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Ackland J, Watson A, Wilkinson TMA, Staples KJ. Interrupting the Conversation: Implications for Crosstalk Between Viral and Bacterial Infections in the Asthmatic Airway. FRONTIERS IN ALLERGY 2021; 2:738987. [PMID: 35386999 PMCID: PMC8974750 DOI: 10.3389/falgy.2021.738987] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 09/20/2021] [Indexed: 12/20/2022] Open
Abstract
Asthma is a heterogeneous, chronic respiratory disease affecting 300 million people and is thought to be driven by different inflammatory endotypes influenced by a myriad of genetic and environmental factors. The complexity of asthma has rendered it challenging to develop preventative and disease modifying therapies and it remains an unmet clinical need. Whilst many factors have been implicated in asthma pathogenesis and exacerbations, evidence indicates a prominent role for respiratory viruses. However, advances in culture-independent detection methods and extensive microbial profiling of the lung, have also demonstrated a role for respiratory bacteria in asthma. In particular, airway colonization by the Proteobacteria species Nontypeable Haemophilus influenzae (NTHi) and Moraxella catarrhalis (Mcat) is associated with increased risk of developing recurrent wheeze and asthma in early life, poor clinical outcomes in established adult asthma and the development of more severe inflammatory phenotypes. Furthermore, emerging evidence indicates that bacterial-viral interactions may influence exacerbation risk and disease severity, highlighting the need to consider the impact chronic airway colonization by respiratory bacteria has on influencing host responses to viral infection. In this review, we first outline the currently understood role of viral and bacterial infections in precipitating asthma exacerbations and discuss the underappreciated potential impact of bacteria-virus crosstalk in modulating host responses. We discuss the mechanisms by which early life infection may predispose to asthma development. Finally, we consider how infection and persistent airway colonization may drive different asthma phenotypes, with a view to identifying pathophysiological mechanisms that may prove tractable to new treatment modalities.
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Affiliation(s)
- Jodie Ackland
- Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, United Kingdom
| | - Alastair Watson
- Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, United Kingdom
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
- College of Medical and Dental Sciences, University of Birmingham, Birmingham, United Kingdom
| | - Tom M. A. Wilkinson
- Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, United Kingdom
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
- Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom
| | - Karl J. Staples
- Clinical and Experimental Sciences, University of Southampton Faculty of Medicine, Southampton, United Kingdom
- NIHR Southampton Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom
- Wessex Investigational Sciences Hub, University of Southampton Faculty of Medicine, Southampton General Hospital, Southampton, United Kingdom
- *Correspondence: Karl J. Staples
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Zhao Y, Zhang Y, Zhou J, Wang L, Shi J, Tan Y, Luo Y, Huang H, Cai Z. Toll-like Receptor 4 Gene Polymorphisms in Chinese Population After Allogeneic Hematopoietic Stem Cell Transplantation. Curr Bioinform 2021. [DOI: 10.2174/1574893615999200818155048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Objectives::
Graft-versus-host disease (GVHD) is the most common complication after
hematopoietic stem cell transplantation (HSCT) and remains to be a major cause of mortality.
Activation of toll-like receptor 4 (TLR-4) by lipopolysaccharide induces the NF-κB signaling
pathway to release critical proinflammatory cytokines and increases the recipient response to
GVHD. In order to clarify the role of TLR-4 in the occurrence of acute GVHD after HSCT, we
collected 208 samples from HSCT recipients and their human lecucyte antigen identical donors to
test the hypothesis that TLR-4polymorphism in the recipients or donors influence the risk of acute
GVHD in allogeneic HSCT recipients.
Methods::
TLR-4 Asp299Gly and Thr399Ile polymorphisms of each sample were examined by
using DNA sequencing and polymerase chain reaction-restriction fragment length polymorphism
methods.
Results::
No homozygous or heterozygous variant alleles of the Asp299Gly or Thr339Ile
polymorphism were detected in any samples in our study. Our results demonstrate that TLR-4
Asp299Gly and Thr399Ile polymorphisms might be very rare in the Chinese population (Eastern
China and Taiwan region).
Conclusion::
The results of this study cannot confirm the role of TLR-4 mutations in the
pathogenesis of GVHD in humans, yet we reach a definite conclusion by a TLR-4 knockout
murine GVHD model in our ongoing project.
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Affiliation(s)
- Yi Zhao
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - Yujie Zhang
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - Jie Zhou
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - Lijuan Wang
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - Jimin Shi
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - Yamin Tan
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - Yi Luo
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - He Huang
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
| | - Zhen Cai
- Department of Bone Marrow Transplantation Center, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang,China
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Jacquet A, Robinson C. Proteolytic, lipidergic and polysaccharide molecular recognition shape innate responses to house dust mite allergens. Allergy 2020; 75:33-53. [PMID: 31166610 DOI: 10.1111/all.13940] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2018] [Revised: 04/05/2019] [Accepted: 05/23/2019] [Indexed: 02/06/2023]
Abstract
House dust mites (HDMs) are sources of an extensive repertoire of allergens responsible for a range of allergic conditions. Technological advances have accelerated the identification of these allergens and characterized their putative roles within HDMs. Understanding their functional bioactivities is illuminating how they interact with the immune system to cause disease and how interrelations between them are essential to maximize allergic responses. Two types of allergen bioactivity, namely proteolysis and peptidolipid/lipid binding, elicit IgE and stimulate bystander responses to unrelated allergens. Much of this influence arises from Toll-like receptor (TLR) 4 or TLR2 signalling and, in the case of protease allergens, the activation of additional pleiotropic effectors with strong disease linkage. Of related interest is the interaction of HDM allergens with common components of the house dust matrix, through either their binding to allergens or their autonomous modulation of immune receptors. Herein, we provide a contemporary view of how proteolysis, lipid-binding activity and interactions with polysaccharides and polysaccharide molecular recognition systems coordinate the principal responses which underlie allergy. The power of the catalytically competent group 1 HDM protease allergen component is demonstrated by a review of disclosures surrounding the efficacy of novel inhibitors produced by structure-based design.
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Affiliation(s)
- Alain Jacquet
- Center of Excellence in Vaccine Research and Development (Chula Vaccine Research Center-Chula VRC) Chulalongkorn University Bangkok Thailand
| | - Clive Robinson
- Institute for Infection and Immunity St George's, University of London London UK
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Priante E, Cavicchiolo ME, Baraldi E. RSV infection and respiratory sequelae. Minerva Pediatr 2018; 70:623-633. [PMID: 30379052 DOI: 10.23736/s0026-4946.18.05327-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
INTRODUCTION The association between respiratory syncytial virus (RSV) infections and long-term respiratory sequelae has long been recognized. It is estimated that individuals with a history of RSV bronchiolitis have 2- to 12-fold higher risk of developing asthma. Although this risk tends to decrease with age, persistent airway obstruction and hyperresponsiveness are observed even 30 years after RSV infection. EVIDENCE ACQUISITION Our data search strategy was designed to address the following questions: What is the epidemiological evidence available on the association between RSV infection and long-term respiratory morbidity? What are the potential pathogenic pathways linking RSV infection to long-term respiratory morbidity? Are there any host genetic backgrounds that can predispose to both severe RSV lower respiratory tract infection and asthma? Are antiviral therapies and RSV prevention measures effective in reducing respiratory morbidities? EVIDENCE SYNTHESIS This article reviews the recent scientific literature on the epidemiological association and pathogenic links between early RSV infection and long-term respiratory morbidities. CONCLUSIONS Nowadays, asthma is increasingly considered a heterogeneous disease, caused by interactions between several host and environmental factors. Understanding the specific causative role of respiratory viruses, and the pathogenic mechanisms through which bronchiolitis predisposes to asthma, is a challenging, but essential starting point for the development of prevention and treatment strategies potentially capable of preserving lung function.
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Affiliation(s)
- Elena Priante
- Unit of Neonatal Intensive Care, Department of Woman's and Child's Health, University of Padua, Padua, Italy
| | - Maria E Cavicchiolo
- Unit of Neonatal Intensive Care, Department of Woman's and Child's Health, University of Padua, Padua, Italy -
| | - Eugenio Baraldi
- Unit of Neonatal Intensive Care, Department of Woman's and Child's Health, University of Padua, Padua, Italy
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Zakeri A, Russo M. Dual Role of Toll-like Receptors in Human and Experimental Asthma Models. Front Immunol 2018; 9:1027. [PMID: 29867994 PMCID: PMC5963123 DOI: 10.3389/fimmu.2018.01027] [Citation(s) in RCA: 79] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2017] [Accepted: 04/24/2018] [Indexed: 12/31/2022] Open
Abstract
Asthma is a chronic airway inflammatory disease that is influenced by the interplay between genetic factors and exposure to environmental allergens, microbes, or microbial products where toll-like receptors (TLRs) play a pivotal role. TLRs recognize a wide range of microbial or endogenous molecules as well as airborne environmental allergens and act as adjuvants that influence positively or negatively allergic sensitization. TLRs are qualitatively and differentially expressed on hematopoietic and non-hematopoietic stromal or structural airway cells that when activated by TLRs agonists exert an immune-modulatory role in asthma development. Therefore, understanding mechanisms and pathways by which TLRs orchestrate asthma outcomes may offer new strategies to control the disease. Here, we aim to review and critically discuss the role of TLRs in human asthma and murine models of allergic airway inflammation, highlighting the complexity of TLRs function in development, exacerbation, or control of airway allergic inflammation.
