To determine how the auto-antibodies (Abs) profiles overlap in chronic hepatitis C infection (CHC) and autoimmune hepatitis (AIH) and correlate to liver disease.METHODSLevels of antinuclear Ab, smooth muscle antibody ...To determine how the auto-antibodies (Abs) profiles overlap in chronic hepatitis C infection (CHC) and autoimmune hepatitis (AIH) and correlate to liver disease.METHODSLevels of antinuclear Ab, smooth muscle antibody (SMA) and liver/kidney microsomal-1 (LKM-1) Ab and markers of liver damage were determined in the sera of 50 patients with CHC infection, 20 AIH patients and 20 healthy controls using enzyme linked immunosorbent assay and other immune assays.RESULTSWe found that AIH patients had more severe liver disease as determined by elevation of total IgG, alkaline phosphatase, total serum bilirubin and serum transaminases and significantly higher prevalence of the three non-organ-specific autoantibodies (auto-Abs) than CHC patients. Antinuclear Ab, SMA and LKM-1 Ab were also present in 36% of CHC patients and related to disease severity. CHC cases positive for auto-Abs were directly comparable to AIH in respect of most markers of liver damage and total IgG. These cases had longer disease duration compared with auto-Ab negative cases, but there was no difference in gender, age or viral load. KLM-1<sup>+</sup> Ab CHC cases showed best overlap with AIH.CONCLUSIONAuto-Ab levels in CHC may be important markers of disease severity and positive cases have a disease similar to AIH. Auto-Abs might have a pathogenic role as indicated by elevated markers of liver damage. Future studies will unravel any novel associations between these two diseases, whether genetic or other.展开更多
A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates...A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR activation.Mechanistically,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling.In Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative phosphorylation.Conversely,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity.The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression.We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA explants.Similar to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals.Consistently,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by Syntenin-1.In conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.展开更多
Pancreatic ductal adenocarcinoma(PDAC)is a highly devastating disease with a dismal 5-year survival rate.PDAC has a complex tumour microenvironment;characterised by a robust desmoplastic stroma,extensive infiltration ...Pancreatic ductal adenocarcinoma(PDAC)is a highly devastating disease with a dismal 5-year survival rate.PDAC has a complex tumour microenvironment;characterised by a robust desmoplastic stroma,extensive infiltration of immunesuppressive cells such as immature myeloid cells,tumour-associated macrophages,neutrophils and regulatory T cells,and the presence of exhausted and senescent T cells.The cross-talk between cells in this fibrotic tumour establishes an immune-privileged microenvironment that supports tumour cell escape from immune-surveillance,disease progression and spread to distant organs.PDAC tumours,considered to be non-immunogenic or cold,express low mutation burden,low infiltration of CD8+cytotoxic lymphocytes that are localised along the invasive margin of the tumour border in the surrounding fibrotic tissue,and often display an exhausted phenotype.Here,we review the role of T cells in pancreatic cancer,examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of T cells as therapy.展开更多
CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia(CLL).Important functional properties are associated with CD5 expression in B ...CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia(CLL).Important functional properties are associated with CD5 expression in B cells,including signal transducer and activator of transcription 3 activation,IL-10 production and the promotion of B-lymphocyte survival and transformation.However,the pathway(s)by which CD5 influences the biology of B cells and its dependence on B-cell receptor(BCR)co-signaling remain unknown.In this study,we show that CD5 expression activates a number of important signaling pathways,including Erk1/2,leading to IL-10 production through a novel pathway independent of BCR engagement.This pathway is dependent on extracellular calcium(Ca2+)entry facilitated by upregulation of the transient receptor potential channel 1(TRPC1)protein.We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression.In this subgroup of CLL patients,small inhibitory RNA(siRNA)for CD5 reduces TRPC1 expression.Furthermore,siRNAs for CD5 or for TRPC1 inhibit IL-10 production.These findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL.展开更多
文摘To determine how the auto-antibodies (Abs) profiles overlap in chronic hepatitis C infection (CHC) and autoimmune hepatitis (AIH) and correlate to liver disease.METHODSLevels of antinuclear Ab, smooth muscle antibody (SMA) and liver/kidney microsomal-1 (LKM-1) Ab and markers of liver damage were determined in the sera of 50 patients with CHC infection, 20 AIH patients and 20 healthy controls using enzyme linked immunosorbent assay and other immune assays.RESULTSWe found that AIH patients had more severe liver disease as determined by elevation of total IgG, alkaline phosphatase, total serum bilirubin and serum transaminases and significantly higher prevalence of the three non-organ-specific autoantibodies (auto-Abs) than CHC patients. Antinuclear Ab, SMA and LKM-1 Ab were also present in 36% of CHC patients and related to disease severity. CHC cases positive for auto-Abs were directly comparable to AIH in respect of most markers of liver damage and total IgG. These cases had longer disease duration compared with auto-Ab negative cases, but there was no difference in gender, age or viral load. KLM-1<sup>+</sup> Ab CHC cases showed best overlap with AIH.CONCLUSIONAuto-Ab levels in CHC may be important markers of disease severity and positive cases have a disease similar to AIH. Auto-Abs might have a pathogenic role as indicated by elevated markers of liver damage. Future studies will unravel any novel associations between these two diseases, whether genetic or other.
