Chronic periodontal disease is associated with single-nucleotide polymorphisms of the human TLR-4 gene

Schröder, Nicolas W.J.; Meister, D; Wolff, Verónica; Christan, C.; Kaner, Doğan; Haban, Vesna; Purucker, Peter; Hermann, Corinna; Moter, Annette; Göbel, Ulf B.; Schumann, Ralf R.

doi:10.1038/sj.gene.6364221

Cited by 100 publications

(133 citation statements)

References 30 publications

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“…For TLR-4, two cosegregating SNPs (Asp299Gly and Thr399Ile) were associated with hyporesponsiveness to inhalation of LPS, the major ligand of TLR-4 (21). In subsequent studies, these SNPs were found to be associated, i.e., with infections caused by Gram-negative bacteria or with periodontitis (22,23). The Arg677Trp polymorphism of TLR-2 was found to be associated with lepromatous leprosy in a Korean population (24), and with tuberculosis in a Tunisian population (25).…”

mentioning

confidence: 98%

Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease

Schröder

Diterich

Zinke

et al. 2005

The Journal of Immunology

170

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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.

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mentioning

confidence: 98%

Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease

Schröder

Diterich

Zinke

et al. 2005

The Journal of Immunology

170

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“…Single nucleotide polymorphisms (SNPs) in TLRs have been correlated with disease conditions such as asthma, endotoxin hyporesponsiveness, sepsis, immunodeficiencies, and atherosclerosis (11)(12)(13)(14)(15)(16)(17)(18). For TLR3, SNP P554S within LRR20 is linked with partial penetrance of herpes simplex virus-associated encephalitis in children (19).…”

Section: Toll-like Receptors (Tlrs)mentioning

confidence: 99%

Secretion of the Human Toll-like Receptor 3 Ectodomain Is Affected by Single Nucleotide Polymorphisms and Regulated by Unc93b1

Hoose

Schreiter³

et al. 2010

Journal of Biological Chemistry

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The innate immune receptor Toll-like receptor 3 (TLR3) can be present on the surface of the plasma membranes of cells and in endolysosomes. The Unc93b1 protein has been reported to facilitate localization of TLR7 and 9 and is required for TLR3, -7, and -9 signaling. We demonstrate that siRNA knockdown of Unc93b1 reduced the abundance of TLR3 on the cell surface without altering total TLR3 accumulation. In addition, siRNA to Unc93b1 reduced the secretion of the TLR3 ectodomain (T3ECD) into the cell medium. Furthermore, two human single nucleotide polymorphisms that affected herpesvirus and influenza virus encephalopathy as well as a natural isoform generated by alternative splicing were found to be impaired for T3ECD secretion and decreased the abundance of TLR3 on the cell surface. The locations of the SNP P554S and the deletion in the isoform led to the identification of a loop in the TLR3 ectodomain that is required for secretion and a second whose presence decreased secretion. Finally, a truncated protein containing the N-terminal 10 leucine-rich repeats of T3ECD was sufficient for secretion in an Unc93b1-dependent manner.Toll-like receptors (TLRs) 2 are a family of receptors that recognize pathogen-associated molecular patterns (PAMPs) and initiate signal transduction pathways to activate innate immune responses and to modulate adaptive immunity responses. There are more than 10 known human TLRs that collectively recognize a remarkable variety of ligands (1). The subcellular location of the different TLRs is related to ligand recognition. TLR3, -7, -8, and -9 recognize nucleic acids in endolysosomal compartments, whereas TLR1, -2, -4, -5, and -6 mainly recognize bacterial products and are located primarily on the cell surface (2-4).TLR3 binds viral double-stranded (ds) RNAs and dsRNA mimics such as poly(I:C), annealed homopolymers of inosinic acid and cytidylic acid. Like other TLRs, TLR3 is a type I transmembrane glycoprotein with a large N-terminal ectodomain (ECD) for ligand binding, a single transmembrane helix, and a C-terminal cytoplasmic Toll-interleukin-1 receptor (TIR) domain. The TLR3 ectodomain (T3ECD) consists of 23 conserved leucine-rich repeats (LRRs) capped at the termini by cysteinerich motifs (5, 6). The T3ECD has 15 predicted N-linked glycosylation sites and two short loops that reside in LRR12 (Loop 1) and LRR20 (Loop 2), respectively (7, 8). The crystal structure of the T3ECD complexed with dsRNA revealed two ligand binding sites, one within the region from LRR19 to LRR21 and the other within the N terminus to LRR3, as well as a dimerization domain in the C-terminal cysteine-rich cap (9, 10).Single nucleotide polymorphisms (SNPs) in TLRs have been correlated with disease conditions such as asthma, endotoxin hyporesponsiveness, sepsis, immunodeficiencies, and atherosclerosis (11-18). For TLR3, SNP P554S within LRR20 is linked with partial penetrance of herpes simplex virus-associated encephalitis in children (19). SNP F303S within LRR11 is linked to pathologies of influenza virus infecti...

