Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells pl...Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.展开更多
Mesenchymal stromal cells(MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation.MSC activation via specific...Mesenchymal stromal cells(MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation.MSC activation via specific receptors is a crucial event for these cells to exert their immunosuppressive response.The aryl-hydrocarbon receptor(Ah R) is a sensitive molecule for external signals and it is expressed in MSCs and,upon positive activation,may potentially regulate the MSC-associated immunomodulatory function.Consequently,signalling pathways linked to Ah R activation can elucidate some of the molecular cascades involved in MSC-mediated immunosuppression.In this minireview,we have noted some important findings concerning MSC regulation via Ah R,highlighting that its activation is associated with improvement in migration and immunoregulation,as well as an increase in pro-regenerative potential.Thus,Ah R-mediated MSC activation can contribute to new perspectives on MSC-based therapies,particularly those directed at immune-associated disorders.展开更多
This paper described T cell proliferative response by an alternative pathway in normal subjects and In patients with malignant diseases. Two McAbs, Anti-CCTl and Lo-CD2-act recognizing two distinct epitopes on E-recep...This paper described T cell proliferative response by an alternative pathway in normal subjects and In patients with malignant diseases. Two McAbs, Anti-CCTl and Lo-CD2-act recognizing two distinct epitopes on E-receptor (CD2) were used to costimulate PBMC. Proliferative responsiveness was measured by 3H-thymidine incorporation. It was found that 82% of 72 nonnal subjects gave proliferative response whereas only 23% of the 93 patients did. The average cpm±SD in patients with bladder cancer (118±2314), kidney cancer (1619±2719) or lymphoma (2518±4057) was significantly lower than that in normal subjects (4935±2314), (P<0.001). These results indicate that T cell proliferation through the alternative pathway was significantly depressed in patients with cancer, and this can be used as a new parameter to monitor the immune status of cancer patients.展开更多
Mast cell activation syndrome(MCAS)includes a group of disorders that result in the inappropriate release of inflammatory mediators from mast cells.These mediators can affect multiple organ systems and lead to signifi...Mast cell activation syndrome(MCAS)includes a group of disorders that result in the inappropriate release of inflammatory mediators from mast cells.These mediators can affect multiple organ systems and lead to significant morbidity,and possible fatality.Although reactions,typically in response to various nonspecific stimuli,are usually mild,they may put those with MCAS at increased risk of anaphylaxis.In this case report,we present two clinical scenarios of MCAS,and identify possible factors triggering mast cell mediator release.We also define a preoperative preventive pathway,outline anesthetic considerations,and discuss the management of immediate hypersensitivity reactions in patients with MCAS.Meticulous preoperative preparation,avoidance of triggers,and development of a plan to treat possible adverse organ responses are paramount of good outcomes.展开更多
The spatial arrangement of activating ligands is known to have great influence on T cell activation.However,independently studying each ligand’s spatial organization parameter that affects T cell activation remains a...The spatial arrangement of activating ligands is known to have great influence on T cell activation.However,independently studying each ligand’s spatial organization parameter that affects T cell activation remains a great challenge.Here,with DNA origami,we precisely organized the CD3ɛantibodies simulating T cell receptor(TCR)ligands and CD28 antibodies simulating co-stimulatory ligands to interrogate the independent role of TCR-ligand spacing and local copy numbers as well as the spacing between TCR ligands and co-stimulatory ligands on T cell activation.We found that T cell activation benefited fromlocally concentrated TCR ligands with a shorter spacing and was maximized by an∼38 nm spacing between TCR ligands and co-stimulatory ligands.The T cell expander constructed based on our findings could efficiently expand CD8+T cells for tumor immunotherapy.Thus,the DNA nanostructurebased ligands’precise arrangement can be a unique tool in studying immune cell activations and cellbased immunotherapies.展开更多
Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells....Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.展开更多
One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell su...One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining.This alteration is observed during cell death processes such as apoptosis,and during physiological responses such as platelet degranulation and membrane repair.Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface.While this response was thought to be indicative of ongoing NK cell death,it may also reflect the regulation of NK cell activation in the absence of cell death.Herein,we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation.Through enforced expression of a lipid scramblase,we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death.In contrast,lipid scrambling attenuates NKcell activation.This response was accompanied by reduced cell surface expression of activating receptors such as 2B4,and by loss of binding of Src family protein tyrosine kinases Fyn and Lck to the inner leaflet of the plasma membrane.Hence,lipid scrambling during NK cell activation is,at least in part,a physiological response that reduces the NK cell activation level.This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.展开更多
