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J Allergy Clin Immunol. 2008 Apr;121(4):1013-9. doi: 10.1016/j.jaci.2007.11.029. Epub 2008 Jan 30.

The Toll-like receptor 2 R753Q mutation modifies cytokine production and Toll-like receptor expression in atopic dermatitis.

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  • 1Department of Clinical Chemistry and Molecular Diagnostics, Central Laboratory, University of Marburg, Marburg, Germany.

Abstract

BACKGROUND:

Impaired host defense mechanisms may crucially modulate the pathogenesis of atopic dermatitis (AD). More than 10% of patients with AD are heterozygous for the Toll-like receptor 2 (TLR-2) R753Q single nucleotide polymorphism (SNP) and exhibit severe eczema.

OBJECTIVE:

To elucidate the functional effect of the TLR-2 mutation and its putative relevance for AD.

METHODS:

Using the human embryonic kidney 293 transfection system, we characterized the properties of the TLR-2 R753Q SNP. Moreover, TLR-2 expression, IL-8 production, and cytokine secretion were analyzed in monocytes and CD4+ T cells of patients with AD with and without the mutant TLR-2 gene.

RESULTS:

Human embryonic kidney 293 transfectants mimicking this heterozygous mutation produced less IL-8 when stimulated with lipoteichoic acid (LTA), heat-inactivated Staphylococcus aureus or triacylated lipopeptides requiring the TLR-2/1 heterodimer. Suppressed production of IL-8 was confirmed in monocytes from patients with mutant AD after stimulation with peptidoglycan. Cell surface TLR-2 expression was severely impaired in CD3/CD28 activated CD4+ T cells of patients with AD bearing the mutant receptor, which could be restored on LTA stimulation. In contrast, LTA decreased TLR-2 expression among nonatopic individuals and patients with AD with the TLR-2 wild-type gene. T cells from patients with AD exhibited markedly suppressed IL-2 production after macrophage-activating lipopeptide-2 activation. However, no difference was found between mutant and wild-type patients with AD for IL-5, TNF-alpha, IFN-gamma, and IL-2 production.

CONCLUSION:

Collectively, the outcome of innate and adaptive immune responses in AD is modulated by the TLR-2 R753Q SNP.

[PubMed - indexed for MEDLINE]
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