Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelo...Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelong need for exogenous insulin therapy.In the pathophysiological landscape of T1D,T helper 17 cells(Th17 cells)and their hallmark cytokine,interleukin(IL)-17,play pivotal roles from disease onset to disease progression.In this narrative mini-review,we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D,providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction.Furthermore,we summarized the main animal and clinical studies that investigated Th17-and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.展开更多
Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the i...Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the infiltration of inflammatory cells into the intestinal mucosa and thus help enhancing intestinal barrier which could be damaged in some metabolic diseases.In this study,the influence of anthocyanin(administered orally)on the alterations(including structure and permeability)of the intestinal mucosa in mice in response to a high fat-high cholesterol(HFHC)diet was investigated.Primary T helper 17(Th17)cells were isolated from mouse intestine tissues to observe the modulatory role of anthocyanin through the transcription phosphorylated STAT 3(p-STAT3).The results indicated that anthocyanin significantly alleviated HFHC-induced impairment in the intestinal structures and permeability in a dose-dependent manner;moreover,anthocyanin appeared to inhibit HFHC induced the expression of p-STAT3,thereby disturbing Th17 cell differentiation.In high-fat diet(HFD,cholesterol level non-modified)-challenged mice selective p-STAT3 inhibitor significantly reversed the effects of anthocyanin,which were decreased amount of interleukin(IL)-17A(produced and released from Th17 cells)and the protected intestinal structure/function.In summary,the results of this study suggest that anthocyanin may attenuate the damage of intestinal barrier in HFHC mice through regulating intestinal STAT3-Th17-IL-17A signal transduction pathway.展开更多
Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that ...Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that the costimulatory molecules OX40 ligand(OX40L)and OX40 play essential roles in the immunological mechanisms of autoimmune diseases.Previously,we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells(PBMCs)of ITP patients.In our present study,OX40L-induced follicular helper T(Tfh)cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator(ICOS),programmed cell death protein-1(PD-1),and cluster of differentiation 40 ligand(CD40L)in vitro.Moreover,aberrant OX40L-OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo,inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model,which might accelerate the progression of ITP.Additionally,signal transduction through the OX40L-OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor(TRAF)-nuclear factor-κB(NF-κB)and Janus kinase(JAK)-signal transducer and activator of transcription(STAT)signaling pathways.Overall,OX40L-OX40 signaling is proposed as a potential novel therapeutic target for ITP.展开更多
Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Per...Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.展开更多
Objective: To investigate the value of peripheral blood helper T cell 17 cell level and monocyte/lymphocyte ratio to predict the prognosis of colorectal cancer patients. Methods: 74 colorectal cancer patients who atte...Objective: To investigate the value of peripheral blood helper T cell 17 cell level and monocyte/lymphocyte ratio to predict the prognosis of colorectal cancer patients. Methods: 74 colorectal cancer patients who attended Hospital 960 from January 2021 to January 2022 were retrospectively analyzed. Clinical data of the patients were collected, including gender, age, and histologic type. Immunohistochemical indexes such as Th17 cell level and monocyte/ lymphocyte ratio in the peripheral blood of patients were also collected. The prognosis of patients after treatment, as well as peripheral blood Th17 and MLR levels, were observed and analyzed. Results: After follow-up after treatment, in the final 74 patients, the prognosis was good in 32 patients, accounting for 43.24%, and the prognosis was bad in 42 patients, accounting for 56.76%. There were no significant differences between the average age and tumor diameters of the good prognosis and poor prognosis groups (P > 0.05). However, the TNM staging, intervention taken, differentiation degree, presence of distant metastasis, presence of lymph node metastasis, Th17 level, and MLR level are significantly different between the two groups (P < 0.05). Conclusion: Peripheral blood Th17 and MLR have predictive value for the prognosis of colorectal cancer patients, and high levels of peripheral blood Th17 and MLR imply poor prognosis. The detection of peripheral blood Th17 and MLR levels is simple and convenient and can be used as indicators to provide a reference for the prognostic assessment of colorectal cancer patients.展开更多
