In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells(HSCs)transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency dis...In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells(HSCs)transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency diseases(PIDs).Despite of some pitfalls at early stage clinical trials,the field of gene therapy has advanced significantly in the last decade with improvements in viral vector safety,preparatory regime for manufacturing high quality virus,automated CD34 cell purification.Hence,the overall outcome from the clinical trials for the different PIDs has been very encouraging.In addition to the viral vector based gene therapy,the recent fast moving forward developments in genome editing using engineered nucleases in HSCs has provided a new promising platform for the treatment of PIDs.This review provides an overall outcome and progress in gene therapy clinical trials for SCID-X,ADA-SCID,WAS,X-CGD,and the recent developments in genome editing technology applied in HSCs for developing potential therapy,particular in the key studies for PIDs.展开更多
Primary immunodeficiency diseases(PIDs)refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections,autoimmunity and increased risk of malignancies.These group of disor...Primary immunodeficiency diseases(PIDs)refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections,autoimmunity and increased risk of malignancies.These group of disorders present with clinical manifestations similar to PIDs with known genetic defects but have either no genetic defect or have a somatic mutation and thus have been labelled as“Phenocopies of PIDs”.These diseases have been further subdivided into those associated with somatic mutations and those associated with presence of auto-antibodies against various cytokines.In this review,we provide an update on clinical manifestations,diagnosis and management of these diseases.展开更多
Primary Immunodeficiency Diseases(PIDs)are increasingly being reported across the World.Several advances have been made in the diagnostic and therapeutic research related to PIDs.With increasing awareness,the field of...Primary Immunodeficiency Diseases(PIDs)are increasingly being reported across the World.Several advances have been made in the diagnostic and therapeutic research related to PIDs.With increasing awareness,the field of PIDs has rapidly evolved in Asia as well.In this review,we summarize the progress that has been made in the field of PIDs in Asian countries;major limitations and challenges faced by the clinicians working in this field in Asia;difference in spectrum of PIDs in Asia from rest of the World;current state of diagnostic and treatment facilities available in various countries in Asia and the future prospects of these diseases in the continent.展开更多
Inflammatory bowel disease(IBD)is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract(GIT).It results either from gene-environment interactions or as a monogenic disease result...Inflammatory bowel disease(IBD)is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract(GIT).It results either from gene-environment interactions or as a monogenic disease resulting from pa-thogenic mutations causing impairment in the protective mechanism of the GIT.Around 10%-15%of patients with very early onset IBDs may have an underlying monogenic condition.Monogenic IBD is very different from complex forms of polygenic IBD in the underlying molecular basis of uncontrolled intestinal inflam-mation,age of onset,extraintestinal comorbidities as well as treatment modality.An in-depth understanding of this distinct form of IBD is essential for deciding an appropriate therapeutic approach as well as prognostication.In this review,we aim to discuss about the epidemiology,clinical presentation,diagnostic approach,therapeutic challenges and latest advances in patients with monogenic IBD.展开更多
BACKGROUND Oral mucositis is often observed with graft-versus-host disease(GVHD);however,the occurrence of oral granuloma is rare.The rapid increase in granulomatous lesions should be distinguished from malignant tumo...BACKGROUND Oral mucositis is often observed with graft-versus-host disease(GVHD);however,the occurrence of oral granuloma is rare.The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients.This case is the youngest pediatric patient with granuloma associated with GVHD.CASE SUMMARY The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules.At the age of 5 mo,she was diagnosed with primary immunodeficiency disease,cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age.After transplantation,GVHD and oral mucositis developed,and tacrolimus was administered.Interestingly,nodules appeared on the lower lip and buccal mucosa,which spontaneously disappeared.Then,a new nodule appeared on the left lateral border of the tongue.Resection was performed and the histopathological diagnosis was granuloma.The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation.CONCLUSION It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered.展开更多
In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies:An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with i...In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies:An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections.Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors,providing innovative precision treatments that can change the natural history of diseases.In this article we review some of these“druggable”inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties.Since the availability of precision treatments can dramatically impact the course of these diseases,preventing the development of organ damage,it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure.展开更多
Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemo...Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemophagocytic lymphohistiocytosis(EBV HLH),extranodal NK/T-cell lymphoma of nasal type(ENKTL),and aggressive NK-cell leukemia(ANKL).However,the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown.A total of 171 nonimmunosuppressed patients with EBV T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed.The 94 gene variants,mostly located in UNCI 3D,LYST,ITK,and PRF1 genes were detected,and mutations covered 28/50(56.00%)of CAEBV-T/NK,31/51(60.78%)of EBV HLH,13/28(46.42%)of ENKTL,and 13/48(27.09%)of ANKL.Most mutations represented monoallelic and missense.Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations(P=0.0284,P=0.0137).Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV*T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.展开更多
With the development of precision medicines based on small molecules,antibodies,RNAs and gene therapy,technological innovation is providing some exciting possibilities to treat the most severe genetic diseases.However...With the development of precision medicines based on small molecules,antibodies,RNAs and gene therapy,technological innovation is providing some exciting possibilities to treat the most severe genetic diseases.However,these treatments do not always lead to a cure for the disease,and there are several factors that may hinder their overall success.Patients living during a period of great medical change and innovation may benefit from these technological advances but may also just face failures,both in terms of frustrated hopes as well as suffering.In this article,we are telling the stories of three children with rare and severe disorders,who live in an age of significant medical changes,bearing the burden of difficult scientific and ethical choices.The first two cases that are suffering respectively from severe immunodeficiency and beta thalassemia have already been described in scientific journals,as well as in popular magazines.Although similar when considering the medical challenges,the two cases had opposite outcomes,which resulted in distinct ethical implications.The third case is a baby with spinal muscular atrophy,living at a time of continued innovation in the treatment of the disease.With these cases,we discuss the challenges of providing correct information and proper counseling to families and patients that are making the bumpy journey on the road of medical innovation.展开更多
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
Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca^(2+)) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP_(3)R), a...Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca^(2+)) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP_(3)R), a homo- or heterotetramer of the IP_(3)R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca^(2+) from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP_(3)R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP_(3)R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca^(2+) signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca^(2+) signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP_(3)R3 in IP_(3)R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype–phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca^(2+) channels and immunodeficiency and identify IP_(3)Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca^(2+)-associated immunodeficiency from store-operated entry to impaired Ca^(2+) mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca^(2+) signaling.展开更多
Cytoskeletal network dysregulation is a pivotal determinant in various immunodeficiencies and autoinflammatory conditions. This report reviews the significance of actin remodeling in disease pathogenesis, focusing on ...Cytoskeletal network dysregulation is a pivotal determinant in various immunodeficiencies and autoinflammatory conditions. This report reviews the significance of actin remodeling in disease pathogenesis, focusing on the Arp2/3 complex and its regulatory subunit actin related protein 2/3 complex subunit 1B (ARPC1B). A spectrum of cellular dysfunctions associated with ARPC1B deficiency, impacting diverse immune cell types, is elucidated. The study presents a patient featuring recurrent and persistent eosinophilia attributed to homozygous ARPC1B mutation alongside concomitant compound heterozygous cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We used ARPC1B antibody to stain the patient’s peripheral blood lymphocytes and those of the control. The defect in the ARPC1B gene in the present patient caused absent/low expression by immunofluorescence microscopy. The intricate interplay between cytoskeletal defects and immunological manifestations underscores the complexity of disease phenotypes, warranting further exploration for targeted therapeutic strategies.展开更多
Lentiviral vectors(LVs),derived from human immunodeficiency virus,are powerful tools for modifying the genes of eukaryotic cells such as hematopoietic stem cells and neural cells.With the extensive and in-depth studie...Lentiviral vectors(LVs),derived from human immunodeficiency virus,are powerful tools for modifying the genes of eukaryotic cells such as hematopoietic stem cells and neural cells.With the extensive and in-depth studies on this gene therapy vehicle over the past two decades,LVs have been widely used in both research and clinical trials.For instance,third-generation and selfinactive LVs have been used to introduce a gene with therapeutic potential into the host genome and achieve targeted delivery into specific tissue.When LVs are employed in leukemia,the transduced T cells recognize and kill the tumor B cells;inβ-thalassemia,the transduced CD34^(+)cells express normalβ-globin;in adenosine deaminase-deficient severe combined immunodeficiency,the autologous CD34^(+)cells express adenosine deaminase and realize immune reconstitution.Overall,LVs can perform significant roles in the treatment of primary immunodeficiency diseases,hemoglobinopathies,B cell leukemia,and neurodegenerative diseases.In this review,we discuss the recent developments and therapeutic applications of LVs.The safe and efficient LVs show great promise as a tool for human gene therapy.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
