Heterozygous Arg753Gln polymorphism of human TLR-2 impairs immune activation by Borrelia burgdorferi and protects from late stage Lyme disease.
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-alpha 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-alpha and IFN-gamma 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.
Schröder
Nicolas W J
NW
Institut für Mikrobiologie und Hygiene, Charité University Medical Center, Berlin, Germany.
Diterich
Isabel
I
Zinke
Antje
A
Eckert
Jana
J
Draing
Christian
C
von Baehr
Volker
V
Hassler
Dieter
D
Priem
Susanne
S
Hahn
Katrin
K
Michelsen
Kathrin S
KS
Hartung
Thomas
T
Burmester
Gerd R
GR
Göbel
Ulf B
UB
Hermann
Corinna
C
Schumann
Ralf R
RR
D000328:Adult; D000483:Alleles; D000818:Animals; D001120:Arginine / Q000235:genetics; D025065:Borrelia burgdorferi / Q000276:immunology*; D002460:Cell Line; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D006580:Genetic Carrier Screening; D020022:Genetic Predisposition to Disease; D005973:Glutamine / Q000235:genetics; D006801:Humans; D015994:Incidence; D008193:Lyme Disease / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D051195:Toll-Like Receptor 2 / Q000172:deficiency / Q000235:genetics*
D016207:Cytokines; C495342:TLR2 protein, human; D051195:Toll-Like Receptor 2; D005973:Glutamine; D001120:Arginine