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Ma PY, Tan JE, Hee EW, Yong DWX, Heng YS, Low WX, Wu XH, Cletus C, Kumar Chellappan D, Aung K, Yong CY, Liew YK. Human Genetic Variation Influences Enteric Fever Progression. Cells 2021; 10:cells10020345. [PMID: 33562108 PMCID: PMC7915608 DOI: 10.3390/cells10020345] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2020] [Revised: 02/02/2021] [Accepted: 02/04/2021] [Indexed: 01/06/2023] Open
Abstract
In the 21st century, enteric fever is still causing a significant number of mortalities, especially in high-risk regions of the world. Genetic studies involving the genome and transcriptome have revealed a broad set of candidate genetic polymorphisms associated with susceptibility to and the severity of enteric fever. This review attempted to explain and discuss the past and the most recent findings on human genetic variants affecting the progression of Salmonella typhoidal species infection, particularly toll-like receptor (TLR) 4, TLR5, interleukin (IL-) 4, natural resistance-associated macrophage protein 1 (NRAMP1), VAC14, PARK2/PACRG, cystic fibrosis transmembrane conductance regulator (CFTR), major-histocompatibility-complex (MHC) class II and class III. These polymorphisms on disease susceptibility or progression in patients could be related to multiple mechanisms in eliminating both intracellular and extracellular Salmonella typhoidal species. Here, we also highlighted the limitations in the studies reported, which led to inconclusive results in association studies. Nevertheless, the knowledge obtained through this review may shed some light on the development of risk prediction tools, novel therapies as well as strategies towards developing a personalised typhoid vaccine.
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Affiliation(s)
- Pei Yee Ma
- School of Postgraduate Studies, International Medical University, Bukit Jalil, Kuala Lumpur 57000, Malaysia;
| | - Jing En Tan
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Edd Wyn Hee
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Dylan Wang Xi Yong
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Yi Shuan Heng
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Wei Xiang Low
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Xun Hui Wu
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Christy Cletus
- School of Pharmacy, International Medical University, Kuala Lumpur 57000, Malaysia; (J.E.T.); (E.W.H.); (D.W.X.Y.); (Y.S.H.); (W.X.L.); (X.H.W.); (C.C.)
| | - Dinesh Kumar Chellappan
- Department of Life Sciences, International Medical University, Kuala Lumpur 57000, Malaysia;
| | - Kyan Aung
- Department of Pathology, International Medical University, Kuala Lumpur 57000, Malaysia;
| | - Chean Yeah Yong
- Department of Microbiology, Faculty of Biotechnology and Biomolecular Sciences, Universiti Putra Malaysia, Selangor 43400, Malaysia;
| | - Yun Khoon Liew
- Department of Life Sciences, International Medical University, Kuala Lumpur 57000, Malaysia;
- Correspondence:
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Khaghanzadeh N, Naderi N, Pournasrollah N, Farahbakhsh E, Kheirandish M, Samiei A. TLR4 Polymorphisms (896A>G and 1196C>T) Affect the Predisposition to Diabetic Nephropathy in Type 2 Diabetes Mellitus. Diabetes Metab Syndr Obes 2020; 13:1015-1021. [PMID: 32308451 PMCID: PMC7138628 DOI: 10.2147/dmso.s238942] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2019] [Accepted: 03/23/2020] [Indexed: 12/13/2022] Open
Abstract
PURPOSE Type 2 diabetes mellitus (T2DM) is a disease with a steadily increasing incidence throughout the world. Some molecules regulating the innate immune responses such as toll-like receptor 4 (TLR4) have shown to be involved in late diabetic complications. This study aimed to investigate the association of TLR4 gene polymorphisms with clinicopathological aspects of T2DM in the Iranian population. PATIENTS AND METHODS Two TLR4 896A>G and 1196C>T polymorphisms were assessed in 100 T2DM patients and 100 healthy controls using sequence-specific primers PCR. Demographic, anthropometric, and biochemical parameters were obtained from the participants. RESULTS After logistic regression, in 1196C>T, a significant association was shown between diabetic nephropathy (DN) and CT genotype (P= 0.04, OR= 4.35, CI= (1.04-18.1)). TG level has increased significantly in both T2DM and control subjects with CT genotype (P= 0.027, OR= 1.005, 95% CI= (1.001-1.01)). For 896A>G variant, a significant association was also detected between AG genotype and increased oral glucose tolerance test (OGTT) level (P= 0.048, OR= 1.003, 95% CI= (1.00-1.005)). CONCLUSION Although minor alleles of 1196C>T and 896A>G variants have not directly been associated with type 2 diabetes, by involving in the dysregulation of serum TG and blood sugar levels, they might increase the risk of DN.
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Affiliation(s)
- Narges Khaghanzadeh
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nadereh Naderi
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Nazanin Pournasrollah
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Elahe Farahbakhsh
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Masoumeh Kheirandish
- Endocrinology and Metabolism Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Afshin Samiei
- Molecular Medicine Research Center, Hormozgan Health Institute, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Department of Immunology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
- Correspondence: Afshin Samiei Department of Immunology, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas7919693116, IranTel +98 76 337103070Fax +98 76 33710371 Email
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The Role of TLR4 Asp299Gly and TLR4 Thr399Ile Polymorphisms in the Pathogenesis of Urinary Tract Infections: First Evaluation in Infants and Children of Greek Origin. J Immunol Res 2019; 2019:6503832. [PMID: 31183391 PMCID: PMC6515008 DOI: 10.1155/2019/6503832] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2019] [Revised: 04/08/2019] [Accepted: 04/10/2019] [Indexed: 01/22/2023] Open
Abstract
Urinary tract infections are one of the most common and serious bacterial infections in a pediatric population. So far, they have mainly been related to age, gender, ethnicity, socioeconomic level, and the presence of underlying anatomical or functional, congenital, or acquired abnormalities. Recently, both innate and adaptive immunities and their interaction in the pathogenesis and the development of UTIs have been studied. The aim of this study was to assess the role and the effect of the two most frequent polymorphisms of TLR4 Asp299Gly and Thr399Ile on the development of UTIs in infants and children of Greek origin. We studied 51 infants and children with at least one episode of acute urinary tract infection and 109 healthy infants and children. We found that 27.5% of patients and 8.26% of healthy children carried the heterozygote genotype for TLR4 Asp299Gly. TLR4 Thr399Ile polymorphism was found to be higher in healthy children and lower in the patient group. No homozygosity for both studied polymorphisms was detected in our patients. In the group of healthy children, a homozygote genotype for TLR4 Asp299Gly (G/G) as well as for TLR4 Thr399Ile (T/T) was showed (1.84% and 0.92 respectively). These results indicate the role of TLR4 polymorphism as a genetic risk for the development of UTIs in infants and children of Greek origin.
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Immune Dysfunction and Albumin-Related Immunity in Liver Cirrhosis. Mediators Inflamm 2019; 2019:7537649. [PMID: 30930689 PMCID: PMC6410448 DOI: 10.1155/2019/7537649] [Citation(s) in RCA: 39] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 01/15/2019] [Accepted: 01/26/2019] [Indexed: 02/07/2023] Open
Abstract
Liver cirrhosis yearly causes 1.2 million deaths worldwide, ranking as the 10th leading cause of death in the most developed countries. High susceptibility to infections along with a significant risk for infection-related mortality justifies the description of liver cirrhosis as the world's most common immunodeficiency syndrome. Liver cirrhosis is an end-stage organic disease hallmarked by a multifaceted immune dysfunction due to deterioration of antimicrobial recognition and elimination mechanisms in macrophages along with an impaired antigen presentation ability in circulating monocytes. Bacterial translocation supports—and is supported by—uncontrolled activation of immune cell responses and/or loss of toll-like receptor (TLR) tolerance, which can turn exaggerated inflammatory responses to systemic inflammation. Lipopolysaccharide (LPS) or endotoxin boosts systemic inflammatory activity through activation of TLR-2- and TLR-4-dependent pathways and facilitate a massive production of cytokines. This, in turn, results into elevated secretion of reactive oxygen species (ROS), which further enhances intestinal hyperpermeability and thus sustains a vicious circle of events widely known as “leaky gut.” Albumin can be of particular benefit in cirrhotic patients with spontaneous bacterial peritonitis and/or hepatorenal syndrome type of acute kidney injury (HRS-AKI) due to anti-inflammatory and antioxidative stress as well as volume-expanding properties and endothelial-stabilizing attributes. However, presence of autoantibodies against albumin in patients with liver cirrhosis has been described. Although previous research suggested that these antibodies should be regarded as naturally occurring antibodies (NOA), the origin of the antialbumin immune response is obscure. High occurrence of NAO/albumin complexes in patients with liver disease might reflect a limited clearance capacity due to bypassing portal circulation. Moreover, high burden of oxidized albumin is associated with less favorable outcome in patients with liver cirrhosis. To date, there is no data available as to whether oxidized forms of albumin result in neoepitopes recognized by the immune system. Nevertheless, it is reasonable to hypothesize that these alterations may have the potential to induce antialbumin immune responses and thus favor systemic inflammation.
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Nelson CP, Erridge C. Are toll-like receptors potential drug targets for atherosclerosis? Evidence from genetic studies to date. Immunogenetics 2018; 71:1-11. [PMID: 30327825 DOI: 10.1007/s00251-018-1092-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2018] [Accepted: 10/09/2018] [Indexed: 01/08/2023]
Abstract
Low-density lipoprotein cholesterol lowering, most notably via statin therapy, has successfully reduced the burden of coronary artery disease (CAD) in recent decades. However, the residual risk remaining even after aggressive lipid lowering has renewed interest in alternative targets. Anti-inflammatory drugs are thought to have much potential in this context, but side effects associated with long-term use of conventional anti-inflammatories, such as NSAIDs and glucocorticoids, preclude their use as preventive agents for CAD. Evidence from epidemiological studies and murine models of atherosclerosis suggests that toll-like receptors (TLRs) may have utility as targets for more focused anti-inflammatories, but it remains unclear if this pathway is causally related to CAD in man. Here, we review recent insight into this question gained from genetic studies of cardiovascular risk and innate immune function, focussing on the potential of Mendelian randomisation approaches based on intracellular-signalling pathways to identify and prioritise targets for drug development.