Background Leukocyte adhesion deficiency type 1 （LAD-l） is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound hea...Background Leukocyte adhesion deficiency type 1 （LAD-l） is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation. Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections. The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity. Methods CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry. The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA. Results CD18 expression level on this patient＇s leukocyte surface was significantly decreased, with normal level in control group, his father and mother. Gene analysis revealed that this patient had a homozygous c.899A〉T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid. His parents were both heterozygous carriers while no such mutation was found in 50 normal controls. Conclusion This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region （HCR） of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1.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
In addition to susceptibility to infections,conventional primary immunodeficiency disorders(PIDs)and inborn errors of immunity(IEI)can cause immune dysregulation,manifesting as lymphoproliferative and/or autoimmune di...In addition to susceptibility to infections,conventional primary immunodeficiency disorders(PIDs)and inborn errors of immunity(IEI)can cause immune dysregulation,manifesting as lymphoproliferative and/or autoimmune disease.Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases,such as arthritis,systemic lupus erythematosus(SLE),and Sjogren’s syndrome(SjS).Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms.Here,we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency,highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.展开更多
基金We thank Dr Alessia Cavazza for helping in the manuscript correction.FZ is supported by the Wellcome Trust(104807/Z/14/Z)ZYZ is supported by National Natural Science Foundation of China(NO.81202316)+1 种基金Foundation from Children’s Hospital of Chongqing Medical University.AJT is supported by both the Wellcome Trust(104807/Z/14/Z)by the National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children NHS Foundation Trust and University College London.
文摘In past two decades the gene therapy using genetic modified autologous hematopoietic stem cells(HSCs)transduced with the viral vector has become a promising alternative option for treating primary immunodeficiency diseases(PIDs).Despite of some pitfalls at early stage clinical trials,the field of gene therapy has advanced significantly in the last decade with improvements in viral vector safety,preparatory regime for manufacturing high quality virus,automated CD34 cell purification.Hence,the overall outcome from the clinical trials for the different PIDs has been very encouraging.In addition to the viral vector based gene therapy,the recent fast moving forward developments in genome editing using engineered nucleases in HSCs has provided a new promising platform for the treatment of PIDs.This review provides an overall outcome and progress in gene therapy clinical trials for SCID-X,ADA-SCID,WAS,X-CGD,and the recent developments in genome editing technology applied in HSCs for developing potential therapy,particular in the key studies for PIDs.
文摘Primary immunodeficiency diseases(PIDs)refer to a heterogenous group of disorders characterized clinically by increased susceptibility to infections,autoimmunity and increased risk of malignancies.These group of disorders present with clinical manifestations similar to PIDs with known genetic defects but have either no genetic defect or have a somatic mutation and thus have been labelled as“Phenocopies of PIDs”.These diseases have been further subdivided into those associated with somatic mutations and those associated with presence of auto-antibodies against various cytokines.In this review,we provide an update on clinical manifestations,diagnosis and management of these diseases.
文摘Primary Immunodeficiency Diseases(PIDs)are increasingly being reported across the World.Several advances have been made in the diagnostic and therapeutic research related to PIDs.With increasing awareness,the field of PIDs has rapidly evolved in Asia as well.In this review,we summarize the progress that has been made in the field of PIDs in Asian countries;major limitations and challenges faced by the clinicians working in this field in Asia;difference in spectrum of PIDs in Asia from rest of the World;current state of diagnostic and treatment facilities available in various countries in Asia and the future prospects of these diseases in the continent.
文摘Inflammatory bowel disease(IBD)is a group of chronic disorders that cause relapsing inflammation in the gastrointestinal tract(GIT).It results either from gene-environment interactions or as a monogenic disease resulting from pa-thogenic mutations causing impairment in the protective mechanism of the GIT.Around 10%-15%of patients with very early onset IBDs may have an underlying monogenic condition.Monogenic IBD is very different from complex forms of polygenic IBD in the underlying molecular basis of uncontrolled intestinal inflam-mation,age of onset,extraintestinal comorbidities as well as treatment modality.An in-depth understanding of this distinct form of IBD is essential for deciding an appropriate therapeutic approach as well as prognostication.In this review,we aim to discuss about the epidemiology,clinical presentation,diagnostic approach,therapeutic challenges and latest advances in patients with monogenic IBD.
