Biallelic TLR4 deficiency in humans - 03/03/23

Doi : 10.1016/j.jaci.2022.08.030

Melania Capitani, PhD ^a, Ahmad A. Al-Shaibi, MSc ^b, Sumeet Pandey, PhD ^a, Lisa Gartner, MSc ^a, Henry Taylor, MD ^a,^c, Satanay Z. Hubrack, MS ^b, Nourhen Agrebi, PhD ^b, Muneera Jassim Al-Mohannadi, MD ^d, Saad Al Kaabi, MD ^d, Thomas Vogl, PhD ^e, Johannes Roth, MD ^e, Daniel Kotlarz, MD, PhD ^f,^g, Christoph Klein, MD, PhD ^f,^h, Adrian K. Charles, MD, FRCPath ⁱ, Vinayan Vijayakumar, MSc ^j, Mohammed Yousuf Karim, MBBChir, FRCPath ^j, Bruce George, MD ^k, Simon P. Travis, MD, PhD ^a,^l, Mamoun Elawad, MD ^m, Bernice Lo, PhD ^b,^n,^⁎^{^{∗
These authors contributed equally to this work.}} , Holm H. Uhlig, MD, DPhil ^a,^l,^o,^⁎
^a Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom
^b Research Branch, Sidra Medicine, Doha
^c Department of Surgery and Cancer, Imperial College London, London
^d Hamad Medical Center, Gastroenterology, Doha
^e Institute of Immunology, and Interdisciplinary Center for Clinical Research, University of Münster, Münster
^f Dr. von Hauner Children’s Hospital, Department of Pediatrics, University Hospital, LMU Munich, Munich
^g Institute of Translational Genomics, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg
^h Deutsche Zentrum für Infektionsforschung (DZIF) and Deutsches Zentrum für Kinder- und Jugendgesundheit, partner site Munich
ⁱ Anatomical Pathology, Sidra Medicine, Doha
^j Hematopathology, Sidra Medicine, Doha
^k Department of Colorectal Surgery, Oxford
^l Oxford Biomedical Research Centre, University of Oxford, Oxford
^m Department of Gastroenterology, Sidra Medicine, Doha
ⁿ College of Health and Life Sciences, Hamad Bin Khalifa University, Doha
^o Department of Paediatrics, University of Oxford, Oxford

^∗Corresponding author: Bernice Lo, PhD, Translational Medicine Department, Sidra Medicine, Al Gharrafa Street, Ar-Rayyan, Doha, Qatar.Translational Medicine DepartmentSidra MedicineAl Gharrafa StreetAr-Rayyan, DohaQatar^∗∗Holm H. Uhlig, MD, PhD, Translational Gastroenterology Unit and Department of Paediatrics,University of Oxford, John Radcliffe Hospital, Headley Way, Headington, Oxford OX3 9DU, UK.Translational Gastroenterology Unit and Department of Paediatrics,University of OxfordJohn Radcliffe HospitalHeadley WayHeadingtonOX3 9DUOxfordUK

Abstract

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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Key words : Inflammatory bowel disease, primary immunodeficiency

Abbreviations used : GnomAD, IBD, LOF, MAF, MD2, MYD88, NF-κB, TLR, WT

Plan

Introduction

Results and discussion

M.C., D.K., C.K., and H.H.U. are supported by The Leona M. and Harry B. Helmsley Charitable Trust (grant no. HBR02270). B.L. is supported by the Sidra Medicine Internal Research Fund (IRF-2017, SDR200018). H.H.U., S.P., and S.P.T. are supported by the Biomedical Research Centre (BRC), which is supported by the National Institute for Health Research (NIHR). The views expressed are those of the author(s) and not necessarily those of the National Health Service (NHS), the NIHR, or the Department of Health.

Disclosure of potential conflict of interest: H. H. Uhlig received research support or consultancy fees from Janssen, UCB Pharma, Eli Lilly, Pfizer, BMS/Celgene, Mestag, OMass, and AbbVie. S. P. Travis received research support from AbbVie, Buhlmann, Celgene, IOIBD, Janssen, Lilly, Pfizer, Takeda, UCB, Vifor, and the Norman Collisson Foundation; consulting fees from AbbVie, Allergan, Αbiomics, Amgen, Arena, Asahi, Astellas, Biocare, Biogen, Boehringer Ingelheim, Bristol-Myers Squibb, Buhlmann, Celgene, Chemocentryx, Cosmo, Enterome, Ferring, Giuliani SpA, GlaxoSmithKline (GSK), Genentech, Immunocore, Immunometabolism, Indigo, Janssen, Lexicon, Lilly, Merck, MSD, Neovacs, Novartis, NovoNordisk, NPS Pharmaceuticals, Pfizer, Proximagen, Receptos, Roche, Sensyne, Shire, Sigmoid Pharma, SynDermix, Takeda, Theravance, Tillotts, Topivert, UCB, VHsquared, Vifor, and Zeria; and speaker fees from AbbVie, Amgen, Biogen, Ferring, Janssen, Pfizer, Shire, Takeda, and UCB (no stocks or share options). M. Capitani is a current employee of SenTcell Ltd and S. Pandey of GSK. The rest of the authors declare that they have no relevant conflicts of interest.

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Vol 151 - N° 3

P. 783 - mars 2023 Retour au numéro

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Biallelic TLR4 deficiency in humans - 03/03/23

Abstract

Background

Objective

Methods

Results

Conclusions

Plan

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