Objective To investigate the expression of B cell activation factor of the TNF family (BAFF) gene between human normal and inflamed fallopian tubes. Methods Tissue samples of human normal fallopian tube (n=20) and...Objective To investigate the expression of B cell activation factor of the TNF family (BAFF) gene between human normal and inflamed fallopian tubes. Methods Tissue samples of human normal fallopian tube (n=20) and inflamed fallopian tube (n=20) were collected. The expression of BAFF gene was determined by the real- time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Results BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells. Both BAFF protein and mRNA in normal fallopian tubes had lower levels than those in inflamed fallopian tubes (P〈0.01). Conclusion BAFF protein and mRNA are present in human tubal tissues. BAFF gene in human inflamed fallopian tube would have a high expression.展开更多
Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twent...Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twenty patients with simple ventricular septal defect (VSD) were chosen as controls, and 30 patients with PH were studied. Plasma levels of ET-1 and NO were measured by radioimmunoassay or colorimetric method. Before cardiopulmonary bypass was established, the specimens from right lung were fixed with formaldehyde solution, embedded with paraffin and stained by SP immunohistochemistry. Intercellular adhesion molecule-1 (ICAM-1) expression was measured through the determination of the light density with computer imaging technology. Results Compared with that of the patients with simple VSD, the light density of ICAM-1 and plasma level of ET-1 increased in patients with PH; but plasma level of NO decreased (P<0.05). Positive correlation was observed between ICAM-1 and ET-1/NO (P<0.05). Conclusion Endothelia cells activation and imbalance of ET-1/NO might play an important role in the development of PH.展开更多
A key feature that distinguishes cancer cells from all other cells is their capability to spread throughout the body.Although how cancer cells collectively migrate by following molecular rules which influence the stat...A key feature that distinguishes cancer cells from all other cells is their capability to spread throughout the body.Although how cancer cells collectively migrate by following molecular rules which influence the state of cell-cell adhesion contacts has been comprehensively formulated,the impact of physical interactions on cell spreading remains less understood.Cumulative effects of physical interactions exist as the interplay between various physical parameters such as(1)tissue surface tension,(2)viscoelasticity caused by collective cell migration,and(3)solid stress accumulated in the cell aggregate core region.This review aims to point out the role of these physical parameters in cancer cell spreading by considering and comparing the rearrangement of various mono-cultured cancer and epithelial model systems such as the fusion of two cell aggregates.While epithelial cells undergo volumetric cell rearrangement driven by the tissue surface tension,which directs cell movement from the surface to the core region of two-aggregate systems,cancer cells rather perform surface cell rearrangement.Cancer cells migrate toward the surface of the two-aggregate system driven by the solid stress while the surface tension is significantly reduced.The solid stress,accumulated in the core region of the two-aggregate system,is capable of suppressing the movement of epithelial cells that can undergo the jamming state transition;however,this stress enhances the movement of cancer cells.We have focused here on the multi-scale rheological modeling approaches that aimed at reproducing and understanding these biological systems.展开更多
Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory ha...Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory has shown that the Qi-invigorating action of Chinese tonifying herbs is linked to increased mitochondrial ATP generation and an enhancement in mitochondrial glutathione redox status. To explore whether Sch B can exert Qi-invigorating actions across various tissues, we investigated the effects of Sch B treatment on mitochondrial ATP generation and glutathione redox status in multiple mouse tissues ex vivo. In line with TCM theory, which posits that Zheng Qi generation relies on the Qi function of the visceral organs, we also examined Sch B’s impact on natural killer cell activity and antigen-induced splenocyte proliferation, both serving as indirect measures of Zheng Qi. Our findings revealed that Sch B treatment consistently enhanced mitochondrial ATP generation and improved mitochondrial glutathione redox status in mouse tissues. This boost in mitochondrial function was associated with stimulated innate and adaptive immune responses, marked by increased natural killer cell activity and antigen-induced T/B cell proliferation, potentially through the increased generation of Zheng Qi.展开更多
Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type ...Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.展开更多
The incidence of liver fibrosis is increasing worldwide,and if left untreated,it will later develop into cirrhosis with a high mortality rate.In this paper,the activation pathway and related mechanism of stellate cell...The incidence of liver fibrosis is increasing worldwide,and if left untreated,it will later develop into cirrhosis with a high mortality rate.In this paper,the activation pathway and related mechanism of stellate cells in liver fibrosis are introduced,and some current therapeutic methods are summarized.These results suggest that stellate cells play an important role in liver fibrosis,and targeted therapy for the purpose of inhibiting the activation of stellate cells and inducing their apoptosis is expected to be an effective regimen to reverse liver fibrosis.However,there are some problems such as insufficient in-depth study of related mechanisms and imperfect experiments.In future animal experiments and clinical trials,more studies can be carried out to provide high-quality protocols for the treatment of liver fibrosis.展开更多
