Furthermore, the cytotoxicity of NK cells against colorectal cancer cells was decreased in overweight and obese subjects. Investigations on underlying killing mechanisms demonstrated a reduced TRAIL expression on NK cells of obese subjects suggesting an impaired death receptor pathway in obesity. The present study gives new insights into an impaired functionality and phenotype of NK cells and NK cell subsets in overweight and obesity. These phenotypic alterations and dysfunction of NK cells might be an explanation for the increased cancer risk in obesity.Granulomatosis with polyangiitis (GPA) is a severe autoimmune vasculitis associated with the presence of anti-neutrophil cytoplasmic antibodies (ANCA) mainly targeting proteinase 3 (PR3), a neutrophilic serine proteinase. PR3-ANCA binding to membrane-bound PR3 on neutrophils induce their auto-immune activation responsible for vascular lesions. However, the correlation between PR3-ANCA level and disease activity remains inconsistent, suggesting the existence of non-pathogenic PR3-ANCA. In order to prove their existence, we immortalized B lymphocytes from blood samples of GPA patients in remission having persistent PR3-ANCA to isolate non-activating PR3-ANCA. We obtained for the first time a non-activating human IgG1κ anti-PR3 monoclonal antibody (mAb) named 4C3. This new mAb binds soluble PR3 with a high affinity and membrane-bound PR3 on an epitope close to the PR3 hydrophobic patch and in the vicinity of the active site. 4C3 is able to bind FcγRIIA and FcγRIIIB and has a G2F glycosylation profile on asparagine 297. 4C3 did not induce activation of neutrophils and could inhibit human polyclonal PR3-ANCA-induced activation suggesting that 4C3 is non-pathogenic. This characteristic relies on the recognized epitope on PR3 rather than to the Fc portion properties. The existence of non-pathogenic PR3-ANCA, which do not activate neutrophils, could explain the persistence of high PR3-ANCA levels in some GPA patients in remission and why PR3-ANCA would not predict relapse. Finally, these results offer promising perspectives particularly regarding the understanding of PR3-ANCA pathogenicity and the development of new diagnostic and therapeutic strategies in GPA.This study compared two 96-well multiplex immunoassay platforms for analytical performance in assessing cytokine concentrations in standards, quality controls and human plasma samples (n = 62), and evaluated assay time requirements. Assays included a bead-based fluorescence MILLIPLEX® assay/Luminex fluorescence platform (LMX) and three kits from Meso Scale Discovery (MSD) in planar electrochemiluminescence format. The LMX kit evaluated 21 cytokines and the MSD kits evaluated 10 cytokines each, with 16 overlapping cytokines between platforms. Both assays provided good reproducibility in standard curves for all analytes. Interassay CVs of shared analytes showed average kit quality control CVs ranging 1.9-18.2% for LMX and 2.4-13.9% for MSD. The MSD platform had lower LLoQs than LMX for 14/16 shared cytokines. For IL-17, the LLoQ was lower with LMX than MSD, and the LLoQs for IL-6 were similar. Although MSD calibration curves indicated lower LLoQs for most of those analytes, many more cytokines in human plasma samples were not detected by MSD than by LMX. The ULoQs were higher in LMX versus MSD assays for 13/16 shared analytes, lower than MSD for IL-17, and equivalent between assays for IL-6 and MIP-1α. Bland-Altman plots indicated that MSD classified 13/16 shared analytes as concentrations lower than by LMX. Time and motion analysis indicated that total mean assay times were 20 h 28 m and 21 h 33 m for LMX and MSD, respectively, including an overnight (17 h) incubation. The MSD assays employed a manufacturer-approved overnight incubation instead of the standard 2-h incubation, which kit instructions suggest might increase detection sensitivity. Hands-on labor time averaged 1 h 37 m for LMX and 2 h 33 m for MSD. In summary, assay selection factors should include selection of specific markers of interest, time and cost considerations, and anticipated cytokine concentrations in prospective samples.Immunological adaptations in pregnancy allow maternal tolerance of the semi-allogeneic fetus but also increase maternal susceptibility to infection. At implantation, the endometrial stroma, glands, arteries and immune cells undergo anatomical and functional transformation to create the decidua, the specialized secretory endometrium of pregnancy. The maternal decidua and the invading fetal trophoblast constitute a dynamic junction that facilitates a complex immunological dialogue between the two. The decidual and peripheral immune systems together assume a pivotal role in regulating the critical balance between tolerance and defense against infection. Throughout pregnancy, this equilibrium is repeatedly subjected to microbial challenge. Acute viral infection in pregnancy is associated with a wide spectrum of adverse consequences for both mother and fetus. Vertical transmission from mother to fetus can cause developmental anomalies, growth restriction, preterm birth and stillbirth, while the mother is predisposptive immunity. Despite extensive progress in unraveling the immunological adaptations of pregnancy, pregnant women remain particularly susceptible to certain acute viral infections and continue to experience mortality rates equivalent to those observed in pandemics several decades ago. Here, we focus specifically on the pregnancy-induced vulnerabilities in innate immunity that contribute to the disproportionately high maternal mortality observed in the following acute viral infections Lassa fever, Ebola virus disease (EVD), dengue fever, hepatitis E, influenza, and novel coronavirus infections.Nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing protein (NLRP) inflammasomes are involved in the molecular pathogenesis of many diseases and disorders. Among NLRPs, the NLRP3 (in humans encoded by the NLRP3 