Toll-like receptor (TLR) 2 and 4 mutations in periodontal disease

Folwaczny, Matthias; Glas, Jürgen; Hp, Török; O, Limbersky; Folwaczny, C

doi:10.1111/j.1365-2249.2004.02383.x

Cited by 111 publications

(126 citation statements)

References 25 publications

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“…The TLR2 Arg753Gln polymorphism which is absent in our population, is similar to that observed in a case-control study among Ghanaian children (Mockenhaupt et al 2006). In European populations the frequency varies between 6-14% (Folwaczny et al 2004, Lorenz et al 2001. Frequent SNPs for TLR2 have been described associated with susceptibility to infectious diseases such as lepromatous leprosy (Kang & Chae 2001) and tuberculosis (Ben-Ali et al 2004).…”

Section: Discussionsupporting

confidence: 86%

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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Section: Discussionsupporting

confidence: 86%

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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“…No association was observed between both TLR4 mutations and chronic periodontitis, which is regarded as an infection with Gram-negative bacteria. The prevalence of Asp299Gly and Thr399Ile mutant alleles was 4·1% and 4·5% among periodontitis patients, respectively, similar to the healthy volunteers [45]. In 527 Hungarian patients with CD compared to 200 healthy controls, no difference between wild-type and heterozygous TLR4 Asp299Gly polymorphisms could be found [50].…”

Section: Discussionmentioning

confidence: 57%

“…At the Thr399Ile missense mutation an isoleucine also replaces a threonine at amino acid 399 in the extracellular matrix of TLR4. Both polymorphisms are frequent and occur at an allelic frequency of approximately 3-4% in accordance with a carriage rate of 6-8% in the Caucasian population [42][43][44][45]. Homozygous mutations occur very rarely.…”

Section: Discussionmentioning

confidence: 89%

Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis

Pabst

Baumgarten

Stremmel

et al. 2006

Clinical and Experimental Immunology

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SummaryThe aetiology of sarcoidosis, an inflammatory granulomatous multi-system disorder, is unclear. It is thought to be the product of an unknown exogenous antigenic stimulus and an endogenous genetic susceptibility. Toll-like receptors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Lipopolysaccharide (LPS), for example, binds to TLR 4. Two different polymorphisms for the TLR4 gene (Asp299Gly and Thr399Ile) have been described recently. This leads to a change in the extracellular matrix function of TLR4 and to impaired LPS signal transduction. We genotyped a total of 141 Caucasian patients with sarcoidosis and 141 healthy unrelated controls for the Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene. The mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis. Among sarcoidosis patients the prevalence for each Asp299Gly and Thr399Ile mutant allele was 15·6% (22/141). In the control group the prevalence was 5·67% (8/141) ( P = = = = 0·07). In the subgroup of patients with acute sarcoidosis there was no difference in the control group ( P = = = = 0·93), but there was a highly significant association between patients with a chronic course of sarcoidosis and TLR4 gene polymorphisms ( P = = = = 0·01).

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“…Determination of the TLR2 and 4 gene mutations was accomplished with PCR and restriction fragment length polymorphism (RFLP) as previously described 20,21 and confirmed by an allele discrimination assay utilizing the ABI 7500 system (Applied Biosystems) for an end point assay of allele carriage. 22 .…”

Section: Genotyping Of Tlr2 and 4 Genesmentioning

confidence: 99%

Gingival epithelial cells heterozygous for Toll-like receptor 4 polymorphisms Asp299Gly and Thr399Ile are hypo-responsive to Porphyromonas gingivalis

et al. 2006

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The Toll-like receptor (TLR)4 is the major sensor for bacterial lipopolysaccharide and its two common co-segregating polymorphisms, Asp299Gly and Thr399Ile, which occur at a frequency of between 6 and 10%, have been associated with infectious diseases, LPS hypo-responsiveness and cardiovascular disease. Porphyromonas gingivalis is a Gram-negative bacterium implicated in chronic periodontitis and is a known TLR4 and TLR2 agonist. We obtained two gingival epithelial cell primary cultures from subjects heterozygous for the TLR4 polymorphism Asp299Gly and compared response characteristics with similar cells from patients (four) with the wild-type TLR4 genes. Cytokine responses and transcriptome profiles of gingival epithelial cell primary culture cells to TNFa challenge were similar for all primary epithelial cell cultures. P. gingivalis challenge, however, gave markedly different responses for Asp299Gly heterozygous and wild-type epithelial cell cultures. The epithelial cells heterozygous for the TLR4 polymorphism Asp299Gly were functionally hypo-responsive, evidenced by differences in BD-2 mRNA expression, mRNA response profile by microarray analysis and by pro-inflammatory and chemokine cytokines at the protein and mRNA level. These findings emphasize variance in human epithelial cell TLRs, linked with Asp299Gly carriage, which results in a hypo-responsive epithelial cell phenotype less susceptible to Gram-negative diseases and associated systemic conditions.

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Toll-like receptor (TLR) 2 and 4 mutations in periodontal disease

Cited by 111 publications

References 25 publications

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

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

Toll-like receptor (TLR) 4 polymorphisms are associated with a chronic course of sarcoidosis

Gingival epithelial cells heterozygous for Toll-like receptor 4 polymorphisms Asp299Gly and Thr399Ile are hypo-responsive to Porphyromonas gingivalis

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