The molecular basis of B cell receptor （BCR）-induced apoptosis during the negative selection of immature B cells is largely unknown. We use transitional immature B cells that are highly susceptible to BCR-induced ap...The molecular basis of B cell receptor （BCR）-induced apoptosis during the negative selection of immature B cells is largely unknown. We use transitional immature B cells that are highly susceptible to BCR-induced apoptosis to show that Pten is selectively required for BCR-mediated initiation of the mitochondrial death pathway. Specifically, deleting Pten, but not other pro-apoptotic molecules, abrogates BCR-elicited apoptosis and improves viability in wild-type immature B cells. We further identify a physiologically and significantly higher intracellular Pten level in immature B cells, as compared to mature B cells, which is responsible for low AKT activity and the propensity to- wards death in immature B cells. Restoration of AKT activity using a constitutive form of AKT or reduction of Pten to a level comparable with that seen in mature B cells rescues immature B cells from BCR-induced apoptosis. Thus, we provide evidence that Pten is an essential mediator of BCR-induced cell death, and that differential regulation of intracellular Pten levels determines whether BCR ligation promotes cell death or survival. Our findings provide a valuable insight into the mechanisms underlying negative selection and clonal deletion of immature B cells.展开更多
Autoimmune neurological disorders,including neuromyelitis optica spectrum disorder,anti-N-methyl-D-aspartate receptor encephalitis,anti-MOG antibody-associated disorders,and myasthenia gravis,are clearly defined by th...Autoimmune neurological disorders,including neuromyelitis optica spectrum disorder,anti-N-methyl-D-aspartate receptor encephalitis,anti-MOG antibody-associated disorders,and myasthenia gravis,are clearly defined by the presence of autoantibodies against neurological antigens.Although these autoantibodies have been heavily studied for their biological activities,given the heterogeneity of polyclonal patient samples,the characteristics of a single antibody cannot be definitively assigned.This review details the findings of polyclonal serum and CSF studies and then explores the advances made by single-cell technologies to the field of antibody-mediated neurological disorders.High-resolution single-cell methods have revealed abnormalities in the tolerance mechanisms of several disorders and provided further insight into the B cells responsible for autoantibody production.Ultimately,several factors,including epitope specificity and binding affinity,finely regulate the pathogenic potential of an autoantibody,and a deeper appreciation of these factors may progress the development of targeted immunotherapies for patients.Access options.展开更多
文摘The molecular basis of B cell receptor （BCR）-induced apoptosis during the negative selection of immature B cells is largely unknown. We use transitional immature B cells that are highly susceptible to BCR-induced apoptosis to show that Pten is selectively required for BCR-mediated initiation of the mitochondrial death pathway. Specifically, deleting Pten, but not other pro-apoptotic molecules, abrogates BCR-elicited apoptosis and improves viability in wild-type immature B cells. We further identify a physiologically and significantly higher intracellular Pten level in immature B cells, as compared to mature B cells, which is responsible for low AKT activity and the propensity to- wards death in immature B cells. Restoration of AKT activity using a constitutive form of AKT or reduction of Pten to a level comparable with that seen in mature B cells rescues immature B cells from BCR-induced apoptosis. Thus, we provide evidence that Pten is an essential mediator of BCR-induced cell death, and that differential regulation of intracellular Pten levels determines whether BCR ligation promotes cell death or survival. Our findings provide a valuable insight into the mechanisms underlying negative selection and clonal deletion of immature B cells.
基金This work was supported by the Australian National Health and Medical Research Council[APP1078643 and APP1183968](NHRMC,Australia)Multiple Sclerosis Research Australia,and a Sydney Research Excellence Initiative grant(University of Sydney,Australia).
文摘Autoimmune neurological disorders,including neuromyelitis optica spectrum disorder,anti-N-methyl-D-aspartate receptor encephalitis,anti-MOG antibody-associated disorders,and myasthenia gravis,are clearly defined by the presence of autoantibodies against neurological antigens.Although these autoantibodies have been heavily studied for their biological activities,given the heterogeneity of polyclonal patient samples,the characteristics of a single antibody cannot be definitively assigned.This review details the findings of polyclonal serum and CSF studies and then explores the advances made by single-cell technologies to the field of antibody-mediated neurological disorders.High-resolution single-cell methods have revealed abnormalities in the tolerance mechanisms of several disorders and provided further insight into the B cells responsible for autoantibody production.Ultimately,several factors,including epitope specificity and binding affinity,finely regulate the pathogenic potential of an autoantibody,and a deeper appreciation of these factors may progress the development of targeted immunotherapies for patients.Access options.