Astragali Radix(AR)is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer(NK)cells.However,owing to the complexity of its com...Astragali Radix(AR)is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer(NK)cells.However,owing to the complexity of its composition,the specific active ingredients in AR that act on NK cells are not clear yet.Cell membrane chromatography(CMC)is mainly used to screen the active ingredients in a complex system of herbal medicines.In this study,a new comprehensive two-dimensional(2D)NK-92MI CMC/C18 column/time-of-flight mass spectrometry(TOFMS)system was established to screen for potential NK cell activators.To obtain a higher column efficiency,3-mercaptopropyltrimethoxysilane-modified silica was synthesized to prepare the NK-92MI CMC column.In total,nine components in AR were screened from this system,which could be washed out from the NK-92MI/CMC column after 10 min,and they showed good affinity for NK-92MI/CMC column.Two representative active compounds of AR,isoastragaloside Ⅰ and astragaloside IV,promoted the killing effect of NK cells on K562 cells in a dose-dependent manner.It can thus suggest that isoastragaloside Ⅰ and astragaloside Ⅳ are the main immunomodulatory components of AR.This comprehensive 2D NK-92MI CMC analytical system is a practical method for screening immune cell activators from other herbal medicines with immunomodulatory effects.展开更多
Interferon(IFN) with antiviral and im-munomodulatory activities is one of the most important therapeutic agents for the treatment of chronic hepatitis. The apoptotic effect of IFN is influenced by cell type and the ty...Interferon(IFN) with antiviral and im-munomodulatory activities is one of the most important therapeutic agents for the treatment of chronic hepatitis. The apoptotic effect of IFN is influenced by cell type and the types of IFN, which suppresses proliferation and induces apoptosis in some cell types while inhibiting apoptosis in others. The aim of this study was to explore the effect of IFNα-2a on Fas expression and the apoptosis rate of peripheral blood cytotoxic T cells (CTLs) in patients with hepatitis B. METHODS:Peripheral blood mononuclear cells were isolated from 26 patients with hepatitis B including 16 patients with chronic hepatitis B and 10 patients with chronic severe hepatitis B. Fas expression and apoptosis rate of CTLs were analyzed with flow cytometry before and after IFNα-2a treatment. RESULTS:Before IFNα-2a treatment, Fas expression and apoptosis rate of CTLs from patients with chronic hepatitis B were significantly higher than those from patients with chronic severe hepatitis B and healthy controls respectively. No significant difference was observed between Fas expression and apoptosis rate of CTLs from patients with chronic severe hepatitis B and healthy controls. After IFNα-2a treatment,Fas expression and apoptosis rate of CTLs from different groups were compared with those before IFNα-2a treatment, showing no significant difference despite alternation of different degree. CONCLUSIONS:Activation induced cell death (AICD) exists in peripheral blood CTLs from patients with hepatitis B. No effect of IFNα-2a exerts on Fas expression and apoptosis rate of Fas in patients with hepatitis B.展开更多
Transplantation of activated transgenic Schwann cells or a fetal spinal cord cell suspension has been widely used to treat spinal cord injury. However, little is known regarding the effects of co-transplantation. In t...Transplantation of activated transgenic Schwann cells or a fetal spinal cord cell suspension has been widely used to treat spinal cord injury. However, little is known regarding the effects of co-transplantation. In the present study, autologous Schwann cells in combination with a fetal spinal cord cell suspension were transplanted into adult Wistar rats with spinal cord injury, and newly generated axonal connections were observed ultrastructurally. Transmission electron microscopic observations showed that the neuroblast first presented cytoplasmic processes, followed by pre- and postsynaptic membranes with low electron density forming a dense projection. The number and types of synaptic vesicles were increased. Synaptic connections developed from single cell body-dendritic synapses into multiple cell body-dendritic and dendrite-dendritic synapses. In addition, the cell organs of the transplanted neuroblast, oligodendroblast and astroblast matured gradually. The blood-brain barrier appeared subsequently. Moreover, neurofilament, histamine, calcitonin-gene-related peptides, and glial fibrillary acidic protein positive fibers were observed in the transplant region. These findings demonstrate that fetal spinal cord cells in the presence of autologous activated Schwann cells can develop into mature synapses in the cavity of injured spinal cords, suggesting the possibility of information exchange through the reconstructed synapse between fetal spinal cord cells and the host.展开更多
Aim: To investigate the activation of the nuclear factor of activated T cells (NFAT) and its function in the corticosterone (CORT)-induced apoptosis of rat Leydig cells. Methods: NFAT in rat Leydig cells was det...Aim: To investigate the activation of the nuclear factor of activated T cells (NFAT) and its function in the corticosterone (CORT)-induced apoptosis of rat Leydig cells. Methods: NFAT in rat Leydig cells was detected by Western blotting and immunohistochemical staining. Cyclosporin A (CsA) was used to evaluate potential involvement of NFAT in the CORT-induced apoptosis of Leydig cells. Intracellular Ca^2+ was monitored in CORT-treated Leydig cells using Fluo-3/AM. After the Leydig cells were incubated with either CORT or CORT plus CsA for 12 h, the levels of NFAT2 in the nuclei and in the cytoplasm were measured by semi-quantitative Western blotting. The role of NFAT2 in CORT- induced Leydig cell apoptosis was further evaluated by observing the effects of NFAT2 overexpression and the inhibition of NFAT2 activation by CsA on FasL expression and apoptosis. Results: We found that NFAT2 was the predominant isoform in Leydig cells. CsA blocked the CORT-induced apoptosis of the Leydig cells. The intracellular Ca^2+ level in the Leydig cells was significantly increased after the CORT treatment. The CORT increased the level of NFAT2 in the nuclei and decreased its level in the cytoplasm. CsA blocked the CORT-induced nuclear translocation of NFAT2 in the Leydig cells. Both CORT-induced apoptosis and FasL expression in the rat Leydig cells were enhanced by the overexpression of NFAT2 and antagonized by CsA. Conclusion: NFAT2 was activated in CORT-induced Leydig cell apoptosis. The effects of NFAT2 overexpression and the inhibition of NFAT2 activation suggest that NFAT2 may potentially play a pro-apoptotic role in CORT-induced Leydig cell apoptosis through the up-regulation of FasL.展开更多