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Affiliation(s)
- Amin Zakeri
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Infectious Diseases, Aarhus University Hospital, Aarhus, Denmark
| | - Momtchilo Russo
- Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
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Zhao J, Shang H, Cao X, Huang Y, Fang X, Zhang S, Xie M, Xie J, Liu X. Association of polymorphisms in TLR2 and TLR4 with asthma risk: An update meta-analysis. Medicine (Baltimore) 2017; 96:e7909. [PMID: 28858111 PMCID: PMC5585505 DOI: 10.1097/md.0000000000007909] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
BACKGROUND Several epidemiological studies have focused on the association between polymorphisms in toll-like receptors (TLRs) and asthma. However, the results remained inconclusive. METHODS We systematically reviewed the database of PubMed, EMBASE, Web of Science, CNKI, and Google scholar for all related articles on TLR polymorphisms and asthma. We used the software STATA 12.0 to conduct the meta-analysis. The heterogeneity and publication bias were examined, respectively. RESULTS Eighteen studies consisting of 3538 asthma cases and 4090 controls were selected into the meta-analysis. The pooled odds ratios (ORs) show that rs3804099 was associated with asthma in dominant model (OR = 1.51, 95% CI = 1.17-1.96, P = .002), and rs4986791 was associated with asthma in additive model (OR = 0.81, 95% CI = 0.64-1.02, P = .07) and dominant model (OR = 0.76, 95% CI = 0.60-0.97, P = .025). CONCLUSION The combined results show that rs3804099 in TLR2 and rs4986791 in TLR4 were significantly associated with asthma risk. Polymorphisms in TLRs play important roles in asthma.
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Abstract
Endotoxin significantly contaminates house dust and is an enhancing factor for asthma severity. Natural exposure to endotoxin in early life could influence immune development and protect from the risk of developing atopy. This article will focus on published data showing that home environmental contamination by endotoxin can participate in chronic airways diseases, in particular asthma.
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Affiliation(s)
- Olivier Michel
- Clinic of Allergology and Respiratory Diseases, Saint-Pierre University Hospital, Free University of Brussels, Brussels, Belgium,
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8
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Vogel SN, Awomoyi AA, Rallabhandi P, Medvedev AE. Mutations in TLR4 signaling that lead to increased susceptibility to infection in humans: an overview. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/09680519050110060801] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022]
Abstract
In this overview, we will present current information on known mutations in the TLR4 signaling pathway that have been associated with increased susceptibility to disease. To date, mutations in the extracellular domain of TLR4 itself, IRAK-4, NEMO (IKKγ), and IκBα have been identified and profoundly affect the host response to infection.
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Affiliation(s)
- Stefanie N. Vogel
- Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland, USA,
| | - Agnes A. Awomoyi
- Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland, USA
| | - Prasad Rallabhandi
- Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland, USA
| | - Andrei E. Medvedev
- Department of Microbiology and Immunology, University of Maryland, Baltimore, Baltimore, Maryland, USA
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Ortiz-Martínez MG, Frías-Belén O, Nazario-Jiménez S, López-Quintero M, Rodríguez-Cotto RI, Jiménez-Vélez BD. A case-control study of innate immunity pathway gene polymorphisms in Puerto Ricans reveals association of toll-like receptor 2 +596 variant with asthma. BMC Pulm Med 2016; 16:112. [PMID: 27495363 PMCID: PMC4974724 DOI: 10.1186/s12890-016-0272-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2016] [Accepted: 07/23/2016] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND For many years, African Dust Storms (ADE) has been thought to be associated with high prevalence of asthma in Puerto Rico (PR). Endotoxins (ENX) have been associated with ADE particulate matter (PM) and are known to promote pro-inflammatory responses in lung cells of susceptible individuals through the Toll-like receptor (TLR2/4) signaling pathways. Genetic variants are plausible contributors to such susceptibility. Therefore, we have evaluated a series of nine single nucleotide polymorphisms (SNPs) in TLR genes, which have been correlated positive and negatively to asthma prevalence and/or risk, in the Puerto Rican asthmatic population. METHODS The following SNPs were evaluated in 62 asthmatics and 61 controls through Taqman® Real Time PCR Assay: TLR4 (+896A/G, +1196C/T, -6687A/G); TLR2 (+596C/T, -16934 T/A, +399A/G, +1349C/T) and CD14 (-159C/T, +1188C/G). Genotypes were assessed for asthma association employing an odds ratio (OR) analysis. RESULTS Minor allele frequencies (n = 123) were determined for those variants as 0.07, 0.06, 0.35, 0.35, 0.37, 0.29, 0.04, 0.35 and 0.11, respectively. Two (+596C/T, +399A/G) TLR2 SNPs showed to be more represented in the asthmatic group by 89 % and 65 %, respectively. TLR4 SNP +896A/G analysis revealed only 1 G/G genotype (2 %) on the asthmatic group. The CD14 SNPs were similarly represented in the Puerto Rican population. Only the TLR2 +596 SNP was found to be significantly associated to asthma (OR = 3.24 for CT, 2.71 for TT) and particularly to females. CONCLUSIONS The identification of TLR SNPs will reveal potential candidates for gene-environment interactions in Puerto Ricans. As far as we know this is the first study to evaluate this type of TLR gene polymorphisms in Puerto Rican asthmatics, contributing to the current knowledge in the Hispanic population.
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Affiliation(s)
- Mario G Ortiz-Martínez
- Department of Biochemistry, University of Puerto Rico-Medical Sciences Campus Main Bldg Lab B-210, San Juan, 00935, Puerto Rico, USA
- Department of Biology, University of Puerto Rico at Humacao, Humacao, Puerto Rico, USA
- Center for Environmental and Toxicological Research, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Orquídea Frías-Belén
- School of Public Health, University of Puerto Rico, Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Sylvette Nazario-Jiménez
- Department of Allergy and Immunology and School of Medicine Clinics, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - María López-Quintero
- Department of Internal Medicine and School of Medicine Clinics, University of Puerto Rico-Medical Sciences Campus, San Juan, 00935, Puerto Rico, USA
| | - Rosa I Rodríguez-Cotto
- Department of Biochemistry, University of Puerto Rico-Medical Sciences Campus Main Bldg Lab B-210, San Juan, 00935, Puerto Rico, USA
- Center for Environmental and Toxicological Research, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico, USA
| | - Braulio D Jiménez-Vélez
- Department of Biochemistry, University of Puerto Rico-Medical Sciences Campus Main Bldg Lab B-210, San Juan, 00935, Puerto Rico, USA.
- Center for Environmental and Toxicological Research, University of Puerto Rico-Medical Sciences Campus, San Juan, Puerto Rico, USA.
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Abbas M, Berka N, Khraiwesh M, Ramadan A, Apprey V, Furbert-Harris P, Quinn T, Brim H, Dunston G. Genetic Polymorphisms of TLR4 and MICA are Associated with Severity of Trachoma Disease in Tanzania. ACTA ACUST UNITED AC 2016; 2. [PMID: 27559544 PMCID: PMC4993598 DOI: 10.16966/2470-1025.116] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023]
Abstract
Aim To examine the association of TLR4 Asp299Gly and MICA exon 5 microsatellites polymorphisms with severity of trachoma in a sub-Saharan East Africa population of Tanzanian villagers. Methods The samples were genotyped for MICA exon 5 microsatellites and the TLR4 299 A/G polymorphism by Restriction Fragment Length Polymorphism (RFLP), and GeneScan®, respectively. The association of TLR4 Asp299Gly and MICA exon 5 microsatellites with inflammatory trachoma (TI) and trichiasis (TI) were examined. Results The results showed an association between TLR4 and MICA polymorphisms and trachoma disease severity, as well as with protection. TLR4 an allele was significantly associated with inflammatory trachoma (p=0.0410), while the G allele (p=0.0410) was associated with protection. Conclusion TLR4 and MICA may modulate the risk of severity to trachoma disease by modulating the immune response to Ct. In addition; the increased frequency of MICA-A9 heterozygote in controls may suggest a positive selection of these alleles in adaptation to environments where Ct is endemic.
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Affiliation(s)
- Muneer Abbas
- Department of Microbiology, Howard University, Washington, DC, USA
| | | | - Mozna Khraiwesh
- Division of Experimental Therapeutics, Department of Drug Discovery, Walter Reed Army Institute of Research, Silver Spring, MD, USA
| | - Ali Ramadan
- Department of Pathology, Howard University Hospital, Washington, DC, USA
| | - Victor Apprey
- Department of Microbiology, Howard University, Washington, DC, USA; Department of Community Health and Family Medicine, Howard University, Washington DC, USA
| | | | - Thomas Quinn
- International Health, School of Medicine, Johns Hopkins University, Baltimore Maryland, USA
| | - Hassan Brim
- Department of Pathology, Howard University Hospital, Washington, DC, USA
| | - Georgia Dunston
- Department of Microbiology, Howard University, Washington, DC, USA
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Lei T, Tang W, Xiong Y, Di Y, Zhang K, Shu X. Association of TLR4 gene polymorphisms with susceptibility to type 2 diabetes mellitus in the Chinese Han population. Int Immunopharmacol 2015; 24:68-71. [DOI: 10.1016/j.intimp.2014.11.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2014] [Revised: 11/10/2014] [Accepted: 11/10/2014] [Indexed: 01/04/2023]
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Tizaoui K, Kaabachi W, Hamzaoui K, Hamzaoui A. Association of Single Nucleotide Polymorphisms in Toll-like Receptor Genes With Asthma Risk: A Systematic Review and Meta-analysis. ALLERGY, ASTHMA & IMMUNOLOGY RESEARCH 2014; 7:130-40. [PMID: 25729620 PMCID: PMC4341334 DOI: 10.4168/aair.2015.7.2.130] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/09/2014] [Revised: 04/13/2014] [Accepted: 05/02/2014] [Indexed: 12/26/2022]
Abstract
Purpose Asthma is a complex disease, with contributions from multiple genes, various genetic backgrounds, and environmental factors. Many human epidemiological studies have demonstrated that single nucleotide polymorphisms (SNPs) in Toll-like receptor (TLR) genes are inconsistently associated with asthma risk. Some have demonstrated differences concerning the study design and effect size, and conflicting results have been reported. A meta-analysis is necessary to determine the magnitude of this association. Methods Following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines, a systematic search and meta-analysis of the literature was conducted to estimate the association of SNPs in TLR genes with asthma risk. We screened the medical literature based on the following keyword searches in MEDLINE and EMBASE databases: 'TLR', 'polymorphism', 'asthma', and their combinations. Results Meta-analysis of eight studies on TLR4 Asp299Gly showed a marginal association of TLR4 with asthma risk (odds ratio [OR]=0.814 [95% confidence interval [CI], 0.652-1.016; P=0.069]) in the recessive model. TLR4 Thr399Ile was not associated with asthma risk under any genetic model. Meta-analysis of four studies on TLR2 Arg753Gln indicated that TLR2 might be significantly associated with asthma in the dominant and codominant models (P=0.029, P=0.030, and P=0.009, respectively). TLR9 -1237 was marginally associated with asthma risk (OR=0.408 [95% CI, 0.163-1.021; P=0.065]) in the codominant model. Analysis using the allele contrast model showed that the major TLR9 -1237 T allele tended to be a significant protective factor with OR=0.689 (95% CI, 0.471-1.007; P=0.055). Conclusions The results showed that TLR4 Asp299Gly, TLR2 Arg753Gln, and TLR9-1237 might contribute significantly to asthma susceptibility. Future genetic association studies would consolidate these findings.
