Polymorphisms In Pattern Recognition Receptors Research Articles

Detection and treatment of skin infection with Staphylococcus aureus in children with atopic dermatitis

Introduction. Atopic dermatitis is a common chronic relapsing inflammatory multifactorial skin disease. Staphylococcus aureus skin colonization increases during disease outbreaks and correlates with the severity of skin symptoms. Purpose - to evaluate the effectiveness of thyrothricin gel as an adjuvant therapy in the treatment of atopic dermatitis and the influence of polymorphisms of pattern recognition receptors on the achieving a therapeutic effect. Materials and methods. This study included patients with atopic dermatitis (n=37) aged 2-18 years from the Allergy Department of the Kyiv City Children’s Clinical Hospital No. 2. Patients were devided into two groups: a group that received thyrothricin gel on the affected skin areas 2 times a day for 7 days (the Group A) and a control group (the Group B) that received only basic symptomatic therapy. SCORAD (SCORing AD) and CDLQI (Children’s Quality of Life Index in Dermatology) scores were recorded before and after treatment, side effects were recorded during the study. Skin swabs were taken in the Group A before and after treatment. Genotyping of polymorphisms rs4696480 in the TLR2 gene, rs7309123 in the Dectin-1 gene were performed using polymerase chain reaction. Results. In both groups of children, improvement was observed in 7 days after treatment (p<0.001). In the Group A, the improvement in ΔSCORAD was 16.6±5.9 points, in the Group B - 8.1±4.5 points. The difference in ΔSCORAD scores between the Groups A and B was statistically significant (W=225.0, p<0.001). The decrease in CDLQI score after treatment was 3.8±1.8 points in the Group A and 2.3±1.25 points in the Group B. A significant decrease in CDLQI score was demonstrated in the intervention group than in the control group after treatment (W=275.5, p=0.004). After treatment, a bacteriological examination of the skin demonstrated the eradication of Staphylococcus aureus: in the Group A, 94.4% of patients were Staphylococcus aureus-negative. Polymorphisms rs4696480 in the TLR2 gene and rs7309123 in the Dectin-1 gene did not affect the speed of achieving the therapeutic effect. Conclusions. The addition of thyrothricin to standard therapy for atopic dermatitis in children with Staphylococcus aureus infection of affected skin may provide significant clinical benefit in SCORAD and CDLQI scores. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of the participating institution. The informed consent of the patients was obtained for conducting the studies. No conflict of interests was declared by the author.

Genetic polymorphisms in pattern recognition receptors are associated with allergic diseases through gene-gene interactions.

There is evidence that suggests variation in gene encoding pattern recognition receptors, the essential components of innate immunity, might be associated with atopic diseases. However, results have been inconclusive. The aim of the study was to determine the individual associations and possible interactive effects of the CD14 (cluster of differentiation 14), TLR4 (toll-like receptor 4) and TLR2 (toll-like receptor 2) polymorphisms on allergic diseases. The CD14 C-159T, TLR4 +896A/G and TLR2 A-16934T polymorphisms were identified in 115 children aged from 6 to 17 years. All subjects were selected using a detailed questionnaire which included questions on symptoms and each one underwent skin prick testing. All single-nucleotide polymorphisms (SNPs) were determined using real-time polymerase chain reaction (PCR) assays. There was no statistically significant correlation between the 3 polymorphisms (CD14 C-159T, TLR4 +896A/G and TLR2/-16934A/T) and either asthma, allergic rhinitis or atopy. We observed that children who were heterozygous or homozygous for both the CD14/-159T and TLR2/-16934A alleles had a 4-fold lower risk for asthma than children who were carriers of the T allele of CD14 but non-carriers of the A allele of TLR2, and an almost 3-fold lower risk for asthma when compared to all other groups. Concerning allergic rhinitis, a similar trend was observed. In addition, the presence of at least 1 A allele in the TLR2/-16934 polymorphism reduced the risk for asthma and allergic rhinitis, but only in children who were homozygous for the common A allele in the TLR4 +896 polymorphism. Our study supports the idea that the CD14, TLR2 and TLR4 polymorphisms may not be directly involved in the development of atopic diseases. However, our results suggest that their impact on the risk of asthma and allergic rhinitis might be modulated by gene-gene interactions.

Polymorphisms in pattern recognition receptor genes of indigenous and White Leghorn breeds of chicken.

