21,558 research outputs found

    9-PAHSA displays a weak anti-inflammatory potential mediated by specific antagonism of chemokine G protein-coupled receptors

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    Introduction: 9-PAHSA belongs to a class of endogenous mammalian bioactive lipids, fatty acid esters of hydroxy fatty acids (FAHFA), that are present in circulation at nanomolar concentrations in mice and humans. Published preclinical data suggest beneficial effects of 9-PAHSA treatment on glucose metabolism as well as modulation of immune function. However, receptor molecules with high affinity towards these lipids have not been identified so far.Methods: In a broad screen of a panel of G protein-coupled receptors (GPCRs) we discovered that 9-PAHSA displays antagonist activity with an IC50 in the micromolar range on selected chemokine receptors, namely, CCR6, CCR7, CXCR4, and CXCR5. The potential immunomodulatory activities in a human cellular model of innate immunity were then investigated.Results and discussion: In our in vitro experiments, a weak anti-inflammatory potential for high concentrations of 9-PAHSA (10–100 µM) could be detected, as treatment reduced the LPS-induced secretion of certain chemokines, such as CXCL10, MIP-1 beta and MCP. Regarding metabolic effects, we re-investigated 9-PAHSA on glucose metabolism and insulin sensitivity in vitro and in mice confirming conclusions from our earlier study that FAHFAs lack glucoregulatory activity following an acute treatment. In conclusion, the specific interactions with a subset of chemokine receptors may contribute to weak anti-inflammatory properties of 9-PAHSA, but further studies are needed to confirm its in anti-inflammatory potential in vivo

    Human granzyme B regulatory B cells prevent effector CD4+CD25- T cell proliferation through a mechanism dependent from lymphotoxin alpha

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    IntroductionHuman Granzyme B (GZMB) regulatory B cells (Bregs) have suppressive properties on CD4+ effector T cells by a mechanism partially dependent on GZMB. Moreover, these cells may be easily induced in vitro making them interesting for cell therapy.MethodsWe characterized this population of in vitro induced GZMB+Bregs using single cell transcriptomics. To investigate their regulatory properties, Bregs or total B cells were also co-cultured with T cells and scRNAseq was used to identify receptor ligand interactions and to reveal gene expression changes in the T cells.ResultsWe find that Bregs exhibit a unique set of 149 genes differentially expressed and which are implicated in proliferation, apoptosis, metabolism, and altered antigen presentation capacity consistent with their differentiated B cells profile. Notably, Bregs induced a strong inhibition of T cell genes associated to proliferation, activation, inflammation and apoptosis compared to total B cells. We identified and validated 5 receptor/ligand interactions between Bregs and T cells. Functional analysis using specific inhibitors was used to test their suppressive properties and we identified Lymphotoxin alpha (LTA) as a new and potent Breg ligand implicated in Breg suppressive properties.DiscussionWe report for the first time for a role of LTA in GZMB+Bregs as an enhancer of GZMB expression, and involved in the suppressive properties of GZMB+Bregs in human. The exact mechanism of LTA/GZMB function in this specific subset of Bregs remains to be determined

    The role of CD180 in hematological malignancies and inflammatory disorders.

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    Toll-like receptors play a significant role in the innate immune system and are also involved in the pathophysiology of many different diseases. Over the past 35 years, there have been a growing number of publications exploring the role of the orphan toll-like receptor, CD180. We therefore set out to provide a narrative review of the current evidence surrounding CD180 in both health and disease. We first explore the evidence surrounding the role of CD180 in physiology including its expression, function and signaling in antigen presenting cells (APCs) (dendritic cells, monocytes, and B cells). We particularly focus on the role of CD180 as a modulator of other TLRs including TLR2, TLR4, and TLR9. We then discuss the role of CD180 in inflammatory and autoimmune diseases, as well as in hematological malignancies of B cell origin, including chronic lymphocytic leukemia (CLL). Based on this evidence we produce a current model for CD180 in disease and explore the potential role for CD180 as both a prognostic biomarker and therapeutic target. Throughout, we highlight specific areas of research which should be addressed to further the understanding of CD180 biology and the translational potential of research into CD180 in various diseases

    Dissecting the mechanisms of transport of herpes simplex virus between Langerhans Cells & dendritic cells in epidermis and dermis following infection of human genital mucosa and skin

