Toll-like receptor 2 expression is decreased on alveolar macrophages in cigarette smokers and COPD patients

BACKROUND: Cigarette smoke exposure including biologically active lipopolysaccharide (LPS) in the particulate phase of cigarette smoke induces activation of alveolar macrophages (AM) and alveolar epithelial cells leading to production of inflammatory mediators. This represents a crucial mechanism in the pathogenesis of chronic obstructive pulmonary disease (COPD). Respiratory pathogens are a major cause of exacerbations leading to recurrent cycles of injury and repair. The interaction between pathogen-associated molecular patterns and the host is mediated by pattern recognition receptors (PRR's). In the present study we characterized the expression of Toll-like receptor (TLR)- 2, TLR4 and CD14 on human AM compared to autologous monocytes obtained from patients with COPD, healthy smokers and non-smokers. METHODS: The study population consisted of 14 COPD patients without evidence for acute exacerbation, 10 healthy smokers and 17 healthy non-smokers stratified according to age. The expression of TLR2, TLR4 and CD14 surface molecules on human AM compared to autologous monocytes was assessed ex vivo using FACS analysis. In situ hybridization was performed on bronchoalveolar lavage (BAL) cells by application of the new developed HOPE-fixative. RESULTS: The expression of TLR2, TLR4 and CD14 on AM from COPD patients, smokers and non-smokers was reduced as compared to autologous monocytes. Comparing AM we detected a reduced expression of TLR2 in COPD patients and smokers. In addition TLR2 mRNA and protein expression was increased after LPS stimulation on non-smokers AM in contrast to smokers and COPD patients. CONCLUSION: Our data suggest a smoke related change in the phenotype of AM's and the cellular response to microbial stimulation which may be associated with impairment of host defenses in the lower respiratory tract

Association of Toll-like receptor 4 (TLR4) with chronic plaque type psoriasis and psoriatic arthritis.

Family studies have provided overwhelming evidence for an underlying genetic component to psoriasis. Toll-like receptors (TLRs) are key transmembrane proteins in both the innate and adaptive immune responses which are known to be integral processes in psoriasis. Recent functional studies support this notion having suggested a role for TLR4 in the pathogenesis of psoriasis. Furthermore a missense polymorphism in the TLR4 gene has been associated with a number of autoimmune conditions, including Crohn diseases, making TLR4 a viable candidate gene for investigation. The aim of this study was to investigate polymorphisms across the TLR4 region with a high-density single nucleotide polymorphism (SNP) panel in a large cohort of patients with chronic plaque type psoriasis. Twenty SNPs were successfully genotyped using Sequenom iPLEX Gold platform in 2826 UK chronic plaque type psoriasis patients including subgroup data on presence of confirmed psoriatic arthritis (n = 1839) and early-onset psoriasis (n = 1466) was available. Allele frequencies for psoriasis patients were compared against imputed Wellcome Trust Case Control Consortium controls (n = 4861). Significant association was observed between a missense variant rs4986790 of TLR4 (Asp229Gly) and plaque type psoriasis (p = 2 × 10(-4)) which was also notable in those with psoriatic arthritis (p = 2 × 10(-4)) and early-onset psoriasis (p = 8 × 10(-4)). We present data suggestive of an association between a functional variant and an intronic variant of TLR4 and chronic plaque type psoriasis and psoriatic arthritis. However, validation of this association in independent cohorts will be necessary

Association of the TLR4 Asp299Gly polymorphism with lung function in relation to body mass index

<p>Abstract</p> <p>Background</p> <p>Previous studies have shown conflicting results for the association between TLR4 polymorphism (Asp299Gly) and lung function. We investigated the influence of TLR4 Asp299Gly, a polymorphism, on lung function in a community population.</p> <p>Methods</p> <p>In 2003, a cross-sectional survey was conducted to assess the respiratory health of residents living in and around the town of Humboldt, Saskatchewan, Canada. There were 2090 adults age 18-79 years who completed a questionnaire that included a medical and smoking history, as well as socio-economic and lifestyle variables. Genetic information and lung function test measurements were available on 1725 subjects (754 males and 971 females) of the 2090 respondents. These subjects were selected for further analysis to investigate the association between TLR4 Asp299Gly genotype and forced expiratory volume in the first second in liters (FEV₁), forced vital capacity in liters (FVC), FEV₁/FVC ratio, and forced expiratory flow rate in liters/second (FEF_25-75). Multivariable linear regression analysis was used to investigate associations.</p> <p>Results</p> <p><b>A</b>djusted mean values of FEV₁and FVC were significantly different between TLR4 wild type and TLR4 variant groups [Mean ± S.E.: (TLR4 wild type - FEV₁: 3.18 ± 0.02, FVC: 3.95 ± 0.03; TLR4 variant - FEV₁: 3.31 ± 0.06, FVC: 4.14 ± 0.07)]. Based on multivariable regression analysis, we observed that body mass index (BMI) was associated with decreased FEV₁/FVC ratio and FEF_25-75in TLR4 variant group but not in wild type group.</p> <p>Conclusion</p> <p>BMI may modify the associations of TLR4 Asp299Gly polymorphism with FEV₁/FVC ratio and FEF_25-75.</p

