Impact of the Multiple Sclerosis-Associated Genetic Variant Gly307Ser on Human CD8 T-Cell Functions.

Background And Objectives: The rs763361 nonsynonymous variant in the gene, which results in a glycine-to-serine substitution at position 307 of the CD226 protein, has been implicated as a risk factor of various immune-mediated diseases, including multiple sclerosis (MS). Compelling evidence suggests that this allele may play a significant role in predisposing individuals to MS by decreasing the immune-regulatory capacity of Treg cells and increasing the proinflammatory potential of effector CD4 T cells. However, the impact of this CD226 gene variant on CD8 T-cell functions, a population that also plays a key role in MS, remains to be determined.

Increased levels of circulating soluble CD226 in multiple sclerosis.

Background: The glycoprotein CD226 plays a key role in regulating immune cell function. Soluble CD226 (sCD226) is increased in sera of patients with several chronic inflammatory diseases but its levels in neuroinflammatory diseases such as multiple sclerosis (MS) are unknown.

Objective: To investigate the presence and functional implications of sCD226 in persons with multiple sclerosis (pwMS) and other neurological diseases.

Vitamin D/CD46 Crosstalk in Human T Cells in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS), in which T-cell migration into the CNS is key for pathogenesis. Patients with MS exhibit impaired regulatory T cell populations, and both Foxp3+ Tregs and type I regulatory T cells (Tr1) are dysfunctional. MS is a multifactorial disease and vitamin D deficiency is associated with disease.

The Secretive Liaison of Particulate Matter and SARS-CoV-2. A Hypothesis and Theory Investigation.

As the novel coronavirus disease sweeps across the world, there is growing speculation on the role that atmospheric factors may have played on the different distribution of SARS-CoV-2, and on the epidemiological characteristics of COVID-19. Knowing the role that environmental factors play in influenza virus outbreaks, environmental pollution and, in particular, atmospheric airborne (particulate matter, PM) has been considered as a potential key factor in the spread and mortality of COVID-19. A possible role of the PM as the virus carrier has also been debated.

Eomes-Dependent Loss of the Co-activating Receptor CD226 Restrains CD8 T Cell Anti-tumor Functions and Limits the Efficacy of Cancer Immunotherapy.

CD8 T cells within the tumor microenvironment (TME) are exposed to various signals that ultimately determine functional outcomes. Here, we examined the role of the co-activating receptor CD226 (DNAM-1) in CD8 T cell function. The absence of CD226 expression identified a subset of dysfunctional CD8 T cells present in peripheral blood of healthy individuals.

Increased IL-2 and Reduced TGF-β Upon T-Cell Stimulation are Associated with GM-CSF Upregulation in Multiple Immune Cell Types in Multiple Sclerosis.

Granulocyte macrophage colony stimulating factor (GM-CSF) is a pro-inflammatory cytokine produced by immune cells. Recent evidence suggests that GM-CSF plays an important role in multiple sclerosis (MS) pathogenesis. We investigated the expression and regulation of GM-CSF in different immune cells in MS.

Differential Expression of HERV-W in Peripheral Blood in Multiple Sclerosis and Healthy Patients in Two Different Ethnic Groups.

Overexpression of the Human endogenous retrovirus W (HERV-W) group of inherited retroviruses has been consistently linked with Multiple Sclerosis (MS). However most of the studies on this link have focused on European genetic groups with a very high risk of MS and it is not clear that this relationship holds for all ethnic groups. This study examined qPCR the RNA expression in peripheral blood of HERV-W (the multiple sclerosis associated retrovirus variant MSRV) of MS patients and healthy controls from two ethnic groups with very different risk rates of MS.

Do Antiretroviral Drugs Protect From Multiple Sclerosis by Inhibiting Expression of MS-Associated Retrovirus?

The expression of human endogenous retroviruses (HERVs) has been associated with Multiple Sclerosis (MS). The MS-related retrovirus (MSRV/HERV-W) has the potential to activate inflammatory immunity, which could promote both susceptibility and progression toward MS. A connection between HERVs and MS is also supported by the observation that people infected with the human immunodeficiency virus (HIV) may have a lower risk of developing MS than the HIV non-infected, healthy population.

The Soluble Form of Toll-Like Receptor 2 Is Elevated in Serum of Multiple Sclerosis Patients: A Novel Potential Disease Biomarker.

Multiple sclerosis (MS) is an immune-mediated inflammatory demyelinating disease of the central nervous system. It was previously shown that toll-like receptor (TLR)-2 signaling plays a key role in the murine experimental autoimmune encephalomyelitis (EAE) model of MS, and that TLR2-stimulation of regulatory T cells (Tregs) promotes their conversion to T helper 17 (Th17) cells. Here, we sought potential sources of TLR2 stimulation and evidence of TLR2 activity in MS patient clinical samples.

EBV Infection Empowers Human B Cells for Autoimmunity: Role of Autophagy and Relevance to Multiple Sclerosis.

The efficacy of B cell depletion therapy in multiple sclerosis indicates their central pathogenic role in disease pathogenesis. The B lymphotropic EBV is a major risk factor in multiple sclerosis, via as yet unclear mechanisms. We reported in a nonhuman primate experimental autoimmune encephalomyelitis model that an EBV-related lymphocryptovirus enables B cells to protect a proteolysis-sensitive immunodominant myelin oligodendrocyte glycoprotein (MOG) epitope (residues 40-48) against destructive processing.

Human endogenous retroviruses and multiple sclerosis: Causation, association, or after-effect?

From the early days of MS discovery, infections have been proposed as a possible cause of the disease. In the last three decades, an association between human endogenous retrovirus expression and MS has been further investigated and confirmed. Nevertheless, the role of such retroviruses in the disease needs clarification.