Myasthenia gravis(MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. T follicular helper(Tfh) cells have been implicated in ma...Myasthenia gravis(MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. T follicular helper(Tfh) cells have been implicated in many autoimmune diseases. However, whether and how Tfh cells are involved in MG remain unclear.Here, we established and studied a widely-used and approved animal model of human MG, the rat model with acetylcholine receptor alpha(AChRa) subunit(RAChR97–116)-induced experimental autoimmune myasthenia gravis(EAMG). This model presented mild bodyweight loss 10 days after the first immunization(representing the early stage of disease) and more obvious clinical manifestations and body-weight loss 7 days after the second immunization(representing the late stage of disease). AChR-specific pre-Tfh cells and mature Tfh cells were detected in these two stages, respectively. In cocultures of Tfh cells and B cells, the number of IgG2 bsecreting B cells and the level of anti-AChR antibodies in the supernatant were higher in the cultures containing EAMG-derived Tfh cells. In immunohistochemistry and immunofluorescence assays, a substantial number of CD4^+/Bcl-6^+ T cells and a greater number of larger germinal centers were observed in lymph node tissues resected from EAMG rats. Based on these results, wehypothesize that an AChR-specific Tfh cell-mediated humoral immune response contributes to the development of EAMG.展开更多
The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulate...The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.展开更多
Clinical trials have shown beneficial effects of probiotics on inflammatory bowel diseases (IBD), although the exact mechanism remains unknown. VSL#3, a mixture of 8 probiotic bacteria, has been confirmed to have adju...Clinical trials have shown beneficial effects of probiotics on inflammatory bowel diseases (IBD), although the exact mechanism remains unknown. VSL#3, a mixture of 8 probiotic bacteria, has been confirmed to have adjunctive therapeutic effects on colitis. T follicular helper (Tfh) cells, a new separate subset of CD4+ T helper cells, have been proved to play a vital role in autoimmunity. The present study aimed to identify the beneficial effect of the probiotic mixture VSL#3 on the mouse model of colitis by regulating Tfh cells. Dextran sulfate sodium (DSS) was used to induce chronic colitis in C57BL/6 mice. VSL#3 (3x109 live bacteria) was given to C57BL/6 mice every other day for 60 days by gavage. The disease activity index (DAI), histological activity index (HAI), colon length and myeloperoxidase (MPO) activity were detected. Immunofluorescence was used to visualize the location of Tfh cells. Immunoglobulins, Tfh cells and plasma cells were quantified by enzyme-linked immunosorbent assay (ELISA), flow cytometry, real-time PCR or Western blotting. The results showed that after DSS treatment, the humoral immunity was disordered in C57BL/6 mice, with increased IgM, IgG and IgA levels in colonic mucus and increased Tfh cells in mesenteric lymph nodes (MLN). VSL#3 treatment showed anti-inflammatory effects as evidenced by reduced DAI score, HAI score and MPO activity. IgM, IgG and IgA levels were significantly reduced in colon mucus, and the number of Tfh cells was markedly decreased in MLN after VSL#3 treatment. It was concluded that VSL#3 alleviates DSS-induced colitis by downregulating Tfh cells, and Tfh cells may become a potential therapeutic target for IBD.展开更多
The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the ear...The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.展开更多
BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in P...BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in PI-IBS.T helper 17(Th17)polarization occurs in IBS.Adenosine and its receptors participate in intestinal inflammation and immune regulation.AIM To investigate the role of Th17 polarization of CD4+T cells regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS A PI-IBS model was established by infecting mice with Trichinella spiralis.The intestinal A2AR and CD4+T lymphocytes were detected by immunohistochemistry,and the inflammatory cytokines were detected by enzyme-linked immunoassay.CD4+T lymphocytes present in the animal’s spleen were separated and cultured with or without A2AR agonist and antagonist.Western blotting and real-time quantitative polymerase chain reaction were performed to determine the effect of A2AR on the cells and intestinal tissue.Cytokine production was determined.The protein and mRNA levels of A2AR associated signaling pathway molecules were also evaluated.Furthermore,A2AR agonist and antagonist were injected into the mouse model and the clinical features were observed.RESULTS The PI-IBS mouse model showed increased expression of ATP and A2AR(P<0.05),and inhibition of A2AR improved the clinical features in PI-IBS,including the abdominal withdrawal reflex and colon transportation test(P<0.05).The number of intestinal CD4+T cells and interleukin-17(IL-17)protein levels increased during PI-IBS,which was reversed by administration of the A2AR antagonist(P<0.05).CD4+T cells expressed A2AR and produced IL-17 in vitro,which was regulated by the A2AR agonist and antagonist.The A2AR antagonist increased the production of IL-17 by CD4+T cells via the Janus kinase-signal transducer and activator of transcriptionreceptor-related orphan receptorγsignaling pathway.CONCLUSION The results of the present study suggested that the upregulation of A2AR increases PI-IBS by promoting the Th17 polarization of CD4+T cells.展开更多
