The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall.In this review,we focus on the intestinal barrier’s relationship with the host...The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall.In this review,we focus on the intestinal barrier’s relationship with the host’s immune system interaction and the external environment,specifically the microbiome.The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens,luminal antigens,or other pro-inflammatory factors.Control over barrier function and the luminal milieu is maintained at the biochemical,cellular,and immunological level.However,disruption to this highly regulated environment can cause disease.Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology.There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences.The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases.This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.展开更多
activation.Therefore,engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70.However,the T cell-intrinsic effect and function of human CD70 remain underexplored.Herein,we describe...activation.Therefore,engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70.However,the T cell-intrinsic effect and function of human CD70 remain underexplored.Herein,we describe that CD70 expression distinguishes proinflammatory CD4^(+)T lymphocytes that display an increased potential to migrate into the central nervous system(CNS).Upregulation of CD70 on CD4^(+)T lymphocytes is induced by TGF-β1 and TGF-β3,which promote a pathogenic phenotype.In addition,CD70 is associated with a TH1 and TH17 profile of lymphocytes and is important for T-bet and IFN-γexpression by both T helper subtypes.Moreover,adoptive transfer of CD70−/−CD4^(+)T lymphocytes induced less severe experimental autoimmune encephalomyelitis(EAE)disease than transfer of WT CD4^(+)T lymphocytes.CD70+CD4^(+)T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice,highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory TH1/TH17 lymphocytes infiltrating the CNS.展开更多
文摘The intestinal barrier is a complex and well-controlled physiological construct designed to separate luminal contents from the bowel wall.In this review,we focus on the intestinal barrier’s relationship with the host’s immune system interaction and the external environment,specifically the microbiome.The bowel allows the host to obtain nutrients vital to survival while protecting itself from harmful pathogens,luminal antigens,or other pro-inflammatory factors.Control over barrier function and the luminal milieu is maintained at the biochemical,cellular,and immunological level.However,disruption to this highly regulated environment can cause disease.Recent advances to the field have progressed the mechanistic understanding of compromised intestinal barrier function in the context of gastrointestinal pathology.There are numerous examples where bowel barrier dysfunction and the resulting interaction between the microbiome and the immune system has disease-triggering consequences.The purpose of this review is to summarize the clinical relevance of intestinal barrier dysfunction in common gastrointestinal and related diseases.This may help highlight the importance of restoring barrier function as a therapeutic mechanism of action in gastrointestinal pathology.
基金T.D.holds a fellowship from the Fonds de Recherche du Québec-Santé(FRQS).L.T.holds scholarships from Universitéde Montréal and CRCHUM.E.P.holds a fellowship from the Multiple Sclerosis Society of Canada(MSSC)and the FRQS.S.Z.is supported by a fellowship from Biogen Canada.C.L.is supported by FRQS.A.P.holds the T1(senior)Canada Research Chair in Multiple Sclerosis.This work was funded by operating grants from the Canadian Institutes of Health Research(MOP 89885,PJI-153195)and from the MSSC(EGID 2382).We thank Jannie Borst for providing us with the CD70−/−mice.We thank Hartmut Wekerle for providing us with the TCR1640 mice.Special thanks to Magdalena Paterka and Volker Siffrin for providing the protocol for CD4+adoptive T cell transfer in RAG null mice.We would also like to thank the imaging platform,the pathology platform,and the flow cytometry platform from the CRCHUM for the excellent technical support and Alice M Roy and Elvia Gonzalez for their excellent technical animal support.
文摘activation.Therefore,engagement of the costimulatory CD27/CD70 pathway is solely dependent on upregulation of CD70.However,the T cell-intrinsic effect and function of human CD70 remain underexplored.Herein,we describe that CD70 expression distinguishes proinflammatory CD4^(+)T lymphocytes that display an increased potential to migrate into the central nervous system(CNS).Upregulation of CD70 on CD4^(+)T lymphocytes is induced by TGF-β1 and TGF-β3,which promote a pathogenic phenotype.In addition,CD70 is associated with a TH1 and TH17 profile of lymphocytes and is important for T-bet and IFN-γexpression by both T helper subtypes.Moreover,adoptive transfer of CD70−/−CD4^(+)T lymphocytes induced less severe experimental autoimmune encephalomyelitis(EAE)disease than transfer of WT CD4^(+)T lymphocytes.CD70+CD4^(+)T lymphocytes are found in the CNS during acute autoimmune inflammation in humans and mice,highlighting CD70 as both an immune marker and an important costimulator of highly pathogenic proinflammatory TH1/TH17 lymphocytes infiltrating the CNS.
