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Publikacije (111)

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J. Knežević, D. Pavlinić, W. A. Rose, C. Leifer, K. Bendelja, J. Gabrilovac, Marijo Parčina, G. Lauc et al.

Background: Human B cells respond to Toll-like receptor (TLR) 9 stimulation by cytokine production. Results: A rare, novel TLR9 allele fails to activate NF-κB in HEK293 cells. Heterozygous carrier B cells show defective IL-6 and IL-10 production. Conclusion: Heterozygosity for this TLR9 allele modifies CpG oligonucleotide responsiveness. Significance: This is the first analysis of human TLR9 variants in primary cells. Toll-like receptors (TLR) are employed by the innate immune system to detect microbial pathogens based on conserved microbial pathogen molecules. For example, TLR9 is a receptor for CpG-containing microbial DNA, and its activation results in the production of cytokines and type I interferons from human B cells and plasmacytoid dendritic cells, respectively. Both are required for mounting an efficient antibacterial or antiviral immune response. These effects are mimicked by synthetic CpG oligodeoxynucleotides (ODN). Although several hyporesponsive TLR9 variants have been reported, their functional relevance in human primary cells has not been addressed. Here we report a novel TLR9 allele, R892W, which is hyporesponsive to CpG ODN and acts as a dominant-negative in a cellular model system. The R892W variant is characterized by increased MyD88 binding and defective co-localization with CpG ODN. Whereas primary plasmacytoid dendritic cells isolated from a heterozygous R892W carrier responded normally to CpG by interferon-α production, carrier B cells showed impaired IL-6 and IL-10 production. This suggests that heterozygous carriage of a hyporesponsive TLR9 allele is not associated with complete loss of TLR9 function but that TLR9 signals elicited in different cell types are regulated differently in human primary cells.

Biljana Macura, D. Bojovic, I. Petric, N. Ćosić, M. Tadić, I. Jarić, J. Knežević, J. Špirić et al.

J. Knežević, D. Pavlinić, J. Gabrilovac, K. Bendelja, A. Kubarenko, B. Petricevic, D. Vrbanec, L. B. Kardum et al.

H. Mu, A. Hasebe, B. Cole, R. Kurt, A. M. Crespo, C. A. P. D. Sousa, C. Blum, E. Sgroe et al.

Biljana Macura, D. Bojovic, I. Petric, N. Ćosić, M. Tadić, I. Jarić, J. Knežević, J. Špirić et al.

G. E. Etokebe, J. Knežević, B. Petricevic, J. Pavelić, D. Vrbanec, Z. Dembić

BACKGROUND Genetic susceptibility to cancer is multifactorial, and it is known that impairment of the immune system could contribute to risk for getting cancer. AIM OF THE STUDY Single-nucleotide polymorphisms (SNPs) of Toll-like receptor (TLR) 2, TLR3, TLR4, and TLR9 genes, which are important for innate immunity, were analyzed for the association with breast cancer. METHODS The SNPs comprised TLR2 (c.597T>C), TLR2 (c.1350T>C), TLR3 (c.1377C>T), TLR4 (c.896A>G), and TLR9 (c.1635A>G). The allelic and genotypic frequencies of these TLR SNPs were compared between patients (n = 130) and controls (n = 101) in a case-control study from Croatia. RESULTS TLR SNPs were not significantly different. From the population genetics viewpoint, we found that a hypomorphic variant of TLR4 (p.Asp299Gly) allele has no specific allelic frequency (8.4%) in the Croatian population (n = 496) compared to other Caucasians (6.5-10%). CONCLUSION These results suggest that polymorphisms in tested TLR genes are not likely to be associated with increased risk for developing breast cancer.

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