Disrupted Ca2+ homeostasis and immunodeficiency in patients with functional IP3 receptor subtype 3 defects

扫码查看

原文链接

万方数据

外文摘要：Calcium signaling is essential for lymphocyte activation,with genetic disruptions of store-operated calcium(Ca2+)entry resulting in severe immunodeficiency.The inositol 1,4,5-trisphosphate receptor(IP3R),a homo-or heterotetramer of the IP3R1-3 isoforms,amplifies lymphocyte signaling by releasing Ca2+ from endoplasmic reticulum stores following antigen stimulation.Although knockout of all IP3R 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 IP3R 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 Ca2+ signaling capacity,the lymphocyte response,and the clinical phenotype of these patients.We observed disrupted Ca2+ signaling in patient-derived fibroblasts and immune cells,with abnormal proliferation and activation responses following T-cell receptor stimulation.Reconstitution of IP3R3 in IP3R 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 Ca2+channels and immunodeficiency and identify IP3Rs as diagnostic targets for patients with specific inborn errors of immunity.These results also extend the known cause of Ca2+-associated immunodeficiency from store-operated entry to impaired Ca2+mobilization from the endoplasmic reticulum,revealing a broad sensitivity of lymphocytes to genetic defects in Ca2+ signaling.

外文关键词：

Primary immunodeficiencyCalcium signallingWhole exome sequencing

作者：

Julika Neumann、Erika Van Nieuwenhove、Lara E.Terry、Frederik Staels、Taylor R.Knebel、Kirsten Welkenhuyzen、Kourosh Ahmadzadeh、Mariah R.Baker、Margaux Gerbaux、Mathijs Willemsen、John S.Barber、Irina I.Serysheva、Liesbeth De Waele、Fran?ois Vermeulen、Susan Schlenner、Isabelle Meyts、David I.Yule、Geert Bultynck、Rik Schrijvers、Stephanie Humblet-Baron、Adrian Liston

展开 >

作者单位：

VIB Center for Brain and Disease Research,Leuven,Belgium

Department of Microbiology and Immunology,KU Leuven,Leuven,Belgium

UZ Leuven,Leuven,Belgium

Department of Pharmacology and Physiology,University of Rochester,Rochester,NY 14526,USA

Laboratory of Molecular and Cellular Signaling,Department of Cellular and Molecular Medicine,Leuven Kankerinstituut,KU Leuven,Leuven,Belgium

Laboratory of Immunobiology,Department Microbiology and Immunology,Rega Institute,KU Leuven,Leuven,Belgium

Department of Biochemistry and Molecular Biology,Structural Biology Imaging Center,McGovern Medical School at The University of Texas Health Science Center at Houston,Houston,TX 77030,USA

Pediatric Department,Academic Children Hospital Queen Fabiola,Université Libre de Bruxelles,Brussels,Belgium

Department of Pediatric Neurology,University Hospitals Leuven,Leuven,Belgium

Department of Pulmonology,University Hospitals Leuven,Leuven,Belgium

Laboratory for Inborn Errors of Immunity,Department of Immunology and Microbiology,KU Leuven,Leuven,Belgium

Laboratory for Allergy and Clinical Immunology and Immunogenetics Research Group,Department of Microbiology,Immunology and Transplantation,KU Leuven,Leuven,Belgium

Immunology Programme,The Babraham Institute,Babraham Research Campus,Cambridge CB22 3AT,UK

展开 >

基金：

VIB Grand Challenges ProgramKU Leuven C1 programEuropean Union's Horizon 2020 research and innovation programBiotechnology and Biological Sciences Research Council(BBSRC)through Institute Strategic ProgramBiotechnology and Biological Sciences Research Council(BBSRC)through Institute Strategic ProgramKU Leuven BOFZAP startup grantResearch Council of the KU LeuvenResearch Council of the KU LeuvenResearch Foundation-FlandersResearch Foundation-FlandersNational Institutes of Health(NIH)NIHWelch Foundation Research GrantAmerican Heart Association grantFWO Scientific Research Network CaSignEuropean Reference Network for Rare Immunodeficiency,Autoinflammatory and Autoimmune Diseases

项目编号：

779295BBS/E/B/000C0427BBS/E/B/000C0428C14/19/99AKUL/19/34G.0818.21NG.0945.22NR01-DE0014756R01GM072804AU-2014-2019033118CDA34110086W0.019.17N739543

出版年：

2023

DOI：

10.1038/s41423-022-00928-4

中国免疫学杂志(英文版)

中国免疫学会

中国免疫学杂志(英文版)

CSTPCDCSCDSCI

影响因子：0.731

ISSN：1672-7681

年,卷(期)：2023.20(1)

参考文献量77