OBJECTIVE: To investigate the gene expression of 4-1BB in peripheral blood mononuclear cells (PBMCs) and its possible significance in clinical liver transplantation. METHODS: Reverse transcription-polymerase chain rea...OBJECTIVE: To investigate the gene expression of 4-1BB in peripheral blood mononuclear cells (PBMCs) and its possible significance in clinical liver transplantation. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene expression of 4-1BB in PBMCs from 22 patients receiving liver transplantation, 13 patients with primary liver carcinoma (PLC), and 12 healthy controls. To determine whether 4-1BB molecule is also expressed on the surface of CD4^+ and CD8^+ T cell, flow cytometry was used to analyse the phenotype of T cell subsets from the blood of liver transplantation patients. RESULTS: 4-1BB mRNA was detected in PBMCs from stable survivors after liver transplantation, but almost not deteeted in PBMCs from PLC patients and healthy controls. Meanwhile, 4-1BB was almost not expressed on the surface of CD4^+ and CD8^+ T cells in healthy controls and PLC patients. A low level of 4-1BB expression, however, was found on the surface of CD4^+ and CD8^+ T cells from the stable survivors after liver transplantation. CONCLUSIONS: This study demonstrates that although patients are stable after liver transplantation, effector T-cells can also be activated through the signal of 4-1BB molecule and persistent irmmune response to grafts. Blockage of 4-1BB/4-1BBL pathway may benefitially reduce the clinical dosage of immunosuppressive agents and prolong the survival of grafts.展开更多
Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cel...Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cells (DCs), has potent adjuvant effects that polarize responses toward Th1. With a calculated molecular weight of 54.8 kDa, Hsp70L1 is smaller in size than Hsp70 but resembles it both structurally and functionally. Hsp70L1 shares common receptors on DCs with Hsp70 and can interact with DCs, promoting DC maturation and stimulating secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and the chemokines IP-10, macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and normal T cell expressed and secreted (RANTES). The induction of interferon-gamma-inducible protein 10 (IP-10) secretion by Hsp70L1 is not shared by Hsp70, and other functional differences include more potent stimulation of DC IL-12p70, CC-chemokine, and CCR7 and CXCR4 expression by Hsp70L1. Immunization of mice with the hybrid peptide Hsp70L1-ovalbumin(OVA)(257-264) induces an OVA(257-264)-specific Th1 response and cytotoxic T lymphocyte (CTL) that results in significant inhibition of E.G7-OVA tumor growth. The ability of Hsp70L1 to activate DCs indicates its potential as a novel adjuvant for use with peptide immunizations; the Hsp70L1 antigen peptide hybrid may serve as a more effective vaccine for the control of cancer and infectious diseases.展开更多
文摘Mast cells are a subtype of white blood cells and are involved in the immune system.These cells contain many chemical substances called mediators,which are involved in the allergic response.The fact that mast cells play a role in many events that require urgent intervention,especially anaphylaxis,has led to a more detailed study of these cells.The diseases also caused by dysfunctions of mast cells have been examined in many circumstances.For instance,mast cell activation syndrome is known as an augmented number of cells due to decreased cell death,resulting in clinical symptoms affecting many systems.The main common symptoms include flushing,hypotension,urticaria,angioedema,headache,vomiting and diarrhea.Although the underlying mechanism is not yet clearly known,we aim to review the literature in a broad perspective and bring together the existing knowledge in the light of the literature due to the diversity of its involvement in the body and the fact that it is a little known syndrome.
基金Supported by Sao Paulo Research Public Foundation FAPESPNational Counsel of Technological and Scientific Development CNPq,No.07/07193-3 and No.12/02270-2
文摘Mesenchymal stromal cells(MSCs) possess great therapeutic advantages due to their ability to produce a diverse array of trophic/growth factors related to cytoprotection and immunoregulation.MSC activation via specific receptors is a crucial event for these cells to exert their immunosuppressive response.The aryl-hydrocarbon receptor(Ah R) is a sensitive molecule for external signals and it is expressed in MSCs and,upon positive activation,may potentially regulate the MSC-associated immunomodulatory function.Consequently,signalling pathways linked to Ah R activation can elucidate some of the molecular cascades involved in MSC-mediated immunosuppression.In this minireview,we have noted some important findings concerning MSC regulation via Ah R,highlighting that its activation is associated with improvement in migration and immunoregulation,as well as an increase in pro-regenerative potential.Thus,Ah R-mediated MSC activation can contribute to new perspectives on MSC-based therapies,particularly those directed at immune-associated disorders.
文摘This paper described T cell proliferative response by an alternative pathway in normal subjects and In patients with malignant diseases. Two McAbs, Anti-CCTl and Lo-CD2-act recognizing two distinct epitopes on E-receptor (CD2) were used to costimulate PBMC. Proliferative responsiveness was measured by 3H-thymidine incorporation. It was found that 82% of 72 nonnal subjects gave proliferative response whereas only 23% of the 93 patients did. The average cpm±SD in patients with bladder cancer (118±2314), kidney cancer (1619±2719) or lymphoma (2518±4057) was significantly lower than that in normal subjects (4935±2314), (P<0.001). These results indicate that T cell proliferation through the alternative pathway was significantly depressed in patients with cancer, and this can be used as a new parameter to monitor the immune status of cancer patients.