文摘BACKGROUND Oral mucositis is often observed with graft-versus-host disease(GVHD);however,the occurrence of oral granuloma is rare.The rapid increase in granulomatous lesions should be distinguished from malignant tumors in patients with GVHD because malignant diseases can develop in those patients.This case is the youngest pediatric patient with granuloma associated with GVHD.CASE SUMMARY The patient was a 1-year and 5-mo-old girl who presented to our department for the management of oral nodules.At the age of 5 mo,she was diagnosed with primary immunodeficiency disease,cord blood transplant was performed at 11 mo and bone marrow transplant at 1 year of age.After transplantation,GVHD and oral mucositis developed,and tacrolimus was administered.Interestingly,nodules appeared on the lower lip and buccal mucosa,which spontaneously disappeared.Then,a new nodule appeared on the left lateral border of the tongue.Resection was performed and the histopathological diagnosis was granuloma.The origin of these nodules were considered to be the fibroblasts activated under inflammation caused by GVHD because the calcineurin inhibitor tacrolimus acted on their proliferation.CONCLUSION It is very important to distinguish oral granulomatous lesions from malignancies if GVHD is present at the base and if immunosuppressive agents and steroids are being administered.
基金Supported by the Italian Ministry of Health RF-2016-02362384the IRCCS Burlo GarofoloNo. RC 24/17
文摘In the last two decades two new paradigms changed our way of perceiving primary immunodeficiencies:An increasing number of immune defects are more associated with inflammatory or autoimmune features rather than with infections.Some primary immune defects are due to hyperactive pathways that can be targeted by specific inhibitors,providing innovative precision treatments that can change the natural history of diseases.In this article we review some of these“druggable”inborn errors of immunity and describe how they can be suspected and diagnosed in diverse pediatric and adult medicine specialties.Since the availability of precision treatments can dramatically impact the course of these diseases,preventing the development of organ damage,it is crucial to widen the awareness of these conditions and to provide practical hints for a prompt detection and cure.
基金the National Natural Science Foundation of China(No.81770211)。
文摘Epstein-Barr virus(EBV)T/NK-cell lymphoproliferative diseases are characterized by clonal expansion of EBV-infected T or NK cells,including chronic active EBV infection of T/NK-cell type(CAEBVT/NK),EBV-associated hemophagocytic lymphohistiocytosis(EBV HLH),extranodal NK/T-cell lymphoma of nasal type(ENKTL),and aggressive NK-cell leukemia(ANKL).However,the role of inherited genetic variants to EBV+T/NK-LPDs susceptibility is still unknown.A total of 171 nonimmunosuppressed patients with EBV T/NK-LPDs and 104 healthy donors were retrospectively collected and a targeted sequencing study covering 15 genes associated with lymphocyte cytotoxicity was performed.The 94 gene variants,mostly located in UNCI 3D,LYST,ITK,and PRF1 genes were detected,and mutations covered 28/50(56.00%)of CAEBV-T/NK,31/51(60.78%)of EBV HLH,13/28(46.42%)of ENKTL,and 13/48(27.09%)of ANKL.Most mutations represented monoallelic and missense.Three-year overall survival rate of patients with CAEBV-T/NK and EBV+HLH was significantly lower in patients with germline mutations than in those without germline mutations(P=0.0284,P=0.0137).Our study provided novel insights into understanding a spectrum of nonimmunosuppressed EBV*T/NK-LPDs with respect to genetic defects associated with lymphocyte cytotoxicity and reminded us that the gene sequencing may be an auxiliary test for diagnosis and risk stratification of EBV+T/NK-LPDs.