gene) is expressed predominantly in macrophages as a component of the inflammasome and is associated with many diseases, including gout, type 2 diabetes, multiple sclerosis, atherosclerosis, and neurological diseases and disorders. Diterpenes containing repeated isoprenoid units in their structure are a member of some essential oils that possess diverse biological activities and are becoming a landmark in the field of drug discovery and development. This review sketches a current scenario of diterpenes or their derivatives acting through NLRPs, especially NLRP3-associated pathways with anti-inflammatory effects. For this, a literature survey on the subject has been undertaken using a number of known databases with specific keywords. Findings from the aforementioned databases suggest that diterpenes and their derivatives can exert anti-inflammatory effects via NLRPs-related pathways. Andrographolide, triptolide, kaurenoic acid, carnosic acid, oridonin, teuvincenone F, and some derivatives of tanshinone IIA and phorbol have been found to act through NLRP3 inflammasome pathways. In conclusion, diterpenes and their derivatives could be one of the promising compounds for the treatment of NLRP3-mediated inflammatory diseases and disorders.In stressful situations, catecholamines modulate mammalian immune function, and in addition, they can be sensed by many bacteria. Catecholamine sensing was also found in the zoonotic gut pathogen Salmonella Typhimurium, probably contributing to the stress-induced increased risk of salmonellosis. Virulence traits such as proliferation and invasiveness are promoted upon bacterial catecholamine sensing, but it is unknown whether S. Typhimurium may also inhibit mammalian immune function in stressful situations. We thus investigated whether supernatants from S. Typhimurium grown in the presence of catecholamines modulate porcine mitogen-induced lymphocyte proliferation. Lymphocyte proliferation was reduced by supernatants from catecholamine-exposed Salmonella in a dose-dependent manner. We further examined whether adrenaline oxidation to adrenochrome, which is promoted by bacteria, could be responsible for the observed effect, but this molecule either enhanced lymphocyte functionality or had no effect. We could thereby exclude adrenochrome as a potential immunomodulating agent produced by S. Typhimurium. This study is the first to demonstrate that bacteria grown in the presence of catecholamine stress hormones alter their growth environment, probably by producing immunomodulating substances, in a way that host immune response is suppressed. These findings add a new dimension to interkingdom signaling and provide novel clues to explain the increased susceptibility of a stressed host to Salmonella infection.Coronavirus disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2), was declared a pandemic by the World Health Organization in March 2020. Severe COVID-19 cases develop severe acute respiratory syndrome, which can result in multiple organ failure, sepsis, and death. The higher risk group includes the elderly and subjects with pre-existing chronic illnesses such as obesity, hypertension, and diabetes. To date, no specific treatment or vaccine is available for COVID-19. Among many compounds, naringenin (NAR) a flavonoid present in citrus fruits has been investigated for antiviral and anti-inflammatory properties like reducing viral replication and cytokine production. In this perspective, we summarize NAR potential anti-inflammatory role in COVID-19 associated risk factors and SARS-CoV-2 infection.Inducible Bronchus Associated Lymphoid Tissue (iBALT) is an ectopic lymphoid tissue associated with severe forms of chronic lung diseases, including chronic obstructive pulmonary disease, rheumatoid lung disease, hypersensitivity pneumonitis and asthma, suggesting that iBALT may exacerbate these clinical conditions. However, despite the link between pulmonary pathology and iBALT formation, the role of iBALT in pathogenesis remains unknown. Here we tested whether the presence of iBALT in the lung prior to sensitization and challenge with a pulmonary allergen altered the biological outcome of disease. We found that the presence of iBALT did not exacerbate Th2 responses to pulmonary sensitization with ovalbumin. https://www.selleckchem.com/products/homoharringtonine.html Instead, we found that mice with iBALT exhibited delayed Th2 accumulation in the lung, reduced eosinophil recruitment, reduced goblet cell hyperplasia and reduced mucus production. The presence of iBALT did not alter Th2 priming, but instead delayed the accumulation of Th2 cells in the lung following challenge and altered the spatial distribution of T cells in the lung. These results suggest that the formation of iBALT and sequestration of effector T cells in the context of chronic pulmonary inflammation may be a mechanism by which the immune system attenuates pulmonary inflammation and prevents excessive pathology.Matrine (MAT), a quinolizidine alkaloid component derived from the root of Sophora flavescens, suppresses experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), by inducing the production of immunomodulatory molecules, e.g., IL-10. In an effort to find the upstream pathway(s) of the mechanism underlying these effects, we have tested certain upregulated immunomodulatory molecules. Among them, we found increased levels of IL-27 and IFN-β, one of the first-line MS therapies. Indeed, while low levels of IFN-β production in sera and type I interferon receptor (IFNAR1) expression in spinal cord of saline-treated control EAE mice were detected, they were significantly increased after MAT treatment. Increased numbers of CD11b+IFN-β+ microglia/infiltrating macrophages were observed in the CNS of MAT-treated mice. The key role of IFN-β induction in the suppressive effect of MAT on EAE was further verified by administration of anti-IFN-β neutralizing antibody, which largely reversed the therapeutic effect of MAT.