Chronic obstructive pulmonary disease(COPD)is a multifaceted syndrome characterized by a dysregulated inflammatory cascade within the respiratory system,primarily triggered by exposure to harmful particles and gases,n...Chronic obstructive pulmonary disease(COPD)is a multifaceted syndrome characterized by a dysregulated inflammatory cascade within the respiratory system,primarily triggered by exposure to harmful particles and gases,notably from cigarette smoke.This inflammatory response is orchestrated by innate immune cells like macrophages and epithelial cells,which recognize danger signals released from damaged cells.Prolonged inflammation prompts an adaptive immune reaction mediated by dendritic cells,culminating in the formation of lymphoid follicles and involving a complex interplay of T and B cells,as well as cytotoxic activity.Additionally,both viral and bacterial infections exacerbate COPD by further igniting inflammatory pathways,perpetuating the chronic inflammatory state.This comprehensive review encapsulates the intricate interplay between innate and adaptive immunity in COPD,with a particular focus on the role of cigarette smoke in its pathogenesis and potential therapeutic targets.展开更多
Information regarding immunocompetence of the adaptive immune system （AIS） in zebrafish Danio rerio remains limited. Here, we stimulated an immune response in fish embryos, larvae and adults using lipopolysaccharide...Information regarding immunocompetence of the adaptive immune system （AIS） in zebrafish Danio rerio remains limited. Here, we stimulated an immune response in fish embryos, larvae and adults using lipopolysaccharide （LPS） and measured the upregulation of a number of AIS-related genes （Rag2, AID, TCRAC, IgLC-1, mIg, slg, IgZ and DAB） 3 and 18 h later. We found that all of the genes evaluated were strongly induced following LPS stimulation, with most of them responding at 8 d post fertilization. This confirms that a functional adaptive immune response is present in D. rerio larvae, and provides a window for further functional analyses.展开更多
Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate ...Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the beststudied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.展开更多
Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great ...Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery.HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion.To impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.展开更多
The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the ...The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.展开更多
Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progressio...Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide （NO） released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Thl cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-γ, （IFN-γ）-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-γ produced by Thl cells.展开更多
Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit an...Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit and eliminate HBV,viral breakthrough may result due to non-adherence to treatment,the emergence of viral resistance,and a long treatment cycle.Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems.Therefore,understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control.This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.展开更多
The interstitial fluids in tissues are constantly drained into the lymph nodes(LNs)as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics.LNs are strategically positioned a...The interstitial fluids in tissues are constantly drained into the lymph nodes(LNs)as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics.LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens.However,for lymph-borne viruses,which disseminate from the entry site to other tissues through the lymphatic system,immune cells in the draining LN(dLN)also play critical roles in curbing systemic viral dissemination during primary and secondary infections.Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells.Regardless of the entry mechanism,infected myeloid antigen-presenting cells,including various subtypes of dendritic cells,inflammatory monocytes,and macrophages,play a critical role in initiating the innate immune response within the dLN.This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons(IFN-Is)and other cytokines and recruit inflammatory monocytes and natural killer(NK)cells.IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease.Additionally,the memory CD8+T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections.This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+T-cells following secondary infection or CD8+T-cell vaccination.展开更多
Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defi...Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defined to guide the development of ICI regimens.Methods Databases,including The Cancer Genome Atlas,Gene Ontology Resource,University of California Santa Cruz Genome Browser,and Pubmed,were used to screen epigenetic modulators,regulators for CD8+T cells,and transcriptional regulators of programmed cell death-ligand 1(PD-L1).Human peripheral blood mononuclear cell(Hu-PBMC)reconstruction mice were adopted for xenograft transplantation.Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed.RNA-sequencing,Western blotting,qPCR and immunohistochemistry were used to assess gene expression.Coculture assays were performed to evaluate the regulation of TNBC cells on T cells.Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility.Results The epigenetic modulator AT-rich interaction domain 1A(ARID1A)gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients.Low ARID1A expression in TNBC,causing an immunosuppressive microenvironment,promoted AIR and inhibited CD8+T cell infiltration and activity through upregulating PD-L1.However,ARID1A did not directly regulate PD-L1 expression.We found that ARID1A directly bound the promoter of nucleophosmin 1(NPM1)and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression,further activating PD-L1 transcription.In Hu-PBMC mice,atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity.In CTR20191353,ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.Conclusions In AIR epigenetics,low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis,leading to poor outcome but sensitivity to ICI treatment.展开更多
With the exception of an extremely small number of cases caused by single gene mutations,most autoimmune diseases result from the complex interplay between environmental and genetic factors.In a nutshell,etiology of t...With the exception of an extremely small number of cases caused by single gene mutations,most autoimmune diseases result from the complex interplay between environmental and genetic factors.In a nutshell,etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage.In recent years,population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity,providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways.In this review,we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics.An overview of the genetic basis of autoimmunity is followed by3 chapters detailing susceptibility genes involved in innate immunity,adaptive immunity and inflammatory cell death processes respectively.With such attempts,we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the‘usual suspects’of a limited subset of validated therapeutic targets.展开更多
Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the und...Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.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
It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus （HBV） infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-lik...It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus （HBV） infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors （TLRs） sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons （IFNs） and pro-inflammatory cytokines. Experimental results from in vitroand in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T- and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.展开更多
The potency of Toll-like receptor 9(TLR9)agonist to drive innate immune response was limited due to immune suppression or tolerance during TLR9 signaling activation in immune cells.Herein we addressed this problem by ...The potency of Toll-like receptor 9(TLR9)agonist to drive innate immune response was limited due to immune suppression or tolerance during TLR9 signaling activation in immune cells.Herein we addressed this problem by introducing hydroxyapatite nanoparticles(HANPs)to CpG ODN(CpG),a TLR9 agonist.The study revealed that HANPs concentration and durationdependently reprogramed the immune response by enhancing the secretion of immunostimulatory cytokines(tumor necrosis factorα(TNFα)or IL-6)while reducing the production of immunosuppressive cytokine(IL-10)in macrophages in response to CpG.Next,the enhanced immune response benefited from increased intracellular Ca2+in macrophage by the addition of HANPs.Further,we found exposure to HANPs impacted the mitochondrial function of macrophages in support of the synthesis of adenosine triphosphate(ATP),the production of nicotinamide adenine dinucleotide(NAD),and reactive oxygen species(ROS)in the presence or absence of CpG.In vaccinated mice model,only one vaccination with a mixture of CpG,HANPs,and OVA,a model antigen,allowed the development of a long-lasting balanced humoral immunity in mice without any histopathological change in the local injection site.Therefore,this study revealed that HANPs could modulate the intracellular calcium level,mitochondrial function,and immune response in immune cells,and suggested a potential combination adjuvant of HANPs and TLR9 agonist for vaccine development.展开更多
In this investigation,we propose and analyze a virus dynamics model with multi-stages of infected cells.The model incorporates the effect of both humoral and cell-mediated immune responses.We consider two modes of tra...In this investigation,we propose and analyze a virus dynamics model with multi-stages of infected cells.The model incorporates the effect of both humoral and cell-mediated immune responses.We consider two modes of transmissions,virus-to-cell and cell-to-cell.Multiple intracellular discrete-time delays have been integrated into the model.The incidence rate of infection as well as the generation and removal rates of all compartments are described by general nonlinear functions.Wc derive five threshold parameters which determine the existence of the equilibria of the model under consideration.A set of conditions on the general functions has been established which is sufficient to investigate the global stability of the five equilibria of the model.The global asymptotic stability of all equilibria is proven by utilizing Lyapunov function and LaSalle’s invariance principle.The theoretical results are illustrated by numerical simulations of the model with specific forms of the general functions.展开更多