Genetic variants in mannose receptor gene (MRC1) confer susceptibility to increased risk of sarcoidosis

<p>Abstract</p> <p>Background</p> <p>Mannose receptor (MR) is a member of the C-type lectin receptor family involved in pathogen molecular-pattern recognition and thought to be critical in shaping host immune response. The aim of this study was to investigate potential associations of genetic variants in the <it>MRC1 </it>gene with sarcoidosis.</p> <p>Methods</p> <p>Nine single nucleotide polymorphisms (SNPs), encompassing the <it>MRC1 </it>gene, were genotyped in a total of 605 Japanese consisting of 181 sarcoidosis patients and 424 healthy controls.</p> <p>Results</p> <p>Suggestive evidence of association between rs691005 SNP and risk of sarcoidosis was observed independent of sex and age in a recessive model (<it>P </it>= 0.001).</p> <p>Conclusions</p> <p>These results suggest that <it>MRC1 </it>is an important candidate gene for sarcoidosis. This is the first study to imply that genetic variants in <it>MRC1</it>, a major member of the C-type lectin, contribute to the development of sarcoidosis.</p

Association between variations in the TLR4 gene and incident type 2 diabetes is modified by the ratio of total cholesterol to HDL-cholesterol

<p>Abstract</p> <p>Background</p> <p>Toll-like receptor 4 (TLR4), the signaling receptor for lipopolysaccharides, is an important member of the innate immunity system. Since several studies have suggested that type 2 diabetes might be associated with changes in the innate immune response, we sought to investigate the association between genetic variants in the <it>TLR4 </it>gene and incident type 2 diabetes.</p> <p>Methods</p> <p>A case-cohort study was conducted in initially healthy, middle-aged subjects from the MONICA/KORA Augsburg studies including 498 individuals with incident type 2 diabetes and 1,569 non-cases. Seven SNPs were systematically selected in the <it>TLR4 </it>gene and haplotypes were reconstructed.</p> <p>Results</p> <p>The effect of <it>TLR4 </it>SNPs on incident type 2 diabetes was modified by the ratio of total cholesterol to high-density lipoprotein cholesterol (TC/HDL-C). In men, four out of seven <it>TLR4 </it>variants showed significant interaction with TC/HDL-C after correction for multiple testing (p < 0.01). The influence of the minor alleles of those variants on the incidence of type 2 diabetes was observed particularly for male patients with high values of TC/HDL-C. Consistent with these findings, haplotype-based analyses also revealed that the effect of two haplotypes on incident type 2 diabetes was modified by TC/HDL-C in men (p < 10^-3). However, none of the investigated variants or haplotypes was associated with type 2 diabetes in main effect models without assessment of effect modifications.</p> <p>Conclusion</p> <p>We conclude that minor alleles of several <it>TLR4 </it>variants, although not directly associated with type 2 diabetes might increase the risk for type 2 diabetes in subjects with high TC/HDL-C. Additionally, our results confirm previous studies reporting sex-related dissimilarities in the development of type 2 diabetes.</p

Nasopharyngeal Bacterial Colonization and Gene Polymorphisms of Mannose-Binding Lectin and Toll-Like Receptors 2 and 4 in Infants

BACKGROUND: Human nasopharynx is often colonized by potentially pathogenic bacteria. Gene polymorphisms in mannose-binding lectin (MBL), toll-like receptor (TLR) 2 and TLR4 have been reported. The present study aimed to investigate possible association between nasopharyngeal bacterial colonization and gene polymorphisms of MBL, TLR2 and TLR4 in healthy infants. METHODOLOGY/PRINCIPAL FINDINGS: From August 2008 to June 2010, 489 nasopharyngeal swabs and 412 blood samples were taken from 3-month-old healthy Finnish infants. Semi-quantitative culture was performed and pyrosequencing was used for detection of polymorphisms in MBL structural gene at codons 52, 54, and 57, TLR2 Arg753Gln and TLR4 Asp299Gly. Fifty-nine percent of subjects were culture positive for at least one of the four species: 11% for Streptococcus pneumoniae, 23% for Moraxella catarrhalis, 1% for Haemophilus influenzae and 25% for Staphylococcus aureus. Thirty-two percent of subjects had variant types in MBL, 5% had polymorphism of TLR2, and 18% had polymorphism of TLR4. Colonization rates of S. pneumoniae and S. aureus were significantly higher in infants with variant types of MBL than those with wild type (p = .011 and p = .024). Colonization rates of S. aureus and M. catarrhalis were significantly higher in infants with polymorphisms of TLR2 and of TLR4 than those without (p = .027 and p = .002). CONCLUSIONS: Our study suggests that there is an association between nasopharyngeal bacterial colonization and genetic variation of MBL, TLR2 and TLR4 in young infants. This finding supports a role for these genetic variations in susceptibility of children to respiratory infections