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Affiliation(s)
- Kalthoum Tizaoui
- Division of Histology and Immunology, Department of Basic Sciences, Faculty of medicine Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Wajih Kaabachi
- Division of Histology and Immunology, Department of Basic Sciences, Faculty of medicine Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Kamel Hamzaoui
- Division of Histology and Immunology, Department of Basic Sciences, Faculty of medicine Tunis, Tunis El Manar University, Tunis, Tunisia
| | - Agnès Hamzaoui
- Division of Histology and Immunology, Department of Basic Sciences, Faculty of medicine Tunis, Tunis El Manar University, Tunis, Tunisia. ; Division of Pulmonology, Unit research: 1 2 SP15"Homeostasis and Cell Immune Dysfunction", A. Mami Hospital, Ariana, Tunisia
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Reynolds SJ, Nonnenmann MW, Basinas I, Davidson M, Elfman L, Gordon J, Kirychuck S, Reed S, Schaeffer JW, Schenker MB, Schlünssen V, Sigsgaard T. Systematic review of respiratory health among dairy workers. J Agromedicine 2014; 18:219-43. [PMID: 23844790 DOI: 10.1080/1059924x.2013.797374] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022]
Abstract
The dairy industry is changing on a global scale with larger, more efficient operations. The impact of this change on worker health and safety, specifically, associations between occupational lung disease and inhalation exposures, has yet to be reported in a comprehensive review of the scientific literature. Therefore, a three-tier process was used to identify information using a keyword search of online databases of scientific literature. Of the 147 citations reviewed, 52 met initial screening criteria, and 30 were included in this review. Dairy workers experience lung conditions such as asthma, chronic obstructive pulmonary disease, hypersensitivity pneumonitis, chronic bronchitis, and cancer. Recent pulmonary function studies have identified obstructive lung changes among dairy farm workers. The increased scale of dairy production with significant changes in technology and work practices has altered inhalation exposure patterns among dairy workers. The inhalation exposure in the dairy work environment may elicit differing inflammatory responses in relation to timing of initial exposure as well as to repeated exposures. Few studies have measured inhalation exposure while simultaneously assessing the impact of the exposure on lung function of dairy farm workers. Even fewer studies have been implemented to assess the impact of aerosol control technology to reduce inhalation exposure. Future research should evaluate worker exposure to aerosols through a task-based approach while utilizing novel methods to assess inhalation exposure and associated inflammatory responses. Finally, potential solutions should be developed and tested to reduce inhalation exposure to inflammatory agents and respiratory diseases in the dairy farm work environment.
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Affiliation(s)
- Stephen J Reynolds
- Department of Environmental and Radiological Health Sciences, Colorado State University, Fort Collins, Colorado 80523, USA.
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14
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Zhou XJ, Cui Y, Cai LY, Xiang JY, Zhang Y. Toll-like receptor 4 polymorphisms to determine acute pancreatitis susceptibility and severity: A meta-analysis. World J Gastroenterol 2014; 20:6666-6670. [PMID: 24914392 PMCID: PMC4047356 DOI: 10.3748/wjg.v20.i21.6666] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2013] [Revised: 01/24/2014] [Accepted: 03/05/2014] [Indexed: 02/06/2023] Open
Abstract
AIM: To investigate the correlation of toll-like receptor 4 (TLR4) gene Asp299Gly and Thr399Ile polymorphisms and acute pancreatitis (AP) risk and severity.
METHODS: To get a more precise estimation of the relationship, a comprehensive search was performed to examine all the eligible studies of TLR4 Asp299Gly and Thr399Ile polymorphisms and AP risk. The odds ratios with 95% confidence intervals were used to assess the strength of the association. Publication bias was analyzed by Begg’s funnel plots.
RESULTS: In total, six studies with 1255 cases and 998 controls were included in this meta-analysis. Totally, no significant associations were found between TLR4 Asp299Gly or Thr399Ile polymorphisms and AP risk using five models with high homogeneity (P > 0.05). Furthermore, stratification analysis by ethnicity or assay also found no significant association in these two polymorphisms (P > 0.05), and TLR4 Asp299Gly was not associated with AP severity (P > 0.05). In addition, no publication bias was found in these studies (P > 0.05).
CONCLUSION: Our current meta-analysis suggests that TLR4 Asp299Gly and Thr399Ile polymorphisms may not be risk factors to AP susceptibility.
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Sahin F, Yıldız P, Kuskucu A, Kuskucu MA, Karaca N, Midilli K. The effect of CD14 and TLR4 gene polymorphisms on asthma phenotypes in adult Turkish asthma patients: a genetic study. BMC Pulm Med 2014; 14:20. [PMID: 24524443 PMCID: PMC3928321 DOI: 10.1186/1471-2466-14-20] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2013] [Accepted: 02/03/2014] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Endotoxins stimulate T helper 1 cell maturation and send a negative signal to T helper 2 polarisation. This causes a decrease IgE levels and prevents atopy (Hygiene hypothesis). It is shown that this response is under genetic control by polymorphisms in CD14 and TLR4 genes in some researchs. We aimed to investigate the effects of genetic variants of CD14 (-) and TLR4 (Asp299Gly, Thr399Ile) genes on asthma phenotypes in adults with asthma. METHODS Asthma patients (n = 131) and healthy control cases (n = 75) were included in the study. Relations between CD14 C-159 T, TLR4 299 and TLR4 399 genotypes and duration of asthma history of allergic rhinitis-dermatitis, total IgE, eosinophil, skin prick test, forced expiratory volume 1 (FEV1) and severity of disease were evaluated. Real time PCR (RT-PCR) was used for genotyping. RESULTS For CD14-159, presence of the C allele (CC + CT) was more frequent among those with low median log (logarithm) IgE levels, but no statistically significant difference in all asthma group (p = 0.09). C allele was significantly correlated with low total IgE levels and T allele with high total IgE levels in atopics (p = 0.04). CC + CT genotype was more frequent in moderate and severe asthma group in atopics (p = 0.049). TLR4 299 and TLR4 399 genotypes and asthma phenotypes were not found to be significantly correlated (p > 0.05). CONCLUSIONS Total IgE levels were found to be low among patients with the CC + CT genotype, and high among patients with the TT genotype contrary to the results of many other studies, which is therefore an important finding. Another important finding was that the C allele is a risk factor for moderate and severe asthma.
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Affiliation(s)
- Füsun Sahin
- Department of Chest Diseases, Yedikule Chest Diseases and Surgery Training and Research Hospital, Zeytinburnu/İstanbul, 34760, Turkey.
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16
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Lei T, Tang W, Xiong Y, Zhai Y, Sun X, Zhang K. Association between the g.14461A>G genetic polymorphism of the TLR4 gene and type 2 diabetes mellitus risk in a Chinese population. Genet Test Mol Biomarkers 2014; 18:257-60. [PMID: 24444085 DOI: 10.1089/gtmb.2013.0441] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
OBJECTIVE Toll-like receptor 4 (TLR4) is an important candidate gene for mediating the susceptibility to type 2 diabetes mellitus (T2DM). The purpose of this study was to investigate the association between the TLR4 gene polymorphisms and T2DM susceptibility. METHODS A total of 671 T2DM patients and 677 healthy controls were recruited in this study. The created restriction site-polymerase chain reaction and DNA sequencing methods have been used to analyze the TLR4 gene polymorphisms. RESULTS One novel genetic polymorphism (g.14461A>G) was found. Our data indicated that the g.14461A>G genetic polymorphism was significantly associated with the increased susceptibility to T2DM in a homozygote comparison (GG vs. AA: odds ratio [OR]=2.09, 95% confidence interval [CI] 1.44-3.04, p<0.001), dominant model (GG/AG vs. AA: OR=1.27, 95% CI 1.03-1.57, p=0.028), recessive model (GG vs. AG/AA OR=1.98, 95% CI 1.39-2.83, p<0.001), and allele contrast (G vs. A: OR=1.33, 95% CI 1.13-1.57, p=0.001). The allele-G might be the risk allele for enhancing the susceptibility to T2DM. CONCLUSION These preliminary findings suggest that the g.14461A>G genetic polymorphism of the TLR4 gene is potentially related to the susceptibility to T2DM in the studied population.
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Affiliation(s)
- Tao Lei
- 1 Department of Endocrinology, Tongji Hospital, Tongji University School of Medicine , Shanghai, People's Republic of China
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17
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Wu Q, Chu HW. Role of infections in the induction and development of asthma: genetic and inflammatory drivers. Expert Rev Clin Immunol 2014; 5:97-109. [PMID: 19885377 DOI: 10.1586/1744666x.5.1.97] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Genetic and environmental factors interact to initiate and even maintain the course of asthma. As one of the highly risky environmental factors, infections in predisposed individuals can promote asthma development and exacerbations and/or prolong symptoms. This review will describe our current understanding of the genetic markers of innate immunity in the induction and development of asthma, the diverse roles of infections in modulating allergic inflammation, host susceptibility to infections and subsequent acute exacerbations in an allergic setting, and the therapeutic or preventive implications of existing knowledge. Current challenges and future directions in basic and clinical research of asthma are also discussed.
