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Biallelic TLR4 deficiency in humans

journal contribution
submitted on 2024-08-26, 10:02 and posted on 2024-08-26, 10:03 authored by Melania Capitani, Ahmad A. Al-Shaibi, Sumeet Pandey, Lisa Gartner, Henry Taylor, Satanay Z. Hubrack, Nourhen Agrebi, Muneera Jassim Al-Mohannadi, Saad Al Kaabi, Thomas Vogl, Johannes Roth, Daniel Kotlarz, Christoph Klein, Adrian K. Charles, Vinayan Vijayakumar, Mohammed Yousuf Karim, Bruce George, Simon P. Travis, Mamoun Elawad, Bernice Lo, Holm H. Uhlig

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.

Other Information

Published in: Journal of Allergy and Clinical Immunology
License: http://creativecommons.org/licenses/by/4.0/
See article on publisher's website: https://dx.doi.org/10.1016/j.jaci.2022.08.030

History

Language

  • English

Publisher

Elsevier

Publication Year

  • 2023

License statement

This Item is licensed under the Creative Commons Attribution 4.0 International License.

Institution affiliated with

  • Hamad Bin Khalifa University
  • College of Health and Life Sciences - HBKU
  • Hamad Medical Corporation
  • Hamad General Hospital - HMC
  • Sidra Medicine
  • Clinical Research Centre - Sidra Medicine

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    College of Health and Life Sciences - HBKU

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