Objective： To investigate and compare the .effects of different concentrations of morphine, fentanyl and tramadol on the differentiation of human adult helper T cells in vitro. Methods： Twenty out-patients without i...Objective： To investigate and compare the .effects of different concentrations of morphine, fentanyl and tramadol on the differentiation of human adult helper T cells in vitro. Methods： Twenty out-patients without immune disease were selected and their peripheral blood was collected. Then the Whole blood of peripheral blood mononuclear cells （PBMCs） were pretreated with different concentration of morphine, fentanyl and tramadol for 24 h. The level of CD4^＋ IFN-γ^＋ IL-2^＋/CD4^＋ IL-4^＋ IL-10^＋ was analyzed by three-color flow cytometry, and the CD4^＋ CCR5^＋ and CD4^＋ CCR3 ^＋ cells were counted to observe the imbalance of Th2/Th2. Results： The number of Th2 increased significantly and the ratio of Th2/Th2 decreased dramatically compared with the control group, and there was a dose-dependent fashion in all drugs. Conclusion： Morphine, fentanyl and tramadol can direct Th0 cells toward Th2 differentiation, especially morphine and fentanyl.展开更多
To obtain the helper plasmids for a reverse genetics system of rabies virus, the cDNAs of the complete open reading frames of the N, P, G, and L genes of rabies street virus stain HN10 were each cloned into expression...To obtain the helper plasmids for a reverse genetics system of rabies virus, the cDNAs of the complete open reading frames of the N, P, G, and L genes of rabies street virus stain HN10 were each cloned into expression vector pVAX1, These four plasmids were identified by restriction enzyme digestion and gene sequencing. The plasmid encoding the N protein was selected to determine the expression effect of these plasmids in NA cells. The results showed that the helper plasmids for a reverse genetics system of rabies street virus strain HN10 had been successfully constructed.展开更多
To compare the helper activities of different avian viruses for propagation of recombinant avian adeno-associated virus （rAAAV）, AAV-293 cells were cotransfected with the AAAV vector pAITR-GFP containing green fluor...To compare the helper activities of different avian viruses for propagation of recombinant avian adeno-associated virus （rAAAV）, AAV-293 cells were cotransfected with the AAAV vector pAITR-GFP containing green fluorescent protein （GFP） gene, the AAAV helper vector pcDNA-ARC expressing the rep and cap genes, and the adenovirus helper vector pHelper expressing Ad5 E2A, E4, and VA-RNA genes. Chicken embryonic fibroblast （CEF） or chicken embryonic liver （CEL） cells were cotransfected with the AAAV vector and the AAAV helper vector, followed by infection with Marek＇s disease virus （MDV）, avian adenovirus, chicken embryo lethal orphan （CELO） virus or infectious bursal disease virus （IBDV）. Infectious rAAAV particles generated by the two strategies were harvested and titrated on CEF and CEL cells. A significantly higher viral titer was obtained with the helper activity provided by the pHelper vector than by MDV or CELO virus. Further experiments showed that rAAAV-mediated green fluorescent protein （gfp） expression was overtly enhanced by MDV or CELO virus super infection or treatment with sodium butyric acid, but not by IBDV super infection. These data demonstrated that MDV and CELO viruses could provide weak helper activity for propagation of rAAAV, and rAAAV- mediated transgene expression could be enhanced by super infection with the helper viruses.展开更多
BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular...BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular complications,AGE are involved in altered metabolism in many tissues,including adipose tissue(AT)where they contribute to reduced glucose uptake and attenuation of insulin sensitivity.AGE are known to contribute to type 1 diabetes(T1D)through promotion of interleukin(IL)-17 secreting T helper(Th17)cells.AIM To investigate whether lean adipose-derived stem cells(ASC)could be able to induce IL-17A secretion,with the help of AGE.METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT,we used the same co-culture model to measure the impact of glycated human serum albumin(G-HSA)on human lean ASC interacting with blood mononuclear cells.IL-17A and pro-inflammatory cytokine secretion were measured by ELISA.Receptor of AGE(RAGE)together with intercellular adhesion molecule 1(ICAM-1),human leukocyte Antigen(HLA)-DR,cluster of differentiation(CD)41,and CD62P surface expressions were measured by cytofluorometry.Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.RESULTS Results showed that whereas 1%G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects,it markedly increased IL-17A,but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals.This was associated with increased expression of RAGE and HLA-DR molecule by cocultured cells.Moreover,RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation.Finally,platelet aggregation and ICAM-1,which are known to be induced by AGE,were not involved in these processes.CONCLUSION Thus,our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT,suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.展开更多
基金Supported by the European Union-NextGenerationEU,through the National Recovery and Resilience Plan of the Republic of Bulgaria,No.BG-RRP-2.004-0008.
