TLR2 Arg753Gln Polymorphisms Research Articles

Toll-like receptor 2-mediated downstream cytokine levels as determinant of malaria pathogenesis.

Toll-like receptors (TLRs) are transmembrane proteins that recognize specific molecular patterns and activate downstream cytokine production usually for the eradication of invading pathogens. The objective of this study was to evaluate the genetic polymorphism of TLR2 Arg753Gln (rs 5743708) and soluble cytokines and TLR2 expression levels in malaria disease cases. The study included prospectively collected 2 ml blood samples from 153 individuals clinically suspected for malaria and confirmed by microscopy and RDT from Assam. Stratification of the study groups was done as healthy control (HC, n=150), uncomplicated malaria (UC-M, n=128) and severe malaria (SM, n=25). The PCR-restriction fragment length polymorphism (RFLP) method was applied for the analysis of TLR2 Arg753Gln polymorphism and following the ELISA for soluble serum TLR2 (sTLR2) and its associated downstream cytokines, viz. tumour necrosis factor (TNF)-α and interferon (IFN)-γ levels. Variation in TLR2 Arg753Gln gene showed no association with the susceptibility and the severity of malarial infection. Soluble TLR2 expression was significantly higher in uncomplicated malaria (UC-M) cases compared to healthy controls (P=0.045) and in terms of SM cases, the expression was also found to be higher in UC-M cases (P=0.078). The TNF-α expression was significantly higher in SM cases compared to both UC-M and control (P=0.003 and P=0.004). Similarly, significantly elevated expression of IFN-γ was noted in SM cases compared to both UC-M (P=0.001) and healthy controls (P<0.001). The present study suggests the association of deregulated TLR2 pathway that leads to the deleterious downstream immune response in the development of malarial pathogenicity.

Investigation of TLR2 and TLR4 Polymorphisms and Sepsis Susceptibility: Computational and Experimental Approaches.

Toll-like receptors (TLR) play an eminent role in the regulation of immune responses to invading pathogens during sepsis. TLR genetic variants might influence individual susceptibility to developing sepsis. The current study aimed to investigate the association of genetic polymorphisms of the TLR2 and TLR4 with the risk of developing sepsis with both a pilot study and in silico tools. Different in silico tools were used to predict the impact of our SNPs on protein structure, stability, and function. Furthermore, in our prospective study, all patients matching the inclusion criteria in the intensive care units (ICU) were included and followed up, and DNA samples were genotyped using real-time polymerase chain reaction (RT-PCR) technology. There was a significant association between TLR2 Arg753Gln polymorphisms and sepsis under the over-dominant model (p = 0.043). In contrast, we did not find a significant difference with the TLR4 Asp299Gly polymorphism with sepsis. However, there was a significant association between TLR4 Asp299Gly polymorphisms and Acinetobacter baumannii infection which is quite a virulent organism in ICU (p = 0.001) and post-surgical cohorts (p = 0.033). Our results conclude that the TLR2 genotype may be a risk factor for sepsis in adult patients.

Pulmonary tuberculosis susceptibility and association with Toll-Like receptor 2 Arg753Gln polymorphism.

Tuberculosis has been a concern of healthcare professionals due to the serious threats it poses on public health safety. However, regardless all the efforts, no appropriate goals for immunological diagnosis or tuberculosis treatment were established. Toll-like receptor 2 is one of the toll-like receptors, which plays a fundamental role in recognizing and hosting defense against Mycobacterium tuberculosis infection. Toll-like receptor 2's genetic polymorphism (arginine-to-glutamine substitution at residue 753 (Arg753Gln)) was linked to negative effects on the function of Toll-like receptor 2 which, in turn, impacts the body's resistance or susceptibility to tuberculosis. The current study aimed at investigating the single Arg753Gln nucleotide polymorphism of the Toll-like receptor 2 gene in patients with tuberculosis infection versus a sample of healthy subjects as controls. A comparative study was conducted to investigate Toll-like receptor 2 polymorphism of the single nucleotide gene Arg753Gln in 30 patients with pulmonary tuberculosis and compare their results with other 20 healthy controls matched by age and sex. TLR-2-Arg polymorphism allele A occurred in 36.7% of the patient group. Homozygous carriers of allele A/A polymorphism occurred in 13.4% compared to 5% among controls, while GA genotype was found in 23.3% among the study group and 10% among controls. The association between GA genotype and pulmonary tuberculosis was found statistically significant (p = 0.002) than other genotypes. Allele frequency for both G and A were (p =0.002) in patient groups and (p =0.000) among the control group. TLR-2 Arg753Gln polymorphisms may have a crucial role in pulmonary tuberculosis susceptibility among Egyptian patients.