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Affiliation(s)
- Christopher P Nelson
- Department of Cardiovascular Sciences, University of Leicester, Leicester, LE3 9QP, UK.,NIHR Leicester Biomedical Research Centre, Glenfield Hospital, Groby Road, Leicester, LE3 9QP, UK
| | - Clett Erridge
- Department of Cardiovascular Sciences, University of Leicester, Leicester, LE3 9QP, UK. .,Department of Biomedical and Forensic Sciences, Anglia Ruskin University, East Rd, Cambridge, CB1 1PT, UK.
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Spurthi KM, Sarikhani M, Mishra S, Desingu PA, Yadav S, Rao S, Maity S, Tamta AK, Kumar S, Majumdar S, Jain A, Raghuraman A, Khan D, Singh I, Samuel RJ, Ramachandra SG, Nandi D, Sundaresan NR. Toll-like receptor 2 deficiency hyperactivates the FoxO1 transcription factor and induces aging-associated cardiac dysfunction in mice. J Biol Chem 2018; 293:13073-13089. [PMID: 29929978 DOI: 10.1074/jbc.ra118.001880] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 06/09/2018] [Indexed: 12/17/2022] Open
Abstract
Toll-like receptors (TLRs) are a family of pattern-recognition receptors involved in innate immunity. Previous studies have shown that TLR2 inhibition protects the heart from acute stress, including myocardial infarction and doxorubicin-induced cardiotoxicity in animal models. However, the role of TLR2 in the development of aging-associated heart failure is not known. In this work, we studied aging-associated changes in structure and function of TLR2-deficient mice hearts. Whereas young TLR2-KO mice did not develop marked cardiac dysfunction, 8- and 12-month-old TLR2-KO mice exhibited spontaneous adverse cardiac remodeling and cardiac dysfunction in an age-dependent manner. The hearts of the 8-month-old TLR2-KO mice had increased fibrosis, cell death, and reactivation of fetal genes. Moreover, TLR2-KO hearts displayed reduced infiltration by macrophages, increased numbers of myofibroblasts and atrophic cardiomyocytes, and higher levels of the atrophy-related ubiquitin ligases MuRF-1 and atrogin-1. Mechanistically, TLR2 deficiency impaired the PI3K/Akt signaling pathway, leading to hyperactivation of the transcription factor Forkhead box protein O1 (FoxO1) and, in turn, to elevated expression of FoxO target genes involved in the regulation of muscle wasting and cell death. AS1842856-mediated chemical inhibition of FoxO1 reduced the expression of the atrophy-related ubiquitin ligases and significantly reversed the adverse cardiac remodeling while improving the contractile functions in the TLR2-KO mice. Interestingly, TLR2 levels decreased in hearts of older mice, and the activation of TLR1/2 signaling improved cardiac functions in these mice. These findings suggest that TLR2 signaling is essential for protecting the heart against aging-associated adverse remodeling and contractile dysfunction in mice.
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Affiliation(s)
- Kondapalli Mrudula Spurthi
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Mohsen Sarikhani
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Sneha Mishra
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Perumal Arumugam Desingu
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Shikha Yadav
- the Department of Biochemistry, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Swathi Rao
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Sangeeta Maity
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Ankit Kumar Tamta
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Shweta Kumar
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Shamik Majumdar
- the Department of Biochemistry, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Aditi Jain
- the Centre for Biosystems Science and Engineering, Indian Institute of Science, Bengaluru, Karnataka 560012, India, and
| | - Aishwarya Raghuraman
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Danish Khan
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Ishwar Singh
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Rosa J Samuel
- the Central Animal Facility, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Subbaraya G Ramachandra
- the Central Animal Facility, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Dipankar Nandi
- the Department of Biochemistry, Indian Institute of Science, Bengaluru, Karnataka 560012, India
| | - Nagalingam R Sundaresan
- From the Department of Microbiology and Cell Biology, Indian Institute of Science, Bengaluru, Karnataka 560012, India,
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Johswich K. Innate immune recognition and inflammation in Neisseria meningitidis infection. Pathog Dis 2017; 75:3059204. [PMID: 28334203 DOI: 10.1093/femspd/ftx022] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Accepted: 02/23/2017] [Indexed: 01/01/2023] Open
Abstract
Neisseria meningitidis (Nme) can cause meningitis and sepsis, diseases which are characterised by an overwhelming inflammatory response. Inflammation is triggered by host pattern recognition receptors (PRRs) which are activated by pathogen-associated molecular patterns (PAMPs). Nme contains multiple PAMPs including lipooligosaccharide, peptidoglycan, proteins and metabolites. Various classes of PRRs including Toll-like receptors, NOD-like receptors, C-type lectins, scavenger receptors, pentraxins and others are expressed by the host to respond to any given microbe. While Toll-like receptors and NOD-like receptors are pivotal in triggering inflammation, other PRRs act as modulators of inflammation or aid in functional antimicrobial responses such as phagocytosis or complement activation. This review aims to give an overview of the various Nme PAMPs reported to date, the PRRs they activate and their implications during the inflammatory response to infection.
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Laine ML, Morré SA, Murillo LS, van Winkelhoff AJ, Peña AS. CD14 and TLR4 Gene Polymorphisms in Adult Periodontitis. J Dent Res 2016; 84:1042-6. [PMID: 16246938 DOI: 10.1177/154405910508401114] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Bacterial deposits, smoking, and host genetic factors play a major role in an individual’s predisposition to periodontitis. Bacterial components are recognized by CD14 and toll-like receptor 4 (TLR4), resulting in a NF-κB-based inflammatory response. We hypothesized that functional CD14 and TLR4 polymorphisms contribute to periodontitis susceptibility. We aimed to investigate the occurrence of CD14-260C>T, TLR4 299Asp>Gly, and 399Thr>Ile gene polymorphisms in adult periodontititis. DNA was collected from 100 patients with severe periodontitis and from 99 periodontally healthy controls. The gene polymorphisms were determined by the PCR technique. The presence of the periodontal pathogens Porphyromonas gingivalis and Actinobacillus actinomycetemcomitans, and whether the subjects smoked, was included in the analyses. The CD14-260T/T genotype was found in 34.0% of periodontitis patients and in 20.2% of controls. Logistic regression analysis adjusted for gender, age, smoking, and prevalence of P. gingivalis and A. actinomycetemcomitans showed an association between the CD14-260T/T genotype and periodontitis (P = 0.004, OR 3.0, 95% CI 1.4–6.9). We conclude that the CD14-260T/T genotype contributes to the susceptibility to severe periodontitis in Dutch Caucasians.
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Affiliation(s)
- M L Laine
- Department of Periodontology, Section of Oral Microbiology, Academic Centre for Dentistry Amsterdam, Van der Boechorsstraat 7, 1081 BT Amsterdam, The Netherlands.
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Kapil S, Duseja A, Sharma BK, Singla B, Chakraborti A, Das A, Ray P, Dhiman RK, Chawla Y. Genetic polymorphism in CD14 gene, a co-receptor of TLR4 associated with non-alcoholic fatty liver disease. World J Gastroenterol 2016; 22:9346-9355. [PMID: 27895422 PMCID: PMC5107698 DOI: 10.3748/wjg.v22.i42.9346] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/31/2016] [Revised: 08/03/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the pathogenic role of toll-like receptor (TLR) gene polymorphisms in patients with non-alcoholic fatty liver disease (NAFLD).
METHODS Two hundred and fifty subjects (NAFLD = 200, healthy volunteers = 50) underwent polymerase chain reaction and restriction fragment length polymorphism to assess one polymorphism in the toll-like receptor 2 (TLR2) gene (A753G), two polymorphisms in the TLR4 gene (TLR4 Asp299Gly and Thr399Ile allele), and two polymorphisms in the cluster of differentiation 14 (CD14) (C-159T and C-550T) gene, a co-receptor of TLR4. Association of TLR gene polymorphisms with NAFLD and its severity was evaluated by genetic models of association.
RESULTS On both multiplicative and recessive models of gene polymorphism association, there was significant association of CD14 C (-159) T polymorphism with NAFLD; patients with TT genotype had a 2.6 fold increased risk of developing NAFLD in comparison to CC genotype. There was no association of TLR2 Arg753Gln, TLR4 Asp299Gly, Thr399Ile, and CD14 C (-550) T polymorphisms with NAFLD. None of the TLR gene polymorphisms had an association with histological severity of NAFLD.
CONCLUSION Patients with CD14 C (-159) T gene polymorphism, a co-receptor of TLR4, have an increased risk of NAFLD development.
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Fox AA, Shernan SK, Body SC. Predictive Genomics of Adverse Events After Cardiac Surgery. Semin Cardiothorac Vasc Anesth 2016; 8:297-315. [PMID: 15583791 DOI: 10.1177/108925320400800404] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Significant, yet highly individual, thrombotic and inflammatory responses to surgery provide an excellent opportunity for insight into the genomic impact upon a patient's postoperative course. Cardiac surgery elicits the most profound perioperative disturbance and is associated with the highest incidence of adverse outcomes of any elective surgical procedure. Thus, cardiac surgical patients are an ideal population in which to evaluate the influence of complex traits on perioperative morbidity and mortality. This review describes the application of fundamental genetics upon the occurrence of adverse outcomes after cardiac surgery and cardiac transplantation. Specific emphases include a brief primer of the principles of genetics concentrating on the effects of variation within the human genome upon clinical outcomes and the differences between so-called Mendelian traits and complex traits. Four important clinical diseases dealt with in this review as examples of the impact of genetic factors on clinical outcomes are the genetics of heparin-induced thrombocytopenia, heart transplantation rejection and vasculopathy, atrial fibrillation, and infection.