The association between human endogenous retroviruses and multiple sclerosis: A systematic review and meta-analysis.

Background: The interaction between genetic and environmental factors is crucial to multiple sclerosis (MS) pathogenesis. Human Endogenous Retroviruses (HERVs) are endogenous viral elements of the human genome whose expression is associated with MS.

Objective: To perform a systematic review and meta-analysis and to assess qualitative and quantitative evidence on the expression of HERV families in MS patients.

EBV Infection and Multiple Sclerosis: Lessons from a Marmoset Model.

Multiple sclerosis (MS) is thought to be initiated by the interaction of genetic and environmental factors, eliciting an autoimmune attack on the central nervous system. Epstein-Barr virus (EBV) is the strongest infectious risk factor, but an explanation for the paradox between high infection prevalence and low MS incidence remains elusive. We discuss new data using marmosets with experimental autoimmune encephalomyelitis (EAE) - a valid primate model of MS.

Lymphocryptovirus Infection of Nonhuman Primate B Cells Converts Destructive into Productive Processing of the Pathogenic CD8 T Cell Epitope in Myelin Oligodendrocyte Glycoprotein.

EBV is the major infectious environmental risk factor for multiple sclerosis (MS), but the underlying mechanisms remain obscure. Patient studies do not allow manipulation in vivo. We used the experimental autoimmune encephalomyelitis (EAE) models in the common marmoset and rhesus monkey to model the association of EBV and MS.

Multiple Sclerosis between Genetics and Infections: Human Endogenous Retroviruses in Monocytes and Macrophages.

The etiology of multiple sclerosis (MS) is still unknown, but there is strong evidence that genetic predisposition associated with environmental factors can trigger the disease. An estimated 30 million years ago, exogenous retroviruses are thought to have integrated themselves into human germ line cells, becoming part of human DNA and being transmitted over generations. Usually such human endogenous retroviruses (HERVs) are silenced or expressed at low levels, but in some pathological conditions, such as MS, their expression is higher than that in the healthy population.

TLR2 stimulation regulates the balance between regulatory T cell and Th17 function: a novel mechanism of reduced regulatory T cell function in multiple sclerosis.

CD4(+)CD25(hi) FOXP3(+) regulatory T cells (Tregs) maintain tolerance to self-Ags. Their defective function is involved in the pathogenesis of multiple sclerosis (MS), an inflammatory demyelinating disease of the CNS. However, the mechanisms of such defective function are poorly understood.

Identification of pathway-based toxicity in the BALB/c 3T3 cell model.

The particulate matter represents one of the most complex environmental mixtures, whose effects on human health and environment vary according to particles characteristics and source of emissions. The present study describes an integrated approach, including in vitro tests and toxicogenomics, to highlight the effects of air particulate matter on toxicological relevant endpoints. Air samples (PM2.

Cancer-related genes transcriptionally induced by the fungicide penconazole.

Penconazole is a systemic triazole fungicide mainly used on grapes. The UE Maximum Residue Level (MRL) for penconazole is set at 0.2ppm in wine and grapes.

Different sensitivity of BALB/c 3T3 cell clones in the response to carcinogens.

Cell transformation assays (CTAs) are currently regarded as the only possible in vitro alternative to animal testing for carcinogenesis studies. CTAs have been proposed as screening tests for the carcinogenic potential of compounds that have no evidence of genotoxicity but present structural alerts for carcinogenicity. We have extensively used the BALB/c 3T3 model based on the A31 cell clone to test single chemicals, complex mixtures and environmental pollutants.

BALB/c 3T3 cell transformation assay for the prediction of carcinogenic potential of chemicals and environmental mixtures.

The prediction of the carcinogenic risk for humans is mostly based on animal experiments. For the last 20 years, however, the scientific community has paid great attention to alternative strategies in compliance with common moral and ethical values. The new European chemical regulation REACH (Reg.

Gene expression changes in medical workers exposed to radiation.

The use of nuclear resources for medical purposes causes considerable concern about occupational exposure. Nevertheless, little information is available regarding the effects of low-dose irradiations protracted over time. We used oligomicroarrays to identify the genes that are transcriptionally regulated by persistent exposure to extremely low doses of ionizing radiation in 28 exposed professionals (mean cumulative effective dose +/- SD, 19 +/- 38 mSv) compared with a matched sample of nonexposed subjects.

Gene expression time-series analysis of camptothecin effects in U87-MG and DBTRG-05 glioblastoma cell lines.

Background: The clinical efficacy of camptothecin (CPT), a drug specifically targeting topoisomerase I (TopoI), is under evaluation for the treatment of malignant gliomas. Due to the high unresponsiveness of these tumours to chemotherapy, it would be very important to study the signalling network that drives camptothecin outcome in this type of cancer cells. To address this issue, we had previously compared the expression profile of human U87-MG glioblastoma cells with that of a CPT-resistant counterpart, giving evidence that the development of a robust inflammatory response was the main transcriptional effect associated with CPT resistance.

A cDNA-microarray analysis of camptothecin resistance in glioblastoma cell lines.

Chemotherapy, as generally available, is of a limited value in curing malignant brain tumors (gliomas), which often develop resistance to drugs, becoming completely unresponsive to any standard therapeutic approach. Camptothecins, a family of topoisomerase I inhibitor drugs, represent a new promising treatment strategy and are currently under evaluation for testing the clinical efficacy. We selected a CPT-resistant sub-line (U87CPT-R) from U87-MG grade III-IV astrocytoma cells, and compared the expression profile of the two cell lines by cDNA-microarray, as a preliminary screening of the molecular mechanisms involved in the acquisition of CPT resistance in glioma cells.