Risk of trachomatous scarring and trichiasis in Gambians varies with SNP haplotypes at the interferon-gamma and interleukin-10 loci

Natividad, Angels; Wilson, Jonathan P.; Koch, Oliver; Holland, Martin J.; Rockett, Kirk A.; Faal, Nkoyo; Jallow, Ousman; Joof, Hassan; Burton, Matthew J.; Alexander, Neal; Kwiatkowski, Dominic P.; Mabey, David; Bailey, Robin L.

doi:10.1038/sj.gene.6364182

Cited by 59 publications

(42 citation statements)

References 57 publications

(56 reference statements)

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“…[11][12]14,16,17 Quantitative association between IL-10 À1082 SNP polymorphism and IL-10 production has been previously demonstrated by unspecific stimulation of lymphocytes with LPS or ConA, 18 but the role of IL-10 counteracting antigen-specific CMI responses has remained unclear. In this study, we demonstrated that IL-10 À1082 SNP is linked to IL-10 secretion as well as to interaction between in vitro infected monocytes and antigen-specific T-cell responses.…”

Section: Discussionmentioning

confidence: 99%

IL-10 polymorphism and cell-mediated immune response to Chlamydia trachomatis

Öhman¹,

Tiitinen

Halttunen

et al. 2006

Genes Immun

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Chlamydia trachomatis infection induces an inflammatory response that is crucial in resolving acute infection but may also play a key role in the pathogenesis of C trachomatis associated infertility. The immune response is linked to cytokine secretion pattern which is influenced by the host genetic background. To study a relationship between interleukin-10 (IL-10) promoter À1082 polymorphism and cell-mediated immune response during C trachomatis infection in vitro, lymphocyte proliferation and cytokine (IL-10, IFN-g, TNF-a, IL-2, IL-4 and IL-5) secretion were analysed in subjects with different IL-10 genotypes. Enhanced IL-10 secretion and reduced antigen-specific lymphocyte proliferative and IFN-g responses were found in subjects with IL-10 À1082 GG genotype when compared to those with À1082 AA genotype. CD14 þ monocytes were main source of IL-10 indicating that these cells are important regulators of the antigen-specific cell-mediated responses during active C trachomatis infection. We conclude that impaired cell-mediated response to C trachomatis is associated with IL-10 genotype in subjects with high IL-10 producing capacity. A comparison of immune markers between subjects with a history of noncomplicated and complicated infection is needed to further understand the confounding factors associated with the development of C trachomatis associated sequelae.

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Section: Discussionmentioning

confidence: 99%

IL-10 polymorphism and cell-mediated immune response to Chlamydia trachomatis

Öhman¹,

Tiitinen

Halttunen

et al. 2006

Genes Immun

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“…We have reported previously disease associations at the IFNg, IL10 and MMP9 loci in these subjects. 41,42 The study and its procedures were approved by the Gambia Government/MRC Ethics Committee (SCC 729/857), the Ethics committees of the London School of Hygiene and Tropical Medicine and of Oxford University, and are in accordance with the Declaration of Helsinki. Subjects diagnosed with trichiasis were offered free corrective surgery.…”

Section: Subjectsmentioning

confidence: 99%

“…Genotypes were determined by the Sequenom system using matrix assisted laser desorption/ionization time-of-flight (MAL-DI-TOF) mass spectrometry as described previously. 41 Primer sequences are available on request.…”

Section: Dna Extraction and Snp Genotypingmentioning

confidence: 99%

“…Full details are described elsewhere. 41 In brief, validated public SNPs of 45% minor allele frequency across the MHC class III genomic region encompassing TNF and its immediate neighbors IkBL and LTA loci were genotyped. After constructing haplotypes and applying the entropy maximization method, we identified a set of five htSNPs that described 90% of the observed haplotypic diversity (Figure 1) in this region.…”

Section: Snp Selectionmentioning

confidence: 99%

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Genetic variation at the TNF locus and the risk of severe sequelae of ocular Chlamydia trachomatis infection in Gambians

et al. 2007

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Tumor necrosis factor (TNF) is thought to be a key mediator of the inflammatory and fibrotic response to Chlamydia trachomatis (Ct) infection. A large matched-pair case-control study investigated putative functional single nucleotide polymorphisms (SNPs) across the major histocompatibility complex (MHC) class III region, including TNF and its immediate neighbors nuclear factor of k light polypeptide gene enhancer in B cells (IkBL), inhibitor like 1 and lymphotoxin alpha (LTA) in relation to the risk of scarring sequelae of ocular Ct infection. Haplotype and linkage disequilibrium analysis demonstrated two haplotypes, differing at position TNF-308, conferring an increased risk of trichiasis. The TNF-308A allele, and its bearing haplotype, correlated with increased TNF production in lymphocyte cultures stimulated with chlamydial elementary body antigen. Thus TNF-308A may determine directly, or be a marker of a high TNF producer phenotype associated with increased risk of sequelae of chlamydial infection. Multivariate analysis provided evidence for the presence of additional risk-associated variants near the TNF locus.

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“…16 In trachoma, several host inflammatory response genes have been identified as contributing to the severity of fibrotic disease leading to conjunctival scarring and trichiasis (turning-in of the eyelashes). [39][40][41] For example, part of the host immune system's initial defense against C. trachomatis infection is the activation and cytotoxic response of natural …”

Section: Host Factorsmentioning

confidence: 99%

Development of a vaccine for Chlamydia trachomatis: challenges and current progress

Hafner¹

2015

VDT

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Abstract:Chlamydia trachomatis remains an enigmatic bacterial pathogen with no vaccine yet available to treat human ocular and genital tract infections caused by tissue-tropic serovars of the organism. Globally, it is the leading cause of preventable blindness as well as the leading cause of bacterial sexually transmitted infections. The pathogen has a range of virulence factors that enable it to successfully evade both the innate and adaptive immune system of the host. The host immune system, although protective, paradoxically is also associated closely with the pathologies of trachoma and pelvic inflammatory disease -disease sequelae of some chlamydial infections and reinfections in some genetically susceptible hosts. In this review, we focus on what is known currently about the pathogenesis of ocular and genital infections caused by this mucosal pathogen. We also discuss novel insights into the pathogenesis of infections caused by the genital and ocular serovars of C. trachomatis, including a discussion of both pathogen and host factors, such as the human microbiota at these mucosal sites as well as the current immunological challenges facing vaccine development. Finally, we discuss the current progress toward development of a vaccine against C. trachomatis. A wide range of recombinant protein antigens are being identified and, hence, are available for vaccine trials. A plasmid-free live strain has recently been produced and evaluated in the mouse (Chlamydia muridarum) and monkey (C. trachomatis) models. The data for ocular infections in the monkey model was particularly encouraging, although the path to regulatory approval of a live vaccine is still uncertain. While still a major challenge, vaccines for ocular and genital C. trachomatis infections are looking more promising.

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Risk of trachomatous scarring and trichiasis in Gambians varies with SNP haplotypes at the interferon-gamma and interleukin-10 loci

Cited by 59 publications

References 57 publications

IL-10 polymorphism and cell-mediated immune response to Chlamydia trachomatis

IL-10 polymorphism and cell-mediated immune response to Chlamydia trachomatis

Genetic variation at the TNF locus and the risk of severe sequelae of ocular Chlamydia trachomatis infection in Gambians

Development of a vaccine for Chlamydia trachomatis: challenges and current progress

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