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    Herpes Simplex Virus (HSV) is a sexually transmitted infection (STI) that the World Health Organisation (WHO) has deemed a priority for a vaccine. CD8 and CD4T cells are important in the control and clearance of HSV, however no known vaccine has been able to stimulate CD8T cells. The dermal dendritic cells (dDCs) are suspected to play a role. Previously the host lab has shown in human tissue that HSV-1 infection of Langerhans cells (LCs) caused apoptosis and migration of LCs to the dermis, where they were phagocytosed by dDCs (termed HSV viral relay). Very little is known about the mechanisms of this relay. The host lab has also identified a second resident epidermal immune cell, Epi-cDC2s, which are infectable by HSV. This thesis aims to unravel the mechanisms involved in the relay. RNA-seq and cell surface phenotyping on human dDCs subsets showed that was differential chemokine receptor expression. Bead-based immunoassays were used to determine the chemokines produced by HSV-1 infected LCs and Epi-cDC2s,and showed HSV infected LCs produced increased CXCR3 ligands, while HSV infected Epi-cDC2s produced increased CCR5 ligands. The importance of these chemokine axes was investigated using chemotaxis assays. An cyclic immunofluorescent microscopy panel was then developed to investigate whether this migration could be seen in situ in HSV infected foreskin explants. Underneath epidermal foci of infection, there was migration of both cDC1s and cDC2s towards the basement membrane. Under foci of infection there was a greater proportion of cDC2s clustering with LCs. The uptake of HSV infected epidermal cells by the dDC subsets was examined using imaging cytometry. Preliminary results suggest that there were no significant differences between the ability of dDCs to phagocytose HSV infected epidermal cells. Understanding the mechanisms and the role of each dDC subset in the HSV viral relay will determine which dDC subsets are crucial for CD8 and CD4 T cell stimulation

    Mechanistic insights into the regulation of inflammatory pathology by A20

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    All tangled up: interactions of the fibrinolytic and innate immune systems

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    The hemostatic and innate immune system are intertwined processes. Inflammation within the vasculature promotes thrombus development, whilst fibrin forms part of the innate immune response to trap invading pathogens. The awareness of these interlinked process has resulted in the coining of the terms “thromboinflammation” and “immunothrombosis.” Once a thrombus is formed it is up to the fibrinolytic system to resolve these clots and remove them from the vasculature. Immune cells contain an arsenal of fibrinolytic regulators and plasmin, the central fibrinolytic enzyme. The fibrinolytic proteins in turn have diverse roles in immunoregulation. Here, the intricate relationship between the fibrinolytic and innate immune system will be discussed

    Immunomodulatory effects of resveratrol on human intestinal mast cell signaling in vitro and mast cell associated enteritis and colitis in mice

