at 2 months post-treatment relative to baseline. This systemic immune response did not occur in short term survivors following DNX-2401 treatment. Overall, these data suggest that an early and robust systemic adaptive immune response could be used as a biomarker for long term survival following DNX-2401 treatment of recurrent glioblastoma independent of other salvage treatments administered following disease progression during the trial. (Clinical Trial.gov registration: NCT02197169).

Expression of Interferon Regulatory Factor 8 (IRF8) and Its Association with Infections in Dialysis Patients.

Patients on dialysis have dysfunctions of innate and adaptive immune system responses. The transcriptional factor IRF8 (interferon regulatory factor 8) is primarily expressed in plasmacytoid cells (pDCs) and myeloid dendritic cells (mDCs), playing a crucial role in the maturation of dendritic cells, monocytes, and macrophages, and contributing to protection against bacterial infections. The current study analyzed the expression patterns of IRF8 and assessed its association with the risk of infections in 79 dialysis patients compared to 44 healthy controls. Different subsets of leukocytes and the intracellular expression of IRF8 were measured using flow cytometry. Compared to the healthy controls, the dialysis patients showed significantly reduced numbers of pDCs and significantly increased numbers of natural killer cells and classical and intermediate monocytes. The dialysis patients exhibited decreased numbers of IRF8-positive dendritic cells (pDC p < 0.001, mDC1 p < 0.001, mDC2 p = 0.005) and increased numbers of IRF8-positive monocytes (p < 0.001). IRF8 expression in pDC, mDC, and classical monocytes was lower in the dialysis patients than in the controls. Dialysis patients who required hospitalization due to infections within one year of follow-up displayed significantly reduced IRF8 expression levels in pDCs compared to patients without such infections (p = 0.04). Our results suggest that reduced IRF8 expression in pDCs is a potential risk factor predisposing dialysis patients to serious infections.

Plasma metabolomics by nuclear magnetic resonance reveals biomarkers and metabolic pathways associated with the control of HIV-1 infection/progression.

How the human body reacts to the exposure of HIV-1 is an important research goal. Frequently, HIV exposure leads to infection, but some individuals show natural resistance to this infection; they are known as HIV-1-exposed but seronegative (HESN). Others, although infected but without antiretroviral therapy, control HIV-1 replication and progression to AIDS; they are named controllers, maintaining low viral levels and an adequate count of CD4+ T lymphocytes. Biological mechanisms explaining these phenomena are not precise. In this context, metabolomics emerges as a method to find metabolites in response to pathophysiological stimuli, which can help to establish mechanisms of natural resistance to HIV-1 infection and its progression. We conducted a cross-sectional study including 30 HESN, 14 HIV-1 progressors, 14 controllers and 30 healthy controls. Plasma samples (directly and deproteinized) were analyzed through Nuclear Magnetic Resonance (NMR) metabolomics to find biomarkers and altered metabolic pathways. The metabolic profile analysis of progressors, controllers and HESN demonstrated significant differences with healthy controls when a discriminant analysis (PLS-DA) was applied. In the discriminant models, 13 metabolites associated with HESN, 14 with progressors and 12 with controllers were identified, which presented statistically significant mean differences with healthy controls. In progressors, the metabolites were related to high energy expenditure (creatinine), mood disorders (tyrosine) and immune activation (lipoproteins), phenomena typical of the natural course of the infection. In controllers, they were related to an inflammation-modulating profile (glutamate and pyruvate) and a better adaptive immune system response (acetate) associated with resistance to progression. In the HESN group, with anti-inflammatory (lactate and phosphocholine) and virucidal (lactate) effects which constitute a protective profile in the sexual transmission of HIV. Concerning the significant metabolites of each group, we identified 24 genes involved in HIV-1 replication or virus proteins that were all altered in progressors but only partially in controllers and HESN. In summary, our results indicate that exposure to HIV-1 in HESN, as well as infection in progressors and controllers, affects the metabolism of individuals and that this affectation can be determined using NMR metabolomics.

Peyer's patch-involved gut microbiota facilitates anti-HBV immunity in mice

BackgroundGut microbiota is crucial for immune homeostasis and is associated with the prognosis of chronic hepatitis B infection. Peyer's patches (PPs), characterized by intestinal mucosa localization, are involved in the gut microbiota-mediated immune response. However, whether and how PPs orchestrate gut microbiota-modulated anti-hepatitis B virus (HBV) response remain elusive. This study aims to elucidate the role of PPs in gut microbiota-mediated anti-HBV adaptive immunity. MethodsWe investigated the effects of gut microbiota and PPs on adaptive immune responses by transcriptomic, phenotypic, and functional analyzes from an HBV mouse model with gut commensal microbiota and PP-depleting interventions. ResultsDepletion of gut microbiota impaired systemic adaptive immune responses, resulting in a delayed HBV antigen clearance. Differentially expressed genes analysis of PPs revealed that pathways related to adaptive immune responses were significantly downregulated in gut microbiota-deficient mice. Notably, the depletion of PPs could abolish gut microbiota-boosted intrahepatic HBV-specific T cell response, leading to a higher serum hepatitis B surface antigen level in mice. ConclusionPPs orchestrate gut microbiota-mediated intrahepatic anti-HBV cellular immunity, underlining the significance of remote manipulating the “gut microbiota-PPs” axis for achieving optimum anti-HBV response.

