Circulating Polymorphonuclear Myeloid-Derived Suppressor Cells (PMN-MDSCs) Have a Biological Role in Patients with Primary Myelofibrosis.

Primary myelofibrosis (PMF) is a myeloproliferative neoplasm characterized by a chronic inflammatory state that plays a relevant role in the disease pathogenesis (as proven by high levels of inflammatory cytokines with prognostic significance and by a persistent oxidative stress) and by extensive neoangiogenesis in bone marrow (BM) and spleen. Myeloid-derived suppressor cells (MDSCs) are immature cells that expand in patients with cancer, sepsis or chronic inflammation, favoring tumor onset and progression mainly through the decrease in immune surveillance and the promotion of neoangiogenesis. In this paper, we evaluated the presence of circulating MDSCs in PMF patients, the plasmatic factors involved in their mobilization/expansion and the correlations with laboratory, genetic and clinical parameters.

VDAC1-interacting molecules promote cell death in cancer organoids through mitochondrial-dependent metabolic interference.

The voltage-dependent anion-selective channel isoform 1 (VDAC1) is a pivotal component in cellular metabolism and apoptosis with a prominent role in many cancer types, offering a unique therapeutic intervention point. Through an -to- approach we identified a set of VA molecules (VDAC Antagonists) that selectively bind to VDAC1 and display specificity toward cancer cells. Biochemical characterization showed that VA molecules can directly interact with VDAC1 with micromolar affinity by competing with the endogenous ligand NADH for a partially shared binding site.

Long-term dynamics of natural killer cells in response to SARS-CoV-2 vaccination: Persistently enhanced activity postvaccination.

Natural Killer (NK) cells play a significant role in the early defense against virus infections and cancer. Recent studies have demonstrated the involvement of NK cells in both the induction and effector phases of vaccine-induced immunity in various contexts. However, their role in shaping immune responses following SARS-CoV-2 vaccination remains poorly understood.

Hepatitis C Virus and the Host: A Mutual Endurance Leaving Indelible Scars in the Host's Immunity.

Hepatitis C virus (HCV) has spread worldwide, and it is responsible for potentially severe chronic liver disease and primary liver cancer. Chronic infection remains for life if not spontaneously eliminated and viral persistence profoundly impairs the efficiency of the host's immunity. Attempts have been made to develop an effective vaccine, but efficacy trials have met with failure.

TLRs: Innate Immune Sentries against SARS-CoV-2 Infection.

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been responsible for a devastating pandemic since March 2020. Toll-like receptors (TLRs), crucial components in the initiation of innate immune responses to different pathogens, trigger the downstream production of pro-inflammatory cytokines, interferons, and other mediators. It has been demonstrated that they contribute to the dysregulated immune response observed in patients with severe COVID-19.

Ceramide present in cholangiocarcinoma-derived extracellular vesicle induces a pro-inflammatory state in monocytes.

Cholangiocarcinoma (CCA) is a rare cancer characterized by a global increasing incidence. Extracellular vesicles (EV) contribute to many of the hallmarks of cancer through transfer of their cargo molecules. The sphingolipid (SPL) profile of intrahepatic CCA (iCCA)-derived EVs was characterized by liquid chromatography-tandem mass spectrometry analysis.

Impaired intratumoral natural killer cell function in head and neck carcinoma.

Natural killer (NK) cells are emerging as unique players in the immune response against cancer; however, only limited data are available on tumor infiltrating NK cells in head and neck squamous cell carcinoma (HNSCC), one of the most common cancer. Occurrence of HNSCC is closely related to the immune microenvironment, and immunotherapy is increasingly being applied to this setting. However, the limited success of this type of treatment in this tumor calls for further investigation in the field.

Defective DNAM-1 Dependent Cytotoxicity in Hepatocellular Carcinoma-Infiltrating NK Cells.