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Affiliation(s)
- Amanda A Fox
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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Yang Y, Tong M, Yi L, Cheng Y, Zhang M, Cao Z, Wang J, Lin P, Cheng S. Identification and characterization of the toll-like receptor 8 gene in the Chinese raccoon dog (Nyctereutes procyonoides). Immunol Lett 2016; 178:50-60. [PMID: 27481482 DOI: 10.1016/j.imlet.2016.07.012] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2016] [Revised: 07/11/2016] [Accepted: 07/25/2016] [Indexed: 10/21/2022]
Abstract
TLR8 is an important sensor of single-stranded RNA (ssRNA) from the viral genome and plays an essential role in innate antiviral responses via the recognition of conserved viral molecular patterns. In this report, TLR8 in the Chinese raccoon dog was characterized and analyzed for the first time. The full-length sequence of raccoon dog TLR8 (RdTLR8) cDNA was cloned by rapid amplification of cDNA ends (RACE) and is 3191bp with a 3117-bp open reading frame (ORF) encoding 1038 amino acids. The putative protein exhibits typical features of the TLR families, with 19 leucine-rich repeats (LRRs) in the extracellular domain and a cytoplasmic TIR domain. Comparative analyses of the RdTLR8 amino acid sequence indicated a 73.6-99.4% sequence identity with dog, horse, pig, sheep, cattle, human and mouse TLR8. Phylogenetic analysis grouped 71 mammalian TLR proteins into five sub-families, wherein RdTLR8 was clustered into a monophyletic TLR8 clade in the TLR9 family, which was completely coincident with the evolutionary relationship among mammals. Quantitative real-time PCR analysis revealed extensive expression of RdTLR8 in tissues from healthy Chinese raccoon dogs with the highest expression in the peripheral blood mononuclear cells (PBMCs) and the lowest expression in the skeletal muscle. HEK293 cells cotransfected with a RdTLR8 expression plasmid and an NF-κB-luciferase reporter plasmid significantly responded to the agonist 3M-002, indicating a functional TLR8 homolog. In addition, raccoon dog PBMCs exposed to the canine distemper virus (CDV) wild strain CDV-PS and the TLR8 agonist 3M-002 showed significant upregulation of RdTLR8 mRNA and proinflammatory cytokines TNF-α and IFN-α, suggesting that RdTLR8 might play an important role in the immune response to viral infections in the Chinese raccoon dog.
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Affiliation(s)
- Yong Yang
- Wu Xi Medical School, Jiangnan University, China; Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Mingwei Tong
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Li Yi
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Yuening Cheng
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Miao Zhang
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Zhigang Cao
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Jianke Wang
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Peng Lin
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China
| | - Shipeng Cheng
- Institute of Special Economic Animal and Plant Science, Chinese Academy of Agricultural Sciences, China.
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Jaeger M, Stappers MHT, Joosten LAB, Gyssens IC, Netea MG. Genetic variation in pattern recognition receptors: functional consequences and susceptibility to infectious disease. Future Microbiol 2016; 10:989-1008. [PMID: 26059622 DOI: 10.2217/fmb.15.37] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
Cells of the innate immune system are equipped with surface and cytoplasmic receptors for microorganisms called pattern recognition receptors (PRRs). PRRs recognize specific pathogen-associated molecular patterns and as such are crucial for the activation of the immune system. Currently, five different classes of PRRs have been described: Toll-like receptors, C-type lectin receptors, nucleotide-binding oligomerization domain-like receptors, retinoic acid-inducible gene I-like receptors and absent in melanoma 2-like receptors. Following their discovery, many sequence variants in PRR genes have been uncovered and shown to be implicated in human infectious diseases. In this review, we will discuss the effect of genetic variation in PRRs and their signaling pathways on susceptibility to infectious diseases in humans.
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Affiliation(s)
- Martin Jaeger
- Department of Internal Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Mark H T Stappers
- Department of Internal Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.,Department of Medical Microbiology & Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.,Faculty of Medicine, Research group of Immunology & Biochemistry, Hasselt University, Hasselt, Belgium
| | - Leo A B Joosten
- Department of Internal Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
| | - Inge C Gyssens
- Department of Internal Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands.,Department of Medical Microbiology & Infectious Diseases, Canisius Wilhelmina Hospital, Nijmegen, The Netherlands.,Faculty of Medicine, Research group of Immunology & Biochemistry, Hasselt University, Hasselt, Belgium
| | - Mihai G Netea
- Department of Internal Medicine, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands
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13
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Lipopolysaccharide responsiveness is an independent predictor of death in patients with chronic heart failure. J Mol Cell Cardiol 2015; 87:48-53. [DOI: 10.1016/j.yjmcc.2015.07.029] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/05/2015] [Revised: 07/28/2015] [Accepted: 07/30/2015] [Indexed: 11/24/2022]
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Parthiban P, Mahendra J. Toll-Like Receptors: A Key Marker for Periodontal Disease and Preterm Birth - A Contemporary Review. J Clin Diagn Res 2015; 9:ZE14-7. [PMID: 26501032 PMCID: PMC4606361 DOI: 10.7860/jcdr/2015/14143.6526] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 07/25/2015] [Indexed: 01/11/2023]
Abstract
The receptors of the innate immune system have evolved to recognize pathogenic bacteria in a complex manner. Out of these immune receptors, the pattern recognition receptors (PRRs) such as Toll like receptors have gained importance off late to play a key role in the activation of cascade of inflammatory cytokines in pathogenesis of preterm birth. Preterm birth has become leading cause of neonatal deaths globally. The concept of oral infection influencing the occurrence of preterm delivery has gained importance. Translocation of periodontal pathogens and inflammatory mediators play role in the pathogenesis of preterm labour. The transmembrane toll like receptors of innate immunity have been recently implicated in the association of periodontal infection and preterm labour. The TLRs are considered as a key marker and TLR blockade can be a critical method for treating women who are exposed to periodontal pathogens. This review is aimed at discussing the role of TLR in periodontal disease and its relationship with preterm birth.
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Affiliation(s)
- Prathahini Parthiban
- Post Graduate Student, Department of Periodontology, Meenakshi Ammal Dental College & Hospital, Chennai, India
| | - Jaideep Mahendra
- Professor, Department of Periodontology, Meenakshi Ammal Dental College & Hospital, Chennai, India
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15
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Velloso LA, Folli F, Saad MJ. TLR4 at the Crossroads of Nutrients, Gut Microbiota, and Metabolic Inflammation. Endocr Rev 2015; 36:245-71. [PMID: 25811237 DOI: 10.1210/er.2014-1100] [Citation(s) in RCA: 187] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Obesity is accompanied by the activation of low-grade inflammatory activity in metabolically relevant tissues. Studies have shown that obesity-associated insulin resistance results from the inflammatory targeting and inhibition of key proteins of the insulin-signaling pathway. At least three apparently distinct mechanisms-endoplasmic reticulum stress, toll-like receptor (TLR) 4 activation, and changes in gut microbiota-have been identified as triggers of obesity-associated metabolic inflammation; thus, they are expected to represent potential targets for the treatment of obesity and its comorbidities. Here, we review the data that place TLR4 in the center of the events that connect the consumption of dietary fats with metabolic inflammation and insulin resistance. Changes in the gut microbiota can lead to reduced integrity of the intestinal barrier, leading to increased leakage of lipopolysaccharides and fatty acids, which can act upon TLR4 to activate systemic inflammation. Fatty acids can also trigger endoplasmic reticulum stress, which can be further stimulated by cross talk with active TLR4. Thus, the current data support a connection among the three main triggers of metabolic inflammation, and TLR4 emerges as a link among all of these mechanisms.
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Affiliation(s)
- Licio A Velloso
- Department of Internal Medicine (L.A.V., F.F., M.J.S.), University of Campinas, 13084-970 Campinas SP, Brazil; and Department of Medicine (F.F.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
| | - Franco Folli
- Department of Internal Medicine (L.A.V., F.F., M.J.S.), University of Campinas, 13084-970 Campinas SP, Brazil; and Department of Medicine (F.F.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
| | - Mario J Saad
- Department of Internal Medicine (L.A.V., F.F., M.J.S.), University of Campinas, 13084-970 Campinas SP, Brazil; and Department of Medicine (F.F.), Division of Diabetes, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229
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16
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Cheng Y, Zhu Y, Huang X, Zhang W, Han Z, Liu S. Association between TLR2 and TLR4 Gene Polymorphisms and the Susceptibility to Inflammatory Bowel Disease: A Meta-Analysis. PLoS One 2015; 10:e0126803. [PMID: 26023918 PMCID: PMC4449210 DOI: 10.1371/journal.pone.0126803] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2014] [Accepted: 04/08/2015] [Indexed: 12/18/2022] Open
Abstract
Background The associations between toll-like receptor 2 (TLR2) and toll-like receptor 4(TLR4) polymorphisms and inflammatory bowel disease (IBD) susceptibility remain controversial. A meta-analysis was performed to assess these associations. Methods A systematic search was performed to identify all relevant studies relating TLR2 and TLR4 polymorphisms and IBD susceptibility. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Subgroup analyses were performed by ethnicity and publication quality. Results Thirty-eight eligible studies, assessing 10970 cases and 7061 controls were included. No TLR2 Arg677Trp polymorphism was found. No significant association was observed between TLR2 Arg753Gln polymorphism and Crohn’s disease (CD) or ulcerative colitis (UC) in all genetic models. Interestingly, TLR4 Asp299Gly polymorphism was significantly associated with increased risk of CD and UC in all genetic models, except for the additive one in CD. In addition, a statistically significant association between TLR4 Asp299Gly polymorphism and IBD was observed among high quality studies evaluating Caucasians, but not Asians. Associations between TLR4 Thr399Ile polymorphisms and CD risk were found only in the allele and dominant models. The TLR4 Thr399Ile polymorphism was associated with UC risk in pooled results as well as subgroup analysis of high quality publications assessing Caucasians, in allele and dominant models. Conclusions The meta-analysis provides evidence that TLR2 Arg753Gln is not associated with CD and UC susceptibility in Asians; TLR4 Asp299Gly is associated with CD and UC susceptibility in Caucasians, but not Asians. TLR4 Thr399Ile may be associated with IBD susceptibility in Caucasians only. Additional well-powered studies of Asp299Gly and other TLR4 variants are warranted.
