A hallmark of systemic lupus erythematosus(SLE)is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies;however,the antibody-independent features of the B-cell compartment in SLE are les...A hallmark of systemic lupus erythematosus(SLE)is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies;however,the antibody-independent features of the B-cell compartment in SLE are less understood.In this study,we performed an extensive examination of B-cell subsets and their proinflammatory properties in a Chinese cohort of new-onset SLE patients.We observed that SLE patients exhibited an increased frequency of transitional B cells compared with healthy donors and rheumatoid arthritis patients.Plasma from SLE patients potently promoted the survival of transitional B cells in a type I IFN-dependent manner,which can be recapitulated by direct IFN-αtreatment.Furthermore,the effect of IFN-αon enhanced survival of transitional B cells was associated with NF-κB pathway activation and reduced expression of the pro-apoptotic molecule Bax.Transitional B cells from SLE patients harbored a higher capacity to produce proinflammatory cytokine IL-6,which was also linked to the overactivated type I IFN pathway.In addition,the frequency of IL-6-producing transitional B cells was positively correlated with disease activity in SLE patients,and these cells were significantly reduced after short-term standard therapies.Thus,the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients,which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.展开更多
Previous studies have shown that the CC chemokine receptor CCR5 is downregulated on monocyte/macrophage(MO/Mw)surfaces in head and neck squamous cell carcinoma(HNSCC)patients(stage IIIB).Ligands(RANTES,MIP-1a and MIP-...Previous studies have shown that the CC chemokine receptor CCR5 is downregulated on monocyte/macrophage(MO/Mw)surfaces in head and neck squamous cell carcinoma(HNSCC)patients(stage IIIB).Ligands(RANTES,MIP-1a and MIP-1b)of this chemokine receptor were also secreted in lesser quantity from MO/Mw of HNSCC patients in comparison with healthy individuals.In an aim to restore this dysregulated receptor–ligand signaling,we have used neem leaf glycoprotein(NLGP),a novel immunomodulator reported from our laboratory.NLGP upregulated CCR5 expression,as evidenced from studies on MO/Mw of peripheral blood from HNSCC patients as well as healthy individuals.Expression of RANTES,MIP-1a and MIP-1b was also upregulated following NLGP treatment of these cells in vitro.Interestingly,NLGP has little effect on the expression of CCR5 and the ligand RANTES in oral cancer cells.This restored CCR5 receptor–ligand signaling seen in MO/Mw was reflected in improved CCR5-dependent,p38 mitogen-activated protein kinase(MAPK)-mediated migration of MO/Mw after NLGP treatment to a standard chemoattractant.NLGP also induces better antigen presentation and simultaneous costimulation to effector T cells by MO/Mw by upregulating human leucocyte antigen(HLA)-ABC,CD80 and CD86.In addition,NLGP-treated MO/Mw-primed T cells can effectively lyse tumor cells in vitro.The effects of NLGP on monocyte migration and T cell-mediated oral tumor cell killing were further demonstrated in transwell assays with or without CCR5 neutralization.These results suggest a new approach in cancer immunotherapy by modulating dysregulated CCR5 signals from MO/Mw.展开更多
基金This work was supported by the National Basic Research Program of China(No.2014CB541904)the National Natural Science Foundation of China(Nos.31470879 81571575 8171101311 and 31770960)+2 种基金the Interdisciplinary Innovation Team,External Cooperation Program(No.GJHZ201312)Key Project QYZDB-SSW-SMC036the Strategic Priority Research Program(No.XDPB0303),Chinese Academy of Sciences.
文摘A hallmark of systemic lupus erythematosus(SLE)is the breaking of B-cell tolerance with the generation of high-affinity autoantibodies;however,the antibody-independent features of the B-cell compartment in SLE are less understood.In this study,we performed an extensive examination of B-cell subsets and their proinflammatory properties in a Chinese cohort of new-onset SLE patients.We observed that SLE patients exhibited an increased frequency of transitional B cells compared with healthy donors and rheumatoid arthritis patients.Plasma from SLE patients potently promoted the survival of transitional B cells in a type I IFN-dependent manner,which can be recapitulated by direct IFN-αtreatment.Furthermore,the effect of IFN-αon enhanced survival of transitional B cells was associated with NF-κB pathway activation and reduced expression of the pro-apoptotic molecule Bax.Transitional B cells from SLE patients harbored a higher capacity to produce proinflammatory cytokine IL-6,which was also linked to the overactivated type I IFN pathway.In addition,the frequency of IL-6-producing transitional B cells was positively correlated with disease activity in SLE patients,and these cells were significantly reduced after short-term standard therapies.Thus,the current study provides a direct link between type I IFN pathway overactivation and the abnormally high frequency and proinflammatory properties of transitional B cells in active SLE patients,which contributes to the understanding of the roles of type I IFNs and B cells in the pathogenesis of SLE.
基金supports from the Indian Council of Medical Research,New Delhi(Grant Nos.3/2/2/131/2007/NCD-III and Immuno/18/11/08/2006-ECD-I)University Grant Commission,New Delhi(Grant No.F.2-3/2000(SA-1)to AB and TC)are acknowledged.
文摘Previous studies have shown that the CC chemokine receptor CCR5 is downregulated on monocyte/macrophage(MO/Mw)surfaces in head and neck squamous cell carcinoma(HNSCC)patients(stage IIIB).Ligands(RANTES,MIP-1a and MIP-1b)of this chemokine receptor were also secreted in lesser quantity from MO/Mw of HNSCC patients in comparison with healthy individuals.In an aim to restore this dysregulated receptor–ligand signaling,we have used neem leaf glycoprotein(NLGP),a novel immunomodulator reported from our laboratory.NLGP upregulated CCR5 expression,as evidenced from studies on MO/Mw of peripheral blood from HNSCC patients as well as healthy individuals.Expression of RANTES,MIP-1a and MIP-1b was also upregulated following NLGP treatment of these cells in vitro.Interestingly,NLGP has little effect on the expression of CCR5 and the ligand RANTES in oral cancer cells.This restored CCR5 receptor–ligand signaling seen in MO/Mw was reflected in improved CCR5-dependent,p38 mitogen-activated protein kinase(MAPK)-mediated migration of MO/Mw after NLGP treatment to a standard chemoattractant.NLGP also induces better antigen presentation and simultaneous costimulation to effector T cells by MO/Mw by upregulating human leucocyte antigen(HLA)-ABC,CD80 and CD86.In addition,NLGP-treated MO/Mw-primed T cells can effectively lyse tumor cells in vitro.The effects of NLGP on monocyte migration and T cell-mediated oral tumor cell killing were further demonstrated in transwell assays with or without CCR5 neutralization.These results suggest a new approach in cancer immunotherapy by modulating dysregulated CCR5 signals from MO/Mw.