文摘Type 1 diabetes(T1D)is a chronic organ-specific autoimmune disorder characterized by a progressive loss of the insulin-secreting pancreatic beta cells,which ultimately results in insulinopenia,hyperglycemia and lifelong need for exogenous insulin therapy.In the pathophysiological landscape of T1D,T helper 17 cells(Th17 cells)and their hallmark cytokine,interleukin(IL)-17,play pivotal roles from disease onset to disease progression.In this narrative mini-review,we discuss the dynamic interplay between Th17 cells and IL-17 in the context of T1D,providing insights into the underlying immunologic mechanisms contributing to the IL-17-immunity-mediated pancreatic beta-cell destruction.Furthermore,we summarized the main animal and clinical studies that investigated Th17-and IL-17-targeted interventions as promising immunotherapies able to alter the natural history of T1D.
基金supported by the National Natural Science Foundation of China(81973022 and 81730090)。
文摘Anthocyanin,as a typical food bioactive molecule,is capable of reversing inflammatory,oxidative and allergic condition thus contributes to intestinal health.We were wondering whether anthocyanin has influence on the infiltration of inflammatory cells into the intestinal mucosa and thus help enhancing intestinal barrier which could be damaged in some metabolic diseases.In this study,the influence of anthocyanin(administered orally)on the alterations(including structure and permeability)of the intestinal mucosa in mice in response to a high fat-high cholesterol(HFHC)diet was investigated.Primary T helper 17(Th17)cells were isolated from mouse intestine tissues to observe the modulatory role of anthocyanin through the transcription phosphorylated STAT 3(p-STAT3).The results indicated that anthocyanin significantly alleviated HFHC-induced impairment in the intestinal structures and permeability in a dose-dependent manner;moreover,anthocyanin appeared to inhibit HFHC induced the expression of p-STAT3,thereby disturbing Th17 cell differentiation.In high-fat diet(HFD,cholesterol level non-modified)-challenged mice selective p-STAT3 inhibitor significantly reversed the effects of anthocyanin,which were decreased amount of interleukin(IL)-17A(produced and released from Th17 cells)and the protected intestinal structure/function.In summary,the results of this study suggest that anthocyanin may attenuate the damage of intestinal barrier in HFHC mice through regulating intestinal STAT3-Th17-IL-17A signal transduction pathway.
基金supported by the National Natural Science Foundation of China(Nos.82172335,81971994,91846103,and 81871709)the Zhejiang Provincial Key Research and Development Program(No.2020C03032),China.
文摘Immune thrombocytopenia(ITP)is a hemorrhagic autoimmune disease characterized by antibody-mediated platelet injury.ITP has complicated immunopathological mechanisms that need further elucidation.It is well known that the costimulatory molecules OX40 ligand(OX40L)and OX40 play essential roles in the immunological mechanisms of autoimmune diseases.Previously,we discovered that the expression of OX40L and OX40 is significantly increased in the peripheral blood mononuclear cells(PBMCs)of ITP patients.In our present study,OX40L-induced follicular helper T(Tfh)cells exhibited an activated phenotype with elevated expression of inducible T-cell costimulator(ICOS),programmed cell death protein-1(PD-1),and cluster of differentiation 40 ligand(CD40L)in vitro.Moreover,aberrant OX40L-OX40 expression might promote the Tfh1-to-Tfh2 shift in vivo,inducing the generation of autoantibodies by enhancing the helper function of Tfh cells for B lymphocytes in a mouse model,which might accelerate the progression of ITP.Additionally,signal transduction through the OX40L-OX40 axis might be related to the activation of tumor necrosis factor receptor-associated factor(TRAF)-nuclear factor-κB(NF-κB)and Janus kinase(JAK)-signal transducer and activator of transcription(STAT)signaling pathways.Overall,OX40L-OX40 signaling is proposed as a potential novel therapeutic target for ITP.
