The following is a summary of “Biallelic TLR4 deficiency in humans,” published in the MARCH 2023 issue of Allergy (& Immunology) by Capitani, et al.
Toll-like receptors (TLRs) are responsible for various host defense and inflammatory responses. TLR4 identifies bacterial component lipopolysaccharide (LPS) from gram-negative bacteria and host-derived endogenous ligands such as S100A8 and S100A9 proteins. The impact of complete TLR4 deficiency on individuals’ phenotype and cellular function is unclear. Therefore, for a study, researchers sought to report the phenotype and cellular function of individuals with complete TLR4 deficiency.
The researchers conducted genome sequencing and investigated exome and genome sequencing databases. In addition, cellular responses were analyzed on primary monocytes, macrophages, and neutrophils, as well as cell lines using flow cytometry, reporter, and cytokine assays.
With a varied phenotype (asymptomatic and inflammatory bowel disease associated with severe perianal Crohn’s disease), they discovered two members of a family of Qatari descent who were homozygous for the stop codon variation p.Q188X in TLR4. In a population database, a third person was found who had homozygous p.Y794X. While TLR2 response was expected, the variations p.Q188X and p.Y794X entirely abolished LPS-induced cytokine responses compared to hypomorphic polymorphisms p.D299G and p.T399I. While antibacterial action against intracellular Salmonella was unaffected, TLR4 loss resulted in a deficit in neutrophil CD62L shedding.
Biallelic TLR4 deficiency in humans causes an inborn immunity error in responding to LPS. It was similar to other known primary immunodeficiencies like myeloid differentiation primary response 88 (MYD88) or the IL-1 receptor-associated kinase 4 (IRAK4) deficiency downstream of TLR4 and TLR2 signaling. The findings suggested that TLR4 deficiency is an important factor to consider in evaluating primary immunodeficiency.