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Capitani, M.* ; Al-Shaibi, A.A.* ; Pandey, S.* ; Gartner, L.* ; Taylor, H.A.* ; Hubrack, S.Z.* ; Agrebi, N.* ; Al-Mohannadi, M.J.* ; Al Kaabi, S.* ; Vogl, T.* ; Roth, J.* ; Kotlarz, D.M. ; Klein, C.* ; Charles, A.K.* ; Vijayakumar, V.* ; Karim, M.Y.* ; George, B.* ; Travis, S.P.* ; Elawad, M.* ; Lo, B.* ; Uhlig, H.H.*

Biallelic TLR4 deficiency in humans.

J. Allergy Clin. Immunol. 151, 783-790.e5 (2023)
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BACKGROUND: Toll-like receptors (TLRs) mediate functions for host defense and inflammatory responses. TLR4 recognizes LPS, a component of gram-negative bacteria as well as host-derived endogenous ligands such as S100A8 and S100A9 proteins. OBJECTIVE: We sought to report phenotype and cellular function of individuals with complete TLR4 deficiency. METHODS: We performed genome sequencing and investigated exome and genome sequencing databases. Cellular responses were studied on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays. RESULTS: We identified 2 individuals in a family of Qatari origin carrying a homozygous stop codon variant p.Q188X in TLR4 presenting with a variable phenotype (asymptomatic and inflammatory bowel disease consistent with severe perianal Crohn disease). A third individual with homozygous p.Y794X was identified in a population database. In contrast to hypomorphic polymorphisms p.D299G and p.T399I, the variants p.Q188X and p.Y794X completely abrogated LPS-induced cytokine responses whereas TLR2 response was normal. TLR4 deficiency causes a neutrophil CD62L shedding defect, whereas antimicrobial activity toward intracellular Salmonella was intact. CONCLUSIONS: Biallelic TLR4 deficiency in humans causes an inborn error of immunity in responding to LPS. This complements the spectrum of known primary immunodeficiencies, in particular myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency that are downstream of TLR4 and TLR2 signaling.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Inflammatory Bowel Disease ; Primary Immunodeficiency; Evolutionary Conservation; Protein; Recognition; Signals
Language english
Publication Year 2023
Prepublished in Year 2022
HGF-reported in Year 2022
ISSN (print) / ISBN 0091-6749
e-ISSN 1097-6825
Journal The journal of allergy and clinical immunology
Quellenangaben Volume: 151, Issue: 3, Pages: 783-790.e5 Article Number: , Supplement: ,
Publisher Elsevier
Publishing Place Amsterdam [u.a.]
Reviewing status Peer reviewed
Institute(s) Institute of Translational Genomics (ITG)
POF-Topic(s) 30205 - Bioengineering and Digital Health
Research field(s) Genetics and Epidemiology
PSP Element(s) G-506700-001
Grants
National Institute for Health Research (NIHR)
Biomedical Research Centre (BRC)
Sidra Medicine Internal Research Fund (IRF)
Leona M. and Harry B. Helmsley Charitable Trust
DOI 10.1016/j.jaci.2022.08.030
WOS ID 000955856300001
Scopus ID 85149072882
PubMed ID 36462956
Erfassungsdatum 2022-12-08
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