基金supported by grants from the National Natural Science Foundation of China(No.82271755,No.81871230)Peking University People's Hospital Scientific Research Development Funds(RZ 2022-06).
文摘Objective This study aimed to investigate the changes of follicular helper T(TFH)and follicular regulatory T(TFR)cell subpopulations in patients with non-small cell lung cancer(NSCLC)and their significance.Methods Peripheral blood was collected from 58 NSCLC patients at different stages and 38 healthy controls.Flow cytometry was used to detect TFH cell subpopulation based on programmed death 1(PD-1)and inducible co-stimulator(ICOS),and TFR cell subpopulation based on cluster determinant 45RA(CD45RA)and forkhead box protein P3(FoxP3).The levels of interleukin-10(IL-10),interleukin-17a(IL-17a),interleukin-21(IL-21),and transforming growth factor-β(TGF-β)in the plasma were measured,and changes in circulating B cell subsets and plasma IgG levels were also analyzed.The correlation between serum cytokeratin fragment antigen 21-1(CYFRA 21-1)levels and TFH,TFR,or B cell subpopulations was further explored.Results The TFR/TFH ratio increased significantly in NSCLC patients.The CD45RA^(+)FoxP3^(int) TFR subsets were increased,with their proportions increasing in stages Ⅱ to Ⅲ and decreasing in stage IV.PD-1^(+)ICOS+TFH cells showed a downward trend with increasing stages.Plasma IL-21 and TGF-β concentrations were increased in NSCLC patients compared with healthy controls.Plasmablasts,plasma IgG levels,and CD45RA^(+)FoxP3^(int) TFR cells showed similar trends.TFH numbers and plasmablasts were positively correlated with CYFRA 21-1 in stages Ⅰ-Ⅲ and negatively correlated with CYFRA 21-1 in stage IV.Conclusion Circulating TFH and TFR cell subpopulations and plasmablasts dynamically change in different stages of NSCLC,which is associated with serum CYFRA 21-1 levels and reflects disease progression.
文摘Objective: To investigate the value of peripheral blood helper T cell 17 cell level and monocyte/lymphocyte ratio to predict the prognosis of colorectal cancer patients. Methods: 74 colorectal cancer patients who attended Hospital 960 from January 2021 to January 2022 were retrospectively analyzed. Clinical data of the patients were collected, including gender, age, and histologic type. Immunohistochemical indexes such as Th17 cell level and monocyte/ lymphocyte ratio in the peripheral blood of patients were also collected. The prognosis of patients after treatment, as well as peripheral blood Th17 and MLR levels, were observed and analyzed. Results: After follow-up after treatment, in the final 74 patients, the prognosis was good in 32 patients, accounting for 43.24%, and the prognosis was bad in 42 patients, accounting for 56.76%. There were no significant differences between the average age and tumor diameters of the good prognosis and poor prognosis groups (P > 0.05). However, the TNM staging, intervention taken, differentiation degree, presence of distant metastasis, presence of lymph node metastasis, Th17 level, and MLR level are significantly different between the two groups (P < 0.05). Conclusion: Peripheral blood Th17 and MLR have predictive value for the prognosis of colorectal cancer patients, and high levels of peripheral blood Th17 and MLR imply poor prognosis. The detection of peripheral blood Th17 and MLR levels is simple and convenient and can be used as indicators to provide a reference for the prognostic assessment of colorectal cancer patients.
