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

Cellular & Molecular Immunology 2023年第1期20卷 11-25页

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 VIB Center for Brain and Disease Research LeuvenBelgium Department of Microbiology and Immunology KU LeuvenLeuvenBelgium UZ Leuven LeuvenBelgium Department of Pharmacology and Physiology University of RochesterRochesterNY14526USA Laboratory of Molecular and Cellular Signaling Department of Cellular and Molecular MedicineLeuven KankerinstituutKU LeuvenLeuvenBelgium Laboratory of Immunobiology Department Microbiology and ImmunologyRega InstituteKU LeuvenLeuvenBelgium Department of Biochemistry and Molecular Biology Structural Biology Imaging CenterMcGovern Medical School at The University of Texas Health Science Center at HoustonHoustonTX77030USA Pediatric Department Academic Children Hospital Queen FabiolaUniversitéLibre de BruxellesBrusselsBelgium Department of Pediatric Neurology University Hospitals LeuvenLeuvenBelgium Department of Pulmonology University Hospitals LeuvenLeuvenBelgium Laboratory for Inborn Errors of Immunity Department of Immunology and MicrobiologyKU LeuvenLeuvenBelgium Laboratory for Allergy and Clinical Immunology and Immunogenetics Research Group Department of MicrobiologyImmunology and TransplantationKU LeuvenLeuvenBelgium Immunology Programme The Babraham InstituteBabraham Research CampusCambridgeCB223ATUK

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

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

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Cellular & Molecular Immunology 2023年第1期20卷 114-114页

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 I.Yule Geert Bultynck rik schrijvers Stephanie Humblet-Baron Adrian Liston VIB Center for Brain and Disease Research Leuven Belgium Department of Microbiology and Immunology KU Leuven Leuven Belgium UZ Leuven Leuven Belgium Immunology Programme The Babraham Institute Babraham Research Campus Cambridge CB22 3AT UK Pediatric Department Academic Children Hospital Queen Fabiola Université Libre de Bruxelles Brussels 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 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 Department of Pediatric Neurology University Hospitals Leuven Leuven Belgium Department of Pulmonology University Hospitals Leuven Leuven Belgium

In this article the statement in the Acknowledgements section was incorrectly given as “MRB and IIS are supported by the NIH R01GM080139 grant (to IIS), the Welch Foundation Research Grant AU-2014-20190331 (to IIS), and the American Heart Association grant 18CDA34110086 (to MRB)” and should have been, “MRB and IIS are supported by the NIH R01GM072804 grant (to IIS), the Welch Foundation Research Grant AU-2014-20190331 (to IIS), and the American Heart Association grant 18CDA34110086 (to MRB).”

关键词： IIS statement knowledge

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