Functional polymorphisms in pattern recognition receptors (PRRs) modulate innate immunity and play a crucial role in resistance or susceptibility to diseases. The present study was carried out to explore polymorphic patterns in the coding sequences of PRR genes TLR3, TLR1LA (TLRs), MDA5, LGP2 (RLRs) and NOD1 (NLR) in chicken breeds of India, namely Ghagus (GH), Nicobari (NB) and the exotic White Leghorn (WLH) breed. Out of 209 SNPs observed in five genes among three breeds, 117 were synonymous (Syn) and 92 were non-synonymous (NS) SNPs. In TLR genes the highest polymorphism was observed in NB (16, 28) compared to GH (14, 16) and WLH (13, 19) breeds. In the MDA5 gene the highest polymorphism was observed in GH (12) compared to NB (eight) and WLH (four) breeds. However, an almost similar level of polymorphism was observed in the LGP2 gene among the three breeds. In the NOD1 gene, the highest polymorphism was observed in NB (27), followed by WLH (11) and GH (10) breeds. The overall highest number of SNPs was observed in NB (90), followed by GH (62) and the WLH (57) breed. With regard to variation in polymorphism among different classes of PRRs, the study revealed the highest polymorphism in TLRs compared to NOD1 and the RLR class of PRRs. Further, the domain locations of various Syn and NS SNPs in each PRR among the three breeds were identified. In silico analysis of NS SNPs revealed that most of them had a neutral effect on protein function. However, two each in TLR1LA and LGP2 and one in the MDA5 gene were predicted to be deleterious to protein function. The present study unravelled extensive polymorphism in the coding sequences of the TLR and NLR class of PRR genes, and the polymorphism was higher in indigenous chicken breeds.

Genetic polymorphisms in pattern recognition receptors and risk of periodontitis: Evidence based on 12,793 subjects

Pattern recognition receptors (PRRs) constitute a pivotal arm of innate immunity. Many studies investigated the association between PRRs polymorphisms and periodontitis risk, which showed inconclusive results. The aim of the meta-analysis was to evaluate the precise association between five widely-evaluated polymorphisms (CD14 −260C/T (rs2569190), Toll-like receptor (TLR) 2 2408G/A (rs5743708), TLR4 896A/G (rs4986790), TLR4 1196C/T (rs4986791), mannose-binding lectin (MBL) codon 54 (rs1800450)) within the PRRs and susceptibility to either chronic (CP) or aggressive periodontitis (AgP). Overall, no significant association was found for the PRRs polymorphisms with either CP or AgP. In the subgroup analyses, TLR4 896G and 1196T alleles yielded a 32% (OR=1.32, 95% CI: 1.04–1.68) and a 37% increased CP risk (OR=1.37, 95% CI: 1.05–1.80) in Caucasians, respectively. Further stratified analyses revealed links between CD14, MBL2 polymorphisms and the severity of CP. This meta-analysis suggested that the periodontitis susceptibility was partly controlled by PRRs polymorphisms involved in the innate immunity.

Gene polymorphisms in pattern recognition receptors and susceptibility to idiopathic recurrent vulvovaginal candidiasis.

Objective: Approximately 5% of women suffer from recurrent vulvovaginal candidiasis (RVVC). It has been hypothesized that genetic factors play an important role in the susceptibility to RVVC. The aim of this study was to assess the effect of genetic variants of genes encoding for pattern recognition receptors (PRRs) on susceptibility to RVVC.Study design: For the study, 119 RVVC patients and 263 healthy controls were recruited. Prevalence of polymorphisms in five PRRs involved in recognition of Candida were investigated in patients and controls. In silico and functional studies were performed to assess their functional effects.Results: Single nucleotide polymorphisms (SNPs) in TLR1, TLR4, CLEC7A, and CARD9 did not affect the susceptibility to RVVC. In contrast, a non-synonymous polymorphism in TLR2 (rs5743704, Pro631His) increased the susceptibility to RVVC almost 3-fold. Furthermore, the TLR2 rs5743704 SNP had deleterious effects on protein function as assessed by in silico analysis, and in vitro functional assays suggested that it reduces production of IL-17 and IFNγ upon stimulation of peripheral blood mononuclear cells with Candida albicans. No effects were observed on serum mannose-binding lectin concentrations.Condensation: This study demonstrates the association of susceptibility to RVVC with genetic variation in TLR2, most likely caused by decreased induction of mucosal antifungal host defense.Conclusion: Genetic variation in TLR2 may significantly enhance susceptibility to RVVC by modulating host defense mechanisms against Candida. Additional studies are warranted to assess systematically the role of host genetic variation for susceptibility to RVVC.

