TLR1 and TLR6 Polymorphisms Are Associated with Susceptibility to Invasive Aspergillosis after Allogeneic Stem Cell Transplantation
Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York, United States Annals of the New York Academy of Sciences
(Impact Factor: 4.38).
12/2005; 1062(1):95-103. DOI: 10.1196/annals.1358.012
Toll-like receptors (TLRs) transmit signals in response to Aspergillus fumigatus conidia and hyphae. In this preliminary study, we examined the association between single nucleotide polymorphisms (SNPs) in TLR1, TLR4, and TLR6 genes and development of invasive aspergillosis (IA) in 127 allogeneic hematopoietic stem cell transplant recipients consisting of 22 patients with IA and 105 unaffected control subjects. The following SNPs and their pairwise interactions were considered in the model: TLR1 (239G > C, 743A > G, 914A > T, 1805G > T), TLR4 (896A > G, 1196C > T), and TLR6 (359T > C, 745C > T, 764C > T). No association was found between donor SNP and the risk of IA. Analysis of recipient SNP data showed that the presence of TLR1 239G > C (Arg80 > Thr) or the presence of both TLR1 743A > G (Asn248 > Ser) and TLR6 745C > T (Ser249 > Pro) is associated with IA (odds ratio = 1.30, 95% confidence interval = 1.13 to 1.50; P < .001). Further analyses using a prospective cohort may enable us to identify TLR polymorphisms associated with the susceptibility to IA within a defined interval among immunocompromised patients.
Available from: Cécile Clercx
- "Recently, Carvalho et al. noted a positive association between TLR4 SNPs and fungal colonization, but not susceptibility to fungal infection . Kesh et al. did not report any positive association of recipient or donor TLR4 SNPs with the incidence of IA in patients undergoing allogeneic stem cell transplantation . In human CRS, there are also discrepancies between studies regarding the role of SNPs in TLR genes. "
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The exact aetiology of canine sino-nasal aspergillosis (SNA) is unknown. In man, dysfunction in innate immunity, particularly in the function of pattern recognition receptors, is implicated in the pathogenesis of inflammatory sino-nasal disease and in fungal diseases. Associations between single nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs) and these diseases have been identified. Similarly, in dogs SNPs in genes encoding TLRs may be important in the pathogenesis of SNA. The aims of the present study were (1) to identify the presence of non-synonymous SNPs in the coding regions of the TLR2, 4 and 9 genes in dogs suffering from SNA, and (2) to investigate the SNP genotypes in dogs with SNA compared with a control population.
Direct sequencing of nine dogs of various breeds with SNA revealed two non-synonymous SNPs in the coding region of TLR2, eight in TLR4 and four in TLR9. These non-synonymous SNPs were further evaluated in a case-control study of affected Golden Retrievers, Labrador Retrievers, Rottweilers and Beaucerons. Genotyping was performed using a combination of allele-specific primers and hydrolysis probe assays in 31 dogs with SNA and 31controls. No significant difference in minor allele frequency was identified between these groups, for all studied SNPs, in any of the four breeds.
These findings do not support a role for non-synonymous SNPs in the TLR 2, 4 and 9 coding regions in the pathogenesis of canine SNA, but do not exclude a role for innate immunity in the pathogenesis of the disease.
Available from: Maria Libera Ascierto
- "Genome-wide association studies showed that polymorphisms of innate components are associated to individual variable response to treatment and to disease progression. Nucleotide polymorphisms of TLRs [TLR-4 (108, 109), TLR-1 and 6 (110)] and of pentraxin-3 (111) are associated to increased risk of invasive aspergillosis or mycosis in bone marrow transplant patients (110, 111). Similarly, TLR3 polymorphisms have been associated to pneumonia development in children with influenza virus infection (112). "
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ABSTRACT: Natural killer (NK) cell function is regulated by a balance between the triggering of activating and inhibitory receptors expressed on their surface. A relevant effort has been focused so far on the study of KIR carriage/expression setting the basis for NK cell education and self-tolerance. Focus on the evolution and regulation of activating NK receptors has lagged behind so far. Our understanding of activating receptor expression and regulation has recently improved by evidences derived from in vitro and in vivo studies. Virus infection - either acute or chronic - determines preferential expansion of NK cells with specific phenotype, activating receptors, and with recall-like functional activity. Studies on patients with viral infection (HIV and HCV) and specific diverging clinical courses confirm that inter-individual differences may exist in baseline expression of natural cytotoxicity receptors (NKp46 and NKp30). The findings that patients with divergent clinical courses have different kinetics of activating receptor density expression upon NK cell activation in vitro provide an additional, time-dependent, functional parameter. Kinetic changes in receptor expression thus represent an additional parameter to basal receptor density expression. Different expression and inducibilities of activating receptors on NK cells contribute to the high diversity of NK cell populations and may help our understanding of the inter-individual differences in innate responses that underlie divergent disease courses.
Available from: Lutz Uharek
- "A retrospective analysis observed a significant association between TLR1 and TLR6 polymorphisms of the recipient and IPA incidence in 127 patients with allogeneic SCT . However, monogenetic mechanisms probably do not explain completely the association due to the multiple detection ways of the pattern recognition receptors. "
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ABSTRACT: Patients with allogeneic stem cell transplantation (SCT) have a high risk of invasive fungal infections (IFIs) even after neutrophil regeneration. Immunological aspects might play a very important role in the IFI development in these patients. Some data are available supporting the identification of high-risk patients with IFI for example patients receiving stem cells from TLR4 haplotype S4 positive donors. Key defense mechanisms against IFI include the activation of neutrophils, the phagocytosis of germinating conidia by dendritic cells, and the fight of the cells of the innate immunity such as monocytes and natural killer cells against germlings and hyphae. Furthermore, immunosuppressive drugs interact with immune effector cells influencing the specific fungal immune defense and antimycotic drugs might interact with immune response. Based on the current knowledge on immunological mechanism in
, the first approaches of an immunotherapy using human T cells are in development. This might be an option for the future of aspergillosis patients having a poor prognosis with conventional treatment.
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