Appropriate in vivo control of plasmacytoid dendritic cell （pDC） recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the ...Appropriate in vivo control of plasmacytoid dendritic cell （pDC） recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies, pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exatnining the functional and antiviral properties of in vivo pDC plasticity. Cellular ＆ Molecular Immunology. 2005;2（6）：411- 417.展开更多
The present study investigated the effect of treatment with methanolic extracts of Yin- and Yang-Chinese tonifying herbs on concanavalin A (Con A)/lipopolysaccharide (LPS)-stimulated splenocyte proliferation (adaptive...The present study investigated the effect of treatment with methanolic extracts of Yin- and Yang-Chinese tonifying herbs on concanavalin A (Con A)/lipopolysaccharide (LPS)-stimulated splenocyte proliferation (adaptive immunity) and natural killer (NK) cell activity (innate immunity) in an ex vivo mouse model. The results indicated that while treatment with most Yin herbal extracts potentiated the Con A/LPS-stimulated splenocyte proliferation, only Yang (but not Yin) herbal extracts stimulated NK cell activity. The differential effects of Yin- and Yang-Chinese tonifying herbs on innate and adaptive immunity are consistent with the Chinese medicine theory which depicts the Yin and Yang functional components of Zheng Qi (vital energy), with the Yang component being responsible for the first line of defense against invading microorganisms (i.e., innate immunity) and the Yin oner serving as a follow-up defensive response (adaptive immunity).展开更多
Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immun...Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.展开更多
Green tea and its bioactive components possess many health-promoting and disease-preventing benefits,especially anti-inflammatory,antioxidant,anticancer,and metabolic modulation effects with multi-target modes of acti...Green tea and its bioactive components possess many health-promoting and disease-preventing benefits,especially anti-inflammatory,antioxidant,anticancer,and metabolic modulation effects with multi-target modes of action.In contrast,the effects and mechanisms of tea and its components on the immune system are rarely reviewed.The study aimed to review the most potent compounds in tea that affect the immune systems and mechanisms associated with it.As a result of in vitro studies,animal models,and human trials,researchers have found that green tea extracts and compounds have the possibility of modulating the innate immune system,adaptive immune system,and intestinal immune system.In immune-related diseases,tea polyphenols are the most significant compounds that modify immune functions,though other compounds are being investigated and cannot be ruled out.The review provides a new perspective on how the immune-regulatory effects of tea and its components are exerted on immune systems,as well as how they affect the emergence and treatment of diseases.展开更多
Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal.However,whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown.In the present ...Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal.However,whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown.In the present study,we discovered that the Nile tilapia(Oreochromis niloticus)encodes key components of the LAT signalosome,namely,LAT,ITK,GRB2,VAV1,SLP-76,GADS,and PLC-γ1.These components are evolutionarily conserved,and CD3εmAb-induced T-cell activation markedly increased their expression.Additionally,at least ITK,GRB2,and VAV1 were found to interact with LAT for signalosome formation.Downstream of the first signal,the NF-κB,MAPK/ERK,and PI3K-AKT pathways were activated upon CD3εmAb stimulation.Furthermore,treatment of lymphocytes with CD28 mAbs triggered the AKT-mTORC1 pathway downstream of the co-stimulatory signal.Combined CD3εand CD28 mAb stimulation enhanced ERK1/2 and S6 phosphorylation and elevated NFAT1,c-Fos,IL-2,CD122,and CD44 expression,thereby signifying T-cell activation.Moreover,rather than relying on the first or co-stimulatory signal alone,both signals were required for T-cell proliferation.Full T-cell activation was accompanied by marked apoptosis and cytotoxic responses.These findings suggest that tilapia relies on dual signaling to maintain an optimal T-cell response,providing a novel perspective for understanding the evolution of the adaptive immune system.展开更多
文摘Chronic obstructive pulmonary disease(COPD)is a multifaceted syndrome characterized by a dysregulated inflammatory cascade within the respiratory system,primarily triggered by exposure to harmful particles and gases,notably from cigarette smoke.This inflammatory response is orchestrated by innate immune cells like macrophages and epithelial cells,which recognize danger signals released from damaged cells.Prolonged inflammation prompts an adaptive immune reaction mediated by dendritic cells,culminating in the formation of lymphoid follicles and involving a complex interplay of T and B cells,as well as cytotoxic activity.Additionally,both viral and bacterial infections exacerbate COPD by further igniting inflammatory pathways,perpetuating the chronic inflammatory state.This comprehensive review encapsulates the intricate interplay between innate and adaptive immunity in COPD,with a particular focus on the role of cigarette smoke in its pathogenesis and potential therapeutic targets.
