Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)matu...Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)maturation.Through fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region.Expression quantitative trait locus(e QTL)analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,which is consistent with the allelic imbalance in RNA-Seq reads(P<0.0001).The MS risk allele is associated with reduced levels of TNFSF14 gene expression(P<0.01)in blood cells from 84 Italian patients with MS and 80 healthy controls(HCs).Interestingly,patients with MS are lower expressors of TNFSF14 compared to HC(P<0.007).Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs(CD11 c+,P=0.035)in 37 HCs,as well as in in vitro monocyte-derived DCs from 22 HCs(P=0.04).Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells,which may play a role in MS pathogenesis.展开更多
CD1d-restricted natural killer T(NKT)cells are innate-like T lymphocytes with protective or pathogenic roles in the development of influenza pneumonia.Here,we show that lung-infiltrated and activated NKT cells are the...CD1d-restricted natural killer T(NKT)cells are innate-like T lymphocytes with protective or pathogenic roles in the development of influenza pneumonia.Here,we show that lung-infiltrated and activated NKT cells are the major cellular source of LIGHT/TNFSF14,which determines the severity of pulmonary pneumonia by highly deteriorative influenza A virus(IAV)infection.Compared to wild-type mice,LIGHT^(-/-)mice exhibit much lower morbidity and mortality to IAV,due to alleviated lung damage and reduced apoptosis of alveolar macrophages(AMs).LIGHT preferentially promotes cell death of lymphotoxin β receptors positive(LTβR^(+))AMs but not herpesvirus entry mediator positive(HVEM^(+))AMs.Therefore,these results suggest that NKT-derived LIGHT augments cell death of the tissue protective AMs in exacerbating lung pathology and susceptibility to fatal influenza infection.Suppression of LIGHT signaling might be a viable option in the treatment of influenza-associated acute respiratory distress syndrome.展开更多
Here,we investigated the antitumor effect of adenovirus-mediated gene transfer of LIGHT,the tumor-necrosis factor(TNF)superfamily member also known as TNFSF14,in the murine A20 B-cell lymphoma.LIGHT gene modification ...Here,we investigated the antitumor effect of adenovirus-mediated gene transfer of LIGHT,the tumor-necrosis factor(TNF)superfamily member also known as TNFSF14,in the murine A20 B-cell lymphoma.LIGHT gene modification resulted in upregulated expression of Fas and the accessory molecule-intercellular adhesion molecule-1(ICAM-1)on A20 cells and led to enhanced A20 cell apoptosis.LIGHT-modified A20 cells effectively stimulated the proliferation of T lymphocytes and interferon(IFN)-c production in vitro.Immunization of BALB/c mice with a LIGHT-modified A20 cell vaccine efficiently elicited protective immunity against challenge with the parental tumor cell line.Adenovirus-mediated gene transfer of LIGHT by intratumoral injection exerted a very potent antitumor effect against pre-existing A20 cell lymphoma in BALB/c mice.This adenovirus-mediated LIGHT therapy induced substantial splenic natural killer(NK)and cytotoxic T lymphocyte(CTL)activity,enhanced tumor infiltration by inflammatory cells and increased chemokine expression of CC chemokine ligand 21(CCL21),IFN-inducible protein-10(IP-10)and monokine induced by IFN-c(Mig)from tumor tissues.Thus,adenovirus-mediated LIGHT therapy might have potential utility for the prevention and treatment of B-cell lymphoma.展开更多
基金supported by the Italian Foundation of Multiple Sclerosis(FISM,2011/R/142015/R/10,2019/R-Multi/033)by the Italian Ministry of Health(RF-2016-02361294)the AGING Project for Department of Excellence at the Department of Translational Medicine(DIMET),Universitàdel Piemonte Orientale,Novara,Italy+1 种基金supported by Consorzio Interuniversitario di Biotecnologie(CIB)partially supported by Multiple MS project(Horizon 2020 European Grant 733161),Stockholm。
