Primary immunodeficiency disorders(PIDs)are rare inborn errors of the immune system.Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying i...Primary immunodeficiency disorders(PIDs)are rare inborn errors of the immune system.Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying infections,autoimmunity,lymphoproliferation,allergy and cancer.Over 150 PID syndromes were characterized in the past 60 years,with an ever growing list of new entities being discovered.Because of their rarity,multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights into the phenotypic and genetic diversities of PIDs.In this article,we summarize our research findings on PIDs in Chinese population in the past 20 years.Close collaboration among various immunology centers,cross-referrals and systematic data analysis constitute the foundation for research on PIDs.Future directions include establishment of a national PID registry,raising awareness of PIDs and securing sufficient resources for patient care and scientific research.展开更多
Activated phosphoinositide 3-kinaseδsyndrome(APDS)is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function(GOF)mutations in the PIK3CD gene.Patients with APDS display abn...Activated phosphoinositide 3-kinaseδsyndrome(APDS)is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function(GOF)mutations in the PIK3CD gene.Patients with APDS display abnormal T cell homeostasis.However,the mechanisms by which PIK3CD GOF contributes to this feature remain unknown.Here,with a cohort of children with PIK3CD GOF mutations from multiple regions of China and a corresponding CRISPR/Cas9 gene-edited mouse model,we reported that hyperactive PI3Kδdisrupted TNaive cell homeostasis in the periphery by intrinsically promoting the growth,proliferation,and activation of TNaive cells.Our results showed that PIK3CD GOF resulted in loss of the quiescence-associated gene expression profile in naive T cells and promoted naive T cells to overgrow,hyperproliferate and acquire an activated functional status.Naive PIK3CD GOF T cells exhibited an enhanced glycolytic capacity and reduced mitochondrial respiration in the resting or activated state.Blocking glycolysis abrogated the abnormal splenic T cell pool and reversed the overactivated phenotype induced by PIK3CD GOF in vivo and in vitro.These results suggest that enhanced aerobic glycolysis is required for PIK3CD GOF-induced overactivation of naive T cells and provide a potential therapeutic approach for targeting glycolysis to treat patients with APDS as well as other immune disorders.展开更多
Migration of polymorphonuclear leukocytes from bloodstream to the site of inflammation is an important event required for surveillance of foreign antigens.This trafficking of leukocytes from bloodstream to the tissue ...Migration of polymorphonuclear leukocytes from bloodstream to the site of inflammation is an important event required for surveillance of foreign antigens.This trafficking of leukocytes from bloodstream to the tissue occurs in several distinct steps and involves several adhesion molecules.Defect in adhesion of leukocytes to vascular endothelium affecting their subsequent migration to extravascular space gives rise to a group of rare primary immunodeficiency diseases(PIDs)known as Leukocyte Adhesion Defects(LAD).Till date,four classes of LAD are discovered with LAD I being the most common form.LAD I is caused by loss of function of common chain,cluster of differentiation(CD)18 of β2 integrin family.These patients suffer from life-threatening bacterial infections and in its severe form death usually occurs in childhood without bone marrow transplantation.LAD II results from a general defect in fucose metabolism.These patients suffer from less severe bacterial infections and have growth and mental retardation.Bombay blood group phenotype is also observed in these patients.LAD III is caused by abnormal integrin activation.LAD III patients suffer from severe bacterial and fungal infections.Patients frequently show delayed detachment of umbilical cord,impaired wound healing and increased tendency to bleed.LAD IV is the most recently described class.It is caused by defects in β2 and α4β1 integrins which impairs lymphocyte adhesion.LAD IV patients have monogenic defect in cystic-fibrosis-transmembraneconductance-regulator(CFTR)gene,resulting in cystic fibrosis.Pathophysiology and genetic etiology of all LAD syndromes are discussed in detail in this paper.展开更多
文摘Primary immunodeficiency disorders(PIDs)are rare inborn errors of the immune system.Patients with PIDs are unique models that exemplify the functional and phenotypic consequences of various immune defects underlying infections,autoimmunity,lymphoproliferation,allergy and cancer.Over 150 PID syndromes were characterized in the past 60 years,with an ever growing list of new entities being discovered.Because of their rarity,multi-center collaboration for pooled data analysis and molecular studies is important to gain meaningful insights into the phenotypic and genetic diversities of PIDs.In this article,we summarize our research findings on PIDs in Chinese population in the past 20 years.Close collaboration among various immunology centers,cross-referrals and systematic data analysis constitute the foundation for research on PIDs.Future directions include establishment of a national PID registry,raising awareness of PIDs and securing sufficient resources for patient care and scientific research.
基金supported by grants from the National Science Foundation of China(81974255)the Public Welfare Scientific Research Project of China(201402012)to X.Z.
文摘Activated phosphoinositide 3-kinaseδsyndrome(APDS)is an autosomal-dominant combined immunodeficiency disorder resulting from pathogenic gain-of-function(GOF)mutations in the PIK3CD gene.Patients with APDS display abnormal T cell homeostasis.However,the mechanisms by which PIK3CD GOF contributes to this feature remain unknown.Here,with a cohort of children with PIK3CD GOF mutations from multiple regions of China and a corresponding CRISPR/Cas9 gene-edited mouse model,we reported that hyperactive PI3Kδdisrupted TNaive cell homeostasis in the periphery by intrinsically promoting the growth,proliferation,and activation of TNaive cells.Our results showed that PIK3CD GOF resulted in loss of the quiescence-associated gene expression profile in naive T cells and promoted naive T cells to overgrow,hyperproliferate and acquire an activated functional status.Naive PIK3CD GOF T cells exhibited an enhanced glycolytic capacity and reduced mitochondrial respiration in the resting or activated state.Blocking glycolysis abrogated the abnormal splenic T cell pool and reversed the overactivated phenotype induced by PIK3CD GOF in vivo and in vitro.These results suggest that enhanced aerobic glycolysis is required for PIK3CD GOF-induced overactivation of naive T cells and provide a potential therapeutic approach for targeting glycolysis to treat patients with APDS as well as other immune disorders.
文摘Migration of polymorphonuclear leukocytes from bloodstream to the site of inflammation is an important event required for surveillance of foreign antigens.This trafficking of leukocytes from bloodstream to the tissue occurs in several distinct steps and involves several adhesion molecules.Defect in adhesion of leukocytes to vascular endothelium affecting their subsequent migration to extravascular space gives rise to a group of rare primary immunodeficiency diseases(PIDs)known as Leukocyte Adhesion Defects(LAD).Till date,four classes of LAD are discovered with LAD I being the most common form.LAD I is caused by loss of function of common chain,cluster of differentiation(CD)18 of β2 integrin family.These patients suffer from life-threatening bacterial infections and in its severe form death usually occurs in childhood without bone marrow transplantation.LAD II results from a general defect in fucose metabolism.These patients suffer from less severe bacterial infections and have growth and mental retardation.Bombay blood group phenotype is also observed in these patients.LAD III is caused by abnormal integrin activation.LAD III patients suffer from severe bacterial and fungal infections.Patients frequently show delayed detachment of umbilical cord,impaired wound healing and increased tendency to bleed.LAD IV is the most recently described class.It is caused by defects in β2 and α4β1 integrins which impairs lymphocyte adhesion.LAD IV patients have monogenic defect in cystic-fibrosis-transmembraneconductance-regulator(CFTR)gene,resulting in cystic fibrosis.Pathophysiology and genetic etiology of all LAD syndromes are discussed in detail in this paper.