基金Supported by the Ministry of Science and Technology (MOST) of China (No. 2008AA09Z409)
文摘Information regarding immunocompetence of the adaptive immune system （AIS） in zebrafish Danio rerio remains limited. Here, we stimulated an immune response in fish embryos, larvae and adults using lipopolysaccharide （LPS） and measured the upregulation of a number of AIS-related genes （Rag2, AID, TCRAC, IgLC-1, mIg, slg, IgZ and DAB） 3 and 18 h later. We found that all of the genes evaluated were strongly induced following LPS stimulation, with most of them responding at 8 d post fertilization. This confirms that a functional adaptive immune response is present in D. rerio larvae, and provides a window for further functional analyses.
基金Supported by The Tonjes-Vagt-Stiftung,Bremen,Germany.
文摘Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the beststudied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.
基金Grants from"Instituto de Salud Carlos Ⅲ",Spain and"European Regional Development Fund(ERDF),a way of making Europe",E.U.,No.PI12/00130"Fundacion de In-vestigacion Medica Mutua Madrilena",Spain,No.8922/2011Lokhande MU was funded by a research grant from"Asoci-acion de Hepatologia Translacional"No.AHT-2010/01,Spain
文摘Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery.HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion.To impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.
文摘The complement system plays a crucial role in the innate defense against common pathogens. Activation of complement leads to robust and efficient proteolytic cascades, which terminate in opsonization and lysis of the pathogen as well as in the generation of the classical inflammatory response through the production of potent proinflammatory molecules. More recently, however, the role of complement in the immune response has been expanded due to observations that link complement activation to adaptive immune responses. It is now appreciated that complement is a functional bridge between innate and adaptive immune responses that allows an integrated host defense to pathogenic challenges. As such, a study of its functions allows insight into the molecular underpinnings of host-pathogen interactions as well as the organization and orchestration of the host immune response. This review attempts to summarize the roles that complement plays in both innate and adaptive immune responses and the consequences of these interactions on host defense.
文摘Inflammatory bowl disease （IBD） is a type 1 T helper cell （Th1）-mediated autoimmune disease. Various studies have revealed that environmental pathogens also play a significant role in the initiation and progression of this disease. Interestingly, the pathogenesis of IBD has been shown to be related to nitric oxide （NO） released from innate immune cells. Although NO is known to be highly toxic to the gut epithelia, there is very little information about the regulation of NO production, One major question in the etiology of IBD is how Thl cells and pathogens interact in the induction of IBD. In present study, we focused on the regulation of NO. We show that macrophages require both interferon-γ, （IFN-γ）-mediated and TLR4-mediated signals for the production of NO, which causes inflammation in the intestine and subsequently IBD. Thus, IBD is the result of concerted actions of innate immune signals, such as the binding of LPS to TLR-4, and adaptive immune signals, such as IFN-γ produced by Thl cells.
基金Supported by National Science Foundation for Young Scientists of China, No.82001687National Major Science and Technology Project for Control and Prevention of Major Infectious Diseases, No.2018ZX10301401+2 种基金National Postdoctoral Program for Innovative Talents, No.BX20190192China Postdoctoral Science Foundation, No.2020M672064National Basic Research Program of China, No.2013CB531503
文摘Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit and eliminate HBV,viral breakthrough may result due to non-adherence to treatment,the emergence of viral resistance,and a long treatment cycle.Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems.Therefore,understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control.This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.