Clinical Implication of Toll-Like Receptors (TLR2 and TLR4) in Acute Myeloid Leukemia Patients.

Backgrounds:Toll-like receptors 2; 4 (TLR2;4) are an essential component of the innate immunity and play an important role in immune-surveillance and immune response to various microorganisms. This study aimed to investigate the association between TLR2 and TLR4 polymorphism and the risk of acquiring severe infections, and impact on AML patient’s outcome. Subjects and methods:Using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP); we analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) in 120 AML patients and 100 healthy control subjects. Results:No significant differences in genotype or alleles frequency between healthy controls and AML patients regarding TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms (P>0.05 for all). Neutropenic fever was detected in 110 out of 120 (91.7%) of the studied AML patients. The sepsis and pneumonia were identified in 20 out of 120 patients (16.7%). The incidence of sepsis was associated with TLR2 Arg753Gln: AG genotypes, A allele and TLR4 Asp299Gly: CT genotype and C allele as compared to other genotypes and alleles. Moreover; TLR2 (Arg753Gln) GG polymorphisms significantly associated with shortest overall survival (OS) and shortest disease-free survival (DFS); while TLR4 polymorphisms affect the DSF only but not OS. In AML patients TLR2 Arg753Gln gene polymorphism is associated with high susceptibility to sepsis and TLR4 (Asp299Gly and Thr399Ile) gene polymorphism is associated with high susceptibility for both pneumonia; and sepsis. Conclusion: TLR2 Arg753Gln (AG; GG genotype) polymorphisms are associated with shortest OS and DFS. Moreover; significant association between TLR2 polymorphisms, TLR4 Arg753Gln polymorphisms and risk of severe infections in AML patients was documented.

Correlation of TLR2 Arg677Trp and Arg753Gln polymorphisms with post-treatment serological test positive in syphilis patients

Correlation of TLR2 Arg677Trp and Arg753Gln polymorphisms with post-treatment serological test positive in syphilis patients

Arg753Gln Polymorphisms in the Toll-Like Receptor 2 Gene are Associated with Cytomegalovirus Infection in Egyptian Bone Marrow Recipients.

Previous studies have shown that cytomegalovirus (CMV) induced innate immune response via activation of Toll-like receptor 2 (TLR2). The association between CMV among specific single-nucleotide polymorphisms (SNPs) in the TLR2 gene was also investigated. This study investigated the relationship between specific SNPs in the TLR2 gene (G>A), TLR2-Arg753Gln (rs5743708), and CMV replication after bone marrow transplantation. The TLR2-Arg753Gln SNP was genotyped in 181 patients after bone marrow transplantation: 83 and 98 patients with and without CMV infection, respectively. CMV load was determined in serially collected blood samples using real-time PCR. Genotyping was performed using specific sequence primer PCR (SSP-PCR), and the results were confirmed by restriction fragment length polymorphism (RFLP) analysis of the PCR-amplified fragments for GG (wild type), GA and AA identification. Roughly, 85% of the patients screened for the presence of the TLR2-Arg753Gln were GG homozygous, and 15% were GA heterozygous; no patients were homozygous for the mutant allele (A). The GA heterozygous allele was more frequent in the CMV-infected group after bone marrow transplantation. To our knowledge, this is a novel observation that supports the notion that the functional missense mutation (TLR2-Arg753Gln polymorphism) is possibly associated with CMV replication after bone marrow transplantation. This suggests a role for TLR2 in the innate immune response of human CMV infection in Egyptian bone marrow recipients.