基金supported by the National Natural Science Foundation of China(81000536,81471227,31371079,31671112 and 81430035)the China Postdoctoral Science Foundation(20100471094)+3 种基金the Returned Overseas Scholars Foundation of the Natural Science Foundation of Heilongjiang Province,China(LC2015029,QC2015022)the Science and Technology Research Project of the Education Department of Heilongjiang Province,China(12541z008)the Heilongjiang Province Postdoctoral Science Foundation(LBH-Q131111)the Open Topic of Key Laboratory of Neurobiology,General Colleges and Universities in Heilongjiang Province,China(2013HLJKLNT-05)
文摘Myasthenia gravis(MG) is a prototypical antibody-mediated neurological autoimmune disease with the involvement of humoral immune responses in its pathogenesis. T follicular helper(Tfh) cells have been implicated in many autoimmune diseases. However, whether and how Tfh cells are involved in MG remain unclear.Here, we established and studied a widely-used and approved animal model of human MG, the rat model with acetylcholine receptor alpha(AChRa) subunit(RAChR97–116)-induced experimental autoimmune myasthenia gravis(EAMG). This model presented mild bodyweight loss 10 days after the first immunization(representing the early stage of disease) and more obvious clinical manifestations and body-weight loss 7 days after the second immunization(representing the late stage of disease). AChR-specific pre-Tfh cells and mature Tfh cells were detected in these two stages, respectively. In cocultures of Tfh cells and B cells, the number of IgG2 bsecreting B cells and the level of anti-AChR antibodies in the supernatant were higher in the cultures containing EAMG-derived Tfh cells. In immunohistochemistry and immunofluorescence assays, a substantial number of CD4^+/Bcl-6^+ T cells and a greater number of larger germinal centers were observed in lymph node tissues resected from EAMG rats. Based on these results, wehypothesize that an AChR-specific Tfh cell-mediated humoral immune response contributes to the development of EAMG.
文摘The mechanism of action of ribavirin(RBV) as an immunomodulatory and antiviral agent and its clinical significance in the future treatment of patients with hepatitis C virus(HCV) infection are reviewed.RBV up-regulates type 1 and/or 2 cytokines to modulate the T helper(Th) 1/2 cell balance to Th1 dominance.Examination of co-stimulatory signaling indicated that RBV down-modulates inducible co-stimulator on Th cells,which contributes to differentiating na?ve Th cells into Th2 cells while reducing their interleukin-10 production.The effects on T-regulatory(Treg) cells were also investigated,and RBV inhibited the differentiation of na?ve Th cells into adaptive Treg cells by downmodulating forkhead box-P3.These findings indicate that RBV mainly down-regulates the activity of Th2 cells,resulting in the maintenance of Th1 activity that contributes to abrogating HCV-infected hepatocytes.Although an interferon-free treatment regimen exhibits almost the same efficacy without serious complications,regimens with RBV will be still be used because of their ability to facilitate the cellular immune response,which may contribute to reducing the development of hepatocellular carcinogenesis in patients infected with HCV.
基金This study was supported by the National Natural Science Foundation of China (Nos.81800984,81170361).
文摘Clinical trials have shown beneficial effects of probiotics on inflammatory bowel diseases (IBD), although the exact mechanism remains unknown. VSL#3, a mixture of 8 probiotic bacteria, has been confirmed to have adjunctive therapeutic effects on colitis. T follicular helper (Tfh) cells, a new separate subset of CD4+ T helper cells, have been proved to play a vital role in autoimmunity. The present study aimed to identify the beneficial effect of the probiotic mixture VSL#3 on the mouse model of colitis by regulating Tfh cells. Dextran sulfate sodium (DSS) was used to induce chronic colitis in C57BL/6 mice. VSL#3 (3x109 live bacteria) was given to C57BL/6 mice every other day for 60 days by gavage. The disease activity index (DAI), histological activity index (HAI), colon length and myeloperoxidase (MPO) activity were detected. Immunofluorescence was used to visualize the location of Tfh cells. Immunoglobulins, Tfh cells and plasma cells were quantified by enzyme-linked immunosorbent assay (ELISA), flow cytometry, real-time PCR or Western blotting. The results showed that after DSS treatment, the humoral immunity was disordered in C57BL/6 mice, with increased IgM, IgG and IgA levels in colonic mucus and increased Tfh cells in mesenteric lymph nodes (MLN). VSL#3 treatment showed anti-inflammatory effects as evidenced by reduced DAI score, HAI score and MPO activity. IgM, IgG and IgA levels were significantly reduced in colon mucus, and the number of Tfh cells was markedly decreased in MLN after VSL#3 treatment. It was concluded that VSL#3 alleviates DSS-induced colitis by downregulating Tfh cells, and Tfh cells may become a potential therapeutic target for IBD.