文摘Among multiple sclerosis(MS)susceptibility genes,the strongest non-human leukocyte antigen(HLA)signal in the Italian population maps to the TNFSF14 gene encoding LIGHT,a glycoprotein involved in dendritic cell(DC)maturation.Through fine-mapping in a large Italian dataset(4,198 patients with MS and3,903 controls),we show that the TNFSF14 intronic SNP rs1077667 is the primarily MS-associated variant in the region.Expression quantitative trait locus(e QTL)analysis indicates that the MS risk allele is significantly associated with reduced TNFSF14 messenger RNA levels in blood cells,which is consistent with the allelic imbalance in RNA-Seq reads(P<0.0001).The MS risk allele is associated with reduced levels of TNFSF14 gene expression(P<0.01)in blood cells from 84 Italian patients with MS and 80 healthy controls(HCs).Interestingly,patients with MS are lower expressors of TNFSF14 compared to HC(P<0.007).Individuals homozygous for the MS risk allele display an increased percentage of LIGHT-positive peripheral blood myeloid DCs(CD11 c+,P=0.035)in 37 HCs,as well as in in vitro monocyte-derived DCs from 22 HCs(P=0.04).Our findings suggest that the intronic variant rs1077667 alters the expression of TNFSF14 in immune cells,which may play a role in MS pathogenesis.
基金supported by the Chinese Academy of Sciences(XDB29030301)the Ministry of Science and Technology(2018ZX10101004002004 and 2018YFC1200703)the National Natural Science Foundation of China(31321001,31621061,81590764,and 31400755)。
文摘CD1d-restricted natural killer T(NKT)cells are innate-like T lymphocytes with protective or pathogenic roles in the development of influenza pneumonia.Here,we show that lung-infiltrated and activated NKT cells are the major cellular source of LIGHT/TNFSF14,which determines the severity of pulmonary pneumonia by highly deteriorative influenza A virus(IAV)infection.Compared to wild-type mice,LIGHT^(-/-)mice exhibit much lower morbidity and mortality to IAV,due to alleviated lung damage and reduced apoptosis of alveolar macrophages(AMs).LIGHT preferentially promotes cell death of lymphotoxin β receptors positive(LTβR^(+))AMs but not herpesvirus entry mediator positive(HVEM^(+))AMs.Therefore,these results suggest that NKT-derived LIGHT augments cell death of the tissue protective AMs in exacerbating lung pathology and susceptibility to fatal influenza infection.Suppression of LIGHT signaling might be a viable option in the treatment of influenza-associated acute respiratory distress syndrome.
基金supported by grants from the National Natural Science Foundation of China(30328011 and 30872377)the National Basic Research Program of China(2004CB518802)the Science and Technology Department of Zhejiang Province(2008C23044).
文摘Here,we investigated the antitumor effect of adenovirus-mediated gene transfer of LIGHT,the tumor-necrosis factor(TNF)superfamily member also known as TNFSF14,in the murine A20 B-cell lymphoma.LIGHT gene modification resulted in upregulated expression of Fas and the accessory molecule-intercellular adhesion molecule-1(ICAM-1)on A20 cells and led to enhanced A20 cell apoptosis.LIGHT-modified A20 cells effectively stimulated the proliferation of T lymphocytes and interferon(IFN)-c production in vitro.Immunization of BALB/c mice with a LIGHT-modified A20 cell vaccine efficiently elicited protective immunity against challenge with the parental tumor cell line.Adenovirus-mediated gene transfer of LIGHT by intratumoral injection exerted a very potent antitumor effect against pre-existing A20 cell lymphoma in BALB/c mice.This adenovirus-mediated LIGHT therapy induced substantial splenic natural killer(NK)and cytotoxic T lymphocyte(CTL)activity,enhanced tumor infiltration by inflammatory cells and increased chemokine expression of CC chemokine ligand 21(CCL21),IFN-inducible protein-10(IP-10)and monokine induced by IFN-c(Mig)from tumor tissues.Thus,adenovirus-mediated LIGHT therapy might have potential utility for the prevention and treatment of B-cell lymphoma.