SARS-CoV-2 Neutralization Assay System using Pseudo-lentivirus

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects humans' lower respiratory tracts and causes coronavirus disease-2019 (COVID-19). Neutralizing antibodies is one of the adaptive immune system responses that can reduce SARS-CoV-2 infection. This study aimed to develop a SARS-CoV-2 neutralization assay system using pseudo-lentivirus.METHODS: The plasmid used for pseudo-lentivirus production was characterized using restriction analysis. The gene encoding for SARS-CoV-2 spike protein was confirmed using sequencing. The transfection pseudo-lentivirus optimal condition was determined by choosing the transfection reagents and adding centrifugation step. Optimal pseudo-lentivirus infection was analysed using fluorescent assay and luciferase assay. The optimal condition of pseudo-lentivirus infection was determined by the target cell type and the number of pseudo-lentiviruses used for neutralization test. SARS-CoV-2 pseudo-lentivirus was used to detect neutralizing antibodies from serum samples.RESULTS: The plasmid used for pseudo-lentivirus production was characterized and confirmed to have no mutations. Lipofectamine 2000 reagent generated pseudo-lentivirus with a higher ability to infect target cells, as indicated by a percentage green fluorescent protein (GFP) of 12.68%. Pseudo-lentivirus centrifuged obtained more stable results in luciferase expression. Optimal pseudo-lentivirus infection conditions were obtained using puromycin-selected HEK 293T-ACE2 cells as target cells. The number of pseudo-lentiviruses used in the neutralization assay system was multiplicity of infection (MOI) 0.075. Serum A samples with a 1:10 dilution had the highest neutralizing antibody activity.CONCLUSION: This study shows that SARS-CoV-2 neutralization assay system using pseudo-lentivirus successfully detected neutralizing antibodies in human serum, which were indicated by a decrease in the percentage of pseudo-lentivirus infections.KEYWORDS: COVID-19, neutralizing antibody, neutralization assay, pseudo-lentivirus, SARS-COV-2

Neo-Adjuvant immunotherapies: Bladder cancer as a platform for drug development targeting mucosal immunity

Bacillus Calmette-Guerin (BCG) is a live attenuated Mycobacterium bovis strain, originally developed as a vaccine against tuberculosis. It is also the only bacterial cancer therapy approved by the US Food & Drug Administration for clinical use. BCG is delivered in the bladder, shortly after tumour resection, for patients with high-risk non-muscle invasive bladder cancer (NMIBC). Modulating mucosal immunity by exposing the urothelium to intravesical BCG has been the main therapeutic strategy for high-risk NMIBC over the last three decades. Thus, BCG provides a benchmark for the clinical development of bacteria—or other live attenuated pathogens—as cancer therapy. Currently, a myriad of immuno-oncology compounds is under clinical evaluation in BCG-unresponsive and BCG-naïve patients as an alternative therapy in the context of worldwide BCG shortages. For patients with non-metastatic muscle-invasive bladder cancer (MIBC), studies investigating neoadjuvant immunotherapy with either anti–PD-1/PD-L1 monoclonal antibodies in monotherapy or in combination with anti–CTLA-4 monoclonal antibodies have shown overall efficacy and acceptable safety profiles prior to radical cystectomy. Emerging clinical investigations are testing synergistic approaches by combining intravesical delivery of drugs with systemic immune checkpoint blockades in the neoadjuvant setting for patients with MIBC. Such novel strategy aims to prime a local anti-tumour immunity and reduce distant metastatic relapses by enhancing a systemic adaptive anti-tumour immune response. Here, we present and discuss some of the most promising clinical trials developing such novel therapeutic approaches.

On the use of a coupled mathematical model for understanding the dynamics of multiple sclerosis

Multiple sclerosis (MS) is characterised by the attack on the myelin sheath, oligodendrocytes, and neurons by immune system cells. For this reason, MS is classified as an autoimmune and demyelinating disease. This work aims to study the influence of both the innate and adaptive immune response activation at the onset and development of MS through the coupling of two mathematical models in different compartments, both based on differential equations. The proposed model is, to the best of our knowledge, the first mathematical model based on differential equations that represent the spatio-temporal dynamics of the innate immune response activation in the brain tissue and the posterior activation of the adaptive cellular and humoral immune system responses in the lymph node through antigen presentation, culminating on the attack to the oligodendrocytes and plaque formation.