Assessment of Toll Like receptor 2 Gene Polymorphism in Children with B Cell Defects and Respiratory Tract Infections

Abstract Acute respiratory tract infections are the most common illnesses in childhood. Respiratory defenses against infection involve a diverse and complex system. Toll-like receptors (TLRs) are a type of pattern recognition receptors (PRRs), recognize pathogen-associated molecular patterns (PAMPs), resulting in initiation of innate immune response and promotion of adaptive immunity. TLR single nucleotide polymorphisms (SNPs) impair the ability to respond properly to TLR ligands and increase susceptibility to infectious or inflammatory diseases. The aim of the work: To examine TLR2 Arginine 677Tryptophan (Arg 677Trp) and Arginine753Glutamine (Arg753Gln) gene polymorphisms in patients with recurrent or chronic respiratory tract infections with or without predominantly antibody deficiency (PAD). Subjects and methods: This cross-sectional case-control study included 30 patients with known PAD with/ or without respiratory tract infections, 20 non-PAD patients with recurrent chest infections and 20 age and sex-matched healthy controls. All children included in the study were subjected to full history taking, complete physical examination and laboratory investigations including CBC, serum immunoglobulins levels and genetic analysis of the TLR2 Arg677Trp and Arg753Gln polymorphisms. Computed tomography (CT) scan of the chest with contrast, pulmonary function tests (PFTs) and Bronchoalveolar lavage (BAL) fluid culture and sensitivity were performed to patients with recurrent and/or chronic chest infections. Results: There was a significant difference in the expression of Arg753Gln polymorphism (p 0.04) between PAD patients with and without recurrent chest infections. Patients with mutant or heterozygote state of this polymorphism had a short diagnosis lag (time elapsed between onset of symptoms and date of diagnosis). There was a significant relationship between this polymorphism and the duration of hospital admission (longer hospital stay in patients with mutant allele). A significant difference between non-PAD patients with recurrent chest infections and healthy controls regarding Arg 677 Trp polymorphism (p 0.04) was elicited. Conclusion: Our results suggest that Arg 677 Trp polymorphism could be a risk factor for increased susceptibility to recurrent and /or chronic respiratory tract infections in patients without PAD, while Arg753Gln polymorphism might be an additional risk factor for severe infections in PAD patients.

Association of TLR2 and TLR4 gene polymorphism with susceptibility to wart infections and their response to candida antigen immunotherapy

Background Warts are prevalent human papilloma virus (HPV) infections which can cause physical and psychological problems. Candida antigen immunotherapy is a safe and promising treatment of warts. Toll-like receptors (TLRs) 2 and 4 gene polymorphisms are implicated in susceptibility and progression of several diseases. Aim To assess the role of TLR2Arg753GLN and TLR4Asp299Gly polymorphisms in susceptibility to HPV wart infections and their possible effect on response to Candida antigen immunotherapy. Patients and methods A total of 78 patients and 78 healthy subjects were enrolled in this case control study. The polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique was used to detect TLR2Arg753GLN and TLR4Asp299Gly genes polymorphisms. Patients’ lesions were injected with Candida antigens and the response was assessed. Results The mutant AA and GG genotypes of TLR2Arg753GLN and TLR4Asp299Gly were significantly detected in patients than controls (p < .001 and p = .01, respectively). Intralesional Candida antigen injections achieved complete and partial clearance in 62.8 and 20.5% of lesions, respectively. No association was found between the studied polymorphisms and response to Candida antigen injections. Conclusions TLR2Arg753GLN and TLR4Asp299Gly polymorphisms are associated with susceptibility to wart infections, but with no effect on their response to Candida immunotherapy.

