Disrupted Ca^(2+) h homeostasis and immunodeficiency in patients with functional IP_(3) receptor subtype 3 defects  

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 François Vermeulen Susan Schlenner Isabelle Meyts David IYule Geert Bultynck Rik Schrijvers Stephanie Humblet-Baron Adrian Liston 

机构地区：[1]VIB Center for Brain and Disease Research,Leuven,Belgium [2]Department of Microbiology and Immunology,KU Leuven,Leuven,Belgium [3]UZ Leuven,Leuven,Belgium [4]Department of Pharmacology and Physiology,University of Rochester,Rochester,NY,14526,USA [5]Laboratory of Molecular and Cellular Signaling,Department of Cellular and Molecular Medicine,Leuven Kankerinstituut,KU Leuven,Leuven,Belgium [6]Laboratory of Immunobiology,Department Microbiology and Immunology,Rega Institute,KU Leuven,Leuven,Belgium [7]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 [8]Pediatric Department,Academic Children Hospital Queen Fabiola,UniversitéLibre de Bruxelles,Brussels,Belgium [9]Department of Pediatric Neurology,University Hospitals Leuven,Leuven,Belgium [10]Department of Pulmonology,University Hospitals Leuven,Leuven,Belgium [11]Laboratory for Inborn Errors of Immunity,Department of Immunology and Microbiology,KU Leuven,Leuven,Belgium [12]Laboratory for Allergy and Clinical Immunology and Immunogenetics Research Group,Department of Microbiology,Immunology and Transplantation,KU Leuven,Leuven,Belgium [13]Immunology Programme,The Babraham Institute,Babraham Research Campus,Cambridge,CB223AT,UK

出　　处：《Cellular & Molecular Immunology》2023年第1期11-25,共15页中国免疫学杂志（英文版）

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);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.0818.21N;G.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).

摘　　要：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.

关 键 词：Primary immunodeficiency Calcium signalling Whole exome sequencing 

分 类 号：R392[医药卫生—免疫学]