基金supported in part by the Department of Anesthesiology and Pain Medicine of University of California Davis Health and NIH grant UL1TR000002 to the University of California Davis Health
文摘Mast cell activation syndrome(MCAS)includes a group of disorders that result in the inappropriate release of inflammatory mediators from mast cells.These mediators can affect multiple organ systems and lead to significant morbidity,and possible fatality.Although reactions,typically in response to various nonspecific stimuli,are usually mild,they may put those with MCAS at increased risk of anaphylaxis.In this case report,we present two clinical scenarios of MCAS,and identify possible factors triggering mast cell mediator release.We also define a preoperative preventive pathway,outline anesthetic considerations,and discuss the management of immediate hypersensitivity reactions in patients with MCAS.Meticulous preoperative preparation,avoidance of triggers,and development of a plan to treat possible adverse organ responses are paramount of good outcomes.
基金supported by the National Research Programs from the Ministry of Science and Technology of China(grant no.2021YFF0701800)the National Natural Science Foundation of China(grant nos.52032008 and 22277071)+1 种基金the Collaborative Innovation Center of Suzhou Nano Science and Technologythe“111”program from the Ministry of Education of China.
文摘The spatial arrangement of activating ligands is known to have great influence on T cell activation.However,independently studying each ligand’s spatial organization parameter that affects T cell activation remains a great challenge.Here,with DNA origami,we precisely organized the CD3ɛantibodies simulating T cell receptor(TCR)ligands and CD28 antibodies simulating co-stimulatory ligands to interrogate the independent role of TCR-ligand spacing and local copy numbers as well as the spacing between TCR ligands and co-stimulatory ligands on T cell activation.We found that T cell activation benefited fromlocally concentrated TCR ligands with a shorter spacing and was maximized by an∼38 nm spacing between TCR ligands and co-stimulatory ligands.The T cell expander constructed based on our findings could efficiently expand CD8+T cells for tumor immunotherapy.Thus,the DNA nanostructurebased ligands’precise arrangement can be a unique tool in studying immune cell activations and cellbased immunotherapies.
基金supported by Saving Sight in Grampian and the Development Trust of the University of Aberdeen。
文摘Dendritic cells(DC)are the major antigen-presenting cells bridging innate and adaptive immunity,a function they perform by converting quiescent DC to active,mature DC with the capacity to activate naı¨ve T cells.They do this by migrating from the tissues to the T cell area of the secondary lymphoid tissues.Here,wedemonstrate thatmyeloid cell-specific genetic deletion of PTP1B(LysM PTP1B)leads to defects in lipopolysaccharide-driven bone marrow-derivedDC(BMDC)activation associated with increased levels of phosphorylated Stat3.We showthatmyeloid cell-specific PTP1Bdeletion also causes decreased migratory capacity of epidermal DC,aswell as reduced CCR7 expression and chemotaxis to CCL19 by BMDC.PTP1B deficiency in BMDC also impairs their migration in vivo.Further,immature LysM PTP1B BMDC display fewer podosomes,increased levels of phosphorylated Src at tyrosine 527,and loss of Src localization to podosome puncta.In co-culture with T cells,LysM PTP1B BMDC establish fewer and shorter contacts than control BMDC.Finally,LysMPTP1BBMDCfail to present antigen to T cells as efficiently as controlBMDC.These data provide first evidence for a key regulatory role for PTP1B in mediating a central DC function of initiating adaptive immune responses in response to innate immune cell activation.
基金supported by grants from the Canadian Institutes of Health Research(CIHR)MT-14429,MOP-82906,and FDN-143338 to A.V.NSFC-31870863 from the National Natural Science Foundation of China to N.W.supported by a Postdoctoral Fellowship from Fonds de recherche du Quebec Santr(FRQS)。
文摘One of the hallmarks of live cells is the asymmetric distribution of lipids across their plasma membrane.Changes in this asymmetry due to lipid"scrambling"result in phosphatidylserine exposure at the cell surface that is detected by annexin V staining.This alteration is observed during cell death processes such as apoptosis,and during physiological responses such as platelet degranulation and membrane repair.Previous studies have shown that activation of NK cells is accompanied by exposure of phosphatidylserine at the cell surface.While this response was thought to be indicative of ongoing NK cell death,it may also reflect the regulation of NK cell activation in the absence of cell death.Herein,we found that NK cell activation was accompanied by rapid phosphatidylserine exposure to an extent proportional to the degree of NK cell activation.Through enforced expression of a lipid scramblase,we provided evidence that activation-induced lipid scrambling in NK cells is reversible and does not lead to cell death.In contrast,lipid scrambling attenuates NKcell activation.This response was accompanied by reduced cell surface expression of activating receptors such as 2B4,and by loss of binding of Src family protein tyrosine kinases Fyn and Lck to the inner leaflet of the plasma membrane.Hence,lipid scrambling during NK cell activation is,at least in part,a physiological response that reduces the NK cell activation level.This effect is due to the ability of lipid scrambling to alter the distribution of membrane-associated receptors and kinases required for NK cell activation.