Variations in Toll-like receptor and nuclear factor-kappa B genes and the risk of glioma

Purpose: Glioblastoma (GBM) is the most aggressive primary brain tumour in the adult nervous system and is associated with a poor prognosis. NF-KB activation is an important driver of the malignant phenotype that confers a negative prognosis in patients with GBM. NF-KB plays a role in Toll-like Receptors (TLR)-induced tumourigenesis. The aim of the present study was to investigate the association of a promoter region polymorphism of NFKB1 gene encoding the p50 subunit of NF-KB, namely -94ins/del ATTG, the most widely discussed the TLR2 Arg753Gln, TLR4Asp299Gly and TLR4Thr399Ile polymorphisms, their combined effects, and the glioma risk.Methods: A group of 120 Glioma patients and 225 control subjects were screened for these four polymorphisms using the PCR-RFLP method.Results: Statistical analysis indicates that the ins/ins genotype of NFKB -94ins/delATTG (p=0.003), and the AA genotype of TLR4Asp299Gly (p < 0.001) are risk factors for glioma and people carrying the ins allele have an approximately 1.47 times susceptibility risk of glioma whereas GG genotype of TLR2Arg753Gln seems to be protective against glioma (p = 0.002). Combined genotype analysis showed that del/ins-GG genotype of TLR2Arg753Gln-NFKB1, del/ins + GG genotype of TLR4Asp299Gly-NFKB1, del/ins-CC genotype of TLR4Thr399Ile-NFKB1 were risk factors for glioma development.Conclusion: NFKB1 -94ins/delATTG and TLR4Asp299Gly polymorphisms are associated with increased glioma cancer risk in a Turkish population.

Toll-like receptor 2, 4 and 9 polymorphisms and their association with ICU-acquired infections in Central Greece

PurposeTo test the potential of four common Toll-like receptor (TLR) polymorphisms to predispose to specific intensive care unit (ICU)-acquired infections and affect outcomes in a Greek ICU. Materials and methodsThe incidence of TLR2-Arg753Gln, TLR4-Asp299Gly, TLR4-Thr399Ile and TLR9-T1237C polymorphisms, and their association with ICU-acquired infections and patients' clinical outcomes were prospectively evaluated The examined genetic polymorphisms were assessed by real-time Polymerase-Chain-Reaction (PCR). ResultsDuring a 15-month period, 224 patients were enrolled and genotyped. The prevalence of genetic polymorphisms for TLR4-Asp299Gly, TLR4-Thr399Ile, mixed TLR4-Asp299Gly/Thr399Ile, TLR9-T1237C and TLR2-Arg753Gln was 14.4%, 14.7%, 11.2%, 24.5% and 2.2%, respectively.TLR4 polymorphisms were associated with increased susceptibility towards specific ICU-acquired infections, i.e. Gram-negative central-nervous-system infections (CNSI), ventilator-associated pneumonia (VAP) and urinary-tract infections (UTI), principally due to multi-drug resistant (MDR) Acinetobacter baumannii, Pseudomonas aeruginosa and Klebsiella pneumonia, respectively (all P < 0.05). TLR9-T1237C polymorphism was associated with lower incidence and fewer relapses of CNSIs and UTIs when compared to mixed TLR4-Asp299Gly/Thr399Ile polymorphism group (P ≤ 0.039).ICU-stay was significantly prolonged in TLR4 polymorphisms (P ≤ 0.0416). ConclusionsCommon TLR-signaling polymorphisms might be implicated in the clinical phenotype of ICU-acquired infections in Central Greece. The possible impact of TLR4 polymorphisms on enhanced susceptibility towards Gram-negative MDR-infections in defined critical-disease states warrants further investigation.Trial Registration Clinical Trials.gov identifier: NCT00932243

Relationship between toll-like receptor 2 R753Q and T16934A polymorphisms and Staphylococcus aureus nasal carriage.