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“…Some reports have shown that TLR-2, TLR-4 and the related signalling pathway play an important role in the initial recognition of T. cruzi and may regulate the initial pro-inflammatory response during infection with the parasite but may also contribute to the severity of the disease (Almeida & Gazzinelli 2001). Genetic variations in TLR genes correlate with several infectious diseases (Schroder et al 2005). Several single-nucleotide polymorphism (SNPs) have been described for the TLR2 and TLR4 genes.…”

mentioning

confidence: 99%

“…Genetic variations in TLR genes correlate with several infectious diseases (Schroder et al 2005). Several single-nucleotide polymorphism (SNPs) have been described for the TLR2 and TLR4 genes.…”

mentioning

confidence: 99%

Polymorphisms of toll-like receptor 2 and 4 genes in Chagas disease

Zafra

Flórez

Morillo

et al. 2008

Mem. Inst. Oswaldo Cruz

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Chagas' disease (CD) is caused by infection with the intracellular protozoan parasite, Trypanosoma cruzi, and is the major cause of cardiomyopathy and heart failure in endemic regions of Colombia and South America (Guhl 1999, WHO 2002. A wide clinical spectrum is observed in the chronic phase of CD, varying from a relatively benign indeterminate form to gastrointestinal compromise or chronic cardiomyopathy that is usually fatal. The fact that only 20-30% of the infected individuals develop cardiomyopathy suggests a differential set of physiopathologic events between infected individuals. Differences in the expression of genes related to the immune response may be involved. In humans there are studies addressing the relation between the major histocompatibility complex genes and CD (Nieto et al. 2000). In addition, the C3F allele has been proposed as a marker for the progression of cardiomyopathy (Messias-Reason et al. 2003). Cytokine and chemokine genes have been implicated in determining increased susceptibility and further development of chagasic heart disease (Calzada et al. 2001, Flórez et al. 2006, Zafra et al. 2007). Genetic susceptibility to T. cruzi infection and the development of cardiomyopathy is complex and heterogeneous and likely involves several genes. The toll-like receptor family (TLRs) is a major class of eukaryotic receptors for microbial pathogens associated molecular patterns (PAMPs) and endogenous ligands. When TLRs recognize PAMPs induce signals responsible for the activation of genes relevant to the host defence including inflammatory and adaptative immunerelated cytokines (Takeda et al. 2003). Some of the microbial components recognized by these receptors have been identified. TLR2 recognizes a variety of microbial components such as lipoproteins from various pathogens, and lipoarabinomannan from mycobacteria and zymosan from fungi, among others. TLR4 recognizes principally lipopolysaccharide from Gram-negative bacteria (Takeda & Akira 2005). In protozoa, Plasmodium falciparum glycosylphosphatidylinositol (GPI) was reported to induce signaling via both TLR-2 and TLR-4 (Krishnegowda et al. 2005). GPI anchors of T. cruzi are recognized by TLR2 ). In addition T. cruzi Tc52 released protein and glycoinositolphospholipid, stimulating murine macrophages via TLR2 and TLR4 (Ouassi et al. 2002, Oliveira et al. 2004. Unmethylated CpG motifs of T. cruzi DNA also stimulate macrophages, dendritic cells and B lymphocytes probably via TLR-9 (Shoda et al. 2001). Some reports have shown that TLR-2, TLR-4 and the related signalling pathway play an important role in the initial recognition of T. cruzi and may regulate the initial pro-inflammatory response during infection with the parasite but may also contribute to the severity of the disease (Almeida & Gazzinelli 2001).Genetic variations in TLR genes correlate with several infectious diseases (Schroder et al. 2005). Several single-nucleotide polymorphism (SNPs) have been described for the TLR2 and TLR4 genes. The TLR2 argin- 28 ine to glutamine subst...

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Chronic periodontal disease is associated with single-nucleotide polymorphisms of the human TLR-4 gene

Cited by 100 publications

References 30 publications

Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease

Heterozygous Arg753Gln Polymorphism of Human TLR-2 Impairs Immune Activation by Borrelia burgdorferi and Protects from Late Stage Lyme Disease

Secretion of the Human Toll-like Receptor 3 Ectodomain Is Affected by Single Nucleotide Polymorphisms and Regulated by Unc93b1

Polymorphisms of toll-like receptor 2 and 4 genes in Chagas disease

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