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    By releasing their pre-stored or de novo synthesized mediators, mast cells (MC) are important immunoregulatory cells responsible for a variety of inflammatory reactions. Although known to be major effector cells in immunoglobuline (Ig) E dependent allergic reactions, MC have been widely shown to play a role in various inflammations of the gut. Diseases of the gastrointestinal tract (GIT) are widespread and multicausal. Those affected suffer from the sometimes severe symptoms and may experience restrictions on their daily life. Even if conventional medication is applied routinely, aim of the past and current research is to establish supportive and/or alternative medication that is based on natural substances. These may be on the basis of small natural components like resveratrol, a stilbene mostly found in grapes. Numerous positive properties are attributed to resveratrol. These are anti-inflammatory, anti-cancerogenic, anti-oxidative, as well as neuroprotective effects. The use of substances of natural origin as so-called nutraceuticals can help to increase the acceptance of medication by those affected, but also to reduce and overcome the side effects associated with conventional treatment. Effects of resveratrol were examined on the reactivity of MC isolated from patients tissue undergoing bowel resection. The results of this work show that resveratrol exhibited potent inhibitory effects on high affinity IgE receptor mediated activation of MC, strongly inhibiting not only MC degranulation, but also gene expression of the pro-inflammatory cytokines C-X-C motif chemokine ligand (CXCL) 8, C-C motif chemokine ligand (CCL) 2, CCL3, CCL4 and tumor necrosis factor (TNF-) α. Ultimately, the intracellular signaling cascade triggered during MC activation via IgE receptor leads to mediator release. Following IgE receptor mediated activation, phosphorylation of signaling molecules like extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription (STAT) 3, occurs. ERK1/2 was found to be responsible for phosphorylation of mitochondrial STAT3, which contributes significantly to MC degranulation. Treatment with resveratrol was able to inhibit the phosphorylation of STAT3 by more than 50 % and that of ERK1/2 by almost 100 %. Furthermore, the experiments performed succeeded in isolating the mitochondrial fraction from relatively low human intestinal MC (hiMC) numbers. Also, in this fraction we could detect phosphorylation of STAT3 and ERK1/2 after MC activation, which was reduced after treatment with resveratrol. Having shown the strong inhibitory effects in vitro, we set out to examine immunomodulatory effects of resveratrol in vivo. Presence and activity of MC are closely related to intestinal inflammations in consequence of food allergy (FA) and inflammatory bowel disease (IBD). In mice, FA can be studied using the ovalbumin (OVA)-induced allergic enteritis model and colitis can be studied using the IL-10 knockout (-/-) mice, which develop a spontaneous form of chronic colitis. We could show that the oral application of resveratrol inhibited the increase of MC numbers in the colon and duodenum of affected animals in both experimental settings. Less pronounced but still visible effects of resveratrol administration were observed in the colon with regard to epithelial damage, cell infiltration and reduction of goblet cell numbers. In all cases, based on a scoring system, the damage decreased to the level of the corresponding controls receiving no additive and in which no allergic enteritis was induced or nor colitis developed. Overall, allergic enteritis resulted in a weaker symptomatology, and IL-10-/- animals showed a delayed appearance of the typical symptoms. The results of this thesis show a strong inhibitory effect of resveratrol on hiMC. This could be detected for mediator release as well as on gene expression levels and in the phosphorylation of the signaling molecules ERK1/2 and STAT3, which we could also identify in the mitochondria of hiMC. We observed positive influences on MC-associated parameters in the OVA enteritis and IL-10-/- colitis mouse models. With regard to its use as nutraceutical, resveratrol could therefore come more of a focus in the future.Mastzellen sind wichtige immunregulatorische Zellen, die durch Freisetzung ihrer in den Granula gespeicherten oder der de novo synthetisierten Mediatoren fĂĽr eine Vielzahl von EntzĂĽndungsreaktionen verantwortlich sind. Mastzellen, die in erster Linie als Haupteffektorzellen bei von Immunoglobulin (Ig) E abhängigen allergischen Reaktionen bekannt sind, spielen auch bei diversen EntzĂĽndungen des Darmes eine Rolle. Erkrankungen des Gastrointestinaltraktes sind weit verbreitet und multikausal. Betroffene leiden aber immer mit unter der teils stark auftretenden Symptomatik und erfahren Einschränkungen im alltäglichen Leben. Auch wenn die herkömmliche Medikation zur Behandlung dieser Störungen routinemäßig Anwendung findet, ist es Ziel der Wissenschaft, eine unterstĂĽtzende sowie Alternativmedikation zu entwickeln, die auf natĂĽrlichen Ausgangssubstanzen, wie z.B. dem in Trauben vorkommenden Stilben Resveratrol, basiert. Resveratrol werden zahlreiche positive Eigenschaften zugeschrieben. Darunter fallen anti-inflammatorische, anti-kanzerogene, antioxidative, als auch neuroprotektive Eigenschaften. Ein