The association among specific single-nucleotide polymorphisms (SNPs) in TLR2 R753Q (rs5743708) and T16934A (rs4696480) and the nasal carriage of Staphylococcus aureus was studied in adults before CABG. The TLR2 polymorphisms were genotyped in 299 consecutive patients prepared for a CABG operation. Genotyping was performed using restriction fragment length polymorphism (RFLP) analysis of PCR-amplified fragments. Two nasal swab cultures were taken within 2 weeks before the operation. Subjects were classified as Staphylococcus aureus carriers if at least one culture was positive while those patients with both cultures found to be negative were classified as non-carriers. The prevalence of nasal S. aureus carriage in the final cohort was 22.1% (66/299), while no MRSA was detected in our study group. No significant differences in the TLR2 polymorphisms were observed between the study and the control groups. No associations were found between TLR2 haplotypes and the covariates of age, sex, NYHA, weight, height, BMI, CAD, smoking status and ESlog score. No differences were found between carriers and noncarriers regarding the allelic distribution of the TLR2 T-16934A SNP. Almost 93% of the patients who were screened for the presence of the TLR2 Arg753Gln (rs5743708) were GG wild type homozygous. Twenty one subjects from the study group (7.1%) were GA heterozygous, while no patient in either group was homozygous for the TLR2 Arg753Gln (rs5743708) mutation. TLR2 Arg753Gln genotyping showed that GA heterozygous patients were detected more frequently in the group of Staphylococcus aureus nasal carriers than in non-carrier adults. Our results suggest that the carrier status for the GA variant of the TLR2 Arg753Gln (rs5743708) polymorphism may be a risk factor for Staphylococcus aureus carriage.

The TLR2 and TLR4 gene polymorphisms in Moroccan visceral leishmaniasis patients

Visceral leishmaniasis (VL) is endemic in the Mediterranean basin and leads to the most severe form of Leishmania infection, lethal if left untreated. However, most infections are sub-clinical or asymptomatic, reflecting the influence of host genetic background on disease outcome. This study aimed to investigate possible association of TLR4 Asp299Gly, TLR4 Thr399Ile and TLR2 Arg753Gln polymorphisms with VL in Moroccan children. We enrolled 119 children with VL caused by Leishmania infantum as well as 138 unrelated children, 95 asymptomatic subjects and 43 healthy individuals who had no evidence of present or past infection. Polymorphisms were genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) and amplification refractory mutation system assay (ARMS-PCR). Results showed significant differences in genotype Thr399Ile and recessive model frequencies between VL and delayed-type hypersensitivity (DTH+) groups (p=0.018, OR=0.414CI 0.195–0.880; p=0.029, OR=0.448CI 0.214–0.938], respectively) by having the amino-acid threonine polymorphism as a reference in the VL group. Concerning the Asp299Gly there were a significant associations when comparing VL vs DTH+ (Asp299Gly genotype p=0.002, OR=0.326CI 0.158–0.671, allele frequencies p=0.033, OR=0.396CI 0.164–0.959, recessive model p=0.002, OR=0.343CI 0.172–0.681) and DTH+ vs DTH- groups (Asp299Gly genotype p=2.160E-4, OR=3.065CI 1.672–5.618, Gly299Gly genotype p=0.047, OR=0.368CI 0.299–0.452, allele frequencies p=1.406E-7, OR=29.571CI 3.907–223.8, recessive model p=4.370E-14, OR=36.965CI 8.629–158.3), by having the aspartic acid polymorphism as a reference these results suggest that the allele A (savage) confer protection against the clinical manifestations but not against the infection. Furthermore, there was a significant association regarding the Arg753Gln genotype (p=0.002, OR=0.326CI 0.158–0.671), allele frequencies (p=0.033, OR=0.396CI 0.164–0.959) and when applying a recessive model (p=0.002, OR=0.343CI 0.172–0.681) in the VL vs DTH+ groups. The same results was observed when comparing DTH+ vs DTH- groups (p=4.136E-6, OR=0.211CI 0.104–0.428), allele frequencies (p=0.008, OR=0.327CI 0.137–0.779) and recessive model (p=1.748E-5, OR=0.244CI 0.124–0.480). The results provide evidence that allele C in Thr399Ile and allele G in Arg753Gln polymorphisms may lead to protection against the clinical disease. Our data provide insights into the possible role of TLR2 and TLR4 variations in VL susceptibility.