基金Supported by the IRCCS Burlo Garofolo,grant No.RC24/17
文摘With the development of precision medicines based on small molecules,antibodies,RNAs and gene therapy,technological innovation is providing some exciting possibilities to treat the most severe genetic diseases.However,these treatments do not always lead to a cure for the disease,and there are several factors that may hinder their overall success.Patients living during a period of great medical change and innovation may benefit from these technological advances but may also just face failures,both in terms of frustrated hopes as well as suffering.In this article,we are telling the stories of three children with rare and severe disorders,who live in an age of significant medical changes,bearing the burden of difficult scientific and ethical choices.The first two cases that are suffering respectively from severe immunodeficiency and beta thalassemia have already been described in scientific journals,as well as in popular magazines.Although similar when considering the medical challenges,the two cases had opposite outcomes,which resulted in distinct ethical implications.The third case is a baby with spinal muscular atrophy,living at a time of continued innovation in the treatment of the disease.With these cases,we discuss the challenges of providing correct information and proper counseling to families and patients that are making the bumpy journey on the road of medical innovation.
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 the VIB Grand Challenges Program,the KU Leuven C1 program,the European Union’s Horizon 2020 research and innovation program under grant agreement No 779295(to AL)the Biotechnology and Biological Sciences Research Council(BBSRC)through Institute Strategic Program Grant funding BBS/E/B/000C0427 and BBS/E/B/000C0428 and the KU Leuven BOFZAP start-up grant(to SH-B)+7 种基金Work in the Bultynck team was supported by grants from the Research Council of the KU Leuven(C14/19/99 and AKUL/19/34)Research Foundation-Flanders(G.0818.21NG.0945.22N)DIY is supported by the National Institutes of Health(NIH)R01-DE0014756 grant.MRB and IIS are supported by the NIH R01GM072804 grant(to IIS)the Welch Foundation Research Grant AU-2014-20190331(to IIS)the American Heart Association grant 18CDA34110086(to MRB)IIS,DIY,and GB are in the FWO Scientific Research Network CaSign(W0.019.17N)IM and RS are FWO senior clinical investigator fellows.IM and RS are members of the European Reference Network for Rare Immunodeficiency,Autoinflammatory and Autoimmune Diseases(project ID No.739543).
文摘Calcium signaling is essential for lymphocyte activation, with genetic disruptions of store-operated calcium (Ca^(2+)) entry resulting in severe immunodeficiency. The inositol 1,4,5-trisphosphate receptor (IP_(3)R), a homo- or heterotetramer of the IP_(3)R1-3 isoforms, amplifies lymphocyte signaling by releasing Ca^(2+) from endoplasmic reticulum stores following antigen stimulation. Although knockout of all IP_(3)R isoforms in mice causes immunodeficiency, the seeming redundancy of the isoforms is thought to explain the absence of variants in human immunodeficiency. In this study, we identified compound heterozygous variants of ITPR3 (a gene encoding IP_(3)R subtype 3) in two unrelated Caucasian patients presenting with immunodeficiency. To determine whether ITPR3 variants act in a nonredundant manner and disrupt human immune responses, we characterized the Ca^(2+) signaling capacity, the lymphocyte response, and the clinical phenotype of these patients. We observed disrupted Ca^(2+) signaling in patient-derived fibroblasts and immune cells, with abnormal proliferation and activation responses following T-cell receptor stimulation. Reconstitution of IP_(3)R3 in IP_(3)R knockout cell lines led to the identification of variants as functional hypomorphs that showed reduced ability to discriminate between homeostatic and induced states, validating a genotype–phenotype link. These results demonstrate a functional link between defective endoplasmic reticulum Ca^(2+) channels and immunodeficiency and identify IP_(3)Rs as diagnostic targets for patients with specific inborn errors of immunity. These results also extend the known cause of Ca^(2+)-associated immunodeficiency from store-operated entry to impaired Ca^(2+) mobilization from the endoplasmic reticulum, revealing a broad sensitivity of lymphocytes to genetic defects in Ca^(2+) signaling.
文摘Cytoskeletal network dysregulation is a pivotal determinant in various immunodeficiencies and autoinflammatory conditions. This report reviews the significance of actin remodeling in disease pathogenesis, focusing on the Arp2/3 complex and its regulatory subunit actin related protein 2/3 complex subunit 1B (ARPC1B). A spectrum of cellular dysfunctions associated with ARPC1B deficiency, impacting diverse immune cell types, is elucidated. The study presents a patient featuring recurrent and persistent eosinophilia attributed to homozygous ARPC1B mutation alongside concomitant compound heterozygous cystic fibrosis transmembrane conductance regulator (CFTR) gene mutations. We used ARPC1B antibody to stain the patient’s peripheral blood lymphocytes and those of the control. The defect in the ARPC1B gene in the present patient caused absent/low expression by immunofluorescence microscopy. The intricate interplay between cytoskeletal defects and immunological manifestations underscores the complexity of disease phenotypes, warranting further exploration for targeted therapeutic strategies.
