Biallelic TLR4 deficiency in humans

Capitani, M; Al-Shaibi, AA; Pandey, S; Gartner, L; Taylor, H; Hubrack, SZ; Agrebi, N; Al-Mohannadi, MJ; Al Kaabi, S; Vogl, T; Roth, J; Kotlarz, D; Klein, C; Charles, AK; Vijayakumar, V; Karim, MY; George, B; Travis, SP; Elawad, M; Lo, B; Uhlig, HH

Journal article

Biallelic TLR4 deficiency in humans

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.

Publication status:: Published

Peer review status:: Peer reviewed

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APA Style

Capitani, M., Al-Shaibi, A. A., Pandey, S., Gartner, L., Taylor, H., Hubrack, S. Z., Agrebi, N., Al-Mohannadi, M. J., Al Kaabi, S., Vogl, T., Roth, J., Kotlarz, D., Klein, C., Charles, A. K., Vijayakumar, V., Karim, M. Y., George, B., Travis, S. P., Elawad, M., … Uhlig, H. H. (2022). Biallelic TLR4 deficiency in humans. Journal of Allergy and Clinical Immunology, 151(3), 783–790.

MLA Style

Capitani, M, et al. “Biallelic TLR4 Deficiency in Humans.” Journal of Allergy and Clinical Immunology, vol. 151, no. 3, 2022, pp. 783–90.

Chicago Style

Capitani, M, AA Al-Shaibi, S Pandey, et al. 2022. “Biallelic TLR4 Deficiency in Humans.” Journal of Allergy and Clinical Immunology 151 (3): 783–90.
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