Evaluation of TLR2 and TLR4 Polymorphisms in Chronic HBV Infection

Aims: Toll - like receptors ( TLR s) play a central role in initiating innate response by mediating inflammatory reactions against a wide range of pathogens. We aimed to determine if TLR2 Arg753Gln, TLR4 Asp299Gly and Thr399Ile polymorphisms are associated with chronic hepatitis B (HBV) infection. Study Design: A case - control study . Methodology: Genomic DNA was obtained from peripheral blood of 100 patients with chronic HBV infection and 108 healthy volunteer controls. The TLR2 and TLR4 polymorphisms were Original Research Article

Polymorphisms of Toll-like receptors (TLR2 and TLR4) are associated with the risk of infectious complications in acute myeloid leukemia

Infectious complications continue to be one of the major causes of morbidity and mortality in patients with acute myeloid leukemia (AML). Several single-nucleotide polymorphisms (SNPs) of Toll-like receptors (TLRs) can affect the genetic susceptibility to infections or even sepsis. We sought to investigate the impact of different SNPs on the incidence of developing sepsis and pneumonia in patients with newly diagnosed AML following induction chemotherapy. We analyzed three SNPs in the TLR2 (Arg753Gln) and TLR4 (Asp299Gly and Thr399Ile) gene in a cohort of 155 patients with AML who received induction chemotherapy. The risk of developing sepsis and pneumonia was assessed by multiple logistic regression analyses. The presence of the TLR2 Arg753Gln polymorphism was significantly associated with pneumonia in AML patients (odds ratio (OR): 10.78; 95% confidence interval (CI): 2.0-58.23; P=0.006). Furthermore, the cosegregating TLR4 polymorphisms Asp299Gly and Thr399Ile were independent risk factors for the development of both sepsis and pneumonia (OR: 3.55; 95% CI: 1.21-10.4, P=0.021 and OR: 3.57, 95% CI: 1.3-9.86, P=0.014, respectively). To our best knowledge, this study represents the first analysis demonstrating that polymorphisms of TLR2 and TLR4 influence the risk of infectious complications in patients with AML undergoing induction chemotherapy.

O-224 Toll-like Receptors Genotype Polymorphism In Egyptian Children With Chronic Viral Hepatitis C

Background Toll-like receptors (TLRs) are important molecules for both innate and adaptive immune responses. The prevalence of TLRs polymorphism varies in different populations and controversial results were reported in HCV patients. We aimed to assess the frequency of TLR2 Arg753Gln, TLR4 Asp294Gly and TLR4 Thr399Ile polymorphisms among Egyptian children with chronic HCV and to study their relation to clinical data. Methods An observational case control study was conducted in Mansoura University Children’s Hospital, Egypt and included 100 Chronic HCV patients (63% males) with mean age of 13 ± 2.8 years in addition to 100 healthy matched controls. Diagnosis of patients relied upon persistently positive HCV PCR for at least 6 months. Eighty two patients received combined pegylated interferon α2b 60 mcg/m 2 /w and ribavirin 15 mg/kg/d. Treatment was continued for 48 weeks for responders (49 patients). All subjects were exposed to history, examination, liver functions, viral markers, HCV PCR and abdominal ultrasound. Liver biopsy was done only for patients. Gene polymorphisms were assessed by restriction fragment length polymorphism. Results Neither patients nor controls had TLR2 Arg753Gln or TLR4 Asp299Gly polymorphisms. Only 3 patients (3%) were heterozygous for TLR4 Thr399Ile polymorphism without significant difference between patients and controls (p = 0.24). No significant correlation was observed between TLR4 Thr399Ile polymorphism and viral load, histologic activity, grade of fibrosis or treatment response (p = 0.96, 0.21, 0.46, 0.49 respectively). Conclusion TLR2 Arg753Gln, TLR4 Asp294Gly and TLR4 Thr399Ile polymorphisms seem to be absent or rare and probably have no role in HCV among Egyptian population.

Lack of association between toll like receptor-2 &amp; toll like receptor-4 gene polymorphisms and Iranian asthmatics risk or features

