Heterozygous Carriage of a Dysfunctional Toll-like Receptor 9 Allele Affects CpG Oligonucleotide Responses in B Cells
| Autor: | William A. Rose, Jelka Gabrilovac, Branka Petričević, Dinko Pavlinić, Ljiljana Bulat-Kardum, Cynthia A. Leifer, Damir Vrbanec, Gordan Lauc, Krešo Bendelja, Isabelle Bekeredjian-Ding, Andriy V. Kubarenko, Zlatko Dembic, Jelena Knežević, Marijo Parcina, Jasminka Pavelić, Alexander N.R. Weber |
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| Rok vydání: | 2012 |
| Předmět: |
novel TLR9 allele
B cells defective IL-6 and IL-10 production Genotype CpG Oligodeoxynucleotide medicine.medical_treatment Lymphocyte Immunology Immunoblotting Enzyme-Linked Immunosorbent Assay Biology Polymerase Chain Reaction Biochemistry Protein Structure Secondary Cell Line Immune system medicine Humans Immunoprecipitation Molecular Biology Alleles B-Lymphocytes Innate immune system NF-kappa B TLR9 hemic and immune systems Sequence Analysis DNA Cell Biology Flow Cytometry Molecular biology Toll-Like Receptor 9 Cytokine medicine.anatomical_structure Oligodeoxyribonucleotides CpG site Mutagenesis Myeloid Differentiation Factor 88 Protein Binding |
| Zdroj: | Journal of Biological Chemistry. 287:24544-24553 |
| ISSN: | 0021-9258 |
| Popis: | 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. 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. |
| Databáze: | OpenAIRE |
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