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Affiliation(s)
- Qun Wu
- Postdoctoral Research Fellow, Department of Medicine, National Jewish Health, 1400 Jackson Street, Room A635, Denver, CO 80206, USA, Tel.: +1 303 398 1589, ,
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18
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Lin YT, Verma A, Hodgkinson CP. Toll-like receptors and human disease: lessons from single nucleotide polymorphisms. Curr Genomics 2013; 13:633-45. [PMID: 23730203 PMCID: PMC3492803 DOI: 10.2174/138920212803759712] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2012] [Revised: 10/08/2012] [Accepted: 10/08/2012] [Indexed: 12/13/2022] Open
Abstract
Toll-like receptors (TLRs), a large group of proteins which recognize various pathogen-associated molecular patterns, are critical for the normal function of the innate immune system. Following their discovery many single nucleotide polymorphisms within TLRs and components of their signaling machinery have been discovered and subsequently implicated in a wide range of human diseases including atherosclerosis, sepsis, asthma, and immunodeficiency. This review discusses the effect of genetic variation on TLR function and how they may precipitate disease.
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Affiliation(s)
- Yi-Tzu Lin
- Department of Medicine, Duke University Medical Center & Mandel Center for Hypertension and Atherosclerosis Research, Durham, NC 27710, USA
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19
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Leong AB, Ramsey CD, Celedón JC. The challenge of asthma in minority populations. Clin Rev Allergy Immunol 2013; 43:156-83. [PMID: 21538075 DOI: 10.1007/s12016-011-8263-1] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
The burden and disparity of asthma in race/ethnic minorities present a significant challenge. In this review, we will evaluate data on asthma epidemiology in minorities, examine potential reasons for asthma disparities, and discuss strategies of intervention and culturally sensitive care.
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Affiliation(s)
- Albin B Leong
- Pediatric Pulmonology and Allergy, Roseville Kaiser Medical Center, 1600 Eureka Road, Roseville, CA 95661, USA.
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20
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TLR4 inactivation protects from graft-versus-host disease after allogeneic hematopoietic stem cell transplantation. Cell Mol Immunol 2012; 10:165-75. [PMID: 23262974 DOI: 10.1038/cmi.2012.58] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
Graft-versus-host disease (GVHD) is the most common complication after hematopoietic stem cell transplantation. To clarify the role of Toll-like receptor 4 (TLR4), which is a major receptor for bacterial lipopolysaccharides (LPS), in the development of acute GVHD, we used a TLR4-knockout (TLR4(-/-)) mouse GVHD model and analyzed the underlying immunological mechanisms. When TLR4(-/-) mice were used as bone marrow and splenocyte cell graft donors or recipients, GVHD symptom occurrence and mortality were delayed compared to wild-type (TLR4(+/+)) mice. In addition, histopathological analyses revealed that in TLR4(-/-)→BALB/c chimeras, liver and small intestine tissue damage was reduced with minimal lymphocytic infiltration. In contrast to TLR4(+/+), TLR4(-/-) mice dendritic cells did not express CD80, CD86, CD40, MHC-II or IL-12 during LPS induction and remained in an immature state. Furthermore, the ability of TLR4(-/-) mice spleen dendritic cells to promote allogeneic T-cell proliferation and, in particular, T-helper cell 1 (Th1) development was obviously attenuated compared with TLR4(+/+) mice dendritic cells, and the levels of interferon-γ (IFN-γ) and IL-10, Th2-cell specific cytokines, were significantly higher in the serum of TLR4(-/-)→BALB/c than in TLR4(+/+)→BALB/c chimeric mice. Overall, our data revealed that TLR4 may play a role in the pathogenesis of GVHD and that targeted TLR4 gene therapy might provide a new treatment approach to reduce the risk of GVHD.
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21
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Sharma S, Poon A, Himes BE, Lasky-Su J, Sordillo JE, Belanger K, Milton DK, Bracken MB, Triche EW, Leaderer BP, Gold DR, Litonjua AA. Association of variants in innate immune genes with asthma and eczema. Pediatr Allergy Immunol 2012; 23:315-23. [PMID: 22192168 PMCID: PMC3412627 DOI: 10.1111/j.1399-3038.2011.01243.x] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
Abstract
BACKGROUND The innate immune pathway is important in the pathogenesis of asthma and eczema. However, only a few variants in these genes have been associated with either disease. We investigate the association between polymorphisms of genes in the innate immune pathway with childhood asthma and eczema. In addition, we compare individual associations with those discovered using a multivariate approach. METHODS Using a novel method, case control based association testing (C2BAT), 569 single nucleotide polymorphisms (SNPs) in 44 innate immune genes were tested for association with asthma and eczema in children from the Boston Home Allergens and Asthma Study and the Connecticut Childhood Asthma Study. The screening algorithm was used to identify the top SNPs associated with asthma and eczema. We next investigated the interaction of innate immune variants with asthma and eczema risk using Bayesian networks. RESULTS After correction for multiple comparisons, 7 SNPs in 6 genes (CARD25, TGFB1, LY96, ACAA1, DEFB1, and IFNG) were associated with asthma (adjusted p-value<0.02), while 5 SNPs in 3 different genes (CD80, STAT4, and IRAKI) were significantly associated with eczema (adjusted p-value < 0.02). None of these SNPs were associated with both asthma and eczema. Bayesian network analysis identified 4 SNPs that were predictive of asthma and 10 SNPs that predicted eczema. Of the genes identified using Bayesian networks, only CD80 was associated with eczema in the single-SNP study. Using novel methodology that allows for screening and replication in the same population, we have identified associations of innate immune genes with asthma and eczema. Bayesian network analysis suggests that additional SNPs influence disease susceptibility via SNP interactions. CONCLUSION Our findings suggest that innate immune genes contribute to the pathogenesis of asthma and eczema, and that these diseases likely have different genetic determinants.
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Affiliation(s)
- Sunita Sharma
- Channing Laboratory, Department of Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA.
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22
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Hussein YM, Awad HA, Shalaby SM, Ali ASA, Alzahrani SS. Toll-like receptor 2 and Toll-like receptor 4 polymorphisms and susceptibility to asthma and allergic rhinitis: a case-control analysis. Cell Immunol 2012; 274:34-8. [PMID: 22402138 DOI: 10.1016/j.cellimm.2012.02.006] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2011] [Revised: 01/02/2012] [Accepted: 02/01/2012] [Indexed: 02/06/2023]
Abstract
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.
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Affiliation(s)
- Yousri M Hussein
- Medical Biochemistry Department, Zagazig University, Zagazig, Egypt.
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23
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Kurowski M, Majkowska-Wojciechowska B, Wardzyńska A, Kowalski ML. Associations of allergic sensitization and clinical phenotypes with innate immune response genes polymorphisms are modified by house dust mite allergen exposure. Arch Med Sci 2011; 7:1029-36. [PMID: 22328887 PMCID: PMC3264996 DOI: 10.5114/aoms.2011.26616] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2011] [Revised: 03/15/2011] [Accepted: 04/09/2011] [Indexed: 11/29/2022] Open
Abstract
INTRODUCTION Polymorphisms within innate immunity genes are associated with allergic phenotypes but results are variable. These associations were not analyzed with respect to allergen exposure. We investigated associations of TLR and CD14 polymorphisms with allergy phenotypes in the context of house dust mite (HDM) exposure. MATERIAL AND METHODS Children, aged 12-16 years (n=326), were recruited from downtown and rural locations and assessed by allergist. Skin prick tests, total and HDM-specific sIgE measurements were done. HDM allergen concentrations in dust were measured. Genetic polymorphisms were identified using restriction fragment length polymorphism (RFLP). RESULTS Allergic rhinitis, asthma and atopy were more prevalent in urban area. Although HDM allergen concentrations were higher in rural households, sIgE were present more frequently in urban children. In the whole population no association was found between HDM exposure and sensitization. In children with CD14/-159CC, CD14/-159TT and TLR9/2848GA genotypes increased exposure to HDM was associated with reduced incidence of allergic rhinitis. Significant associations of increased HDM exposure with reduced incidence of atopy were found for the whole population and subjects with CD14/-159CC, CD14/-1359GT, TLR4/896AA and TLR9/2848GA genotypes. Among children with CD14/-159CC and CD14/-1359GG significant positive correlation between HDM allergen concentrations in household and sensitization to HDM was observed. In contrast, protective effect of high HDM allergen exposure against specific sensitization was seen in subjects with TLR4/896 AG. CONCLUSIONS Development of specific sensitization and allergy may be associated with innate immune response genes polymorphisms and is modified by allergen exposure.
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Affiliation(s)
- Marcin Kurowski
- Department of Immunology, Rheumatology and Allergy, Medical University of Lodz, Poland
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24
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Voronko OE, Dmitrieva-Zdorova EV, Latysheva EA, Aksenova MG, Storozhakov GI, Bodoev NV, Archakov AI. CARD15 and TLR4 polymorphisms in atopic bronchial asthma. Mol Biol 2011. [DOI: 10.1134/s0026893311040121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
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Kovach MA, Standiford TJ. Toll like receptors in diseases of the lung. Int Immunopharmacol 2011; 11:1399-406. [PMID: 21624505 PMCID: PMC3575025 DOI: 10.1016/j.intimp.2011.05.013] [Citation(s) in RCA: 69] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2011] [Revised: 05/11/2011] [Accepted: 05/12/2011] [Indexed: 12/16/2022]
Abstract
The lung is in continuous contact with a diverse array of infectious agents, foreign antigens, and host-derived danger signals. To sample this expansive internal and external milieu, both resident myeloid and stromal/structure cells of the lung express a full complement of toll like receptors (TLRs) which recognize pathogen-associated molecular patterns (PAMPs) and endogenous danger-associated molecular patterns (DAMPs). TLRs play a vital role in immune host defense against bacterial, mycobacterial, fungal, and viral pathogens of the lung. Additionally, TLRs contribute to disease pathogenesis in non-infectious pulmonary disorders, including airway disease, acute lung injury, and interstitial lung disease. In this review, TLR biology in the context of experimental infectious and non-infectious lung disease is discussed, and correlates to human lung disease, including therapeutic implications of these findings, are defined.
