Human PLCG2 haploinsufficiency results in a novel natural killer cell immunodeficiency.

Autor: Alinger JB; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Mace EM; Departments of Pediatrics, Baylor College of Medicine, Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY., Porter JR; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Mo., Mah-Som AY; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Daugherty AL; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Li S; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Throm AA; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Pingel JT; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Saucier N; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Yao A; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Chinn IK; Departments of Pediatrics, Baylor College of Medicine, Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex., Lupski JR; Departments of Molecular and Human Genetics, Baylor College of Medicine, Texas Children's Hospital, Houston, Tex., Ehlayel M; Hamad Medical Center, Doha, Qatar., Keller M; Children's National Medical Center, Washington, DC., Bowman GR; Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, St Louis, Mo., Cooper MA; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo., Orange JS; Departments of Pediatrics, Baylor College of Medicine, Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Center for Human Immunobiology, Texas Children's Hospital, Houston, Tex; Department of Pediatrics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY., French AR; Division of Rheumatology, Department of Pediatrics, St Louis Children's Hospital, Washington University School of Medicine, St Louis, Mo. Electronic address: french_a@wustl.edu.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2024 Jan; Vol. 153 (1), pp. 216-229. Date of Electronic Publication: 2023 Sep 13.
DOI: 10.1016/j.jaci.2023.09.002
Abstrakt: Background: Although most individuals effectively control herpesvirus infections, some suffer from severe and/or recurrent infections. A subset of these patients possess defects in natural killer (NK) cells, lymphocytes that recognize and lyse herpesvirus-infected cells; however, the genetic etiology is rarely diagnosed. PLCG2 encodes a signaling protein in NK-cell and B-cell signaling. Dominant-negative or gain-of-function variants in PLCG2 cause cold urticaria, antibody deficiency, and autoinflammation. However, loss-of-function variants and haploinsufficiency have not been reported to date.
Objectives: The investigators aimed to identify the genetic cause of NK-cell immunodeficiency in 2 families and herein describe the functional consequences of 2 novel loss-of-function variants in PLCG2.
Methods: The investigators employed whole-exome sequencing in conjunction with mass cytometry, microscopy, functional assays, and a mouse model of PLCG2 haploinsufficiency to investigate 2 families with NK-cell immunodeficiency.
Results: The investigators identified novel heterozygous variants in PLCG2 in 2 families with severe and/or recurrent herpesvirus infections. In vitro studies demonstrated that these variants were loss of function due to haploinsufficiency with impaired NK-cell calcium flux and cytotoxicity. In contrast to previous PLCG2 variants, B-cell function remained intact. Plcg2 +/- mice also displayed impaired NK-cell function with preserved B-cell function, phenocopying human disease.
Conclusions: PLCG2 haploinsufficiency represents a distinct syndrome from previous variants characterized by NK-cell immunodeficiency with herpesvirus susceptibility, expanding the spectrum of PLCG2-related disease.
(Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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