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Affiliation(s)
- Yang Cheng
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Yun Zhu
- Liver Tumor Center, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Xiuping Huang
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Wei Zhang
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Zelong Han
- First clinical college, Southern Medical University, Guangzhou, Guangdong Province, China
| | - Side Liu
- Department of Digestion, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong Province, China
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17
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Goutaki M, Haidopoulou K, Pappa S, Tsakiridis P, Frydas E, Eboriadou M, Hatzistylianou M. The role of TLR4 and CD14 polymorphisms in the pathogenesis of respiratory syncytial virus bronchiolitis in greek infants. Int J Immunopathol Pharmacol 2015; 27:563-72. [PMID: 25572736 DOI: 10.1177/039463201402700412] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Clinical manifestations of respiratory syncytial virus (RSV) infection vary from minimal disease to severe acute bronchiolitis. The structural complex of TLR4/CD14 participates in the virus recognition as a component of natural immune response. Genetic variations of TLR4/CD14 may explain great variations in disease severity. The aim of this study was to investigate the possible role of polymorphisms of TLR4, Asp299Gly and Thr399Ile and CD14, C-159T and C-550T in the development of RSV bronchiolitis. Our study included two groups of Greek infants and young children (A and B). Group A consisted of 50 infants ≤2 years of age hospitalised with bronchiolitis and group B of 99 previously healthy children aged 4-14 years (control group) with a free past medical history. RSV was identified by PCR of genetic material that was extracted from nasopharyngeal samples collected from all patients. Blood samples were used to extract DNA and by using the PCR-RFLP method we performed TLR4 and CD14 genotyping. We found no association between TLR4 polymorphisms (Asp299Gly and Thr399Ile) and the development of acute bronchiolitis. For CD14 polymorphisms, a positive association was found between the C-159T and the development of bronchiolitis (p=0.05) but not for the other loci. There were no differences detected in the frequencies of the four polymorphisms studied among infants with RSV and non-RSV bronchiolitis. It is concluded that protein CD14 may have a functional role in the viral conjunction to the structural complex TLR4/CD14. The association between the polymorphism C-159T and the manifestation of disease found in our study points out that the severity in the development of acute bronchiolitis is not specified exclusively by the pathogen, but the immune response of the host also plays a significant role. More extensive multicentric studies need to take place, in order to lead to safer conclusions.
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Affiliation(s)
- M Goutaki
- 4th Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - K Haidopoulou
- 4th Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - S Pappa
- 2nd Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - P Tsakiridis
- 2nd Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - E Frydas
- 2nd Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - M Eboriadou
- 4th Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - M Hatzistylianou
- 2nd Department of Pediatrics, School of Medicine, Aristotle University of Thessaloniki, Thessaloniki, Greece
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18
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Nieto JC, Sánchez E, Román E, Vidal S, Oliva L, Guarner-Argente C, Poca M, Torras X, Juárez C, Guarner C, Soriano G. Cytokine production in patients with cirrhosis and TLR4 polymorphisms. World J Gastroenterol 2014; 20:17516-17524. [PMID: 25516666 PMCID: PMC4265613 DOI: 10.3748/wjg.v20.i46.17516] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/13/2014] [Revised: 04/22/2014] [Accepted: 06/26/2014] [Indexed: 02/06/2023] Open
Abstract
AIM To analyze the cytokine production by peripheral blood cells from cirrhotic patients with and without TLR4 D299G and/or T399I polymorphisms. METHODS The study included nine patients with cirrhosis and TLR4 D299G and/or T399I polymorphisms, and 10 wild-type patients matched for age, sex and degree of liver failure. TLR4 polymorphisms were determined by sequence-based genotyping. Cytokine production by peripheral blood cells was assessed spontaneously and also after lipopolysaccharide (LPS) and lipoteichoic acid (LTA) stimulation. RESULTS Patients with TLR4 polymorphisms had a higher incidence of previous hepatic encephalopathy than wild-type patients (78% vs 20%, P = 0.02). Spontaneous production of interleukin (IL)-6 and IL-10 was lower in patients with TLR4 polymorphisms than in wild-type patients [IL-6: 888.7 (172.0-2119.3) pg/mL vs 5540.4 (1159.2-26053.9) pg/mL, P < 0.001; IL-10: 28.7 (6.5-177.1) pg/mL vs 117.8 (6.5-318.1) pg/mL, P = 0.02]. However, the production of tumor necrosis factor-α, IL-6 and IL-10 after LPS and LTA stimulation was similar in the two groups. CONCLUSION TLR4 polymorphisms were associated with a distinctive pattern of cytokine production in cirrhotic patients, suggesting that they play a role in the development of cirrhosis complications.
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Sipeki N, Antal-Szalmas P, Lakatos PL, Papp M. Immune dysfunction in cirrhosis. World J Gastroenterol 2014; 20:2564-2577. [PMID: 24627592 PMCID: PMC3949265 DOI: 10.3748/wjg.v20.i10.2564] [Citation(s) in RCA: 116] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 12/25/2013] [Accepted: 01/20/2014] [Indexed: 02/06/2023] Open
Abstract
Innate and adaptive immune dysfunction, also referred to as cirrhosis-associated immune dysfunction syndrome, is a major component of cirrhosis, and plays a pivotal role in the pathogenesis of both the acute and chronic worsening of liver function. During the evolution of the disease, acute decompensation events associated with organ failure(s), so-called acute-on chronic liver failure, and chronic decompensation with progression of liver fibrosis and also development of disease specific complications, comprise distinct clinical entities with different immunopathology mechanisms. Enhanced bacterial translocation associated with systemic endotoxemia and increased occurrence of systemic bacterial infections have substantial impacts on both clinical situations. Acute and chronic exposure to bacteria and/or their products, however, can result in variable clinical consequences. The immune status of patients is not constant during the illness; consequently, alterations of the balance between pro- and anti-inflammatory processes result in very different dynamic courses. In this review we give a detailed overview of acquired immune dysfunction and its consequences for cirrhosis. We demonstrate the substantial influence of inherited innate immune dysfunction on acute and chronic inflammatory processes in cirrhosis caused by the pre-existing acquired immune dysfunction with limited compensatory mechanisms. Moreover, we highlight the current facts and future perspectives of how the assessment of immune dysfunction can assist clinicians in everyday practical decision-making when establishing treatment and care strategies for the patients with end-stage liver disease. Early and efficient recognition of inappropriate performance of the immune system is essential for overcoming complications, delaying progression and reducing mortality.
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20
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Suryadevara NC, Neela VSK, Kovvali S, Pydi SS, Jain S, Siva Sai KSR, Valluri VL, Spurgeon AMPJ. Genetic association of G896A polymorphism of TLR4 gene in leprosy through family-based and case-control study designs. Trans R Soc Trop Med Hyg 2013; 107:777-82. [PMID: 24169261 DOI: 10.1093/trstmh/trt084] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
BACKGROUND Polymorphisms in TLR4 may change the function of the protein and alter the efficiency of immune response of host to infection. The high relevance of host gene polymorphisms with outcome of Mycobacterium leprae infection led us to study the genetic association of TLR4 G896A polymorphism in order to identify its risk among contacts of affected leprosy patients. METHODS For case-control study design a total of 628 individuals were recruited; 17 multicase leprosy families which included 32 case-parent trios were considered for family-based study. Genotyping was done using PCR-RFLP method. RESULTS In case-control study AA genotype was positively associated while GA genotype was negatively associated with leprosy. In family based transmission disequilibrium test (TDT) analysis allele G was found to be over transmitted to the affected individuals. CONCLUSION Case-control study suggests that homozygous AA genotype may confer susceptibility and heterozygous GA genotype may confer resistance to leprosy, while allele A was observed to increase risk and that of allele G may confer resistance to leprosy. No strong transmission disequilibrium was detected in family-based TDT analysis, possibly due to lower number of trios. In contrast to case-control data allele G was over transmitted to the affected ones in TDT analysis. To conclude, the frequencies of genotypes in household contacts were almost the same as in leprosy patients, suggesting that contacts with AA genotype may be at higher risk of leprosy and may therefore require prophylactic inputs.
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21
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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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22
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Bouma G, Baggen JM, van Bodegraven AA, Mulder CJJ, Kraal G, Zwiers A, Horrevoets AJ, van der Pouw Kraan CTM. Thiopurine treatment in patients with Crohn's disease leads to a selective reduction of an effector cytotoxic gene expression signature revealed by whole-genome expression profiling. Mol Immunol 2013; 54:472-81. [PMID: 23454163 DOI: 10.1016/j.molimm.2013.01.015] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2012] [Revised: 01/16/2013] [Accepted: 01/21/2013] [Indexed: 12/30/2022]
Abstract
Crohn's disease (CD) is characterized by chronic inflammation of the gastrointestinal tract, as a result of aberrant activation of the innate immune system through TLR stimulation by bacterial products. The conventional immunosuppressive thiopurine derivatives (azathioprine and mercaptopurine) are used to treat CD. The effects of thiopurines on circulating immune cells and TLR responsiveness are unknown. To obtain a global view of affected gene expression of the immune system in CD patients and the treatment effect of thiopurine derivatives, we performed genome-wide transcriptome analysis on whole blood samples from 20 CD patients in remission, of which 10 patients received thiopurine treatment, compared to 16 healthy controls, before and after TLR4 stimulation with LPS. Several immune abnormalities were observed, including increased baseline interferon activity, while baseline expression of ribosomal genes was reduced. After LPS stimulation, CD patients showed reduced cytokine and chemokine expression. None of these effects were related to treatment. Strikingly, only one highly correlated set of 69 genes was affected by treatment, not influenced by LPS stimulation and consisted of genes reminiscent of effector cytotoxic NK cells. The most reduced cytotoxicity-related gene in CD was the cell surface marker CD160. Concordantly, we could demonstrate an in vivo reduction of circulating CD160(+)CD3(-)CD8(-) cells in CD patients after treatment with thiopurine derivatives in an independent cohort. In conclusion, using genome-wide profiling, we identified a disturbed immune activation status in peripheral blood cells from CD patients and a clear treatment effect of thiopurine derivatives selectively affecting effector cytotoxic CD160-positive cells.