Background: Natural killer (NK) cells play a key role in immune surveillance and response to tumors, their function regulated by NK cell receptors and their ligands. The DNAM-1 activating receptor recognizes the CD155 molecule expressed in several tumor cells, such as hepatocellular carcinoma (HCC). This study aims to investigate the role of the DNAM-1/CD155 axis in mediating the NK cell response in patients with HCC.

The polymorphism L412F in inhibits autophagy and is a marker of severe COVID-19 in males.

The polymorphism L412F in TLR3 has been associated with several infectious diseases. However, the mechanism underlying this association is still unexplored. Here, we show that the L412F polymorphism in TLR3 is a marker of severity in COVID-19.

Common, low-frequency, rare, and ultra-rare coding variants contribute to COVID-19 severity.

The combined impact of common and rare exonic variants in COVID-19 host genetics is currently insufficiently understood. Here, common and rare variants from whole-exome sequencing data of about 4000 SARS-CoV-2-positive individuals were used to define an interpretable machine-learning model for predicting COVID-19 severity. First, variants were converted into separate sets of Boolean features, depending on the absence or the presence of variants in each gene.

High Frequencies of Functional Virus-Specific CD4 T Cells in SARS-CoV-2 Subjects With Olfactory and Taste Disorders.

Olfactory and taste disorders (OTD) are commonly found as presenting symptoms of SARS-CoV-2 infection in patients with clinically mild COVID-19. Virus-specific T cells are thought to play an important role in the clearance of SARS-CoV-2; therefore the study of T cell specific immune responses in patients with mild symptoms may help to understand their possible role in protection from severe disease. We evaluated SARS-CoV-2-specific T cell responses to four different peptide megapools covering all SARS-CoV-2 proteins during the acute phase of the disease in 33 individuals with mild or no other symptom beside OTD and in 22 age-matched patients with severe infection.

A new algorithm shows superior ability to discriminate liver fibrosis stages in chronic hepatitis C.

Previous evidence suggests that sialic acid-binding Ig-like lectin 7 (Siglec-7) protein is significantly increased in patients with chronic hepatitis C virus (HCV) infection and directly correlates with clinical parameters of liver inflammation and fibrosis. The aim of this study was to determine the diagnostic value of Siglec-7 as a non-invasive tool to assess liver fibrosis in patients with chronic hepatitis C in a cross-sectional study. Serum levels of Siglec-7 were retrospectively tested in 1007 consecutive patients with chronic HCV infection recruited at three different European sites and data examined by the 'imperfect gold-standard' statistical analysis.

Association of Toll-like receptor 7 variants with life-threatening COVID-19 disease in males: findings from a nested case-control study.

Background: Recently, loss-of-function variants in TLR7 were identified in two families in which COVID-19 segregates like an X-linked recessive disorder environmentally conditioned by SARS-CoV-2. We investigated whether the two families represent the tip of the iceberg of a subset of COVID-19 male patients.

Methods: This is a nested case-control study in which we compared male participants with extreme phenotype selected from the Italian GEN-COVID cohort of SARS-CoV-2-infected participants (<60 y, 79 severe cases versus 77 control cases).

An Anti-MICA/B Antibody and IL-15 Rescue Altered NKG2D-Dependent NK Cell Responses in Hepatocellular Carcinoma.

Natural killer (NK) cells play a pivotal role in cancer immune surveillance, and activating the receptor/ligand interaction may contribute to control the development and evolution of hepatocellular carcinoma (HCC). We investigated the role of the natural killer group 2 member D (NKG2D) activating receptor and its ligand, the major histocompatibility complex class I chain-related protein A and B (MICA/B) in patients with cirrhosis and HCC subjected to surgical resection, patients with cirrhosis and no HCC, and healthy donors (HD). The NKG2D-mediated function was determined in peripheral blood (PB), in tumor-infiltrating lymphocytes (NK-TIL), and in matched surrounding liver tissue (NK-LIL).

