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Published on: July 26, 2017
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Biallelic TLR4 deficiency in humans
Melania Capitani1, Ahmad A Al-Shaibi2, Sumeet Pandey1
1Translational Gastroenterology Unit, University of Oxford, Oxford, United Kingdom.
The Journal of Allergy and Clinical Immunology
|December 3, 2022
Summary
Complete Toll-like receptor 4 (TLR4) deficiency in humans results in an inborn error of immunity. This condition impairs responses to lipopolysaccharide (LPS) but leaves TLR2 responses and antimicrobial activity intact.
Area of Science:
- Immunology
- Genetics
- Microbiology
Background:
- Toll-like receptors (TLRs) are crucial for host defense and inflammatory responses.
- TLR4 specifically recognizes lipopolysaccharide (LPS) from gram-negative bacteria and endogenous ligands like S100A8/S100A9 proteins.
Purpose of the Study:
- To characterize the phenotype and cellular functions of individuals with complete TLR4 deficiency.
- To investigate the genetic basis and functional consequences of absent TLR4 signaling.
Main Methods:
- Genome and exome sequencing were employed to identify genetic variants.
- Cellular responses were assessed in primary monocytes, macrophages, neutrophils, and cell lines.
- Techniques included flow cytometry, reporter assays, and cytokine analysis.
Main Results:
- Identified homozygous stop codon variants (p.Q188X, p.Y794X) in TLR4 in affected individuals.
- These variants completely abolished LPS-induced cytokine responses but preserved TLR2 responses.
- TLR4 deficiency led to a neutrophil CD62L shedding defect, while intracellular Salmonella antimicrobial activity remained functional.
Conclusions:
- Biallelic TLR4 deficiency constitutes a human inborn error of immunity affecting LPS response.
- This finding expands the spectrum of primary immunodeficiencies, particularly those affecting TLR and downstream signaling pathways (MYD88, IRAK4).