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Affiliation(s)
- G Bouma
- VU University Medical Center, Deptartment of Gastroenterology, Amsterdam, The Netherlands
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No evidence for involvement of the toll-like receptor (TLR) 4 gene Asp299Gly and Thr399Ile polymorphisms in susceptibility to primary gouty arthritis. Rheumatol Int 2012; 33:2937-41. [DOI: 10.1007/s00296-012-2547-5] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/25/2012] [Accepted: 10/21/2012] [Indexed: 01/30/2023]
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Association of TLR4 gene non-missense single nucleotide polymorphisms with rheumatoid arthritis in Chinese Han population. Rheumatol Int 2012; 33:1283-8. [DOI: 10.1007/s00296-012-2536-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Accepted: 10/21/2012] [Indexed: 10/27/2022]
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25
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Stappers MHT, Janssen NAF, Oosting M, Plantinga TS, Arvis P, Mouton JW, Joosten LAB, Netea MG, Gyssens IC. A role for TLR1, TLR2 and NOD2 in cytokine induction by Bacteroides fragilis. Cytokine 2012; 60:861-9. [PMID: 22998942 DOI: 10.1016/j.cyto.2012.08.019] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2012] [Revised: 08/15/2012] [Accepted: 08/18/2012] [Indexed: 01/01/2023]
Abstract
Bacteroides fragilis, an intestinal flora commensal microorganism, is frequently isolated from abscesses and soft tissue infections. This study aimed to identify pattern recognition receptors (PRRs) involved in B. fragilis recognition and to characterize the induced cytokine profile. Human PBMCs were stimulated with heat-killed B. fragilis and cytokine levels were determined by ELISA. Roles of individual PRRs were assessed using specific blockers of receptor signaling pathways and PBMCs carrying single nucleotide polymorphisms of PRR genes. Cell lines expressing human TLR2 or TLR4 were employed to assess TLR-specificity of B. fragilis. TLR1, TLR2 and NOD2 were the main PRRs responsible for recognition of B. fragilis, while TLR4, TLR6, NOD1 and Dectin-1 were not involved. B. fragilis induced strong IL-6 and IL-8, moderate IL-1β and TNF-α, and poor IL-10, IL-17, IL-23 and IFN-γ production. This study identifies the receptor pathways of the innate immune response to B. fragilis, and thus provides new insights in the host defense against B. fragilis.
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Affiliation(s)
- Mark H T Stappers
- Department of Medicine, Radboud University Nijmegen Medical Centre, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands
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Defective IL-1A expression in patients with Crohn’s disease is related to attenuated MAP3K4 signaling. Hum Immunol 2012; 73:912-9. [DOI: 10.1016/j.humimm.2012.06.004] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2011] [Revised: 05/21/2012] [Accepted: 06/13/2012] [Indexed: 11/18/2022]
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Riad A, Meyer zu Schwabedissen H, Weitmann K, Herda LR, Dörr M, Empen K, Kieback A, Hummel A, Reinthaler M, Grube M, Klingel K, Nauck M, Kandolf R, Hoffmann W, Kroemer HK, Felix SB. Variants of Toll-like receptor 4 predict cardiac recovery in patients with dilated cardiomyopathy. J Biol Chem 2012; 287:27236-43. [PMID: 22645142 DOI: 10.1074/jbc.m112.369728] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
The clinical course of patients with dilated cardiomyopathy (DCM) varies from cardiac recovery to end stage heart failure. The etiology of this variability is largely unknown. In this study, we investigated the impact of coding polymorphisms of the innate immune protein Toll-like receptor 4 (TLR4) on left ventricular performance in patients with DCM. Two variants of TLR4 (rs4986790, TLR4 c.1187A→G, p.299D→G and rs4986791,TLR4 c.1487C→T, p.T399I) were investigated in 158 patients with DCM. Other reasons for heart failure were excluded by coronary angiography, myocardial biopsy, and echocardiography. Risk factors, age, gender, or treatment did not differ among the groups. At the follow-up evaluation (median 4.0-5.4 months), patients carrying the TLR4 wild type gene displayed cardiac recovery under intense medical heart failure therapy indexed by reduced left ventricular dilation, improved left ventricular ejection fraction, and reduced NT-probrain natriuretic peptide blood level when compared with the initial evaluation. In contrast, patients carrying both the rs4986790 and the rs4986791 variant showed significantly reduced improvement of left ventricular ejection fraction (p = 0.006) and left ventricular dilation (p = 0.015) at the follow-up evaluation when compared with carriers of the wild type gene under the same treatment conditions. In addition, NT-probrain natriuretic peptide level in carriers of both TLR4 variants did not change significantly at the follow up when compared with the first evaluation. Among patients with DCM, the presence of the TLR4 variants rs4986790 and rs4986791 predicts impaired cardiac recovery independently of medical treatment or cardiac risk factors.
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Affiliation(s)
- Alexander Riad
- Department of Cardiology and Pulmonology, Universitätsmedizin Greifswald, 17475 Greifswald, Germany.
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Genetic Diversity of Toll-Like Receptors and Immunity to M. leprae Infection. J Trop Med 2012; 2012:415057. [PMID: 22529866 PMCID: PMC3317006 DOI: 10.1155/2012/415057] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2011] [Accepted: 12/02/2011] [Indexed: 12/31/2022] Open
Abstract
Genetic association studies of leprosy cohorts across the world have identified numerous polymorphisms which alter susceptibility and outcome to infection with Mycobacterium leprae. As expected, many of the polymorphisms reside within genes that encode components of the innate and adaptive immune system. Despite the preponderance of these studies, our understanding of the mechanisms that underlie these genetic associations remains sparse. Toll-like receptors (TLRs) have emerged as an essential family of innate immune pattern recognition receptors which play a pivotal role in host defense against microbes, including pathogenic strains of mycobacteria. This paper will highlight studies which have uncovered the association of specific TLR gene polymorphisms with leprosy or tuberculosis: two important diseases resulting from mycobacterial infection. This analysis will focus on the potential influence these polymorphic variants have on TLR expression and function and how altered TLR recognition or signaling may contribute to successful antimycobacterial immunity.
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Villaseñor-Cardoso MI, Ortega E. Polymorphisms of innate immunity receptors in infection by parasites. Parasite Immunol 2012; 33:643-53. [PMID: 21851363 DOI: 10.1111/j.1365-3024.2011.01327.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
The innate immune system is the first line of defence against infection by pathogenic bacteria, virus and parasites and is also responsible for initiating an adaptive immune response. In contrast to the receptors of adaptive immunity (TCRs and antibodies) which are generated by gene recombination, receptors of the innate immune system are encoded in the germline and are thus inherited from generation to generation. Although evolutionarily selected, the genes encoding the innate recognition receptors show variations among individuals, and these polymorphisms may have an impact on the ability of an individual to deal with an infection. In recent years, several polymorphisms have been identified in innate recognition receptors, and efforts are being made to determine whether these polymorphisms are associated with a higher or lower susceptibility to infectious diseases. These studies will allow a better understanding of the role of innate receptors in specific diseases and are valuable in the design of preventive or therapeutic interventions to fight the disease. In this review, we summarize studies aimed at determining the influence of polymorphisms in innate recognition receptors on the susceptibility to diseases caused by parasites.
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Affiliation(s)
- M I Villaseñor-Cardoso
- Departamento de Inmunología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, México City, DF, Mexico
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Noreen M, Shah MAA, Mall SM, Choudhary S, Hussain T, Ahmed I, Jalil SF, Raza MI. TLR4 polymorphisms and disease susceptibility. Inflamm Res 2012; 61:177-88. [PMID: 22277994 DOI: 10.1007/s00011-011-0427-1] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2011] [Revised: 10/07/2011] [Accepted: 12/22/2011] [Indexed: 12/29/2022] Open
Abstract
Toll-like receptors (TLRs) play a central role in the regulation of the host immune system. Each TLR recognizes specific pathogen-associated molecular patterns (PAMPs). TLR4 is one of the well characterized pathogen recognition receptors (PRRs) that recognizes the lipopolysaccharide (LPS) of Gram-negative bacteria, some conserved structures from fungal to mycobacterial pathogens and some endogenous ligands. A complex signaling cascade initiates after the ligand binds to the TLR4 ectodomain, leading to the activation of multiple inflammatory genes. Genetic variations greatly influence immune responses towards pathogenic challenges and disease outcome. In this review, we summarize various reports regarding TLR4 polymorphisms and disease susceptibility.
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Affiliation(s)
- Mamoona Noreen
- NUST Centre of Virology and Immunology, National University of Sciences and Technology, H-12, Islamabad, Pakistan.
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Nicolaou G, Goodall AH, Erridge C. Diverse bacteria promote macrophage foam cell formation via Toll-like receptor-dependent lipid body biosynthesis. J Atheroscler Thromb 2011; 19:137-48. [PMID: 22123216 DOI: 10.5551/jat.10249] [Citation(s) in RCA: 42] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/11/2022] Open
Abstract
AIM Atherosclerotic lesions contain DNA signatures from a wide variety of bacteria, although little is known of how exposure to these organisms may modulate the accumulation of lipids in macrophages. METHODS To address this, a panel of nine bacteria representing those most frequently reported to be present in human atheroma were examined for their potential to promote lipid accumulation in human primary monocytes and murine J774 macrophages. RESULTS All bacteria examined, and defined stimulants of Toll-like receptors (TLRs) 2, 3, 4, 5 and 9, induced lipid body formation and cholesterol ester accumulation in a dose-dependent manner. The mechanisms of bacteria-mediated foam cell formation were found to be dependent on TLR2 and/or TLR4 signalling, but independent of lipoprotein oxidation pathways, since lipid accumulation was significantly inhibited by the TLR4 inhibitors polymyxin-B and TAK-242, or the TLR2 and TLR4 inhibitor oxidised palmitoyl-arachidonyl-phosphatidyl-choline, but not by the scavenger receptor blocker polyinosinic acid or the antioxidant butylated hydroxytoluene. A number of genes involved in lipid body biosynthesis, including perilipin-A, stearoyl-coenzyme-A desaturase 1, fatty acid synthase and HMG-CoA reductase were upregulated in response to TLR4 stimulation. CONCLUSIONS The bacterial debris observed in human atheroma, which is currently considered to be harmless, may have potential to contribute to disease progression via TLR-dependent lipid body formation in macrophages.
