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Review
. 2008 May-Jun;14(5-6):346-52.
doi: 10.2119/2007-00135.Ferwerda.

Functional consequences of toll-like receptor 4 polymorphisms

Bart Ferwerda  1 , Matthew Bb McCall, Karlijn Verheijen, Bart-Jan Kullberg, André Jam van der Ven, Jos Wm Van der Meer, Mihai G Netea
Affiliations
Review

Functional consequences of toll-like receptor 4 polymorphisms

Bart Ferwerda et al. Mol Med. 2008 May-Jun.

Abstract

Toll-like receptor 4 (TLR4) is an important pathogen recognition receptor that recognizes mainly lipopolysaccharide (LPS) of Gram-negative bacteria, but also structures from fungal and mycobacterial pathogens, as well as endogenous ligands. Two nonsynonymous polymorphisms of TLR4, Asp299Gly and Thr399Ile, have been suggested to alter the function of the receptor. Some, but not all, studies have proposed that these polymorphisms lead to reduced cytokine response and increased susceptibility to Gram-negative infections. In this review, we compare studies that assessed the effect of the Asp299Gly and Thr399Ile polymorphisms on susceptibility to Gram-negative infections and examine the phenotypic consequences of these polymorphisms. In addition, we review the geographical distribution of TLR4 polymorphisms and present a model for evolutionary pressures on the TLR4 genetic make-up.

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Figures

Figure 1
Figure 1
Schematic overview of the LPS TLR4 signaling pathway. Recognition of LPS is established by the interplay between lipopolysaccharide-binding proteins (LBPs) and CD14 that transfer the LPS to the MD-2/TLR4 complex. Dimerization of TLR4 then initiates downstream intracellular signaling transduction through Toll-interleukin-1 receptor (TIR) domains and several adaptor molecules. Eventually, the intracellular signaling results in the activation of specific pro-inflammatory cytokine profiles by the MYD88-dependent or TRIF-dependent pathway.
Figure 2
Figure 2
Distribution of TLR4 haplotypes and associated cytokine phenotypes across the 3 continents of the Old World. It shows that Africa, Asia, and Europe each have their own distinct haplotype, based on the alleles found, shown in white. The phenotypic end point is shown on the top of the figure, where the expected cytokine production following TLR4 stimulations is presented. When the geographic distribution of Asp299Gly and Thr399Ile polymorphisms is taken into account, it illustrates that research preformed in Europe has looked at the cosegregated Asp299Gly/Thr399Ile haplotype, whose cytokine phenotype does not differ from the wild-type TLR4 cytokine response. This also explains the large number of studies, performed in Europe, that did not find any association between TLR4 polymorphisms and susceptibility to disease. In contrast, the Asp299Gly/WT haplotype, that is found almost exclusively in Africa, has a stronger pro-inflammatory cytokine response compared with wild-type TLR4.
Figure 3
Figure 3
Circle diagrams with the frequency of the study results and outcomes (below) of TLR4 polymorphism from the PubMed search. This search revealed that more than half of the studies do not find any association between susceptibility to infection and TLR4 polymorphisms (n = 157). In the top diagrams, the frequencies of the methodologies used are presented in the studies that showed a positive effect or no association of the investigated TLR4 polymorphisms. This figure shows that the majority of studies are based on genetic association studies, and a minority measured cytokine production following LPS stimulation of either whole blood or PBMCs. Overall, the contrast between study outcomes measuring the functional effects of TLR4 polymorphisms and of those looking at the role these have in susceptibility is revealed.
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