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Affiliation(s)
- Melissa A Kovach
- Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, MI 48109, United States
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26
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Rigoli L, Briuglia S, Caimmi S, Ferraú V, Gallizzi R, Leonardi S, La Rosa M, Salpietro C. Gene-environment interaction in childhood asthma. Int J Immunopathol Pharmacol 2011; 24:41-47. [PMID: 22032786 DOI: 10.1177/03946320110240s409] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
The importance of early life environmental influences on the etiology of asthma is implied by the observed geographic and temporal variation in the prevalence of the disease among children. There is evidence pointing to the role of exposure to allergen, various aspects of diet and hygiene-related factors in the etiology of asthma. There is also evidence that heritable factors influence the impact of hygiene-related exposures on the risk of having asthma. A number of important gene-environment interactions have been identified. These interactions point to the biology of environmental exposures as the involved genetic variation is suggestive of certain underlying mechanisms. Polymorphisms within genes coding for the toll-like receptor-lipopolysaccharide (TLR-LPS) signalling pathway may underlie variations in effects of hygiene-related exposures, including specifically endotoxin, on the risk of developing allergic sensitization and allergic disease. This review presents recent findings illustrating the role of gene-environment interactions in childhood asthma susceptibility.
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Affiliation(s)
- L Rigoli
- Department of Pediatrics, Unit of Pediatric Genetics and Immunology, University of Messina, Italy.
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27
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Wu P, Hartert TV. Evidence for a causal relationship between respiratory syncytial virus infection and asthma. Expert Rev Anti Infect Ther 2011; 9:731-45. [PMID: 21905783 PMCID: PMC3215509 DOI: 10.1586/eri.11.92] [Citation(s) in RCA: 165] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Respiratory syncytial virus (RSV) infects all children early in life, is the most common cause of infant lower respiratory tract infections, and causes disease exacerbations in children with asthma. Episodes of lower respiratory tract infection in early life are associated with asthma development. Whether RSV infection early in life directly causes asthma or simply identifies infants who are genetically predisposed to develop subsequent wheezing is debatable. Recent studies suggest that these two explanations are not mutually exclusive, and are likely both important in asthma development. An open-label study of RSV immunoprophylaxis administered to preterm infants reduced recurrent wheezing by 50%. Clinical trials of infant RSV prevention, delay or severity reduction on the outcome of childhood asthma would confirm the causal relationship between RSV infection and asthma, and offer a primary prevention strategy.
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Affiliation(s)
- Pingsheng Wu
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Center for Health Services Research, 6107 MCE, Nashville, TN 37232-8300, USA
- Department of Biostatistics, Vanderbilt University School of Medicine, Vanderbilt University Medicinal Center, S2406 Medical Center North, Nashville, TN 37232-2158, USA
| | - Tina V Hartert
- Division of Allergy, Pulmonary and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Center for Health Services Research, 6107 MCE, Nashville, TN 37232-8300, USA
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28
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Fuchs B, Braun A. Modulation of asthma and allergy by addressing toll-like receptor 2. J Occup Med Toxicol 2011; 3 Suppl 1:S5. [PMID: 18315836 PMCID: PMC2259399 DOI: 10.1186/1745-6673-3-s1-s5] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Toll-like receptors play an important role in innate and adaptive immunity and in balancing immune responses with tolerance. TLR2 is related to protection against allergies and allergic asthma by sensing pathogen associated patterns as lipoproteins and lipopeptides. A constant Th1 triggering is thought to prevent Th2 related disorders. TLR2 is expressed on a variety of cells, both structural as well as immune cells. Importantly, TLR2 is also expressed on dendritic cells, which are thought to be one of the key players of initiating and maintaining immune responses. Therefore, TLR2 on dendritic cells is a good target for modulating immunity either to Th1 or Th2 responses, or induction of tolerance. TLR2 agonists show high immunomodulatory and adjuvantic capacity. This makes TLR2 agonisation a promising approach for pharmaceutical intervention of allergic disorders.
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Affiliation(s)
- Barbara Fuchs
- Department of Immunology, Allergology and Immunotoxicology, Fraunhofer Institute of Toxicology and Experimental Medicine, Nikolai-Fuchs-Str, 1, 30625 Hannover, Germany.
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29
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Cho HJ, Kim SH, Kim JH, Choi H, Son JK, Hur GY, Park HS. Effect of Toll-like receptor 4 gene polymorphisms on work-related respiratory symptoms and sensitization to wheat flour in bakery workers. Ann Allergy Asthma Immunol 2011; 107:57-64. [PMID: 21704886 DOI: 10.1016/j.anai.2011.04.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 03/04/2011] [Accepted: 04/04/2011] [Indexed: 01/08/2023]
Abstract
BACKGROUND Bakery workers are exposed to flour allergens and endotoxins, which interact to induce allergic responses and respiratory symptoms. We hypothesized that Toll-like receptor 4 (TLR4) may be involved in the development of work-related respiratory symptoms and sensitization to wheat flour. OBJECTIVE To investigate the genetic contribution of TLR4 to respiratory symptoms and sensitization to wheat flour in bakery workers, we performed a genetic association study of TLR4 in Korean bakery workers. METHODS A total of 381 workers completed a questionnaire regarding work-related symptoms. Skin prick tests with common and occupational allergens were done, and specific antibodies to wheat flour were measured by enzyme-linked immunosorbent assay. Two single-nucleotide polymorphisms (SNPs) of the TLR4 gene (-2027A>G and -1608T>C) were genotyped, and the functional effects of the polymorphisms were analyzed using the luciferase reporter and electrophoretic mobility shift assay. RESULTS Homozygotes for the -2027G and -1608C alleles exhibited a lower prevalence of work-related lower respiratory symptoms than carriers of the -2027AA/AG (P = .007) and -1608TT/TC (P =.021) genotypes. Furthermore, haplotype analysis indicated that workers with the haplotype 2, ht2 [GC], had fewer work-related lower respiratory symptoms (P = .021). The ht2 [GC] construct showed lower promoter activity than the haplotype 1, ht1[AT], in both BEAS-2B (P = .001) and U937 cells (P = .007). CONCLUSION Bakery workers carrying the TLR4 variants are at lower risk of developing work-related chest symptoms. This finding suggests that the TLR4 gene may be involved in allergic sensitization to wheat flour as well as endotoxin-induced respiratory symptoms in endotoxin-allergen-exposed workers and that carriers of TLR4 variants are less affected by environmental exposure.
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Affiliation(s)
- Hyun Joo Cho
- Department of Allergy and Clinical Immunology, Ajou University School of Medicine, Suwon, Korea
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Heine H. TLRs, NLRs and RLRs: innate sensors and their impact on allergic diseases--a current view. Immunol Lett 2011; 139:14-24. [PMID: 21554901 DOI: 10.1016/j.imlet.2011.04.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2011] [Revised: 04/19/2011] [Accepted: 04/20/2011] [Indexed: 12/25/2022]
Abstract
Charles Janeway first wrote 1989 about how important recognition of "certain characteristics or patterns common on infectious agents but absent from the host" would be for our immune response [1]. Surprisingly, it almost took 10 years before his ideas would lead to the revolutionary findings that fundamentally changed the view of the innate immune system over the past decade. Recognition of invading microorganisms belongs to the primary tasks of the innate immune system and is achieved through different families of innate immune sensors. Among these, Toll-like receptors (TLRs), nucleotide-binding domain and leucine-rich repeat containing receptors (NLRs) and Rig-I-like receptors (RLRs) have drawn major interests over the last decade. These receptor families are targeted by overlapping classes of pathogens and share functional domains and signal transduction pathways (see Fig. 1 and Table 1 for an overview of their structural organization, ligands, adaptors and activated pathways). This current view describes our present knowledge about these three main innate immune receptor families and their importance for adaptive immune responses such as asthma and allergy.
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Affiliation(s)
- Holger Heine
- Research Center Borstel - Leibniz-Center for Medicine and Biosciences, Division of Innate Immunity, Section of Immunoregulation, Parkallee 22, 23845 Borstel, Germany.
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31
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Tesse R, Pandey RC, Kabesch M. Genetic variations in toll-like receptor pathway genes influence asthma and atopy. Allergy 2011; 66:307-16. [PMID: 21039600 DOI: 10.1111/j.1398-9995.2010.02489.x] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Innate immunity is a pivotal defence system of higher organisms. Based on a limited number of receptors, it is capable of recognizing pathogens and to initiate immune responses. Major components of these innate immunity pathogen recognition receptors are the toll-like receptors (TLRs), a family of 11 in humans. They are all membrane bound and through dimerization and complex downstream signaling, TLRs elicit a variety of specific and profound effects. In recent years, the role of TLRs signaling was not only investigated in infection and inflammation but also in allergy. Fuelled by the hygiene hypothesis, which suggests that allergies develop because of a change in microbial exposure and associated immune signals early in life, it had been speculated that alterations in TLRs signaling could influence allergy development. Thus, TLR genes, genetic variations of these genes, and their association with asthma and other atopic diseases were investigated in recent years. This review provides an overview of TLR genetics in allergic diseases.
