title: Heterozygous carriage of a dysfunctional Toll-like receptor 9 allele affects CpG oligonucleotide responses in B cells.
abstract: 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.
authors.affiliation: Laboratories of Molecular Oncology, Division of Molecular Medicine, Ruðer Bosković Institute, 10000 Zagreb, Croatia. jknezev@irb.hr
authors.forename: Jelena
authors.initials: J
authors.lastname: Knezević
authors.forename: Dinko
authors.initials: D
authors.lastname: Pavlinić
authors.forename: William A
authors.initials: WA
authors.lastname: Rose
authors.forename: Cynthia A
authors.initials: CA
authors.lastname: Leifer
authors.forename: Kreso
authors.initials: K
authors.lastname: Bendelja
authors.forename: Jelka
authors.initials: J
authors.lastname: Gabrilovac
authors.forename: Marijo
authors.initials: M
authors.lastname: Parcina
authors.forename: Gordan
authors.initials: G
authors.lastname: Lauc
authors.forename: Andriy V
authors.initials: AV
authors.lastname: Kubarenko
authors.forename: Branka
authors.initials: B
authors.lastname: Petricevic
authors.forename: Damir
authors.initials: D
authors.lastname: Vrbanec
authors.forename: Ljiljana
authors.initials: L
authors.lastname: Bulat-Kardum
authors.forename: Isabelle
authors.initials: I
authors.lastname: Bekeredjian-Ding
authors.forename: Jasminka
authors.initials: J
authors.lastname: Pavelić
authors.forename: Zlatko
authors.initials: Z
authors.lastname: Dembić
authors.forename: Alexander N R
authors.initials: AN
authors.lastname: Weber
mesh_terms: D000483:Alleles; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism*; D002460:Cell Line; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005838:Genotype; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D016296:Mutagenesis; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D016133:Polymerase Chain Reaction; D011485:Protein Binding / Q000235:genetics / Q000502:physiology; D017433:Protein Structure, Secondary; D017422:Sequence Analysis, DNA; D051217:Toll-Like Receptor 9 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*
chemical_list: C408982:CPG-oligonucleotide; C507779:MYD88 protein, human; D053594:Myeloid Differentiation Factor 88; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D051217:Toll-Like Receptor 9