文摘The interstitial fluids in tissues are constantly drained into the lymph nodes(LNs)as lymph through afferent lymphatic vessels and from LNs into the blood through efferent lymphatics.LNs are strategically positioned and have the appropriate cellular composition to serve as sites of adaptive immune initiation against invading pathogens.However,for lymph-borne viruses,which disseminate from the entry site to other tissues through the lymphatic system,immune cells in the draining LN(dLN)also play critical roles in curbing systemic viral dissemination during primary and secondary infections.Lymph-borne viruses in tissues can be transported to dLNs as free virions in the lymph or within infected cells.Regardless of the entry mechanism,infected myeloid antigen-presenting cells,including various subtypes of dendritic cells,inflammatory monocytes,and macrophages,play a critical role in initiating the innate immune response within the dLN.This innate immune response involves cellular crosstalk between infected and bystander innate immune cells that ultimately produce type I interferons(IFN-Is)and other cytokines and recruit inflammatory monocytes and natural killer(NK)cells.IFN-I and NK cell cytotoxicity can restrict systemic viral spread during primary infections and prevent serious disease.Additionally,the memory CD8+T-cells that reside or rapidly migrate to the dLN can contribute to disease prevention during secondary viral infections.This review explores the intricate innate immune responses orchestrated within dLNs that contain primary viral infections and the role of memory CD8+T-cells following secondary infection or CD8+T-cell vaccination.
基金National Science and Technology Major Project.Grant Number:2020ZX09201-013。
文摘Background Immune checkpoint inhibitors(ICIs)shed new light on triple-negative breast cancer(TNBC),but only a minority of patients demonstrate response.Therefore,adaptive immune resistance(AIR)needs to be further defined to guide the development of ICI regimens.Methods Databases,including The Cancer Genome Atlas,Gene Ontology Resource,University of California Santa Cruz Genome Browser,and Pubmed,were used to screen epigenetic modulators,regulators for CD8+T cells,and transcriptional regulators of programmed cell death-ligand 1(PD-L1).Human peripheral blood mononuclear cell(Hu-PBMC)reconstruction mice were adopted for xenograft transplantation.Tumor specimens from a TNBC cohort and the clinical trial CTR20191353 were retrospectively analyzed.RNA-sequencing,Western blotting,qPCR and immunohistochemistry were used to assess gene expression.Coculture assays were performed to evaluate the regulation of TNBC cells on T cells.Chromatin immunoprecipitation and transposase-accessible chromatin sequencing were used to determine chromatin-binding and accessibility.Results The epigenetic modulator AT-rich interaction domain 1A(ARID1A)gene demonstrated the highest expression association with AIR relative to other epigenetic modulators in TNBC patients.Low ARID1A expression in TNBC,causing an immunosuppressive microenvironment,promoted AIR and inhibited CD8+T cell infiltration and activity through upregulating PD-L1.However,ARID1A did not directly regulate PD-L1 expression.We found that ARID1A directly bound the promoter of nucleophosmin 1(NPM1)and that low ARID1A expression increased NPM1 chromatin accessibility as well as gene expression,further activating PD-L1 transcription.In Hu-PBMC mice,atezolizumab demonstrated the potential to reverse ARID1A deficiency-induced AIR in TNBC by reducing tumor malignancy and activating anti-tumor immunity.In CTR20191353,ARID1A-low patients derived more benefit from pucotenlimab compared to ARID1A-high patients.Conclusions In AIR epigenetics,low ARID1A expression in TNBC contributed to AIR via the ARID1A/NPM1/PD-L1 axis,leading to poor outcome but sensitivity to ICI treatment.
文摘With the exception of an extremely small number of cases caused by single gene mutations,most autoimmune diseases result from the complex interplay between environmental and genetic factors.In a nutshell,etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage.In recent years,population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity,providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways.In this review,we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics.An overview of the genetic basis of autoimmunity is followed by3 chapters detailing susceptibility genes involved in innate immunity,adaptive immunity and inflammatory cell death processes respectively.With such attempts,we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the‘usual suspects’of a limited subset of validated therapeutic targets.
基金funded by the Spanish Ministry of Economy and Competitiveness,No.PID(2019)-106498GB-100 (to MVS)by the Instituto de Salud CarlosⅢ,Fondo Europeo de Desarrollo Regional"Una manera de hacer Europa",No.PI19/00071 (to MAB)+2 种基金the RETICS subprograms of Spanish Networks OftoRed,Nos.RD16/0008/0026 (to DGB) and RD16/0008/0016 (to DGB)RICORS Terav,No.RD16/0011/0001 (to DGB)from Instituto de Salud CarlosⅢby the Fundacion Seneca,Agencia de Cienciay Tecnologia Región de Murcia,No.19881/GERM/15 (all to MVS)
文摘Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.