基金The National Natural Science Foundation of China,Nos.30871118,30971325,81270129 and 81470268(FL)grants from Department of Science and Technology of Sichuan Province,Nos.09ZQ026-020 and 2009SZ0190(FL)
文摘The transcription factor forkhead box protein A2(FOXA2, also known as hepatocyte nuclear factor 3β or transcription factor 3β), has been found to play pivotal roles in multiple phases of mammalian life, from the early development to the organofaction, and subsequently in homeostasis and metabolism in the adult. In the embryonic development period, FOXA2 is require d for the formation of the primitive node and notochord, and its absence results in embryonic lethality. Moreover, FOXA2 plays an important role not only in lung development, but also in T helper type 2(Th2)-mediated pulmonary inflammation and goblet cell hyperplasia. In this article, the role of FOXA2 in lung development and Th2-mediated pulmonary inflammation, as well as in goblet cell hyperplasia, is reviewed. FOXA2 deletion in airway epithelium results into Th2-mediated pulmonary inflammation and goblet cell hyperplasia in developing lung. Leukotriene pathway and signal transducers and activators of transcription 6 pathway may mediate this inflammation through recruitment and activation of denditric cell during lung developments. FOXA2 is a potential treatment target for lung diseases with Th2 inflammation and goblet cell hyperplasia, such as asthma and chronic obstructive pulmonary disease.
基金Supported by National Natural Science Foundation of China,No.81160057,No.81860102,and No.82060102.
文摘BACKGROUND Post-infectious irritable bowel syndrome(PI-IBS)is generally regarded as a functional disease.Several recent studies have reported the involvement of lowgrade inflammation and immunological dysfunction in PI-IBS.T helper 17(Th17)polarization occurs in IBS.Adenosine and its receptors participate in intestinal inflammation and immune regulation.AIM To investigate the role of Th17 polarization of CD4+T cells regulated by adenosine 2A receptor(A2AR)in PI-IBS.METHODS A PI-IBS model was established by infecting mice with Trichinella spiralis.The intestinal A2AR and CD4+T lymphocytes were detected by immunohistochemistry,and the inflammatory cytokines were detected by enzyme-linked immunoassay.CD4+T lymphocytes present in the animal’s spleen were separated and cultured with or without A2AR agonist and antagonist.Western blotting and real-time quantitative polymerase chain reaction were performed to determine the effect of A2AR on the cells and intestinal tissue.Cytokine production was determined.The protein and mRNA levels of A2AR associated signaling pathway molecules were also evaluated.Furthermore,A2AR agonist and antagonist were injected into the mouse model and the clinical features were observed.RESULTS The PI-IBS mouse model showed increased expression of ATP and A2AR(P<0.05),and inhibition of A2AR improved the clinical features in PI-IBS,including the abdominal withdrawal reflex and colon transportation test(P<0.05).The number of intestinal CD4+T cells and interleukin-17(IL-17)protein levels increased during PI-IBS,which was reversed by administration of the A2AR antagonist(P<0.05).CD4+T cells expressed A2AR and produced IL-17 in vitro,which was regulated by the A2AR agonist and antagonist.The A2AR antagonist increased the production of IL-17 by CD4+T cells via the Janus kinase-signal transducer and activator of transcriptionreceptor-related orphan receptorγsignaling pathway.CONCLUSION The results of the present study suggested that the upregulation of A2AR increases PI-IBS by promoting the Th17 polarization of CD4+T cells.
文摘Objective： To investigate and compare the .effects of different concentrations of morphine, fentanyl and tramadol on the differentiation of human adult helper T cells in vitro. Methods： Twenty out-patients without immune disease were selected and their peripheral blood was collected. Then the Whole blood of peripheral blood mononuclear cells （PBMCs） were pretreated with different concentration of morphine, fentanyl and tramadol for 24 h. The level of CD4^＋ IFN-γ^＋ IL-2^＋/CD4^＋ IL-4^＋ IL-10^＋ was analyzed by three-color flow cytometry, and the CD4^＋ CCR5^＋ and CD4^＋ CCR3 ^＋ cells were counted to observe the imbalance of Th2/Th2. Results： The number of Th2 increased significantly and the ratio of Th2/Th2 decreased dramatically compared with the control group, and there was a dose-dependent fashion in all drugs. Conclusion： Morphine, fentanyl and tramadol can direct Th0 cells toward Th2 differentiation, especially morphine and fentanyl.