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Affiliation(s)
- R Tesse
- Center for Pediatrics, Clinic for Pediatric Pneumology, Allergology and Neonatology, Hannover Medical School, Hannover, Germany
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32
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Knothe S, Mutschler V, Rochlitzer S, Winkler C, Ebensen T, Guzman CA, Hohlfeld J, Braun A, Muller M. Local treatment with BPPcysMPEG reduces allergic airway inflammation in sensitized mice. Immunobiology 2010; 216:110-7. [PMID: 20619481 DOI: 10.1016/j.imbio.2010.05.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2010] [Revised: 05/01/2010] [Accepted: 05/01/2010] [Indexed: 11/30/2022]
Abstract
According to the hygiene hypothesis, triggering the immune system with microbial components during childhood balances the inherent Th2 bias. In contrast, specific immunotherapy involves exposure of the patient to the allergen in order to achieve desensitization to subsequent contact. In a human in vitro allergy model the potential of the TLR2/6 agonist BPPcysMPEG to modulate antigen presenting cells and allergen-specific immune responses was evaluated. Specific immunomodulation via co-administration of the allergen and BPPcysMPEG enhanced expression of co-stimulatory molecules on DC and increased secretion of the proinflammatory cytokine TNF-α. Acting as an adjuvant, BPPcysMPEG elevated allergen-specific immune responses in co-culture with autologous lymphocytes. Although administration of BPPcysMPEG alone enhanced expression of co-stimulatory molecules on DC, proliferation of autologous lymphocytes was not induced. Based on this finding, the potential of BPPcysMPEG to reduce allergic airway inflammation by preventive modulation of the innate immune system via TLR2/6 agonization was investigated in mice. Local administration of BPPcysMPEG altered cellular influx and cell composition in BAL fluid. Furthermore, the Th2-associated cytokines IL-4 and IL-5 were diminished. Allergen-specific restimulation of cells from mediastinal lymph nodes and splenocytes suggested an alteration of immune responses. The treatment with BPPcysMPEG induced a Th1-dominated cytokine milieu in mediastinal lymph nodes, while allergen-specific immune responses in splenocytes were diminished. The co-administration of allergen and BPPcysMPEG reduced cytokine secretion upon restimulation in mediastinal lymph nodes and splenocytes. From these data we conclude that BPPcysMPEG was able to influence the immune system with regard to subsequent allergen contact by TLR2/6 agonization.
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Affiliation(s)
- S Knothe
- Fraunhofer Institute for Toxicology and Experimental Medicine (ITEM), Department of Immunology, Allergology and Immunotoxicology, Hannover, Germany
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Najmi N, Kaur G, Sharma SK, Mehra NK. Human Toll-like receptor 4 polymorphisms TLR4 Asp299Gly and Thr399Ile influence susceptibility and severity of pulmonary tuberculosis in the Asian Indian population. ACTA ACUST UNITED AC 2010; 76:102-9. [PMID: 20403143 DOI: 10.1111/j.1399-0039.2010.01481.x] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
Genetic polymorphisms in Toll-like receptor 4, TLR4 896 A/G (Asp299Gly) and 1196 C/T (Thr399Ile) have been reported to influence TLR4 function and the innate host immune response to mycobacteria. We investigated the effect of these single nucleotide polymorphisms on susceptibility and severity of pulmonary tuberculosis (PTB) in the Asian Indian population. A significantly increased frequency of TLR4 Asp299Gly mutation was observed in the patient group (17%) as compared with healthy controls [8.8%, chi(2) = 10.7, P = 0.001,odds ratio (OR ) = 2.1]. On the other hand, the TLR4 Thr399Ile mutation occurred with comparable frequencies in the two groups (12.6% among patients and 9% in healthy controls). The PTB patients were categorized on the basis of their bacillary load as 3+, 2+, 1+, negative and on the extent of lung involvement as having minimal, moderate, and far-advanced lung disease. The 299Gly mutant occurred in homozygous state (GG) only in patients with high bacillary load (3+) and those with far-advanced lung disease. Similarly, the mutant 399Ile was significantly pronounced in these patients in the homozygous state (TT). The present data suggest that TLR4 substitutions at residues 299 and 399 are associated with pulmonary TB, particularly, the most severe disease.
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Affiliation(s)
- N Najmi
- Department of Transplant Immunology and Immunogenetics, All India Institute of Medical Sciences, New Delhi, India
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Kang I, Oh YK, Lee SH, Jung HM, Chae SC, Lee JH. Identification of polymorphisms in the Toll-like receptor gene and the association with allergic rhinitis. Eur Arch Otorhinolaryngol 2010; 267:385-389. [PMID: 19763595 DOI: 10.1007/s00405-009-1100-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Accepted: 09/03/2009] [Indexed: 01/11/2023]
Abstract
The TLRs gene encodes the principal innate immunity receptor in humans. The TLR2 Arg753Gln and Arg677Trp polymorphisms have been associated with a reduced response of monocytes and cell lines to challenge with mycobacteria. The TLR4 Asp299Gly and Thr399Ile polymorphisms have been associated with a reduction in the inflammatory responses to lipopolysaccharide in humans. It has been suggested that TLR2 and TLR4 polymorphisms may be associated with allergic responses; thus, we hypothesized that TLR2 and TLR4 polymorphisms may modify the relative risk for development of allergic rhinitis. The Taqman assay and high-resolution melt (HRM) were used for genotyping. We analyzed two single nucleotide polymorphisms (SNPs; 597T>C and 1350T>C) in the TLR2 gene and 1 SNP (4216G>C) in the TLR4 gene. We compared the genotype of these SNPs in patients with allergic rhinitis and controls without allergic rhinitis. We also estimated the haplotype frequencies between the two groups. The genotype and allele frequencies of the 597T>C and 1350T>C SNPs in the TLR2 gene were not significantly different between the patients with allergic rhinitis and controls (P > 0.05). The genotype and allele frequencies of 4216G>C in the TLR4 gene were not significantly different between the patients with allergic rhinitis and controls (P > 0.05). Haplotype analysis of the following two different (597)-(1350) major haplotypes (frequency >0.05) were present in the TLR2 gene: T-C and C-C. The C-C haplotype was positively associated with allergic rhinitis (P = 0.048). Our study suggests that the TLR2 gene polymorphisms might be susceptible to the development of allergic rhinitis. Further functional studies of TLR2 genetics in light of the associations with allergic rhinitis inflammation would help clarify the role of TLR2 genetics in clinical evaluations.
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MESH Headings
- Adult
- Alleles
- Female
- Gene Frequency/genetics
- Genetic Predisposition to Disease/genetics
- Genotype
- Haplotypes
- Humans
- Immunity, Innate/genetics
- Immunity, Innate/immunology
- Male
- Monocytes/immunology
- Nasal Mucosa/metabolism
- Polymerase Chain Reaction
- Polymorphism, Genetic/genetics
- Polymorphism, Single Nucleotide/genetics
- RNA, Messenger/genetics
- Rhinitis, Allergic, Perennial/genetics
- Rhinitis, Allergic, Perennial/immunology
- Rhinitis, Allergic, Seasonal/genetics
- Rhinitis, Allergic, Seasonal/immunology
- Risk
- Toll-Like Receptor 2/genetics
- Toll-Like Receptor 4/genetics
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Affiliation(s)
- Inhong Kang
- Department of Pathology, Institute of Wonkwang Medical Science, Wonkwang University School of Medicine, Iksan, Chonbuk, South Korea
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Opitz B, van Laak V, Eitel J, Suttorp N. Innate immune recognition in infectious and noninfectious diseases of the lung. Am J Respir Crit Care Med 2010; 181:1294-309. [PMID: 20167850 DOI: 10.1164/rccm.200909-1427so] [Citation(s) in RCA: 198] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Diseases of the respiratory tract are among the leading causes of death in the world population. Increasing evidence points to a key role of the innate immune system with its pattern recognition receptors (PRRs) in both infectious and noninfectious lung diseases, which include pneumonia, chronic obstructive pulmonary disease, acute lung injury, pneumoconioses, and asthma. PRRs are capable of sensing different microbes as well as endogenous molecules that are released after cell damage. This PRR engagement is the prerequisite for the initiation of immune responses to infections and tissue injuries which can be beneficial or detrimental to the host. PRRs include the Toll-like receptors, NOD-like receptors, RIG-I-like receptors, and cytosolic DNA sensors. The PRRs and their signaling pathways represent promising targets for prophylactic and therapeutic interventions in various lung diseases.
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Affiliation(s)
- Bastian Opitz
- Department of Internal Medicine/Infectious Diseases and Pulmonary Medicine, Charité-Universitätsmedizin Berlin, Augustenburger Platz 1, Berlin, Germany.