文摘Objective To investigate the expression of B cell activation factor of the TNF family (BAFF) gene between human normal and inflamed fallopian tubes. Methods Tissue samples of human normal fallopian tube (n=20) and inflamed fallopian tube (n=20) were collected. The expression of BAFF gene was determined by the real- time reverse transcription polymerase chain reaction (RT-PCR) and immunohistochemistry. Results BAFF immunostaining appeared on the cellular membrane and in the cytoplasm of tubal epithelial cells. Both BAFF protein and mRNA in normal fallopian tubes had lower levels than those in inflamed fallopian tubes (P〈0.01). Conclusion BAFF protein and mRNA are present in human tubal tissues. BAFF gene in human inflamed fallopian tube would have a high expression.
基金this work was supported by Xi'an Science and technology Research Fund (GG04134)
文摘Objective To explore the correlation between endothelia cells activation and cytokines (ET-1, NO) levels in patients with pulmonary hypertension (PH), and to discuss their roles in the development of PH. Methods Twenty patients with simple ventricular septal defect (VSD) were chosen as controls, and 30 patients with PH were studied. Plasma levels of ET-1 and NO were measured by radioimmunoassay or colorimetric method. Before cardiopulmonary bypass was established, the specimens from right lung were fixed with formaldehyde solution, embedded with paraffin and stained by SP immunohistochemistry. Intercellular adhesion molecule-1 (ICAM-1) expression was measured through the determination of the light density with computer imaging technology. Results Compared with that of the patients with simple VSD, the light density of ICAM-1 and plasma level of ET-1 increased in patients with PH; but plasma level of NO decreased (P<0.05). Positive correlation was observed between ICAM-1 and ET-1/NO (P<0.05). Conclusion Endothelia cells activation and imbalance of ET-1/NO might play an important role in the development of PH.
基金This work was supported by the Ministry of Education,Science and Technological Development of The Republic of Serbia(Contract No.451-03-68/2022-14/200135).
文摘A key feature that distinguishes cancer cells from all other cells is their capability to spread throughout the body.Although how cancer cells collectively migrate by following molecular rules which influence the state of cell-cell adhesion contacts has been comprehensively formulated,the impact of physical interactions on cell spreading remains less understood.Cumulative effects of physical interactions exist as the interplay between various physical parameters such as(1)tissue surface tension,(2)viscoelasticity caused by collective cell migration,and(3)solid stress accumulated in the cell aggregate core region.This review aims to point out the role of these physical parameters in cancer cell spreading by considering and comparing the rearrangement of various mono-cultured cancer and epithelial model systems such as the fusion of two cell aggregates.While epithelial cells undergo volumetric cell rearrangement driven by the tissue surface tension,which directs cell movement from the surface to the core region of two-aggregate systems,cancer cells rather perform surface cell rearrangement.Cancer cells migrate toward the surface of the two-aggregate system driven by the solid stress while the surface tension is significantly reduced.The solid stress,accumulated in the core region of the two-aggregate system,is capable of suppressing the movement of epithelial cells that can undergo the jamming state transition;however,this stress enhances the movement of cancer cells.We have focused here on the multi-scale rheological modeling approaches that aimed at reproducing and understanding these biological systems.
文摘Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory has shown that the Qi-invigorating action of Chinese tonifying herbs is linked to increased mitochondrial ATP generation and an enhancement in mitochondrial glutathione redox status. To explore whether Sch B can exert Qi-invigorating actions across various tissues, we investigated the effects of Sch B treatment on mitochondrial ATP generation and glutathione redox status in multiple mouse tissues ex vivo. In line with TCM theory, which posits that Zheng Qi generation relies on the Qi function of the visceral organs, we also examined Sch B’s impact on natural killer cell activity and antigen-induced splenocyte proliferation, both serving as indirect measures of Zheng Qi. Our findings revealed that Sch B treatment consistently enhanced mitochondrial ATP generation and improved mitochondrial glutathione redox status in mouse tissues. This boost in mitochondrial function was associated with stimulated innate and adaptive immune responses, marked by increased natural killer cell activity and antigen-induced T/B cell proliferation, potentially through the increased generation of Zheng Qi.
基金supported by the Natural Science Foundation of Anhui Province of China,No.2208085Y32Scientific Research Plan Project of Anhui Province of China,No.2022AH020076the Chen Xiao-Ping Foundation for the Development of Science and Technology of Hubei Province,No.CXPJJH12000005-07-115(all to CT).
文摘Calcium influx into neurons triggers neuronal death during cerebral ischemia/reperfusion injury.Various calcium channels are involved in cerebral ischemia/reperfusion injury.Cav3.2 channel is a main subtype of T-type calcium channels.T-type calcium channel blockers,such as pimozide and mibefradil,have been shown to prevent cerebral ischemia/reperfusion injury-induced brain injury.However,the role of Cav3.2 channels in cerebral ischemia/reperfusion injury remains unclear.Here,in vitro and in vivo models of cerebral ischemia/reperfusion injury were established using middle cerebral artery occlusion in mice and high glucose hypoxia/reoxygenation exposure in primary hippocampal neurons.The results showed that Cav3.2 expression was significantly upregulated in injured hippocampal tissue and primary hippocampal neurons.We further established a Cav3.2 gene-knockout mouse model of cerebral ischemia/reperfusion injury.Cav3.2 knockout markedly reduced infarct volume and brain water content,and alleviated neurological dysfunction after cerebral ischemia/reperfusion injury.Additionally,Cav3.2 knockout attenuated cerebral ischemia/reperfusion injury-induced oxidative stress,inflammatory response,and neuronal apoptosis.In the hippocampus of Cav3.2-knockout mice,calcineurin overexpression offset the beneficial effect of Cav3.2 knockout after cerebral ischemia/reperfusion injury.These findings suggest that the neuroprotective function of Cav3.2 knockout is mediated by calcineurin/nuclear factor of activated T cells 3 signaling.Findings from this study suggest that Cav3.2 could be a promising target for treatment of cerebral ischemia/reperfusion injury.
