The opposing effects of two gene defects in STX11 and SLP76 on the disease in a patient with an inborn error of immunity.

Autor: Mansour R; Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon., El-Hassan R; Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon., El-Orfali Y; Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon., Saidu A; Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon., Al-Kalamouni H; Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon., Chen Q; Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass., Benamar M; Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass., Dbaibo G; Department of Biochemistry, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon; Research Center of Excellence in Immunity and Infections, American University of Beirut, Beirut, Lebanon., Hanna-Wakim R; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon., Chatila TA; Division of Immunology, Boston Children's Hospital, Boston, Mass; Department of Pediatrics, Harvard Medical School, Boston, Mass., Massaad MJ; Department of Experimental Pathology, Immunology, and Microbiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon; Division of Pediatric Infectious Diseases, Department of Pediatrics and Adolescent Medicine, American University of Beirut Medical Center, Beirut, Lebanon; Center for Infectious Diseases Research, American University of Beirut, Beirut, Lebanon; Research Center of Excellence in Immunity and Infections, American University of Beirut, Beirut, Lebanon. Electronic address: mm257@aub.edu.lb.
Jazyk: angličtina
Zdroj: The Journal of allergy and clinical immunology [J Allergy Clin Immunol] 2023 Dec; Vol. 152 (6), pp. 1597-1606. Date of Electronic Publication: 2023 Aug 16.
DOI: 10.1016/j.jaci.2023.08.005
Abstrakt: Background: Inborn errors of immunity are mostly monogenic. However, disease phenotype and outcome may be modified by the coexistence of a second gene defect.
Objective: We sought to identify the genetic basis of the disease in a patient who experienced bleeding episodes, pancytopenia, hepatosplenomegaly, and recurrent pneumonia that resulted in death.
Methods: Genetic analysis was done using next-generation sequencing. Protein expression and phosphorylation were determined by immunoblotting. T-cell proliferation and F-actin levels were studied by flow cytometry.
Results: The patient harbored 2 homozygous deletions in STX11 (c.369_370del, c.374_376del; p.V124fs60∗) previously associated with familial hemophagocytic lymphohistiocytosis and a novel homozygous missense variant in SLP76 (c.767C>T; p.T256I) that resulted in an approximately 85% decrease in SLP76 levels and absent T-cell proliferation. The patient's heterozygous family members showed an approximately 50% decrease in SLP76 levels but normal immune function. SLP76-deficient J14 Jurkat cells did not express SLP76 and had decreased extracellular signal-regulated kinase signaling, basal F-actin levels, and polymerization following T-cell receptor stimulation. Reconstitution of J14 cells with T256I mutant SLP76 resulted in low protein expression and abnormal extracellular signal-regulated kinase phosphorylation and F-actin polymerization after T-cell receptor activation compared with normal expression and J14 function when wild-type SLP76 was introduced.
Conclusions: The hypomorphic mutation in SLP76 tones down the hyperinflammation due to STX11 deletion, resulting in a combined immunodeficiency that overshadows the hemophagocytic lymphohistiocytosis phenotype. To our knowledge, this study represents the first report of the opposing effects of 2 gene defects on the disease in a patient with an inborn error of immunity.
(Copyright © 2023 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
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