© 2014 Pourfathollah et al; licensee Herbert Publications Ltd. This is an Open Access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0). This permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction Asthma is a complex and chronic disease in which allergeninduced inflammatory processes in the airways contribute to the development of symptoms, such as wheezing, cough, dyspnea and breathlessness [1]. Asthma is considered to be the most common chronic disease and the leading cause of hospitalization in schoolchildren [2,3]. Control of asthma and response to medication is different in patients, and different asthmatics show various levels of asthma severity and progress which would depend on multiple factors especially genetic composition of patients. The need for management of medication and control of asthma make us improve our knowledge about pathogenesis of asthma and role of different elements that contribute to airway inflammation or influence signs and symptoms [4,5]. Asthma is believed to be a complex disorder involving genetic and environmental factors [6]. Many allergens and environmental microorganisms have pattern molecules on their surfaces, and these molecules interact with pattern-recognition receptors, which are part of the innate immune system. Among the known pattern-recognition receptors for microbial products, toll-like receptors (TLRs) are an evolutionarily conserved group of molecules expressed in antigen-presenting cells and epithelial cells [7]. TLRs recognize microbial patterns and play a crucial role in linking innate and adaptive immunity inducing a proinflammatory immune response that may counterbalance allergic diathesis. They initiate intracellular signaling pathways, bind to downstream protein kinases, induce activation of transcription factors, and initiate transcription of inflammatory cytokines and other host response elements [8]. Among TLRs, TLR4 recognizes lipopolysaccharide, a cell wall component of Abstract Introduction: Asthma as chronic inflammatory airway disease is considered to be the most common chronic disease that is involving genetic and environmental factors. Toll like receptors (TLRs) and other inflammatory mediators are important in modulation of inflammation. In this study we evaluated the role of TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms in the asthma susceptibility, progress, control levels and lung functions in Iranian subjects. Methods: On 99 asthmatic patients and 120 normal subjects, TLR2 Arg753Gln and TLR4 Asp299Gly polymorphism were evaluated by PCR-RFLP method recruiting Msp1 and Nco1 restriction enzymes, respectively. IgE serum levels by ELISA technique were determined and asthma diagnosis, treatment and control levels were considered using standard schemes and criteria. Results: Our results indicated that the genotype and allele frequencies of the TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms were not significantly different between control subjects and asthmatics (p>0.05) or even in asthma features such as IgE levels, asthma history and pulmonary factors (p>0.05). Conclusions: Meanwhile some previous studies indicated TLRs and their polymorphisms role in asthma incidence and features, our data demonstrated that TLR2 Arg753Gln and TLR4 Asp299Gly gene variants were not risk factor of asthma or its features in Iranian patients. Genetic complexity, ethnicity, influence of other genes or polymorphisms may overcome these polymorphisms in our asthmatics.

Toll-like receptor polymorphisms and vasculitis susceptibility: meta-analysis and systematic review

The aim of this study was to determine whether toll-like receptor (TLR) polymorphisms confers susceptibility to vasculitis. A literature search was conducted using the PubMed and Embase. A meta-analysis on the associations between the TLR4 Asp299Gly polymorphisms and vasculitis was carried out using allele contrast, dominant, and codominant models and a systematic review of other TLR polymorphisms. Fourteen studies involving 2,064 patients and 2,481 controls were included in this systematic review, which comprised nine on Behcet's disease (BD), three on giant cell arteritis (GCA), and one on Henoch-Schenlein purpura (HSP). Meta-analysis of six studies showed a significant association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis and GCA (Odds ratio [OR]=1.368, 95% confidence interval [CI]=1.300-1.815, p=0.030; OR=1.523, 95% CI=1.099-2.112, p=0.012). Under a random effects model, the adjusted ORs calculated using the trim and fill technique revealed an association between the Gly/Gly+Gly/Asp genotype of the TLR4 Asp299Gly polymorphism and vasculitis (OR=1.544, 95% CI=1.091-2.185, p<0.05). Stratification by vasculitis type using the codominant model showed the trend for the association with GCA (OR=1.569, 95% CI=0.970-2.538, p=0.066). There were three studies on the TLR2 Arg753Gln polymorphism and two on the TLR4 Thr399Ile polymorphism; no association with vasculitis was evident. Among the TLR2, TLR7, and TLR9 polymorphisms included in this review, one Asian study revealed a significant association between the TLR7 rs5743733 and rs3853839 with BD (p=0.002, 0.036) and one Asian study showed an association of TLR9 rs352140 with BD (p=0.009). This meta-analysis demonstrates that the TLR4 Asp299Gly polymorphism may confer susceptibility to GCA. The review of published data suggests that other TLR polymorphisms such as TLR7 and TLR9 may play a role in vasculitis.

Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: A case–control analysis

The aim of the study was to investigate whether polymorphisms in genes encoding Toll-like receptors (TLR2 and TLR4) may modify relative risk for development of asthma or allergic rhinitis. The results showed that the genotype and allele frequencies of the TLR2 Arg753Gln and TLR4 Asp299Gly polymorphisms were not significantly different between asthmatic children or allergic rhinitis when compared to controls (p>0.05 for each) or even when compared further with IgE level. However, it was shown that the mutant allele of TLR2 or TLR4 polymorphisms were significantly associated with the moderate–severe group compared to the mild group in both atopic asthmatics and allergic rhinitis group (p>0.001 for each). In conclusion, our study demonstrates a lack of association of TLR2 and TLR4 polymorphisms with asthma and allergic rhinitis but suggests significant association between these genetic variants and the disease severity.

Relationship between the TLR2 and TLR4 gene polymorphisms with a predisposition to certain urogenital infections

The distribution of the TLR2 Arg753Gln, TLR4 Asp299Gly and TLR4 Thr399Ile polymorphisms among residents of Poltavsky region was studied. The relationship between these polymorphisms and the presence of diseases caused by urogenital infections was also studied. The population control group was a random sample of residents of Poltavsky region (n = 299); the group of patients with urogenital diseases consisted of 156 individuals. PCR and subsequent restriction analysis were used to enable the genotyping of the following TLR polymorphisms in these groups: Arg753Gln, Asp299Gly, and TLR4 Thr399Ile. We found a statistically significant correlation between the presence of allele A of the TLR2 gene (p = 0.0018) and allele G of the TLR4 gene (p = 0.085) and the presence of urogenital diseases.

Relationship between toll-like receptor 2 nonsynonymous single nucleotide polymorphisms and the effectiveness of Bacille Calmette-Guérin immunotherapy in preventing recurrence of superficial bladder cancer: A prospective study

Background: Intravesical Bacille Calmette-Guérin (BCG) immunotherapy has been used for several decades as a prophylactic approach against recurrence of superficial bladder cancer. However, its effectiveness has been both variable and unpredictable. Typically, cancer BCG-immunotherapy aims to redirect or modulate both innate and adaptive immune responses. The consequences of gene polymorphisms in several key immuno-regulatory molecules on the heterogeneity of the response to BCG-immunotherapy have been investigated. Objective: The aim of this study was to evaluate the association of toll-like receptor (TLR) 2 polymorphisms (arginine to glutamine substitution at position 753 [Arg753Gln] and arginine to tryptophan substitution at position 677 [Arg677Trp]) and the outcome of BCG-immunotherapy. Methods: This prospective study was conducted during a 3-year period from June 2006 to July 2009. Consecutive patients were recruited during a 1-year period and followed for 2 years at the Department of Urology, Charles Nicolle Hospital, Tunis, Tunisia. Patients with superficial bladder tumors at stage Ta (noninvasive papillary carcinoma) or T1 (where the tumor has grown from the layer of cells lining the bladder into the connective tissue below but has not grown into the muscle layer of the bladder) of any grade were eligible; carcinoma in situ cases were excluded. The TLR2 Arg753Gln and Arg677Trp polymorphisms were studied in peripheral blood DNA from patients treated with BCG-immunotherapy after transurethral resection. Results: A total of 112 consecutive patients were enrolled (101 men and 11 women; mean age, 63.9 years [range, 25–85 years]) and completed the 2-year followup. Polymerase chain reaction amplification followed by direct sequencing of the region containing the TLR2 single-nucleotide polymorphism (SNP) of interest did not detect Arg753Gln or Arg677Trp in any of the study participants belonging to either of 2 groups: responders (n = 67) and nonresponders (n = 45) to BCG-immunotherapy. Conclusions: No patients included in the study were found to have the 2 known TLR2 nonsynonymous SNPs, and the relative importance of these polymorphisms could not be definitely determined. However, a significant proportion of patients without these polymorphisms responded to BCG-immunotherapy, suggesting that these genetic variants are not critical in the effectiveness of this approach for preventing recurrence of the tumor.