基金Fund Project:General Program of National Natural Science Foundation of China(No.81774236)General Program of National Natural Science Foundation of China(No.81960841)。
文摘The incidence of liver fibrosis is increasing worldwide,and if left untreated,it will later develop into cirrhosis with a high mortality rate.In this paper,the activation pathway and related mechanism of stellate cells in liver fibrosis are introduced,and some current therapeutic methods are summarized.These results suggest that stellate cells play an important role in liver fibrosis,and targeted therapy for the purpose of inhibiting the activation of stellate cells and inducing their apoptosis is expected to be an effective regimen to reverse liver fibrosis.However,there are some problems such as insufficient in-depth study of related mechanisms and imperfect experiments.In future animal experiments and clinical trials,more studies can be carried out to provide high-quality protocols for the treatment of liver fibrosis.
基金supported by the National Natural Science Foundation of China(Grant Nos.:82073814,81973291,82122066,and 82003909)the Rising-Star Program of Shanghai Science and Technology Committee(Grant No.:19QA1411500).
文摘Astragali Radix(AR)is a clinically used herbal medicine with multiple immunomodulatory activities that can strengthen the activity and cytotoxicity of natural killer(NK)cells.However,owing to the complexity of its composition,the specific active ingredients in AR that act on NK cells are not clear yet.Cell membrane chromatography(CMC)is mainly used to screen the active ingredients in a complex system of herbal medicines.In this study,a new comprehensive two-dimensional(2D)NK-92MI CMC/C18 column/time-of-flight mass spectrometry(TOFMS)system was established to screen for potential NK cell activators.To obtain a higher column efficiency,3-mercaptopropyltrimethoxysilane-modified silica was synthesized to prepare the NK-92MI CMC column.In total,nine components in AR were screened from this system,which could be washed out from the NK-92MI/CMC column after 10 min,and they showed good affinity for NK-92MI/CMC column.Two representative active compounds of AR,isoastragaloside Ⅰ and astragaloside IV,promoted the killing effect of NK cells on K562 cells in a dose-dependent manner.It can thus suggest that isoastragaloside Ⅰ and astragaloside Ⅳ are the main immunomodulatory components of AR.This comprehensive 2D NK-92MI CMC analytical system is a practical method for screening immune cell activators from other herbal medicines with immunomodulatory effects.
文摘Interferon(IFN) with antiviral and im-munomodulatory activities is one of the most important therapeutic agents for the treatment of chronic hepatitis. The apoptotic effect of IFN is influenced by cell type and the types of IFN, which suppresses proliferation and induces apoptosis in some cell types while inhibiting apoptosis in others. The aim of this study was to explore the effect of IFNα-2a on Fas expression and the apoptosis rate of peripheral blood cytotoxic T cells (CTLs) in patients with hepatitis B. METHODS:Peripheral blood mononuclear cells were isolated from 26 patients with hepatitis B including 16 patients with chronic hepatitis B and 10 patients with chronic severe hepatitis B. Fas expression and apoptosis rate of CTLs were analyzed with flow cytometry before and after IFNα-2a treatment. RESULTS:Before IFNα-2a treatment, Fas expression and apoptosis rate of CTLs from patients with chronic hepatitis B were significantly higher than those from patients with chronic severe hepatitis B and healthy controls respectively. No significant difference was observed between Fas expression and apoptosis rate of CTLs from patients with chronic severe hepatitis B and healthy controls. After IFNα-2a treatment,Fas expression and apoptosis rate of CTLs from different groups were compared with those before IFNα-2a treatment, showing no significant difference despite alternation of different degree. CONCLUSIONS:Activation induced cell death (AICD) exists in peripheral blood CTLs from patients with hepatitis B. No effect of IFNα-2a exerts on Fas expression and apoptosis rate of Fas in patients with hepatitis B.
基金the Tianjin Science and Technology Commission Key Project,No.07JCZDJC08000the Natural Science Foundation of China, No.30772193,30571876National High-Tech R&D Program of China (863 Program),No.2007AA04Z235
文摘Transplantation of activated transgenic Schwann cells or a fetal spinal cord cell suspension has been widely used to treat spinal cord injury. However, little is known regarding the effects of co-transplantation. In the present study, autologous Schwann cells in combination with a fetal spinal cord cell suspension were transplanted into adult Wistar rats with spinal cord injury, and newly generated axonal connections were observed ultrastructurally. Transmission electron microscopic observations showed that the neuroblast first presented cytoplasmic processes, followed by pre- and postsynaptic membranes with low electron density forming a dense projection. The number and types of synaptic vesicles were increased. Synaptic connections developed from single cell body-dendritic synapses into multiple cell body-dendritic and dendrite-dendritic synapses. In addition, the cell organs of the transplanted neuroblast, oligodendroblast and astroblast matured gradually. The blood-brain barrier appeared subsequently. Moreover, neurofilament, histamine, calcitonin-gene-related peptides, and glial fibrillary acidic protein positive fibers were observed in the transplant region. These findings demonstrate that fetal spinal cord cells in the presence of autologous activated Schwann cells can develop into mature synapses in the cavity of injured spinal cords, suggesting the possibility of information exchange through the reconstructed synapse between fetal spinal cord cells and the host.