Einsatz von Substanzen natĂĽrlichen Ursprungs als sogenanntes Nutraceutical kann einerseits dazu dienen, die Akzeptanz der Medikation bei Betroffenen zu erhöhen, aber auch, die mit der herkömmlichen Behandlungsmethode verbundenen, Nebenwirkungen zu mindern und zu ĂĽberwinden. Effekte von Resveratrol wurden auf die Reaktivität von Mastzellen, isoliert aus humanen intestinalen Resektionspräparaten (hiMC), geprĂĽft. Die Ergebnisse dieser Arbeit verdeutlichen, dass das Stilben starke inhibitorische Wirkung auf IgE-Rezeptor vermittelte Aktivierung von Mastzellen zeigt und dabei nicht nur die Mastzelldegranulation, sondern auch die Genexpression der pro-inflammatorischen Zytokine C-X-C motif chemokine ligand (CXCL) 8, C-C motif chemokine ligand (CCL) 2, CCL3, CCL4 und tumor necrosis factor (TNF-) α stark hemmt. Die, im Zuge der Mastzellaktivierung via IgE-Rezeptor, ausgelöste intrazelluläre Signalkaskade fĂĽhrt letztlich zur MediatorausschĂĽttung. Im Verlauf der Signalkaskade kommt es zur Phosphorylierung, d.h. der Aktivierung der SignalmolekĂĽle extracellular signal-regulated kinase (ERK) 1/2 und signal transducer and activator of transcription (STAT) 3. Dabei ist ERK1/2 fĂĽr die Phosphorylierung von mitochondrialem STAT3 verantwortlich, welches maĂźgeblich zur Mastzelldegranulation beiträgt. Die Behandlung mit Resveratrol fĂĽhrte dabei zur Hemmung der Phosphorylierung von STAT3 um mehr als 50 %, sowie die von ERK1/2 um fast 100 %. Des Weiteren gelang es uns, die mitochondriale Fraktion aus relativ geringen Mengen humaner intestinaler Mastzellen (hiMC) zu isolieren. Auch in dieser Fraktion konnten wir die Phosphorylierung von ERK1/2 und STAT3 nach Mastzellaktivierung detektieren, die nach einer Behandlung mit Resveratrol ebenfalls verringert war. Nachdem die stark hemmende Wirkung von Resveratrol in vitro gezeigt wurde, sollten die immunmodulatorischen Wirkungen auch in vivo ĂĽberprĂĽft werden. Das Vorhandensein und die Aktivität von MC stehen in engem Zusammenhang mit EntzĂĽndungen des Darms als Ursache von Nahrungsmittelallergien sowie chronisch-entzĂĽndlicher Darmerkrankungen (CED). Im Mausmodell kann man Nahrungsmittelallergie mit Hilfe einer Ovalbumin (OVA)-induzierten allergischen Enteritis und CED mit Hilfe der IL-10 knockout (-/-) Maus, bei der es zu einer spontan auftretenden chronischen Colitis kommt, experimentell untersuchen. Wir konnten zeigen, dass die orale Gabe von Resveratrol bei betroffenen Tieren im Allergiemodell (OVA) als auch im Modell der murinen Colitis (IL-10-/-) zu einer Hemmung des Anstiegs der Mastzellanzahl im Gewebe von Colon und Duodenum betroffener Tiere fĂĽhrte. Weniger stark ausgeprägte, aber dennoch sichtbare Effekte bei einer Resveratrol-Gabe konnten im Colon im Hinblick auf Epithelschädigung und bei der IL-10-/- Colitis auch im Hinblick auf Zellinfiltration sowie Reduktion der Anzahl an Gobletzellen beobachtet werden. In allen Fällen verringerten sich die Schädigungen auf das Level der jeweiligen Kontrolltiere ohne allergische Enteritis bzw. Colitis. Insgesamt kam es bei der allergischen Enteritis zu einer schwächer ausgeprägten Symptomatik, bei IL-10-/- Tieren kam es insgesamt zu einem verzögerten Auftreten der typischen Symptomatiken. Die Ergebnisse dieser Promotionsarbeit zeigen eine stark inhibitorische Wirkung von Resveratrol auf hiMC. Diese lieĂźen sich sowohl bei der Mediatorfreisetzung als auch auf Genexpressionslevel und in der Phosphorylierung der SignalmolekĂĽle ERK1/2 und STAT3 zeigen, bei denen es gelungen ist, sie auch in den Mitochondrien von hiMC nachzuweisen. Auch im Mausmodell bei der Untersuchung einer allergisch induzierten Enteritis sowie einer murinen Colitis aufgrund eines IL-10-/- konnten wir positive EinflĂĽsse auf Mastzell-assoziierte Parameter beobachten. Im Hinblick auf die Verwendung als Nutraceutical könnte Resveratrol deshalb zukĂĽnftig mehr in den Fokus rĂĽcken

    Monoclonal antibody: a cell specific immunotherapy to treat cancer

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    Fundamentally, the therapy technique which is utilized in malignancy immunotherapy, monoclonal antibodies (mAb), is one of them, and it is used extensively as a treatment for the disease. To achieve more successful treatment, novel combination treatments and treatment procedures must be created. The purpose of this study is the improvement of mAb treatment and detail late advance and new limits, particularly in cancer therapy. With various keywords, we searched Google Scholar, PubMed, and Scopus for monoclonal antibody therapy as an alternate form of chemotherapy. The number of patients who received each therapy regimen, and the recovery rate are all displayed in this study, also a comparative study between monotherapy and chemotherapy. The result showed that rituximab had a greater overall response rate than other drugs, at 68%. In the combination treatment group (monotherapy+chemotherapy), 100% of patients had adverse events, compared to 84.2 percent in the monotherapy group. The pharmaceutical industry's fastest-growing medications, monoclonal antibodies are increasingly being examined in Clinical trials as stand-alone treatments or in conjunction with other therapies. It has a promising future since it will provide better tailored therapy and combination therapy for the treatment of cancer
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