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Affiliation(s)
- Giovanna Nicolaou
- Department of Cardiovascular Sciences, Glenfield Hospital, Leicester, UK
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Plantinga TS, Ioana M, Alonso S, Izagirre N, Hervella M, Joosten LAB, van der Meer JWM, de la Rúa C, Netea MG. The evolutionary history of TLR4 polymorphisms in Europe. J Innate Immun 2011; 4:168-75. [PMID: 21968286 DOI: 10.1159/000329492] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2011] [Accepted: 05/13/2011] [Indexed: 12/16/2022] Open
Abstract
Infections exert important evolutionary pressures shaping the human genome, especially on genes involved in host defense. A crucial step for host defense is recognition of pathogens by pattern recognition receptors on innate immune cells, among which Toll-like receptor 4 (TLR4) is one of the best known. Genetic variation in TLR4 (Asp299Gly, Thr399Ile) has been recently described. Haplotype frequencies of these polymorphisms differ among African, Asian and European populations, suggesting evolutionary pressures exerted by local infections. The TLR4 299Gly/399Ile haplotype, characteristic mainly of European populations, has relatively high frequency in the Iberian peninsula. This region is also described as refuge area during the last glacial maximum 20,000 years ago, from which repopulation of Europe took place. We speculate that a genetic bottleneck in the Iberian peninsula could have promoted the increased frequency of this haplotype by genetic drift. This hypothesis is supported by three arguments: (1) the West-East gradient of prevalence in the haplotype among European populations; (2) ancient DNA from Neolithic burials in the Iberian peninsula, dated 6,600-4,500 years before present, confirmed the relatively high frequency of this haplotype in the region, and (3) no functional differences between this haplotype and wild-type TLR4 have been found. In contrast, the disappearance of the 299Gly/399Thr haplotype in Europe is most likely due to negative selection due to sepsis. In conclusion, differences in distribution of TLR4 polymorphisms Asp299Gly and Thr399Ile in European populations are most likely due to a combination of population migration events combined with selection due to sepsis.
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Affiliation(s)
- Theo S Plantinga
- Department of Medicine, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
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Izmailova OV, Shlykova OA, Bobrova NO, Kaidashev IP. Relationship between the TLR2 and TLR4 gene polymorphisms with a predisposition to certain urogenital infections. CYTOL GENET+ 2011. [DOI: 10.3103/s0095452711040050] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Cuda C, Badawi A, Karmali M, El-Sohemy A. Polymorphisms in Toll-like receptor 4 are associated with factors of the metabolic syndrome and modify the association between dietary saturated fat and fasting high-density lipoprotein cholesterol. Metabolism 2011; 60:1131-5. [PMID: 21306745 DOI: 10.1016/j.metabol.2010.12.006] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/05/2010] [Revised: 12/10/2010] [Accepted: 12/13/2010] [Indexed: 01/21/2023]
Abstract
Toll-like receptor 4 (TLR4) is a protein of the innate immune system hypothesized to mediate some of the effects of a high-fat diet on inflammation and insulin resistance. As both these factors are associated with the metabolic syndrome (MetS), genetic variation in TLR4 may affect the relationship between dietary lipids and MetS. The objective of the study was to determine whether 2 polymorphisms in TLR4 (rs4986790 Asp299Gly and rs5030728 G>A) modify the relationship between dietary fat and markers of the MetS. Participants were healthy young men and women of various ethnocultural backgrounds. Dietary intake was estimated using a 1-month semiquantitative food frequency questionnaire, and fasting blood samples were taken for genotyping and biomarker measurement. The Asp299Gly polymorphism in TLR4 was associated with increased insulin, homeostasis model assessment of insulin resistance (P < .05), and homeostasis model assessment of β-cell function (P < .05) and family history of diabetes (P = .0002). The intronic polymorphism rs5030728 modified the relationship between dietary saturated fatty acids (SFAs) and high-density lipoprotein (HDL) cholesterol (P = .003 for interaction). The SFA intake was inversely associated with HDL cholesterol among individuals homozygous for the G allele (β = -0.015 ± 0.007 mmol/L, P = .04), whereas a positive relationship was observed for heterozygotes (β = 0.025 ± 0.01 mmol/L, P = .02). There was no association between dietary SFAs and HDL cholesterol among individuals homozygous for the A allele. These observations suggest that both diet and innate immunity may interact to influence components of the MetS.
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Affiliation(s)
- Cristina Cuda
- Department of Nutritional Sciences Faculty of Medicine University of Toronto, Toronto (ON), Canada M5S 3E2
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Ahmad-Nejad P, Denz C, Zimmer W, Wacker J, Bugert P, Weiss C, Quintel M, Neumaier M. The presence of functionally relevant toll-like receptor polymorphisms does not significantly correlate with development or outcome of sepsis. Genet Test Mol Biomarkers 2011; 15:645-51. [PMID: 21721932 DOI: 10.1089/gtmb.2010.0258] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
AIMS Members of the toll-like receptor (TLR) family have been shown to play important roles in inflammatory responses. Single-nucleotide polymorphisms (SNPs) altering receptor activity may either have detectable effects or might be without results due to compensatory mechanisms. We determined the genotype frequencies of functionally relevant SNPs in TLR2, 4 and 5 in critically ill patients (n=150) from a multidisciplinary surgical intensive care unit (ICU). The inflammatory response (procalcitonin, C-reactive protein, white blood count) and clinical classification (Acute Physiology and Chronic Health Evaluation Score II, Simplified Acute Physiology Score II, Sepsis-related Organ Failure Assessment) were monitored daily. RESULTS The genetic polymorphisms correlate with neither development nor outcome of sepsis. No correlations were found between C-reactive protein or WBC and the investigated SNPs. In patients in the ICU with abdominal surgery and multiple trauma, the TLR2-R753Q SNP was associated with infection at ICU admission (p<0.01); and for carriers of the TLR4-D299G SNP, a trend was observed (p=0.0776). Patients with multiple trauma carrying the TLR4-D299G SNP displayed significantly higher levels of procalcitonin (p=0.0212). CONCLUSIONS None of the investigated SNPs clearly predicted outcome of sepsis-related multiorgan failure. TLR2-R753Q SNP may be a useful marker to identify patients with high risk to develop infections at ICU admission but should be validated in larger studies. Future SNP-arrays investigating predisposition for infection should include this SNP alone or in combination with other functionally relevant SNPs.
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Affiliation(s)
- Parviz Ahmad-Nejad
- Institute for Clinical Chemistry, University Hospital Mannheim, Mannheim, Germany
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Shaw AC, Panda A, Joshi SR, Qian F, Allore HG, Montgomery RR. Dysregulation of human Toll-like receptor function in aging. Ageing Res Rev 2011; 10:346-53. [PMID: 21074638 DOI: 10.1016/j.arr.2010.10.007] [Citation(s) in RCA: 149] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2010] [Revised: 10/22/2010] [Accepted: 10/25/2010] [Indexed: 12/19/2022]
Abstract
Studies addressing immunosenescence in the immune system have expanded to focus on the innate as well as the adaptive responses. In particular, aging results in alterations in the function of Toll-like receptors (TLRs), the first described pattern recognition receptor family of the innate immune system. Recent studies have begun to elucidate the consequences of aging on TLR function in human cohorts and add to existing findings performed in animal models. In general, these studies show that human TLR function is impaired in the context of aging, and in addition there is evidence for inappropriate persistence of TLR activation in specific systems. These findings are consistent with an overarching theme of age-associated dysregulation of TLR signaling that likely contributes to the increased morbidity and mortality from infectious diseases found in geriatric patients.
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Casanova JL, Abel L, Quintana-Murci L. Human TLRs and IL-1Rs in host defense: natural insights from evolutionary, epidemiological, and clinical genetics. Annu Rev Immunol 2011; 29:447-91. [PMID: 21219179 DOI: 10.1146/annurev-immunol-030409-101335] [Citation(s) in RCA: 251] [Impact Index Per Article: 17.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Toll-like receptors (TLRs) and interleukin-1 receptors (IL-1Rs) have TIR intracellular domains that engage two main signaling pathways, via the TIR-containing adaptors MyD88 (which is not used by TLR3) and TRIF (which is used only by TLR3 and TLR4). Extensive studies in inbred mice in various experimental settings have attributed key roles in immunity to TLR- and IL-1R-mediated responses, but what contribution do human TLRs and IL-1Rs actually make to host defense in the natural setting? Evolutionary genetic studies have shown that human intracellular TLRs have evolved under stronger purifying selection than surface-expressed TLRs, for which the frequency of missense and nonsense alleles is high in the general population. Epidemiological genetic studies have yet to provide convincing evidence of a major contribution of common variants of human TLRs, IL-1Rs, or their adaptors to host defense. Clinical genetic studies have revealed that rare mutations affecting the TLR3-TRIF pathway underlie herpes simplex virus encephalitis, whereas mutations in the TIR-MyD88 pathway underlie pyogenic bacterial diseases in childhood. A careful reconsideration of the contributions of TLRs and IL-1Rs to host defense in natura is required.
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Affiliation(s)
- Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, The Rockefeller University, New York, NY 10021, USA.