Immunity and Tolerance to Fungi in Hematopoietic Transplantation: Principles and Perspectives

Resistance and tolerance are two complementary host defense mechanisms that increase fitness in response to low-virulence fungi. Resistance is meant to reduce pathogen burden during infection through innate and adaptive immune mechanisms, whereas tolerance mitigates the substantial cost of resistance to host fitness through a multitude of anti-inflammatory mechanisms, including immunological tolerance. In experimental fungal infections, both defense mechanisms are activated through the delicate equilibrium between Th1/Th17 cells, which provide antifungal resistance, and regulatory T cells limiting the consequences of the ensuing inflammatory pathology. Indoleamine 2,3-dioxygenase (IDO), a rate-limiting enzyme in the tryptophan catabolism, plays a key role in induction of tolerance against fungi. Both hematopoietic and non-hematopoietic compartments contribute to the resistance/tolerance balance against Aspergillus fumigatus via the involvement of selected innate receptors converging on IDO. Several genetic polymorphisms in pattern recognition receptors influence resistance and tolerance to fungal infections in human hematopoietic transplantation. Thus, tolerance mechanisms may be exploited for novel diagnostics and therapeutics against fungal infections and diseases.

Genomic survey of polymorphisms in pattern recognition receptors and their possible relationship to infections in pigs

Recent progress in the accumulation of pig genomic information has enabled us to comprehensively explore polymorphisms in pig genes. One of our targets for exploration has been the genes encoding molecules related to pathogen recognition, such as pattern recognition receptors (PRRs). PRRs play a role in the innate immune system, and possess various members such as Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-like helicases (RLHs), and C-type lectin-like receptors (CLRs). PRRs are required for the monitoring of pathogens; therefore, polymorphisms in PRRs may influence molecular functions such as ligand recognition. There have been many studies on the relationship between polymorphisms within PRR genes and disease susceptibility in humans and mice. Our studies have revealed that porcine PRR genes possess many nonsynonymous polymorphisms, particularly in regions encoding the ectodomains of TLRs localized on the cell surface. The genes encoding TLRs located on the membrane of intracellular compartments, and cytoplasmic PRRs such as NLRs and RLHs, also possessed nonsynonymous polymorphisms. Several observations indicate that there are relationships between polymorphisms in PRR or related genes and disease susceptibility in livestock animals including pig. Such information may contribute to breeding aimed at disease resistance, and effective vaccine design.

Polymorphisms in pattern recognition receptors and their relationship to infectious disease susceptibility in pigs

BackgroundPattern recognition receptors (PRRs), including Toll-like receptors (TLRs), are censoring receptors for molecules derived from bacteria, viruses, and fungi. The PRR system is a prerequisite for proper responses to pathogens, for example by cytokine production, resulting in pathogen eradication. Many cases of polymorphisms in PRR genes affecting the immune response and disease susceptibility are known in humans and mice.MethodsWe surveyed polymorphisms in pig genes encoding PRRs and investigated the relationship between some of the detected polymorphisms and molecular function or disease onset.ResultsNonsynonymous polymorphisms abounded in pig TLR genes, particularly in the region corresponding to the ectodomains of TLRs expressed on the cell surface. Intracellular TLRs such as TLR3, TLR7, and TLR8, and other intracellular PRRs, such as the peptidoglycan receptor NOD2 and viral RNA receptors RIG-I and MDA5, also possessed nonsynonymous polymorphisms. Several of the polymorphisms influenced molecular functions such as ligand recognition. Polymorphisms in the PRR genes may be related to disease susceptibility in pigs: pigs with a particular allele of TLR2 showed an increased tendency to contract pneumonia.ConclusionsWe propose the possibility of pig breeding aimed at disease resistance by the selection of PRR gene alleles that affect pathogen recognition.

Single nucleotide polymorphisms of pattern recognition receptors and chronic periodontitis

