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


CONCLUSIONS
Collectively, the outcome of innate and adaptive immune responses in AD is modulated by the TLR-2 R753Q SNP.
Mrabet-Dahbi
Salima
S
Department of Clinical Chemistry and Molecular Diagnostics, Central Laboratory, University of Marburg, Marburg, Germany.
Dalpke
Alexander H
AH
Niebuhr
Margarete
M
Frey
Markus
M
Draing
Christian
C
Brand
Stephanie
S
Heeg
Klaus
K
Werfel
Thomas
T
Renz
Harald
H
D019943:Amino Acid Substitution / Q000235:genetics / Q000276:immunology; D001120:Arginine / Q000235:genetics; D002460:Cell Line; D016207:Cytokines / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D003876:Dermatitis, Atopic / Q000235:genetics* / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000276:immunology; D006580:Genetic Carrier Screening; D005973:Glutamine / Q000235:genetics; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000235:genetics* / Q000502:physiology; D051216:Toll-Like Receptor 6 / Q000096:biosynthesis / Q000235:genetics
D016207:Cytokines; D012333:RNA, Messenger; C495342:TLR2 protein, human; C495368:TLR6 protein, human; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6; D005973:Glutamine; D001120:Arginine