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Iliadi A, Makrythanasis P, Tzetis M, Tsipi M, Traeger-Synodinos J, Ioannou PC, Rapti A, Kanavakis E, Christopoulos TK. Association of TLR4 Single-Nucleotide Polymorphisms and Sarcoidosis in Greek Patients. Genet Test Mol Biomarkers 2009; 13:849-53. [DOI: 10.1089/gtmb.2009.0117] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Affiliation(s)
- Alexandra Iliadi
- Laboratory of Analytical Chemistry, Department of Chemistry, Athens University, Athens, Greece
| | - Periklis Makrythanasis
- Department of Medical Genetics, Medical School, University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece
- Department of Genetic Medicine and Development, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Maria Tzetis
- Department of Medical Genetics, Medical School, University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece
| | - Maria Tsipi
- Department of Medical Genetics, Medical School, University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece
| | - Jan Traeger-Synodinos
- Department of Medical Genetics, Medical School, University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece
| | - Penelope C. Ioannou
- Laboratory of Analytical Chemistry, Department of Chemistry, Athens University, Athens, Greece
| | - Aggeliki Rapti
- 6th Department of Respiratory Medicine, Sotiria Chest Disease Hospital, Athens, Greece
| | - Emmanuel Kanavakis
- Department of Medical Genetics, Medical School, University of Athens, “Aghia Sofia” Children's Hospital, Athens, Greece
| | - Theodore K. Christopoulos
- Department of Chemistry, University of Patras, Patras, Greece
- Foundation for Research and Technology Hellas, Institute of Chemical Engineering and High Temperature Chemical Processes (FORTH/ICE-HT), Patras, Greece
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Simpson A, Martinez FD. The role of lipopolysaccharide in the development of atopy in humans. Clin Exp Allergy 2009; 40:209-23. [PMID: 19968655 DOI: 10.1111/j.1365-2222.2009.03391.x] [Citation(s) in RCA: 66] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Atopy is a highly prevalent condition and remains the single biggest risk factor for asthma. Although atopy has a heritable component, the time frame of the increase in the prevalence indicates that it is not due to genetic factors alone. The relationship between allergen exposure and sensitization is complex. Lipopolysaccharide (LPS) and its bioactive moiety endotoxin are common to all gram-negative bacteria, and have been used as a surrogate of microbial load. Endotoxin can be readily measured in dust collected from homes. Some studies have demonstrated a clear inverse dose-response relationship between exposure to endotoxin and the risk of atopy but this finding has not been reproduced in all studies. Our innate immune system recognizes LPS readily via the LPS signal transduction pathway, which has the trimolecular complex of CD14/TLR4/MD2 at the core. A common single-nucleotide polymorphism in the promoter region of CD14 rs2569190 C to T (CD14/-260 or CD14/-159) has been associated with elevated sCD14. Although early studies suggested that this variant was associated with more severe atopy, this finding was not uniformly replicated. It has now been demonstrated in four independent populations that high exposure to endotoxin in the domestic environment is protective against the development of atopy, but only among carriers of the C allele, that is, the environmental exposure is only relevant when taken in the context of the genotype. Furthermore, this interaction is biologically plausible. We propose that neither the environmental exposure nor the genotype in isolation is sufficient to cause complex diseases like asthma and atopy, but disease results from the one acting in the context of the other, of which CD14 and endotoxin is one example contributing to the risk for atopy.
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Affiliation(s)
- A Simpson
- Manchester Academic Health Science Centre, NIHR Translational Research Facility in Respiratory Medicine, University Hospital of South Manchester NHS Foundation Trust, The University of Manchester, Manchester, UK.
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Pahwa P, Karunanayake CP, Rennie DC, Chen Y, Schwartz DA, Dosman JA. Association of the TLR4 Asp299Gly polymorphism with lung function in relation to body mass index. BMC Pulm Med 2009; 9:46. [PMID: 19772581 PMCID: PMC2759902 DOI: 10.1186/1471-2466-9-46] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2008] [Accepted: 09/21/2009] [Indexed: 12/20/2022] Open
Abstract
Background 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. Methods 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 (FEF25-75). Multivariable linear regression analysis was used to investigate associations. Results Adjusted mean values of FEV1 and 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 FEF25-75 in TLR4 variant group but not in wild type group. Conclusion BMI may modify the associations of TLR4 Asp299Gly polymorphism with FEV1/FVC ratio and FEF25-75.
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Affiliation(s)
- Punam Pahwa
- Canadian Centre for Health and Safety in Agriculture, R.U.H., Saskatchewan, Canada.
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Abstract
PURPOSE OF REVIEW The increase in prevalence of allergic diseases, in particular of asthma, poses great difficulties to healthcare institutions in industrialized countries. According to the hygiene hypothesis, a linkage exists between exposure towards microbes in early childhood and the development of allergies; however, the original view that stimulation of the host's immune system by microbes exclusively protects against the development of allergies and asthma has been challenged by recent studies, which are summarized in this review. RECENT FINDINGS Recent studies in mice revealed that infection with a series of microbes in the context of allergen exposure enhances antigen sensitization. Furthermore, in studies using purified toll-like receptor ligands and live bacteria, innate immune activation via MyD88 has been shown to be a causative factor in sensitization. The view that innate immune activation, under circumstances yet to be elucidated, may be a causative factor for the development of allergies is backed by epidemiologic data showing a protective effect of genetic variants, which impair toll-like receptor signaling. CONCLUSION Recent studies in mice suggest that innate immune stimulation via microbes or their compounds, in a dose and time-dependent manner, can cause allergen sensitization, and this notion has lately been supported by epidemiologic data.
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Boyle RJ, Morley R, Mah LJ, Kivivuori S, Tang MLK. Reduced membrane bound CD14 expression in the cord blood of infants with a family history of allergic disease. Clin Exp Allergy 2009; 39:982-90. [DOI: 10.1111/j.1365-2222.2009.03227.x] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
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Daley D, Lemire M, Akhabir L, Chan-Yeung M, He JQ, McDonald T, Sandford A, Stefanowicz D, Tripp B, Zamar D, Bosse Y, Ferretti V, Montpetit A, Tessier MC, Becker A, Kozyrskyj AL, Beilby J, McCaskie PA, Musk B, Warrington N, James A, Laprise C, Palmer LJ, Paré PD, Hudson TJ. Analyses of associations with asthma in four asthma population samples from Canada and Australia. Hum Genet 2009; 125:445-59. [PMID: 19247692 DOI: 10.1007/s00439-009-0643-8] [Citation(s) in RCA: 87] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2008] [Accepted: 02/13/2009] [Indexed: 11/28/2022]
Abstract
Asthma, atopy, and related phenotypes are heterogeneous complex traits, with both genetic and environmental risk factors. Extensive research has been conducted and over hundred genes have been associated with asthma and atopy phenotypes, but many of these findings have failed to replicate in subsequent studies. To separate true associations from false positives, candidate genes need to be examined in large well-characterized samples, using standardized designs (genotyping, phenotyping and analysis). In an attempt to replicate previous associations we amalgamated the power and resources of four studies and genotyped 5,565 individuals to conduct a genetic association study of 93 previously associated candidate genes for asthma and related phenotypes using the same set of 861 single-nucleotide polymorphisms (SNPs), a common genotyping platform, and relatively harmonized phenotypes. We tested for association between SNPs and the dichotomous outcomes of asthma, atopy, atopic asthma, and airway hyperresponsiveness using a general allelic likelihood ratio test. No SNP in any gene reached significance levels that survived correction for all tested SNPs, phenotypes, and genes. Even after relaxing the usual stringent multiple testing corrections by performing a gene-based analysis (one gene at a time as if no other genes were typed) and by stratifying SNPs based on their prior evidence of association, no genes gave strong evidence of replication. There was weak evidence to implicate the following: IL13, IFNGR2, EDN1, and VDR in asthma; IL18, TBXA2R, IFNGR2, and VDR in atopy; TLR9, TBXA2R, VDR, NOD2, and STAT6 in airway hyperresponsiveness; TLR10, IFNGR2, STAT6, VDR, and NPSR1 in atopic asthma. Additionally we found an excess of SNPs with small effect sizes (OR < 1.4). The low rate of replication may be due to small effect size, differences in phenotypic definition, differential environmental effects, and/or genetic heterogeneity. To aid in future replication studies of asthma genes a comprehensive database was compiled and is available to the scientific community at http://genapha.icapture.ubc.ca/.
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Affiliation(s)
- Denise Daley
- James Hogg iCAPTURE Center, University of British Columbia (UBC), 1081 Burrard Street, Vancouver, BC, V6Z 1Y6, Canada
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Innate microbial sensors and their relevance to allergy. J Allergy Clin Immunol 2008; 122:846-58; quiz 858-60. [PMID: 19000576 DOI: 10.1016/j.jaci.2008.10.002] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2008] [Revised: 10/02/2008] [Accepted: 10/02/2008] [Indexed: 01/01/2023]
Abstract
The innate immune system oversees the gateway to immunity with its microbial sensors. Innate microbial sensors are germ line-encoded receptors with genetically predetermined specificities for microbes. The readiness and effectiveness of the innate immune system to provide immediate and appropriate responses at the host-environment interface is dependent on its sensitive and comprehensive microbial detection systems. The purpose of this review is to provide an overview of innate microbial sensors, our growing understanding of their diverse repertoire, and their elegant structural and functional approaches to microbial recognition. Their relevance to allergic disease is also discussed: the potential recognition and uptake of allergens by some of these receptors, inhibited expression of other microbial sensors by allergic immune responses and inflammation, and their upregulation by microbial exposures in early life that may help to protect against the development of allergic immune responses and disease.
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Lipopolysaccharide-induced immune responses in relation to the TLR4(Asp299Gly) gene polymorphism. CLINICAL AND VACCINE IMMUNOLOGY : CVI 2008; 15:1878-83. [PMID: 18927069 DOI: 10.1128/cvi.00241-08] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
Altered microbial exposure is a possible explanation for the increase of allergies in the Western world. However, genetic factors influence microbially induced immune responses. We have investigated the TLR4(Asp299Gly) gene polymorphism and its possible association with receptor expression of circulating peripheral blood monocytes and the in vitro cytokine responses and phosphorylation of intracellular signaling proteins in peripheral blood mononuclear cells (PBMC) stimulated with lipopolysaccharide (LPS) from Escherichia coli and Salmonella enterica serotype Typhimurium. We studied 34 of the predominant haplotype TLR4 Asp299 (AA) and 8 heterozygote Asp299Gly (AG) individuals. TLR4 expression levels were similar in the two genotype groups. Serovar Typhimurium LPS induced interleukin-12p70 from PBMC, and the degree of phosphorylation of the intracellular signaling protein IkappaBalpha in PBMC was lower in the AG than the AA group (P=0.03 and P=0.04, respectively). These results were not seen, however, when PMBC were stimulated with E. coli-derived LPS. Based on these results, we propose that TLR4(Asp299Gly) gene polymorphism and the bacterial origin of LPS should be considered when environmental LPS exposure is evaluated in disease risk or protection.
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Reismann P, Rácz K, Tulassay Z. [Polymorphisms of the Toll-like receptor 4 gene and their potential role in infectious diseases and chronic inflammatory disorders]. Orv Hetil 2008; 149:1791-1799. [PMID: 18805765 DOI: 10.1556/oh.2008.28452] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The Toll-like receptor 4 is a key mediator of the innate immune response. Besides its main ligand, the Gram-negative bacterial lipopolysaccharides, other molecules such as heat-shock protein 60, oxidized low density lipoprotein and fibronectin can also bind to the receptor. Activation of the Toll-like receptor induces the production of proinflammatory cytokines. There is increasing evidence showing that the Toll-like receptor 4 plays a role not only in the immune reaction against infectious agents but also in chronic non-infectious inflammatory diseases, such as atherosclerosis, diabetes mellitus and inflammatory bowel disease. This review briefly summarizes recent knowledge on the Toll-like receptor 4, its common co-segregation polymorphisms and the impact of these polymorphisms on various human diseases.