A phase II study of the vitamin D analogue Seocalcitol in patients with inoperable hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is a common malignant tumour, which has a poor prognosis. Surgical resection can be curative but most patients are inoperable and most chemotherapy agents have minimal activity in this disease. Seocalcitol, a vitamin D analogue, induces differentiation and inhibits growth in cancer cell lines and in vivo. The vitamin D receptor is expressed in hepatocytes and more abundantly in HCC cells. In total, 56 patients with inoperable advanced HCC were included in an uncontrolled study of oral Seocalcitol treatment for up to 1 year ( with possible extension for responders). The dose was titrated according to serum calcium levels. The treatment effect was evaluated by regular CT scans. Out of 33 patients evaluable for tumour response, two had complete response (CR), 12 stable disease and 19 progressive disease. The CRs appeared after 6 and 24 months of treatment, and lasted for 29 and at least 36 months ( patient still in remission when data censored). Seocalcitol was well tolerated; the most frequent toxicity was hypercalcaemia and related symptoms. Most patients tolerated a daily dose of 10 mug of Seocalcitol. This is the first study showing activity, by reduction in tumour dimensions, of a differentiating agent in patients with an advanced bulky, solid tumour. Seocalcitol may have an effect in the treatment of HCC, especially in early disease when a prolonged treatment can be instituted. The survival benefit with or without tumour response should be determined in controlled studies

Common Variants of TLR1 Associate with Organ Dysfunction and Sustained Pro-Inflammatory Responses during Sepsis

Background: Toll-like receptors (TLRs) are critical components for host pathogen recognition and variants in genes participating in this response influence susceptibility to infections. Recently, TLR1 gene polymorphisms have been found correlated with whole blood hyper-inflammatory responses to pathogen-associated molecules and associated with sepsis-associated multiorgan dysfunction and acute lung injury (ALI). We examined the association of common variants of TLR1 gene with sepsis-derived complications in an independent study and with serum levels for four inflammatory biomarker among septic patients. Methodology/Principal Findings: Seven tagging single nucleotide polymorphisms of the TLR1 gene were genotyped in samples from a prospective multicenter case-only study of patients with severe sepsis admitted into a network of intensive care units followed for disease severity. Interleukin (IL)-1 b, IL-6, IL-10, and C-reactive protein (CRP) serum levels were measured at study entry, at 48 h and at 7th day. Alleles -7202G and 248Ser, and the 248Ser-602Ile haplotype were associated with circulatory dysfunction among severe septic patients (0.001<=p <= 0.022), and with reduced IL-10 (0.012<= p <=0.047) and elevated CRP (0.011<= p <=0.036) serum levels during the first week of sepsis development. Additionally, the -7202GG genotype was found to be associated with hospital mortality (p =0.017) and ALI (p =0.050) in a combined analysis with European Americans, suggesting common risk effects among studies Conclusions/Significance: These results partially replicate and extend previous findings, supporting that variants of TLR1 gene are determinants of severe complications during sepsis

Tolllike receptor 4 (TLR4) polymorphisms in Tunisian patients with Crohn's disease: genotype-phenotype correlation

<p>Abstract</p> <p>Background</p> <p>The immune responses to bacterial products through the pattern recognition receptor (PRR) play a pivotal role in pathogenesis of Crohn's disease. A recent study described an association between CD and some gene coding for bacterial receptor like NOD2/CARD15 gene and TLR4. In this study, we sought to determine whether TLR4 gene was associated with Crohn's disease (CD) among the Tunisian population and its correlation with clinical manifestation of the disease.</p> <p>Methods</p> <p>90 patients with CD and 80 healthy individuals are genotyped for the <it>Asp299Gly </it>and <it>Thr399Ile </it>polymorphisms by restriction fragment length polymorphism analysis.</p> <p>Results</p> <p>The allele and genotype frequency of the TLR4 polymorphisms did not differ between patients and controls. The genotype-phenotype correlation permitted to show that the <it>Thr399Ile </it>polymorphism was associated with early onset disease.</p> <p>Conclusion</p> <p>this study reported the absence of association between CD and TLR4 gene in the Tunisian population, but this gene could play a role in clinical expression of the disease.</p