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.
文摘It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus （HBV） infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors （TLRs） sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons （IFNs） and pro-inflammatory cytokines. Experimental results from in vitroand in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T- and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.
基金supported by Sichuan Science and Technology Program(Nos.2020YFS0039 and 2020YFH0008)the National Natural Science Foundation of China(Nos.81901685 and 32171333)the Fundamental Research Funds for the Central Universities(No.YJ201915).
文摘The potency of Toll-like receptor 9(TLR9)agonist to drive innate immune response was limited due to immune suppression or tolerance during TLR9 signaling activation in immune cells.Herein we addressed this problem by introducing hydroxyapatite nanoparticles(HANPs)to CpG ODN(CpG),a TLR9 agonist.The study revealed that HANPs concentration and durationdependently reprogramed the immune response by enhancing the secretion of immunostimulatory cytokines(tumor necrosis factorα(TNFα)or IL-6)while reducing the production of immunosuppressive cytokine(IL-10)in macrophages in response to CpG.Next,the enhanced immune response benefited from increased intracellular Ca2+in macrophage by the addition of HANPs.Further,we found exposure to HANPs impacted the mitochondrial function of macrophages in support of the synthesis of adenosine triphosphate(ATP),the production of nicotinamide adenine dinucleotide(NAD),and reactive oxygen species(ROS)in the presence or absence of CpG.In vaccinated mice model,only one vaccination with a mixture of CpG,HANPs,and OVA,a model antigen,allowed the development of a long-lasting balanced humoral immunity in mice without any histopathological change in the local injection site.Therefore,this study revealed that HANPs could modulate the intracellular calcium level,mitochondrial function,and immune response in immune cells,and suggested a potential combination adjuvant of HANPs and TLR9 agonist for vaccine development.
文摘In this investigation,we propose and analyze a virus dynamics model with multi-stages of infected cells.The model incorporates the effect of both humoral and cell-mediated immune responses.We consider two modes of transmissions,virus-to-cell and cell-to-cell.Multiple intracellular discrete-time delays have been integrated into the model.The incidence rate of infection as well as the generation and removal rates of all compartments are described by general nonlinear functions.Wc derive five threshold parameters which determine the existence of the equilibria of the model under consideration.A set of conditions on the general functions has been established which is sufficient to investigate the global stability of the five equilibria of the model.The global asymptotic stability of all equilibria is proven by utilizing Lyapunov function and LaSalle’s invariance principle.The theoretical results are illustrated by numerical simulations of the model with specific forms of the general functions.
基金the National Outstanding Youth Foundation of China(No.30525042) National Key Basic Research Program of China(No.2001CB51003).
文摘Appropriate in vivo control of plasmacytoid dendritic cell （pDC） recruitment and activation is a fundamental requirement for defense against viral infection. During this process, a pivotal event that influences the outcome of viral infection is the production of high levels of type I interferon by pDCs. In particular, recent research findings showed that pDCs not only shape the nature of innate resistance, but are also responsible for the successful transition from innate to adaptive immunity for viral resistance. In addition, pDCs can differentiate into antigen presenting cells that may regulate tolerance to a given pathogen. Importantly, in a series of recent clinical studies, pDCs appeared to be defective in number and function in conditions of chronic viral diseases such as infected with HIV-1, HBV or HCV. pDC-associated clinical antiviral therapy is also emerging. This review describes research findings exatnining the functional and antiviral properties of in vivo pDC plasticity. Cellular ＆ Molecular Immunology. 2005;2（6）：411- 417.