基金supported in part by awards from the Department of Veteran’s Affairs MERIT Award BX002286,CX002565,IK6BX006474the National Institutes of Health NIH R01 AI167155,NIH R41 AI147697the Innovative Research Award from the Rheumatology Research Foundation(RRF,no number assigned).
文摘A novel rheumatoid arthritis(RA)synovial fluid protein,Syntenin-1,and its receptor,Syndecan-1(SDC-1),are colocalized on RA synovial tissue endothelial cells and fibroblast-like synoviocytes(FLS).Syntenin-1 exacerbates the inflammatory landscape of endothelial cells and RA FLS by upregulating transcription of IRF1/5/7/9,IL-1β,IL-6,and CCL2 through SDC-1 ligation and HIF1α,or mTOR activation.Mechanistically,Syntenin-1 orchestrates RA FLS and endothelial cell invasion via SDC-1 and/or mTOR signaling.In Syntenin-1 reprogrammed endothelial cells,the dynamic expression of metabolic intermediates coincides with escalated glycolysis along with unchanged oxidative factors,AMPK,PGC-1α,citrate,and inactive oxidative phosphorylation.Conversely,RA FLS rewired by Syntenin-1 displayed a modest glycolytic-ATP accompanied by a robust mitochondrial-ATP capacity.The enriched mitochondrial-ATP detected in Syntenin-1 reprogrammed RA FLS was coupled with mitochondrial fusion and fission recapitulated by escalated Mitofusin-2 and DRP1 expression.We found that VEGFR1/2 and Notch1 networks are responsible for the crosstalk between Syntenin-1 rewired endothelial cells and RA FLS,which are also represented in RA explants.Similar to RA explants,morphological and transcriptome studies authenticated the importance of VEGFR1/2,Notch1,RAPTOR,and HIF1αpathways in Syntenin-1 arthritic mice and their obstruction in SDC-1 deficient animals.Consistently,dysregulation of SDC-1,mTOR,and HIF1αnegated Syntenin-1 inflammatory phenotype in RA explants,while inhibition of HIF1αimpaired synovial angiogenic imprint amplified by Syntenin-1.In conclusion,since the current therapies are ineffective on Syntenin-1 and SDC-1 expression in RA synovial tissue and blood,targeting this pathway and its interconnected metabolic intermediates may provide a novel therapeutic strategy.
文摘Pancreatic ductal adenocarcinoma(PDAC)is a highly devastating disease with a dismal 5-year survival rate.PDAC has a complex tumour microenvironment;characterised by a robust desmoplastic stroma,extensive infiltration of immunesuppressive cells such as immature myeloid cells,tumour-associated macrophages,neutrophils and regulatory T cells,and the presence of exhausted and senescent T cells.The cross-talk between cells in this fibrotic tumour establishes an immune-privileged microenvironment that supports tumour cell escape from immune-surveillance,disease progression and spread to distant organs.PDAC tumours,considered to be non-immunogenic or cold,express low mutation burden,low infiltration of CD8+cytotoxic lymphocytes that are localised along the invasive margin of the tumour border in the surrounding fibrotic tissue,and often display an exhausted phenotype.Here,we review the role of T cells in pancreatic cancer,examine the complex interactions of these crucial effector units within pancreatic cancer stroma and shed light on the increasingly attractive use of T cells as therapy.
文摘CD5 is constitutively expressed on T cells and a subset of mature normal and leukemic B cells in patients with chronic lymphocytic leukemia(CLL).Important functional properties are associated with CD5 expression in B cells,including signal transducer and activator of transcription 3 activation,IL-10 production and the promotion of B-lymphocyte survival and transformation.However,the pathway(s)by which CD5 influences the biology of B cells and its dependence on B-cell receptor(BCR)co-signaling remain unknown.In this study,we show that CD5 expression activates a number of important signaling pathways,including Erk1/2,leading to IL-10 production through a novel pathway independent of BCR engagement.This pathway is dependent on extracellular calcium(Ca2+)entry facilitated by upregulation of the transient receptor potential channel 1(TRPC1)protein.We also show that Erk1/2 activation in a subgroup of CLL patients is associated with TRPC1 overexpression.In this subgroup of CLL patients,small inhibitory RNA(siRNA)for CD5 reduces TRPC1 expression.Furthermore,siRNAs for CD5 or for TRPC1 inhibit IL-10 production.These findings provide new insights into the role of CD5 in B-cell biology in health and disease and could pave the way for new treatment strategies for patients with B-CLL.
