Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage lyme disease

Nicolas W.J. Schröder, Isabel Diterich, Antje Zinke, Jana Eckert, Christian Draing, Volker V. Baehr, Dieter Hassler, Susanne Priem, Katrin Hahn, Kathrin S. Michelsen, Thomas Hartung, Gerd R. Burmester, Ulf B. Göbel, Corinna Hermann, Ralf R. Schumann

Research output: Contribution to journalArticle

Abstract

Lyme disease (LD) is caused by Borrelia burgdorferi and displays different stages, including localized, early disseminated, and persistent infection, all of which are associated with profound inflammatory reactions in the host. Induction of proinflammatory cytokines by B. burgdorferi is mainly mediated by outer surface proteins interacting with TLR-2/TLR-1 heterodimers. In this study, we show that TNF-α induction by Borrelia lysate was impaired in heterozygous TLR-2 knockout mice, while reactivity to lipoteichoic acid, another TLR-2 ligand signaling via TLR-2/TLR-6 heterodimers, was unaffected. Blood from individuals heterozygous for the TLR-2 polymorphism Arg753Gln was tested for cytokine release upon stimulation with Borrelia lysate, and induction of TNF-α and IFN-γ was significantly lower as compared with individuals not exhibiting this variation. Overexpression of TLR-2 carrying the Arg753Gln polymorphism in HEK 293 cells led to a significantly stronger impairment of activation by TLR-2/TLR-1 ligands as compared with TLR-2/TLR-6 ligands. To study whether heterozygosity for the Arg753Gln variant of TLR-2 influenced susceptibility for LD, we analyzed 155 patients for this polymorphism. The Arg753Gln variant occurs at a significantly lower frequency in LD patients as compared with matched controls (5.8 vs 13.5%, odds ratio 0.393, 95% confidence interval 0.17-0.89, p = 0.033), with an even more pronounced difference when late stage disease was observed (2.3 vs 12.5%, odds ratio 0.163, 95% confidence interval 0.04-0.76, p = 0.018). These data suggest that Arg753Gln may protect from the development of late stage LD due to a reduced signaling via TLR-2/TLR-1.

Original languageEnglish (US)
Pages (from-to)2534-2540
Number of pages7
JournalJournal of Immunology
Volume175
Issue number4
DOIs
StatePublished - Aug 15 2005
Externally publishedYes

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Schröder, N. W. J., Diterich, I., Zinke, A., Eckert, J., Draing, C., Baehr, V. V., Hassler, D., Priem, S., Hahn, K., Michelsen, K. S., Hartung, T., Burmester, G. R., Göbel, U. B., Hermann, C., & Schumann, R. R. (2005). Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage lyme disease. Journal of Immunology, 175(4), 2534-2540. https://doi.org/10.4049/jimmunol.175.4.2534