Spatiotemporal local and abscopal cell death and immune responses to histotripsy focused ultrasound tumor ablation.

Histotripsy is a novel focused ultrasound tumor ablation modality with potent immunostimulatory effects. To measure the spatiotemporal kinetics of local andabscopal responses to histotripsy, C57BL/6 mice bearing bilateral flank B16 melanoma or Hepa1-6 hepatocellular carcinoma tumors were treated with unilateral sham or partial histotripsy. Treated and contralateral untreated (abscopal) tumors were analyzed using multicolor immunofluorescence, digital spatial profiling, RNA sequencing (RNASeq), and flow cytometry. Unilateral histotripsy triggered abscopal tumor growth inhibition. Within the ablation zone, early high mobility group box protein 1 (HMGB1) release and necroptosis were accompanied by immunogenic cell death transcriptional responses in tumor cells and innate immune activation transcriptional responses in infiltrating myeloid and natural killer (NK) cells. Delayed CD8+ T cell intratumoral infiltration was spatiotemporally aligned with cancer cell features of ferroptosis; this effect was enhanced by CTLA-4 blockade and recapitulated in vitro when tumor-draining lymph node CD8+ T cells were co-cultured with tumor cells. Inoculation with cell-free tumor fractions generated by histotripsy but not radiation or freeze/thaw conferred partial protection from tumor challenge. We propose that histotripsy may evoke local necroptotic immunogenic cell death, priming systemic adaptive immune responses and abscopal ferroptotic cancer cell death.

Unique Characteristics of Neonatal T Cells

Birth causes complex changes in the individual physiology and organ systems and certainly poses a big immune challenge. The sudden encounter with an antigen full world, with the exposure to food antigens, and the colonization of the skin and mucosa with microbiota, require a tolerant immune system. Nevertheless, neonates must also be able to deal with pathogens, which makes their immune system unique. T lymphocytes are responsible for the coordination of the adaptive immune system response, the elimination of infected cells and the type of immune response and memory. It has been shown that neonatal cells have intrinsic differences with adult cells, biased towards an innate response and a tolerant phenotype. In the perinatal period, the immune system changes from basal signaling and innate like responses, towards stimulus-specific signals, which increase with gestational age. After birth the cells of the immune system continue to change both in composition and function. In this review, we present the intrinsic differences of neonatal CD4+ and CD8+ T cells, as compared with adult naïve cells. A specific transcriptome profile is present in both CD4+ and CD8+ neonatal T cells, with overexpression of homeobox transcription factors. These cells also present differences in cell signaling and metabolic characteristics, which result in unique functional capabilities. Neonatal CD4+ T cells respond differently from adult cells, with a high production of IL-8, a prevalent Th2 over Th1 profile, and an innate inflammatory response. The neonatal period is one of the most vulnerable periods of life, with a high morbidity and mortality rate, approaching on average 17 deaths per 1000 live births worldwide. A better understanding of the neonatal immune system will help to ensure a better care of this vulnerable population.

Clinical and Prognostic Significance of Baseline Serum Vitamin D Levels in Hospitalized Egyptian Covid-19 Patients.

Vitamin D is a hormone with essential roles in both cellular metabolism and immunity. It controls calcium homeostasis and modulates innate and adaptive immune system responses. Many studies suggested an association between vitamin D deficiency and clinical outcomes of covid-19 infection, while others failed to document such a relation. The present study aimed to evaluate the clinical and prognostic significance of baseline vitamin D levels in hospitalized Egyptian covid-19 patients. The present retrospective study included 300 hospitalized covid-19 patients. Patients were submitted to standard clinical, laboratory, and radiological assessment. According to vitamin D levels, patients were classified to have normal levels (≥30), insufficient levels (20-29) or deficient levels (<20). According to their vitamin D levels, patients were classified into those with normal vitamin D (n=135), others with vitamin D insufficiency (n=114), and a third group with vitamin D deficiency (n=51). Patients with normal vitamin D levels and vitamin D insufficiency are significantly younger [median (IQR): 49.0 (39.0-57.0) versus 51.0 (40.0-61.0) and 55.0 (43.0-62.0) years, respectively, p=0.012] and had less frequency of severe disease (24.4% versus 40.4% and 51.0%, respectively) when compared with those with vitamin D deficiency. Moreover, they had significantly lower levels of D dimer [median (IQR): 1.5 (0.9-2.5) versus 1.8 (0.9-3.1) and 2.0 (1.0-3.2)], CRP [median (IQR): 58.0 (30.0-120.0) versus 76.0 (42.5-160.0) and 105.0 (74.0-208.0), respectively, p<0.001], ferritin [median (IQR): 458.0 (240.0-759.0) versus 606.0 (433.8-897.8) and 820.0 (552.0-1087.0), respectively, p<0.001], and procalcitonin [median (IQR): 290.0 (152.0-394.0) versus 372.5 (227.0-530.5) and 443.0 (272.0-575.0), respectively, p<0.001]. Only lower vitamin D levels were significant predictors of mortality in multivariate analysis [OR (95% CI): 0.88 (0.84-0.92), p<0.001]. Low vitamin D levels are related to exaggerated inflammatory response, disease severity, and poor clinical outcome in hospitalized covid-19 patients.