基金National High Technology Research and Development Program of China (2006AA02Z110, 2007AA02Z402)Major Program of the National Natural Science Foundation of China (30630049)
文摘To obtain the helper plasmids for a reverse genetics system of rabies virus, the cDNAs of the complete open reading frames of the N, P, G, and L genes of rabies street virus stain HN10 were each cloned into expression vector pVAX1, These four plasmids were identified by restriction enzyme digestion and gene sequencing. The plasmid encoding the N protein was selected to determine the expression effect of these plasmids in NA cells. The results showed that the helper plasmids for a reverse genetics system of rabies street virus strain HN10 had been successfully constructed.
基金the National Natural Science Foundation of China （30571373）.
文摘To compare the helper activities of different avian viruses for propagation of recombinant avian adeno-associated virus （rAAAV）, AAV-293 cells were cotransfected with the AAAV vector pAITR-GFP containing green fluorescent protein （GFP） gene, the AAAV helper vector pcDNA-ARC expressing the rep and cap genes, and the adenovirus helper vector pHelper expressing Ad5 E2A, E4, and VA-RNA genes. Chicken embryonic fibroblast （CEF） or chicken embryonic liver （CEL） cells were cotransfected with the AAAV vector and the AAAV helper vector, followed by infection with Marek＇s disease virus （MDV）, avian adenovirus, chicken embryo lethal orphan （CELO） virus or infectious bursal disease virus （IBDV）. Infectious rAAAV particles generated by the two strategies were harvested and titrated on CEF and CEL cells. A significantly higher viral titer was obtained with the helper activity provided by the pHelper vector than by MDV or CELO virus. Further experiments showed that rAAAV-mediated green fluorescent protein （gfp） expression was overtly enhanced by MDV or CELO virus super infection or treatment with sodium butyric acid, but not by IBDV super infection. These data demonstrated that MDV and CELO viruses could provide weak helper activity for propagation of rAAAV, and rAAAV- mediated transgene expression could be enhanced by super infection with the helper viruses.
文摘BACKGROUND Advanced glycation end products(AGE)are a marker of various diseases including diabetes,in which they participate to vascular damages such as retinopathy,nephropathy and coronaropathy.Besides those vascular complications,AGE are involved in altered metabolism in many tissues,including adipose tissue(AT)where they contribute to reduced glucose uptake and attenuation of insulin sensitivity.AGE are known to contribute to type 1 diabetes(T1D)through promotion of interleukin(IL)-17 secreting T helper(Th17)cells.AIM To investigate whether lean adipose-derived stem cells(ASC)could be able to induce IL-17A secretion,with the help of AGE.METHODS As we have recently demonstrated that ASC are involved in Th17 cell promotion when they are harvested from obese AT,we used the same co-culture model to measure the impact of glycated human serum albumin(G-HSA)on human lean ASC interacting with blood mononuclear cells.IL-17A and pro-inflammatory cytokine secretion were measured by ELISA.Receptor of AGE(RAGE)together with intercellular adhesion molecule 1(ICAM-1),human leukocyte Antigen(HLA)-DR,cluster of differentiation(CD)41,and CD62P surface expressions were measured by cytofluorometry.Anti-RAGE specific monoclonal antibody was added to co-cultures in order to evaluate the role of RAGE in IL-17A production.RESULTS Results showed that whereas 1%G-HSA only weakly potentiated the production of IL-17A by T cells interacting with ASC harvested from obese subjects,it markedly increased IL-17A,but also interferon gamma and tumor necrosis factor alpha production in the presence of ASC harvested from lean individuals.This was associated with increased expression of RAGE and HLA-DR molecule by cocultured cells.Moreover,RAGE blockade experiments demonstrated RAGE specific involvement in lean ASC-mediated Th-17 cell activation.Finally,platelet aggregation and ICAM-1,which are known to be induced by AGE,were not involved in these processes.CONCLUSION Thus,our results demonstrated that G-HSA potentiated lean ASC-mediated IL-17A production in AT,suggesting a new mechanism by which AGE could contribute to T1D pathophysiology.