Periodontitis is a multifactorial disease influenced partly by genetics. Activation of pattern recognition receptors (PRRs) can lead to the up-regulation of inflammatory pathways, resulting in periodontal tissue destruction. Hence, functional polymorphisms located in PRRs can explain differences in host susceptibility to periodontitis. This study investigated single nucleotide polymorphisms of PRRs including toll-like receptor (TLR)2 (G2408A), TLR4 (A896G), TLR9 (T1486C), TLR9 (T1237C) and CD14 (C260T) in patients with chronic periodontitis and in periodontally healthy subjects. One-hundred and fourteen patients with chronic periodontitis and 77 periodontally healthy subjects were genotyped using TaqMan® allelic discrimination assays. Fisher's exact test and chi-square analyses were performed to compare genotype and allele frequencies. The frequency of subjects with the CC genotype of CD14 (C260T) (24.6% in the chronic periodontitis group vs. 13% in the periodontally healthy group) and those expressing the T allele of CD14 (C260T) (CT and TT) (75.4% in the chronic periodontitis group vs. 87% in the periodontally healthy group) was statistically different among groups (p = 0.04). Homozygocity for the C allele of the CD14 (C260T) polymorphism (CC) was associated with a two--fold increased susceptibility to periodontitis (p = 0.04; odds ratio, 2.49; 95% confidence interval, 1.06-6.26). Individuals with the CC genotype of TLR9 (T1486C) (14.9% in the chronic periodontitis group vs. 28.6% in the periodontally healthy group) and those expressing the T allele of TLR9 (T1486C) (CT and TT) (85.1% in the chronic periodontitis group vs. 71.4% in the periodontally healthy group) were also significantly differently distributed between groups without adjustment (p = 0.03). Further analysis of nonsmokers revealed a significant difference in the distribution of genotypes between groups for TLR9 (T1486C; p = 0.017) and CD14 (C260T; p = 0.03), polymorphisms again without adjustment. The CC genotype of CD14 (C260T) is related to susceptibility to chronic periodontitis in Caucasians. In addition, differences observed in the distribution of TLR9 (T1486C) genotypes between groups warrant further investigation.

Immunogenetics of invasive aspergillosis

Invasive aspergillosis is one of the most important infections in hematopoietic stem cell transplant recipients, with an incidence rate of 5-15% and an associated mortality of 30-60%. It remains unclear why certain patients develop invasive aspergillosis while others, undergoing identical transplant regimen and similar post transplant immunosuppression, do not. Over the last decade, pattern recognition receptors such as Toll-like receptors (TLRs) and the C-type lectin receptors (CLRs) have emerged as critical components of the innate immune system. By detecting specific molecular patterns from invading microbes and initiating inflammatory and subsequent adaptive immune responses, pattern recognition receptors are strategically located at the molecular interface of hosts and pathogens. Polymorphisms in pattern recognition receptors and downstream signaling molecules have been associated with increased or decreased susceptibility to infections, suggesting that their detection may have an increasing impact on the treatment and prevention of infectious diseases in the coming years. Infectious risk stratification may be particularly relevant for patients with hematologic malignancies, because of the high prevalence and severity of infections in this population. This review summarizes the innate immune mechanisms involved in Aspergillus fumigatus detection and the role of host genetic polymorphisms in susceptibility to invasive aspergillosis.

NOD1 gene E266K polymorphism is associated with disease susceptibility but not with disease phenotype or NOD2/CARD15 in Hungarian patients with Crohn's disease

Background NOD1/CARD4, a member of the pattern-recognition receptor family, is a perfect candidate as a susceptibility gene for Crohn's disease. Since only limited and conflicting data are available on G796A polymorphisms in inflammatory bowel disease patients, we set out to study the effect of this polymorphism on the susceptibility and course of Crohn's disease in the Hungarian population. Methods Four hundred thirty-four unrelated Crohn's disease patients (age at presentation: 28.6 ± 9.6 years, female/male: 210/224, duration of Crohn's disease: 8.2 ± 6.9 years) and 200 healthy subjects (blood donors) and 136 non-inflammatory bowel disease gastrointestinal controls with chronic gastritis were investigated. NOD1 G796A was detected by using polymerase chain reaction/restriction fragment length polymorphism. Detailed clinical phenotypes were determined by reviewing the medical charts. Results The frequencies of the variant alleles of NOD1 G796A differed significantly between the Crohn's disease patients and both healthy (GG 49.5% vs. 67%; AG 41.5% vs. 28%; and AA 9.0% vs. 5.2%; p < 0.0001) and non-inflammatory bowel disease controls with chronic gastritis. Carriage of the single nucleotide polymorphism of NOD1 G796A proved to be a highly significant risk factor for Crohn's disease compared to both healthy ( p < 0.0001, OR: 2.1, 95% CI: 1.5–2.9) and non-inflammatory bowel disease controls with chronic gastritis ( p = 0.008). Significant associations were not found between the different genotypes and the demographic data on the patients or the clinical characteristics of Crohn's disease. The different polymorphisms of pattern-recognition receptors (e.g. NOD2/CARD15 SNP8, SNP12 and SNP13 mutations, the TLR4 D299G polymorphism and NOD1 G796A) did not reveal a mutual basis. Conclusions Our results suggest that carriage of the NOD1 G796A mutation increases susceptibility for Crohn's disease in the Hungarian population.