Etiology of IBD-Is It Still a Mystery?

Inflammatory bowel diseases (IBD), including colitis ulcerosa and Crohn’s disease, are chronic diseases of the gastrointestinal tract for which the cause has not been fully understood. However, it is known that the etiology is multifactorial. The multidirectional network of interactions of environmental, microbiological and genetic factors in predisposed persons lead to an excessive and insufficiently inhibited reaction of the immune system, leading to the development of chronic inflammation of the gastrointestinal walls, the consequence of which is the loss of the function that the intestine performs, inter alia, through the process of fibrosis. Detailed knowledge of the pathways leading to chronic inflammation makes it possible to pharmacologically modulate disorders and effectively treatthese diseases. In this review, we described the primary and adaptive immune system response in the gut and the known immune pathogenetic pathways leading to the development of IBD. We also described the process leading to intestinal tissue fibrosis, which is an irreversible consequence of untreated IBD.

Environmental factors influencing the risk of ANCA-associated vasculitis.

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of diseases characterized by inflammation and destruction of small and medium-sized blood vessels. Clinical disease phenotypes include microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA). The incidence of AAV has been on the rise in recent years with advances in ANCA testing. The etiology and pathogenesis of AAV are multifactorial and influenced by both genetic and environmental factors, as well as innate and adaptive immune system responses. Multiple case reports have shown that sustained exposure to silica in an occupational environment resulted in a significantly increased risk of ANCA positivity. A meta-analysis involving six case-control studies showed that silica exposure was positively associated with AAV incidence. Additionally, exposure to air pollutants, such as carbon monoxide (CO), is a risk factor for AAV. AAV has seasonal trends. Studies have shown that various environmental factors stimulate the body to activate neutrophils and expose their own antigens, resulting in the release of proteases and neutrophil extracellular traps, which damage vascular endothelial cells. Additionally, the activation of complement replacement pathways may exacerbate vascular inflammation. However, the role of environmental factors in the etiology of AAV remains unclear and has received little attention. In this review, we summarized the recent literature on the study of environmental factors, such as seasons, air pollution, latitude, silica, and microbial infection, in AAV with the aim of exploring the relationship between environmental factors and AAV and possible mechanisms of action to provide a scientific basis for the prevention and treatment of AAV.

MiRNA-REGULATED PATHWAYS OF CD8+ T CELLS IN TNBC MOUSE MODEL

Objective: Triple negative breast cancer, which constitutes 20% of all breast cancer is the most aggressive breast cancer subtype. Although breast cancer is known as immune cold, recent studies have revealed that there is an immune response on the basis of subtypes. miRNAs are involved in regulating many biological processes of CD8+ T lymphocytes, which are adaptive immune system cells that effectively destroy tumor cells. Our aim is to examine the regulative roles of miRNAs in CD8+ T lymphocytes during the formation of triple negative breast tumors in mice. Materials and Methods:4T1 cells and Balb/c mice were used for the allograft breast cancer model. After 2 weeks, tumor-bearing and control mice were sacrificed, and spleens were harvested for CD8+ T cell isolation. Following RNA isolation, miRNA microarray analysis was performed. Differentially expressed miRNAs between the groups were detected. DIANA-mirPath web tool was used to investigate the target genes of miRNAs and in which pathways these genes are enriched. Results: Microarray analysis indicated that 41 miRNAs are differentially expressed in CD8+ T cells from tumor-bearing mice compared to the control group. The KEGG analysis results showed that the targets of differentially expressed miRNAs were significantly enriched in immune response-related pathways like ECM-receptor interaction, PI3K-Akt signaling, and tryptophan metabolism pathways. Conclusion: The pathways in which miRNA-target genes are enriched are associated with T cell metabolism and cell survival. It may be concluded that there are changes in the systemic adaptive immune response during TNBC formation and that miRNAs regulate these changes.