文摘The present study investigated the effect of treatment with methanolic extracts of Yin- and Yang-Chinese tonifying herbs on concanavalin A (Con A)/lipopolysaccharide (LPS)-stimulated splenocyte proliferation (adaptive immunity) and natural killer (NK) cell activity (innate immunity) in an ex vivo mouse model. The results indicated that while treatment with most Yin herbal extracts potentiated the Con A/LPS-stimulated splenocyte proliferation, only Yang (but not Yin) herbal extracts stimulated NK cell activity. The differential effects of Yin- and Yang-Chinese tonifying herbs on innate and adaptive immunity are consistent with the Chinese medicine theory which depicts the Yin and Yang functional components of Zheng Qi (vital energy), with the Yang component being responsible for the first line of defense against invading microorganisms (i.e., innate immunity) and the Yin oner serving as a follow-up defensive response (adaptive immunity).
基金supported by grants from the National Natural Science Foundation of China(81971495 and 91442117)CAMS Innovation Fund for Medical Sciences(2019-I2M-5-035)+2 种基金the National Science Foundation of Jiangsu Province(BRA2017533 and BK20191490)the State Key Laboratory of Reproductive Medicine(SKLRM-K202001)the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials。
文摘Organ transplant rejection(OTR)is a complex immune reaction involving multiple cells,and it determines graft survival and patient prognosis.At present,most transplant recipients are administered a combination of immunosuppressive and biological agents to protect them from OTR.However,immunosuppressive agents negatively impact the immune system of the patients,causing them to suffer from serious complications,such as chronic infection and malignant tumors.Therefore,a thorough understanding of the mechanisms involved in immune tolerance and immune rejection with regard to organ transplant(OT)is essential for developing better treatment options and improving patient outcomes.This article reviews the role of immune cells in OTR and organ transplant tolerance(OTT),including the novel cell therapies that are currently under clinical trials for transplant recipients.
基金supported by College Student Innovation and Entrepreneurship Training(202110069122)Tianjin Key R&D Plan-Key Projects Supported by Science and Technology(19YFZCSN00010)Tianjin Agricultural Science and Technology Achievements Transformation and Promotion Project(202101120)。
文摘Green tea and its bioactive components possess many health-promoting and disease-preventing benefits,especially anti-inflammatory,antioxidant,anticancer,and metabolic modulation effects with multi-target modes of action.In contrast,the effects and mechanisms of tea and its components on the immune system are rarely reviewed.The study aimed to review the most potent compounds in tea that affect the immune systems and mechanisms associated with it.As a result of in vitro studies,animal models,and human trials,researchers have found that green tea extracts and compounds have the possibility of modulating the innate immune system,adaptive immune system,and intestinal immune system.In immune-related diseases,tea polyphenols are the most significant compounds that modify immune functions,though other compounds are being investigated and cannot be ruled out.The review provides a new perspective on how the immune-regulatory effects of tea and its components are exerted on immune systems,as well as how they affect the emergence and treatment of diseases.
基金supported by the National Key Research and Development Program(2022YFD2400804)National Natural Science Foundation of China(32022086,31972822)Natural Science Foundation of Shanghai(20ZR1417500)。
文摘Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal.However,whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown.In the present study,we discovered that the Nile tilapia(Oreochromis niloticus)encodes key components of the LAT signalosome,namely,LAT,ITK,GRB2,VAV1,SLP-76,GADS,and PLC-γ1.These components are evolutionarily conserved,and CD3εmAb-induced T-cell activation markedly increased their expression.Additionally,at least ITK,GRB2,and VAV1 were found to interact with LAT for signalosome formation.Downstream of the first signal,the NF-κB,MAPK/ERK,and PI3K-AKT pathways were activated upon CD3εmAb stimulation.Furthermore,treatment of lymphocytes with CD28 mAbs triggered the AKT-mTORC1 pathway downstream of the co-stimulatory signal.Combined CD3εand CD28 mAb stimulation enhanced ERK1/2 and S6 phosphorylation and elevated NFAT1,c-Fos,IL-2,CD122,and CD44 expression,thereby signifying T-cell activation.Moreover,rather than relying on the first or co-stimulatory signal alone,both signals were required for T-cell proliferation.Full T-cell activation was accompanied by marked apoptosis and cytotoxic responses.These findings suggest that tilapia relies on dual signaling to maintain an optimal T-cell response,providing a novel perspective for understanding the evolution of the adaptive immune system.