基金Acknowledgment This work was supported by a grant from National Natural Science Foundation of China (30570681).
文摘Aim: To investigate the activation of the nuclear factor of activated T cells (NFAT) and its function in the corticosterone (CORT)-induced apoptosis of rat Leydig cells. Methods: NFAT in rat Leydig cells was detected by Western blotting and immunohistochemical staining. Cyclosporin A (CsA) was used to evaluate potential involvement of NFAT in the CORT-induced apoptosis of Leydig cells. Intracellular Ca^2+ was monitored in CORT-treated Leydig cells using Fluo-3/AM. After the Leydig cells were incubated with either CORT or CORT plus CsA for 12 h, the levels of NFAT2 in the nuclei and in the cytoplasm were measured by semi-quantitative Western blotting. The role of NFAT2 in CORT- induced Leydig cell apoptosis was further evaluated by observing the effects of NFAT2 overexpression and the inhibition of NFAT2 activation by CsA on FasL expression and apoptosis. Results: We found that NFAT2 was the predominant isoform in Leydig cells. CsA blocked the CORT-induced apoptosis of the Leydig cells. The intracellular Ca^2+ level in the Leydig cells was significantly increased after the CORT treatment. The CORT increased the level of NFAT2 in the nuclei and decreased its level in the cytoplasm. CsA blocked the CORT-induced nuclear translocation of NFAT2 in the Leydig cells. Both CORT-induced apoptosis and FasL expression in the rat Leydig cells were enhanced by the overexpression of NFAT2 and antagonized by CsA. Conclusion: NFAT2 was activated in CORT-induced Leydig cell apoptosis. The effects of NFAT2 overexpression and the inhibition of NFAT2 activation suggest that NFAT2 may potentially play a pro-apoptotic role in CORT-induced Leydig cell apoptosis through the up-regulation of FasL.
文摘OBJECTIVE: To investigate the gene expression of 4-1BB in peripheral blood mononuclear cells (PBMCs) and its possible significance in clinical liver transplantation. METHODS: Reverse transcription-polymerase chain reaction (RT-PCR) was used to determine the gene expression of 4-1BB in PBMCs from 22 patients receiving liver transplantation, 13 patients with primary liver carcinoma (PLC), and 12 healthy controls. To determine whether 4-1BB molecule is also expressed on the surface of CD4^+ and CD8^+ T cell, flow cytometry was used to analyse the phenotype of T cell subsets from the blood of liver transplantation patients. RESULTS: 4-1BB mRNA was detected in PBMCs from stable survivors after liver transplantation, but almost not deteeted in PBMCs from PLC patients and healthy controls. Meanwhile, 4-1BB was almost not expressed on the surface of CD4^+ and CD8^+ T cells in healthy controls and PLC patients. A low level of 4-1BB expression, however, was found on the surface of CD4^+ and CD8^+ T cells from the stable survivors after liver transplantation. CONCLUSIONS: This study demonstrates that although patients are stable after liver transplantation, effector T-cells can also be activated through the signal of 4-1BB molecule and persistent irmmune response to grafts. Blockage of 4-1BB/4-1BBL pathway may benefitially reduce the clinical dosage of immunosuppressive agents and prolong the survival of grafts.
文摘Heat shock proteins (HSPs) are reported to act as effective adjuvants to elicit anti-tumor and anti-infection immunity. Here, we report that Hsp70-like protein 1 (Hsp70L1), a novel HSP derived from human dendritic cells (DCs), has potent adjuvant effects that polarize responses toward Th1. With a calculated molecular weight of 54.8 kDa, Hsp70L1 is smaller in size than Hsp70 but resembles it both structurally and functionally. Hsp70L1 shares common receptors on DCs with Hsp70 and can interact with DCs, promoting DC maturation and stimulating secretion of the proinflammatory cytokines interleukin 12p70 (IL-12p70), IL-1beta, tumor necrosis factor-alpha (TNF-alpha), and the chemokines IP-10, macrophage inflammatory protein-1alpha (MIP-1alpha), MIP-1beta, and normal T cell expressed and secreted (RANTES). The induction of interferon-gamma-inducible protein 10 (IP-10) secretion by Hsp70L1 is not shared by Hsp70, and other functional differences include more potent stimulation of DC IL-12p70, CC-chemokine, and CCR7 and CXCR4 expression by Hsp70L1. Immunization of mice with the hybrid peptide Hsp70L1-ovalbumin(OVA)(257-264) induces an OVA(257-264)-specific Th1 response and cytotoxic T lymphocyte (CTL) that results in significant inhibition of E.G7-OVA tumor growth. The ability of Hsp70L1 to activate DCs indicates its potential as a novel adjuvant for use with peptide immunizations; the Hsp70L1 antigen peptide hybrid may serve as a more effective vaccine for the control of cancer and infectious diseases.