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Affiliation(s)
- Péter Reismann
- Semmelweis Egyetem, Altalános Orvostudományi Kar II. Belgyógyászati Klinika Budapest Szentkirályi u. 46. 1088.
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Senthilselvan A, Rennie D, Chénard L, Burch LH, Babiuk L, Schwartz DA, Dosman JA. Association of polymorphisms of toll-like receptor 4 with a reduced prevalence of hay fever and atopy. Ann Allergy Asthma Immunol 2008; 100:463-8. [PMID: 18517079 DOI: 10.1016/s1081-1206(10)60472-3] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
Abstract
BACKGROUND The response to innate immune stimuli seems to be critical to conditioning adaptive immunity. Early exposure to endotoxin initiates immune responses that have been shown to alter the risk of asthma and allergic diseases. The toll-like receptor 4 (TLR4) gene encodes the principal innate immunity receptor in humans for bacterial endotoxin. Polymorphisms in the TLR4 gene may regulate the effects of endotoxin exposure and could play a role in the development of asthma and atopy-related phenotypes. OBJECTIVE To investigate the association between TLR4 polymorphisms and allergic phenotypes in nonsmokers. METHODS The data from 915 nonsmoking students were available for the study. The TLR4 299 and 399 polymorphisms were genotyped using mouthwash samples. The TLR4 299 and 399 polymorphisms were grouped together to define the TLR4 polymorphic group. Skin prick tests were conducted in a subgroup of healthy participants. A brief questionnaire was administered to determine demographic characteristics and chronic health conditions. RESULTS The prevalence of hay fever was 0% in the TLR4 polymorphic group and 7.5% in the wild-type group (P = .01). After controlling for age group and sex using logistic regression, the odds of having hay fever were reduced by 88% (P = .009) in the TLR4 polymorphic group compared with the wild-type group. In a subgroup analysis, the association between TLR4 polymorphisms and atopy was only observed among females. CONCLUSIONS To our knowledge, this study is the first to report an association between TLR4 polymorphisms and atopy-related phenotypes in a nonsmoking population. Further investigation of the role of TLR4 polymorphisms in asthma and atopy-related phenotypes is warranted.
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Affiliation(s)
- Ambikaipakan Senthilselvan
- Department of Public Health Sciences, School of Public Health, University of Alberta, Edmonton, Alberta, Canada.
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Toll-like receptor heterodimer variants protect from childhood asthma. J Allergy Clin Immunol 2008; 122:86-92, 92.e1-8. [PMID: 18547625 DOI: 10.1016/j.jaci.2008.04.039] [Citation(s) in RCA: 109] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2007] [Revised: 04/05/2008] [Accepted: 04/14/2008] [Indexed: 01/13/2023]
Abstract
BACKGROUND Early exposure to microbes reduces the risk for asthma. Toll-like receptors (TLRs) represent a major group of receptors for the specific recognition of pathogen-associated molecular patterns of microbes capable of activating innate and adaptive immunity. OBJECTIVE Because TLRs can influence key events in the induction and perpetuation of asthma and atopy, we sought to determine whether genetic alterations in TLR genes affect asthma risk. METHODS We systematically evaluated putatively functional genetic variants in all 10 human TLR genes for their association with different asthma phenotypes in a case-control study (n = 1872) by using matrix-assisted laser desorption/ionization time-of-flight genotyping. For polymorphisms showing association with atopic asthma, effects on gene and protein expression were studied by means of RT-PCR and flow cytometry ex vivo. T-cell cytokine production was evaluated by means of ELISA after stimulation of the respective TLRs with specific ligands. RESULTS Protective effects on atopic asthma were identified for single nucleotide polymorphisms in TLR1 (odds ratio [OR], 0.54; 95% CI, 0.37-0.81; P = .002), TLR6 (OR, 0.54; 95% CI, 0.37-0.79; P = .003), and TLR10 (OR, 0.58; 95% CI, 0.39-0.86; P = .006), all capable of forming heterodimers with TLR2. Effects remained significant after correction for multiple comparisons. PBMCs of minor allele carriers showed increased levels of the respective TLR mRNA and proteins, augmented inflammatory responses, increased T(H)1 cytokine expression, and reduced T(H)2-associated IL-4 production after specific stimulation. CONCLUSION These results suggest that functional relevant TLR1 and TLR6 variants are directly involved in asthma development.
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Zhang D, Zheng H, Zhou Y, Yu B, Li J. TLR and MBL gene polymorphisms in severe acute pancreatitis. Mol Diagn Ther 2008; 12:45-50. [PMID: 18288881 DOI: 10.1007/bf03256267] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023]
Abstract
BACKGROUND AND OBJECTIVE Mannose-binding lectin (MBL) and toll-like receptor (TLR)-4 gene polymorphisms have been implicated in inflammatory episodes in a number of studies. In view of the inflammatory nature of acute pancreatitis, we aimed to determine the predictive value of two point mutations in the promoter region at position -550 (H/L variants) and -221 (X/Y variants) of the MBL2 gene, and the Asp299Gly and 119C>A polymorphisms of the TLR4 gene on the occurrence of severe acute pancreatitis (SAP). METHODS The study included 132 patients with SAP, 106 with mild acute pancreatitis (MAP), and 121 healthy volunteers. Genotypes were determined using restriction fragment length polymorphism analysis of PCR products and by allele-specific PCR. RESULTS No significant difference in genotype frequency was noted between the patients with acute pancreatitis and controls for any of the gene loci studied. The distributions of the HY/HY, HY/LY, LY/LY, and LY/LX genotypes of MBL2 gene promoter and 119C>A genotype of the TLR4 gene were similar in patients with mild or severe acute pancreatitis. HY/LX genotype frequency was significantly higher in patients with SAP compared with MAP (26% vs 14%; p = 0.028). CONCLUSION Results indicate that the MBL2 HY/LX genotype plays an important role in the determination of disease severity to acute pancreatitis.
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Affiliation(s)
- DianLiang Zhang
- Department of General Surgery, Affiliated Hospital of Qingdao University Medial College, Qingdao, Shandong Province, China.
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High-throughput microtiter well-based bioluminometric genotyping of two single-nucleotide polymorphisms in the toll-like receptor-4 gene. Anal Biochem 2008; 376:235-41. [DOI: 10.1016/j.ab.2008.02.012] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2007] [Revised: 02/12/2008] [Accepted: 02/12/2008] [Indexed: 12/19/2022]
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Abstract
The course of every infection is different. The same pathogen can lead to subclinical, mild, severe or lethal infections in individuals. But is this just chance or determined by individual differences--on the side of the host as well as on the side of the pathogen? If so, we might need to consider these variations for treatment decisions. Indeed, we now understand that genetic polymorphisms and health status represent inborn and acquired risk factors. Similarly, pathogens impress with an increasing number of already identified virulence factors and host response modifiers. The emerging, more complex, view of the factors determining course and outcome of infections promises to enable more tailored and thus, hopefully, more effective treatment decisions.
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Affiliation(s)
- Corinna Hermann
- Biochemical Pharmacology, University of Konstanz, Konstanz, Germany.
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Kim YS, Hwang YJ, Kim SY, Yang SM, Lee KY, Park IB. Rarity of TLR4 Asp299Gly and Thr399Ile polymorphisms in the Korean population. Yonsei Med J 2008; 49:58-62. [PMID: 18306470 PMCID: PMC2615260 DOI: 10.3349/ymj.2008.49.1.58] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
PURPOSE Activation of the innate immune system and chronic low-grade inflammation are thought to be involved in the pathogenesis of atherosclerosis and also thought to be associated with type 2 diabetes and its complications. As a receptor for bacterial lipopolysaccharide and heat-shock proteins, Toll-like receptor 4 (TLR4) is one of the central regulators of the immune response. Recent studies have reported an association between TLR4 polymorphisms and diabetes and its complications in Caucasian populations. MATERIALS AND METHODS In this study, we analyzed the association between TLR4 gene polymorphisms in patients with features of type 2 diabetes and healthy controls in Korea. Two polymorphisms of the TLR4 gene (Asp299Gly and Thr399Ile) were examined in 225 diabetic patients and 153 healthy controls using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and single-strand conformation polymorphism (SSCP). RESULTS No Asp299Gly or Thr399Ile mutations were detected in any of the 378 subjects. Seven subjects from each group who had slightly different SSCP patterns were selected for sequencing, but we found no TLR4 polymorphisms on Exon3. The Asp299Gly and Thr399Ile TLR4 gene polymorphisms were absent in both groups, which was similar to the results for Japanese and Chinese Han subjects. CONCLUSION Our data and other Asian data suggest that a racial difference can be found in the frequency of the TLR4 polymorphism.
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Affiliation(s)
- Yeun Sun Kim
- Department of Endocrinology, Gachon University of Medicine and Science, Gil Medical Center, Incheon, Korea
| | - You Jin Hwang
- Division of Biological Science, Gachon University of Medicine and Science, Incheon, Korea
| | - Sung Yong Kim
- Department of Endocrinology, Gachon University of Medicine and Science, Gil Medical Center, Incheon, Korea
| | - Sun Mee Yang
- Department of Endocrinology, Gachon University of Medicine and Science, Gil Medical Center, Incheon, Korea
| | - Ki Young Lee
- Department of Endocrinology, Gachon University of Medicine and Science, Gil Medical Center, Incheon, Korea
| | - Ie Byung Park
- Department of Endocrinology, Gachon University of Medicine and Science, Gil Medical Center, Incheon, Korea
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