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Bhuvanendran S, Hussin HM, Meran LP, Anthony AA, Zhang L, Burch LH, Phua KK, Ismail A, Balaram P. Toll-like receptor 4 Asp299Gly and Thr399Ile polymorphisms and typhoid susceptibility in Asian Malay population in Malaysia. Microbes Infect 2011; 13:844-51. [PMID: 21612766 DOI: 10.1016/j.micinf.2011.04.007] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2011] [Revised: 04/10/2011] [Accepted: 04/18/2011] [Indexed: 12/19/2022]
Abstract
Typhoid fever is a major health problem with frequent outbreaks in Kelantan, Malaysia. Prevalence of TLR4 gene polymorphisms varies with ethnic groups (0-20%) and predisposean individual to gram-negative infections. The prevalence rate of TLR4 Asp299Gly and Thr399lle polymorphisms in the Malay population or the influence of these on typhoid fever susceptibility is not yet reported. 250 normal and 304 susceptible Malay individuals were investigated for these polymorphisms using allele-specific PCR and analysed for its association with typhoid fever susceptibility. The total prevalence of polymorphisms in the normal population was 4.8% in comparison to 12.5% in the susceptible population (p = 0.002). An increased frequency of both polymorphisms was observed in the susceptible population (p < 0.01) with no homozygous mutants observed. Co-segregation was observed in 2% of controls and 3.6% of the susceptible individuals. This study, for the first time, reports the prevalence of TLR4 gene polymorphisms in the Malay population and suggests that these polymorphisms confer a higher risk for typhoid, infection. The higher incidence of typhoid fever in Kelantan could be attributed to the higher percentage of Malays (95%) in this state. In order to reduce the incidence of this disease, people with these polymorphisms, can be prioritised for prophylactic strategies.
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Affiliation(s)
- Saatheeyavaane Bhuvanendran
- Institute for Research in Molecular Medicine, Health Campus, Universiti Sains Malaysia, 16150 Kubang Kerian, Kelantan, Malaysia
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Abstract
Despite the availability of effective treatment for several decades, leprosy remains an important medical problem in many regions of the world. Infection with Mycobacterium leprae can produce paucibacillary disease, characterized by well-formed granulomas and a Th1 T-cell response, or multibacillary disease, characterized by poorly organized cellular infiltrates and Th2 cytokines. These diametric immune responses confer states of relative resistance or susceptibility to leprosy, respectively, and have well-defined clinical manifestations. As a result, leprosy provides a unique opportunity to dissect the genetic basis of human in vivo immunity. A series of studies over the past 40 years suggests that host genes influence the risk of leprosy acquisition and the predilection for different clinical forms of the disease. However, a comprehensive, cellular, and molecular view of the genes and variants involved is still being assembled. In this article, we review several decades of human genetic studies of leprosy, including a number of recent investigations. We emphasize genetic analyses that are validated by the replication of the same phenotype in independent studies or supported by functional experiments demonstrating biological mechanisms of action for specific polymorphisms. Identifying and functionally exploring the genetic and immunological factors that underlie human susceptibility to leprosy have yielded important insights into M. leprae pathogenesis and are likely to advance our understanding of the immune response to other pathogenic mycobacteria. This knowledge may inform new treatment or vaccine strategies for leprosy or tuberculosis.
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Balistreri CR, Caruso C, Listì F, Colonna-Romano G, Lio D, Candore G. LPS-mediated production of pro/anti-inflammatory cytokines and eicosanoids in whole blood samples: biological effects of +896A/G TLR4 polymorphism in a Sicilian population of healthy subjects. Mech Ageing Dev 2011; 132:86-92. [PMID: 21238472 DOI: 10.1016/j.mad.2010.12.005] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2010] [Revised: 11/22/2010] [Accepted: 12/23/2010] [Indexed: 12/19/2022]
Abstract
Toll-like receptors (TLRs) are the principal mediators of rapid microbial recognition: the lipopolysaccharide (LPS) receptor TLR4 seems to have a paradigmatic role. Single nucleotide polymorphisms (SNPs) in the TLR4 gene, such as +896A/G, known to attenuate receptor signaling, have been described. The +896A/G SNP is significantly less frequent in patients with myocardial infarction, Alzheimer's disease or prostate cancer, whereas it is overrepresented in centenarians. To clarify and confirm the biological effects of +896A/G SNP and its role in the pathophysiology of age-related diseases and longevity, we assessed the levels of IL-6, TNF-α, IL-10 and eicosanoids (LTB4 and PGE2) in LPS-stimulated whole blood samples in vitro of 50 young healthy Sicilians, screened for the presence of this SNP. To evaluate the possible influence of SNPs in PTGS2 and 5-Lo genes on eicosanoid production, the enrolled individuals were also genotyped for -765G/C PTGS2 and -1708G/A 5-Lo SNPs. Both pro-inflammatory cytokines and eicosanoids were significantly lower in carriers bearing the TLR4 mutation, whereas the anti-inflammatory IL-10 values were higher. On the basis of data reported herein, some suggestions can be drawn. First, pathogen load, by interacting with the host genotype, determines the type and intensity of inflammatory responses, according to the pro-inflammatory status and tissue injury, implicated in the pathophysiology of major age-related diseases. Second, adequate control of inflammatory response might reduce the risk of these diseases, and, reciprocally, might increase the chance of extended survival in an environment with reduced antigen (that is, pathogen) load.
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Affiliation(s)
- Carmela Rita Balistreri
- Department of Pathobiology and Medical and Forensic Biotechnologies, University of Palermo, Palermo, Italy.
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Nogueira E, Salomao R, Brunialti MKC, Ozaki KS, Marques GDM, Cenedeze MA, Câmara NOS, Pacheco-Silva A. Expression of TLR-4 and -2 in peripheral mononuclear cells in renal transplant patients with TLR-4 gene polymorphism. Int Immunopharmacol 2010; 10:1481-5. [PMID: 20951669 DOI: 10.1016/j.intimp.2010.09.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2010] [Revised: 09/03/2010] [Accepted: 09/10/2010] [Indexed: 10/18/2022]
Abstract
INTRODUCTION TLR-4 has also been identified as a receptor for endogenous alarmins, which are increased post transplantation. TLR-4 has also been associated with a polymorphism that could impact graft outcome. OBJECTIVE To assess the expression of TLR-4 in kidney transplant patients carrying or not a polymorphism. METHODS TLR-4 polymorphism (A299G/T399I) was studied in 200 renal transplant patients. Healthy volunteers were also enrolled as control group. The polymorphism analysis was performed using restriction enzymes technique (RFLP). Functionality of TLR-4 polymorphism was assessed in samples from controls by quantification of TNF-α after LPS stimulus. TLR-4 and -2 expressions were also analyzed by flow cytometry. RESULTS TLR-4 polymorphism was present in 8.5% of renal transplant patients. This polymorphism was associated with impairment in TNF-α secretion. In general, in renal transplant patients, TLR-4 expression in monocytes and in neutrophils was lower than in health volunteers. TLR-2 and TLR-4 expressions in healthy volunteers with A299G/T399I TLR-4 polymorphism was higher than in wild-type genotype healthy volunteers (p<0.01 and p<0.05, respectively), and also higher than A299G/T399I TLR-4 polymorphism renal transplant patients (p<0.05). TLR-2 expression on neutrophils in wild-type genotype renal transplant patients was higher compared to wild-type genotype healthy volunteers, and was also higher in relation to A299G/T399I kidney transplanted patients (p<0.01). CONCLUSION Stable renal transplant patients with TLR-4 polymorphism have a lower expression of TLR-4 and TLR-2 receptors in peripheral mononuclear cells, which ultimately indicate a less responsiveness for alarmins.
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Affiliation(s)
- Eliana Nogueira
- Laboratory of Clinical and Experimental Immunology, Nephrology Division, Federal University of São Paulo (UNIFESP), Brazil.
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Aoyagi Y, Nagata S, Kudo T, Fujii T, Wada M, Chiba Y, Ohtsuka Y, Yamashiro Y, Shimizu T, Ohkusa T. Peroxisome proliferator-activated receptor γ 2 mutation may cause a subset of ulcerative colitis. Pediatr Int 2010; 52:729-34. [PMID: 20591056 DOI: 10.1111/j.1442-200x.2010.03195.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
AIM Previous studies suggest the homeostasis between acquisition of tolerance to the indigenous microflora and protective immune responses appears to be disrupted in inflammatory bowel disease (IBD). Some experimental studies indicate peroxisome proliferator-activated receptor γ (PPARγ) has been implicated as a regulator of intestinal inflammatory responses. In addition, the toll-like receptor (TLR)-4 can regulate expression of PPARγ in colonic epithelial cells. We attempted to demonstrate whether the functional imbalance between TLRs and PPARγ could lead to the onset and some polymorphisms of those genes could contribute to susceptibility to IBD. METHODS RT-PCR analysis were performed to detect TLR4 and PPARγ mRNA associated with those of P65 of NFκB, TNFα, MyD88, NOD2/CARD15, TLR-2,5,9, in the diseased colonic mucosa in ulcerative colitis (UC; n = 13) and Crohn's disease (CD; n = 7) compared with normal controls (n = 18). Consequently, we genotyped UC (n = 29) and CD (n = 10) compared with normal controls (n = 134) for the prevalence of suspicious mutations. RESULTS In a subset of UC patients who were revealed to carry PPARγ Pro12Ala mutation later, impaired expression of normal PPARγ mRNA was noted in the diseased mucosa accompanied with upregulations of MyD88 TLR-4, 5, 9, P65 and TNFα in mRNA levels. The prevalence of PPARγ Pro12Ala mutation was more frequently found in UC patients compared with CD patients and normal controls (P < 0.05). CONCLUSIONS These findings suggested that imbalances between TLRs and PPARγ in response to luminal bacteria could lead to colonic inflammation in some UC patients. Alternative explanations will be needed for the onset of the rest of UC and CD.