Unique immunological profile in patients with COVID-19.

The relationship between severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host immunity is poorly understood. We performed an extensive analysis of immune responses in 32 patients with severe COVID-19, some of whom succumbed. A control population of healthy subjects was included.

Natural Killer Cell Responses in Hepatocellular Carcinoma: Implications for Novel Immunotherapeutic Approaches.

Hepatocellular carcinoma (HCC) still represents a significant complication of chronic liver disease, particularly when cirrhosis ensues. Current treatment options include surgery, loco-regional procedures and chemotherapy, according to specific clinical practice guidelines. Immunotherapy with check-point inhibitors, aimed at rescuing T-cells from exhaustion, has been applied as second-line therapy with limited and variable success.

Adaptive Natural Killer Cell Functional Recovery in Hepatitis C Virus Cured Patients.

Background And Aims: Current evidence suggests that dysfunctional natural killer (NK) cell responses during hepatitis C virus (HCV) infection can be restored after viral eradication with direct acting antivirals (DAAs). However, the fate of the recently described adaptive NK cell population, endowed with increased ability to mediate antibody-dependent cell-mediated cytotoxicity (ADCC), during HCV infection is poorly defined, while no study has explored the effects of DAAs on this NK subset.

Approach And Results: We performed multicolor flow cytometry to investigate CD57 FcεRIγ adaptive and FcεRIγ conventional NK cell phenotype and function before and after DAA treatment in 59 patients chronically infected with HCV, 39 with advanced liver fibrosis, and 20 with mild-moderate liver fibrosis.

Human Monoclonal Antibodies as Adjuvant Treatment of Chronic Hepatitis B Virus Infection.

Despite the availability of an effective prophylactic vaccine leading to sterilizing immunity, hepatitis B virus (HBV) is responsible for chronic liver disease in more than 250 million individuals, potentially leading to cirrhosis and hepatocellular carcinoma. Antiviral drugs able to completely suppress virus replication are indeed available but they are, by and large, unable to eradicate the virus. Several alternative new treatment approaches are currently being developed but none have so far captured the interest of clinicians for possible clinical development.

Decreased interferon-γ production by NK cells from KIR haplotype B carriers in hepatitis C virus infection.

Background And Aims: Different population genetics studies showed that interactions between killer-cell immunoglobulin-like receptors (KIR) and HLA play a role in viral disease outcome, but functional correlates are missing. Building upon our previous work pointing to a regulatory role for KIR3DL1/DS1 in hepatitis C virus (HCV) infection, we analysed whether its expression may affect natural killer (NK) cell function in the presence or absence of its principal ligand HLA-Bw4 in KIR haplotype A and B carriers, which are characterized by a different representation of activating and inhibitory KIRs.

Methods: We performed KIR and HLA class I genotypic analysis in 54 healthy donors (HD) and 50 HCV+ subjects and examined NK cell cytokine secretion and degranulation in the context of KIR3DL1-HLA-Bw4 match stratified by KIR haplotype.

Deficient Natural Killer Cell NKp30-Mediated Function and Altered NCR3 Splice Variants in Hepatocellular Carcinoma.

The activating natural cytotoxicity receptor NKp30 is critical for natural killer (NK) cell function and tumor immune surveillance. The natural cytotoxicity receptor-3 (NCR3) gene is transcribed into several splice variants whose physiological relevance is still incompletely understood. In this study, we investigated the role of NKp30 and its major ligand B7 homolog 6 (B7-H6) in patients with hepatocellular carcinoma (HCC).

Altered natural killer cell cytokine profile in type 2 autoimmune hepatitis.

Type 2 autoimmune hepatitis (AIH-2) is a rare disease presenting in early childhood. The immunopathogenetic mechanisms are poorly characterized, although a defect of regulatory T cells (Treg) has been shown. There is virtually no information on innate immune responses and natural killer (NK) cells in particular.