基金supported by the National Key Research and Development Program of China(2020YFC2008302)the Sichuan Science and Technology program(2019YFG0266)the 1.3.5 project for disciplines of excellence,West China Hospital,Sichuan University(ZYJC18028,2021HXFH064).
文摘Lentiviral vectors(LVs),derived from human immunodeficiency virus,are powerful tools for modifying the genes of eukaryotic cells such as hematopoietic stem cells and neural cells.With the extensive and in-depth studies on this gene therapy vehicle over the past two decades,LVs have been widely used in both research and clinical trials.For instance,third-generation and selfinactive LVs have been used to introduce a gene with therapeutic potential into the host genome and achieve targeted delivery into specific tissue.When LVs are employed in leukemia,the transduced T cells recognize and kill the tumor B cells;inβ-thalassemia,the transduced CD34^(+)cells express normalβ-globin;in adenosine deaminase-deficient severe combined immunodeficiency,the autologous CD34^(+)cells express adenosine deaminase and realize immune reconstitution.Overall,LVs can perform significant roles in the treatment of primary immunodeficiency diseases,hemoglobinopathies,B cell leukemia,and neurodegenerative diseases.In this review,we discuss the recent developments and therapeutic applications of LVs.The safe and efficient LVs show great promise as a tool for human gene therapy.
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Background Leukocyte adhesion deficiency type 1 （LAD-l） is a rare, autosomal recessive inherited immunodeficiency disease characterized by recurrent severe bacterial infection, impaired pus formation, poor wound healing, associated with the mutation in the CD18 gene responsible for the ability of the leucocytes to migrate from the blood stream towards the site of inflammation. Correct and early diagnosis of LAD-1 is vital to the success of treatment and prevention of aggressive infections. The purpose of this study was to collect the clinical findings of the disease and to identify the genetic entity. Methods CD18 expression in the peripheral blood leukocytes from the patient, his parents and normal control was measured with flow cytometry. The entire coding regions of the CD18 gene were screened with direct sequencing genomic DNA. Results CD18 expression level on this patient＇s leukocyte surface was significantly decreased, with normal level in control group, his father and mother. Gene analysis revealed that this patient had a homozygous c.899A〉T missense mutation in exon 8 of CD18 gene, causing the substitution of Asp to Val at the 300 amino acid. His parents were both heterozygous carriers while no such mutation was found in 50 normal controls. Conclusion This study disclosed a novel point mutation Asp 300 Val located in a highly conserved region （HCR） of CD18 and confirmed the heterogeneity of the mutations causing LAD-1, indicating it was quite beneficial to establish correct and early diagnosis in children with severe LAD-1.
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.
基金funding by the DZIF TTU 07.806_00(German Centre for Infection Research)the Deutsche Forschungsgemeinschaft(DFG,German Research Foundation)under Germany’s Excellence Strategy–EXC 2155“RESIST”–Project ID 39087428+1 种基金the German Federal Ministry of Education and Research(BMBF,01GM1910E)the Rosemarie-Germscheid Foundation.
文摘In addition to susceptibility to infections,conventional primary immunodeficiency disorders(PIDs)and inborn errors of immunity(IEI)can cause immune dysregulation,manifesting as lymphoproliferative and/or autoimmune disease.Autoimmunity can be the prominent phenotype of PIDs and commonly includes cytopenias and rheumatological diseases,such as arthritis,systemic lupus erythematosus(SLE),and Sjogren’s syndrome(SjS).Recent advances in understanding the genetic basis of systemic autoimmune diseases and PIDs suggest an at least partially shared genetic background and therefore common pathogenic mechanisms.Here,we explore the interconnected pathogenic pathways of autoimmunity and primary immunodeficiency,highlighting the mechanisms breaking the different layers of immune tolerance to self-antigens in selected IEI.