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Affiliation(s)
- Yo Aoyagi
- Department of Pediatrics, Juntendo University School of Medicine, Tokyo, Japan
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Guarner-Argente C, Sánchez E, Vidal S, Román E, Concepción M, Poca M, Sánchez D, Juárez C, Soriano G, Guarner C. Toll-like receptor 4 D299G polymorphism and the incidence of infections in cirrhotic patients. Aliment Pharmacol Ther 2010; 31:1192-1199. [PMID: 20222908 DOI: 10.1111/j.1365-2036.2010.04291.x] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Toll-like receptor (TLR) 4 genetic polymorphisms, mainly D299G, have been associated with increased predisposition to infection in several populations. AIM To retrospectively analyse the relationship between the presence of the TLR4 D299G polymorphism and the incidence of bacterial infections in cirrhotic patients. METHODS We included 111 consecutive cirrhotic patients hospitalized with ascites and we determined the presence of the TLR4 D299G polymorphism by PCR-RFLP (polymerase chain reaction-restriction fragment length polymorphism) and its relationship with the incidence of previous bacterial infections. RESULTS Ten out of 111 (9%) cirrhotic patients presented with the TLR4 D299G polymorphism. The mean follow-up from first decompensation of cirrhosis until current admission was longer in D299G polymorphism patients than in wild-type patients (53.8 +/- 40.7 vs. 35.4 +/- 48.3 months, P = 0.03). D299G polymorphism patients showed a trend towards a higher incidence of history of previous infections (80% vs. 56.4%, P = 0.19), as well as a higher number of infections (2.8 +/- 2.3 vs. 1.0 +/- 1.3, P = 0.01) and bacteriaemias (0.4 +/- 1.0 vs. 0.04 +/- 0.2, P = 0.02) per patient than wild-type patients. CONCLUSIONS Toll-like receptor 4 D299G polymorphism could influence not only the predisposition to bacterial infections but also the evolution of the disease in cirrhotic patients. Further prospective studies in larger series of patients are warranted.
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Affiliation(s)
- C Guarner-Argente
- Department of Gastroenterology, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain
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Lack of association of TLR4 gene Asp299Gly and Thr399Ile polymorphisms with rheumatoid arthritis in Chinese Han population of Yunnan Province. Rheumatol Int 2010; 30:1249-52. [PMID: 20306049 DOI: 10.1007/s00296-010-1400-y] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2009] [Accepted: 02/27/2010] [Indexed: 12/27/2022]
Abstract
Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by chronic inflammation of synovium and subsequent joint destruction. Recently, genetic polymorphisms within the toll-like receptor 4 (TLR4) genes have been reported to be associated with RA. To analyze the association between the genetic polymorphisms within TLR4 gene and the susceptibility to RA in Chinese people, two functional variants, Asp299Gly and Thr399Ile, in the TLR4 gene were genotyped using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and direct sequencing techniques from 213 RA patients and 247 ethnically matched controls. None polymorphisms of Asp299Gly and Thr399Ile were detected in all RA cases and controls, which indicates that there is no relevance between these two SNPs and RA in the Chinese Han population. Further studies with extended single nucleotide polymorphisms (SNP) should be performed.
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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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Zouiten-Mekki L, Kharrat M, Karoui S, Serghimi M, Fekih M, Matri S, Kallel L, Boubaker J, Filali A, Chaabouni H. Tolllike receptor 4 (TLR4) polymorphisms in Tunisian patients with Crohn's disease: genotype-phenotype correlation. BMC Gastroenterol 2009; 9:62. [PMID: 19664207 PMCID: PMC2736969 DOI: 10.1186/1471-230x-9-62] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2009] [Accepted: 08/07/2009] [Indexed: 01/25/2023] Open
Abstract
Background The immune responses to bacterial products through the pattern recognition receptor (PRR) play a pivotal role in pathogenesis of Crohn's disease. A recent study described an association between CD and some gene coding for bacterial receptor like NOD2/CARD15 gene and TLR4. In this study, we sought to determine whether TLR4 gene was associated with Crohn's disease (CD) among the Tunisian population and its correlation with clinical manifestation of the disease. Methods 90 patients with CD and 80 healthy individuals are genotyped for the Asp299Gly and Thr399Ile polymorphisms by restriction fragment length polymorphism analysis. Results The allele and genotype frequency of the TLR4 polymorphisms did not differ between patients and controls. The genotype-phenotype correlation permitted to show that the Thr399Ile polymorphism was associated with early onset disease. Conclusion this study reported the absence of association between CD and TLR4 gene in the Tunisian population, but this gene could play a role in clinical expression of the disease.
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Poikonen K, Lajunen T, Silvennoinen-Kassinen S, Leinonen M, Saikku P. Effects of CD14, TLR2, TLR4, LPB, and IL-6 Gene Polymorphisms onChlamydia pneumoniaeGrowth in Human MacrophagesIn Vitro. Scand J Immunol 2009; 70:34-9. [DOI: 10.1111/j.1365-3083.2009.02267.x] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/01/2022]
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Bochud PY, Sinsimer D, Aderem A, Siddiqui MR, Saunderson P, Britton S, Abraham I, Tadesse Argaw A, Janer M, Hawn TR, Kaplan G. Polymorphisms in Toll-like receptor 4 (TLR4) are associated with protection against leprosy. Eur J Clin Microbiol Infect Dis 2009; 28:1055-65. [PMID: 19430824 DOI: 10.1007/s10096-009-0746-0] [Citation(s) in RCA: 59] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2009] [Accepted: 03/31/2009] [Indexed: 11/29/2022]
Abstract
Accumulating evidence suggests that polymorphisms in Toll-like receptors (TLRs) influence the pathogenesis of mycobacterial infections, including leprosy, a disease whose manifestations depend on host immune responses. Polymorphisms in TLR2 are associated with an increased risk of reversal reaction, but not susceptibility to leprosy itself. We examined whether polymorphisms in TLR4 are associated with susceptibility to leprosy in a cohort of 441 Ethiopian leprosy patients and 197 healthy controls. We found that two single nucleotide polymorphisms (SNPs) in TLR4 (896G>A [D299G] and 1196C>T [T399I]) were associated with a protective effect against the disease. The 896GG, GA and AA genotypes were found in 91.7, 7.8 and 0.5% of leprosy cases versus 79.9, 19.1 and 1.0% of controls, respectively (odds ratio [OR] = 0.34, 95% confidence interval [CI] 0.20-0.57, P < 0.001, additive model). Similarly, the 1196CC, CT and TT genotypes were found in 98.1, 1.9 and 0% of leprosy cases versus 91.8, 7.7 and 0.5% of controls, respectively (OR = 0.16, 95% CI 0.06--.40, P < 0.001, dominant model). We found that Mycobacterium leprae stimulation of monocytes partially inhibited their subsequent response to lipopolysaccharide (LPS) stimulation. Our data suggest that TLR4 polymorphisms are associated with susceptibility to leprosy and that this effect may be mediated at the cellular level by the modulation of TLR4 signalling by M. leprae.
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Affiliation(s)
- P-Y Bochud
- Institute for Systems Biology, Seattle, WA, USA.
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Greene JA, Moormann AM, Vulule J, Bockarie MJ, Zimmerman PA, Kazura JW. Toll-like receptor polymorphisms in malaria-endemic populations. Malar J 2009; 8:50. [PMID: 19317913 PMCID: PMC2667436 DOI: 10.1186/1475-2875-8-50] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2008] [Accepted: 03/24/2009] [Indexed: 02/01/2023] Open
Abstract
Background Toll-like receptors (TLR) and related downstream signaling pathways of innate immunity have been implicated in the pathogenesis of Plasmodium falciparum malaria. Because of their potential role in malaria pathogenesis, polymorphisms in these genes may be under selective pressure in populations where this infectious disease is endemic. Methods A post-PCR Ligation Detection Reaction-Fluorescent Microsphere Assay (LDR-FMA) was developed to determine the frequencies of TLR2, TLR4, TLR9, MyD88-Adaptor Like Protein (MAL) single nucleotide polymorphisms (SNPs), and TLR2 length polymorphisms in 170 residents of two regions of Kenya where malaria transmission is stable and high (holoendemic) or episodic and low, 346 residents of a malaria holoendemic region of Papua New Guinea, and 261 residents of North America of self-identified ethnicity. Results The difference in historical malaria exposure between the two Kenyan sites has significantly increased the frequency of malaria protective alleles glucose-6-phoshpate dehydrogenase (G6PD) and Hemoglobin S (HbS) in the holoendemic site compared to the episodic transmission site. However, this study detected no such difference in the TLR2, TLR4, TLR9, and MAL allele frequencies between the two study sites. All polymorphisms were in Hardy Weinberg Equilibrium in the Kenyan and Papua New Guinean populations. TLR9 SNPs and length polymorphisms within the TLR2 5' untranslated region were the only mutant alleles present at a frequency greater than 10% in all populations. Conclusion Similar frequencies of TLR2, TLR4, TLR9, and MAL genetic polymorphisms in populations with different histories of malaria exposure suggest that these innate immune pathways have not been under strong selective pressure by malaria. Genotype frequencies are consistent with Hardy-Weinberg Equilibrium and the Neutral Theory, suggesting that genetic drift has influenced allele frequencies to a greater extent than selective pressure from malaria or any other infectious agents in these populations.
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Affiliation(s)
- Jennifer A Greene
- Center for Global Health and Diseases, Case Western Reserve University, Cleveland OH, USA.
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Abstract
Understanding the host genetic susceptibility to typhoid fever may provide a better understanding of pathogenesis and help in the development of new therapeutics and vaccines. Here we determine the genetic variation within the human TLR4 gene encoding the principal receptor for bacterial endotoxin recognition in typhoid fever patients. It is possible that genetic variants of TLR4 could detrimentally affect the innate immune response against S. typhi infection. Mutation detection and genotyping of TLR4 was performed on DNA from 414 Vietnamese typhoid fever patients and 372 population controls. dHPLC detected a total of 10 polymorphisms within the upstream and exonic regions of TLR4, of which 7 are novel. Two SNPs, T4025A and C4215G, were more frequent in typhoid cases than in controls however due to their low allele frequencies they showed borderline significance (T4025A: OR 1.9, 95%CI 0.9–4.3, P 0.07 and C4215G: OR 6.7, 95%CI 0.8–307, P 0.04). Six missense mutations were identified, with 5/6 positioned in the ectoplasmic domain. Four missense mutations and one promoter SNP (A-271G) were only present in typhoid cases, albeit at low allele frequencies. Here we determined the extent of genetic variation within TLR4 in a Vietnamese population and suggest that TLR4 may be involved in defense against typhoid fever in this population.
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