TLR4 Asp299Gly Research Articles

Polymorphisms of toll-like receptor 2 and 4 genes in rheumatoid arthritis and systemic lupus erythematosus.

Human toll-like receptors (TLRs) participate in the innate response and signal the activation of adaptive immunity. Therefore, these TLRs may be important in autoimmune diseases such as rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE). We investigated, by using a polymerase chain reaction restriction-fragment length polymorphism method, the possible association between the polymorphisms of TLR2 (Arg677Trp and Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) genes with the susceptibility or severity of RA and SLE. Our study population consisted of 122 patients with SLE, 224 patients with RA, and a control group of 199 healthy individuals. The TLR2 polymorphisms were very rare in our population; no individual carrying the TLR2-Arg677Trp polymorphism was observed, whereas the TLR2-Arg753Gln polymorphism was present in only 1% of the total population. We found no statistically significant differences in the TLR4-Asp299Gly and the TLR4-Thr399Ile genotype or allele distribution between SLE patients, RA patients, and control individuals. Similarly, no association was found with any of the demographic and clinical parameters tested either in RA or in SLE patients. In conclusion, a case-control study was used to analyze, for the first time, the influence of TLR2 and TLR4 gene polymorphism on the predisposition and clinical characteristics of SLE and RA but provided no evidence for association of TLR2 or TLR4 gene polymorphism with either disease in the population under study.

Variation in Toll-like receptor 4 and susceptibility to group A meningococcal meningitis in Gambian children.

Meningitis is an important cause of childhood mortality in sub-Saharan Africa. A case-control study investigating the role of the Toll-like receptor 4 gene in host susceptibility to Group A Neisseria meningitidis meningitis was conducted in 524 Gambian children. There was no association between a functional Toll-like receptor 4 gene polymorphism and meningitis, suggesting that this variant is not a major determinant of disease in this population.

The Tlr4 Asp299gly substitution, protection against ulcerative colitis or a switch to Crohn's disease?

The Tlr4 Asp299gly substitution, protection against ulcerative colitis or a switch to Crohn's disease?

The relevance of the TLR4 Asp299gly gene polymorphism in the susceptibility to duodenal ulcer and severity of gastric antral inflammation

The relevance of the TLR4 Asp299gly gene polymorphism in the susceptibility to duodenal ulcer and severity of gastric antral inflammation

Mutations in the gene for toll-like receptor 4 and multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system with heterogeneous pathological features, disease courses and genetical backgrounds. In this study we determined whether genetic variants of toll-like receptor (TLR) 4, which confer substantial differences in the inflammation elicited by bacterial lipopolysaccharide, are related to the development of MS. We found no differences in the frequencies of the cosegregating TLR4 Asp299Gly and Thr399Ile polymorphisms between Austrian MS patients (11.6%) and age-matched controls (13.7%). Furthermore, we could not detect any influence of these mutations on clinical parameters and serum levels of soluble adhesion molecules of MS patients. Our data indicate that these TLR4 polymorphisms have no influence on the incidence, progression and inflammatory parameters of MS.

Polymorphisms of TLR4: Rapid Genotyping and Reduced Response to Lipopolysaccharide of TLR4 Mutant Alleles

Pathogen recognition receptors such as Toll-like receptors (TLRs), which recognize pathogen-associated molecular patterns, lead to the activation of innate immunity. Genetic variations in these receptors may lead to an altered host immune response to pathogens. We developed homogeneous fluorescence-based PCR assays as well as matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF-MS) genotyping assays to detect TLR4 polymorphisms. These assays were compared with restriction fragment length polymorphism (RFLP) analysis. Peripheral blood monocytes from donors with differing genotypes were prepared and exposed to bacterial products in vitro. The abundance of mRNAs of the proinflammatory cytokines interleukin (IL)-1 beta, IL-6, and tumor necrosis factor-alpha from these monocytes were monitored by real-time reverse transcription-PCR. By our homogeneous PCR method, the allele frequencies were 5.6% for the TLR4 Asp299Gly and 6.0% for the TLR4 Thr399Ile polymorphism in 116 healthy German Caucasians. Nine incorrect genotype calls were detected in the RFLP analysis and two in the TaqMan genotype analysis. MALDI-TOF-MS allowed clear detection of all TLR4 alleles. Monocytes from donors homozygous for the TLR4 mutant alleles Asp299Gly and Thr399Ile were lipopolysaccharide hyporesponsive and exhibited median effective concentrations (EC(50)s) approximately fourfold higher than those of monocytes carrying wild-type or heterozygous alleles. In contrast, a TLR2 agonist elicited similar responses in monocytes irrespective of the TLR4 genotype. Homogeneous fluorescence-based PCR assays provide a specific and sensitive method for high-throughput genotyping of TLR4 mutations. The newly developed PCR and MALDI-TOF-MS assays may be useful to evaluate the presence of TLR4 polymorphisms in patients to predict susceptibility to bacterial infection.