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Correlation between TLR2, TLR3, TLR4, and TLR9 polymorphisms and susceptibility to and prognosis of severe hepatitis among the newborns.

ABSTRACT: BACKGROUND:This study was aimed to explore how toll-like receptor 2 (TLR2), TLR3, TLR4 and TLR9 influenced the risk and prognosis of severe hepatitis among the Chinese newborns. METHODS:Altogether 135 newborns diagnosed with severe hepatitis and 140 healthy newborns were included in this study. Totally 12 single nucleotide polymorphisms (SNPs) within TLR2, TLR3, TLR4, and TLR9 were chosen and genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using the logistic regression. The univariate and multivariate analyses were used to analyze independent factors for prognosis of severe hepatitis among the Chinese newborns. RESULTS:The SNPs within TLR2 [ie, rs1898830 (A>G) and rs3804100 (T>C)], TLR3 [ie, rs1879026 (G>T)], TLR4 [ie, rs2149356 (T>G)], and TLR9 [ie, rs187084 (T>C), rs352139 (A>G), and rs352140 (C>T)] were significantly associated with modified risk of neonatal severe hepatitis (all P<.05). Furthermore, rs1898830, rs1879026, rs187084 and rs352139 were also demonstrated to modulate the prognosis [ie, aspartate aminotransferase (AST)/alanine transaminase (ALT)>1.5] of newborns with severe hepatitis (all P<.05). Interestingly, the haplotype A-C-G-G-C-A-T were associated with higher susceptibility to neonatal severe hepatitis, and the newborns carrying haplotype A-C-G-G-C-A-T appeared to be correlated with more favorable prognosis (all P<.05). CONCLUSIONS:Certain SNPs and haplotypes within TLR2, TLR3, TLR4, and TLR9 can be considered as the potentially treatment targets for neonatal severe hepatitis.

SUBMITTER: Qiu X

PROVIDER: S-EPMC6817216 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Correlation between TLR2, TLR3, TLR4, and TLR9 polymorphisms and susceptibility to and prognosis of severe hepatitis among the newborns.

Qiu Xiao X Dong Yubin Y Cao Yaqin Y Luo Yingmei Y

Journal of clinical laboratory analysis 20170713 3

<h4>Background</h4>This study was aimed to explore how toll-like receptor 2 (TLR2), TLR3, TLR4 and TLR9 influenced the risk and prognosis of severe hepatitis among the Chinese newborns.<h4>Methods</h4>Altogether 135 newborns diagnosed with severe hepatitis and 140 healthy newborns were included in this study. Totally 12 single nucleotide polymorphisms (SNPs) within TLR2, TLR3, TLR4, and TLR9 were chosen and genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP ...[more]

PMID: 28703296

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Project description:BackgroundInterleukin-17 (IL-17) acts as a key regulator in central nervous system (CNS) inflammation. ?? T cells are an important innate source of IL-17. Both IL-17+ ?? T cells and microglia, the major resident immune cells of the brain, are involved in various CNS disorders such as multiple sclerosis and stroke. Also, activation of Toll-like receptor (TLR) signaling pathways contributes to CNS damage. However, the mechanisms underlying the regulation and interaction of these cellular and molecular components remain unclear.ObjectiveIn this study, we investigated the crosstalk between ?? T cells and microglia activated by TLRs in the context of neuronal damage. To this end, co-cultures of IL-17+ ?? T cells, neurons, and microglia were analyzed by immunocytochemistry, flow cytometry, ELISA and multiplex immunoassays.ResultsWe report here that IL-17+ ?? T cells but not naïve ?? T cells induce a dose- and time-dependent decrease of neuronal viability in vitro. While direct stimulation of ?? T cells with various TLR ligands did not result in up-regulation of CD69, CD25, or in IL-17 secretion, supernatants of microglia stimulated by ligands specific for TLR2, TLR4, TLR7, or TLR9 induced activation of ?? T cells through IL-1? and IL-23, as indicated by up-regulation of CD69 and CD25 and by secretion of vast amounts of IL-17. This effect was dependent on the TLR adaptor myeloid differentiation primary response gene 88 (MyD88) expressed by both ?? T cells and microglia, but did not require the expression of TLRs by ?? T cells. Similarly to cytokine-primed IL-17+ ?? T cells, IL-17+ ?? T cells induced by supernatants derived from TLR-activated microglia also caused neurotoxicity in vitro. While these neurotoxic effects required stimulation of TLR2, TLR4, or TLR9 in microglia, neuronal injury mediated by bone marrow-derived macrophages did not require TLR signaling. Neurotoxicity mediated by IL-17+ ?? T cells required a direct cell-cell contact between T cells and neurons.ConclusionTaken together, these results point to a crucial role for microglia activated through TLRs in polarization of ?? T cells towards neurotoxic IL-17+ ?? T cells.

Project description:BackgroundThe inflammatory bowel diseases (IBD), Crohn's disease (CD) and ulcerative colitis (UC), result from the combined effects of susceptibility genes and environmental factors. Polymorphisms in genes regulating inflammation may explain part of the genetic heritage.MethodsUsing a candidate gene approach, 39 mainly functional single nucleotide polymorphisms (SNPs) in 26 genes regulating inflammation were assessed in a clinical homogeneous group of severely diseased patients consisting of 624 patients with CD, 411 patients with UC and 795 controls. The results were analysed using logistic regression.ResultsSixteen polymorphisms in 13 genes involved in regulation of inflammation were associated with risk of CD and/or UC (p ≤ 0.05). The polymorphisms TLR2 (rs1816702), NFKB1 (rs28362491), TNFRSF1A (rs4149570), IL6R (rs4537545), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk of CD and the polymorphisms TLR2 (rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs352139), LY96 (rs11465996), NFKBIA (rs696), TNFA (rs1800629), TNFRSF1A (rs4149570), IL10 (rs3024505), IL23R (rs11209026), PTPN22 (rs2476601) and PPARG (rs1801282) were associated with risk of UC. When including all patients (IBD) the polymorphisms TLR2 (rs4696480 and rs1816702), TLR4 (rs1554973 and rs12377632), TLR9 (rs187084), TNFRSF1A (rs4149570), IL6R (rs4537545), IL10 (rs3024505), IL23R (rs11209026) and PTPN22 (rs2476601) were associated with risk. After Bonferroni correction for multiple testing, both the homozygous and the heterozygous variant genotypes of IL23R G>A(rs11209026) (OR(CD,adj): 0.38, 95% CI: 0.21-0.67, p = 0.03; OR(IBD,adj) 0.43, 95% CI: 0.28-0.67, p = 0.007) and PTPN22 1858 G>A(rs2476601) (OR(CD,unadj) 0.54, 95% CI: 0.41-0.72, p = 7*10-4; OR(IBD,unadj): 0.61, 95% CI: 0.48-0.77, p = 0.001) were associated with reduced risk of CD.ConclusionThe biological effects of the studied polymorphisms suggest that genetically determined high inflammatory response was associated with increased risk of CD. The many SNPs found in TLRs suggest that the host microbial composition or environmental factors in the gut are involved in risk of IBD in genetically susceptible individuals.

Dataset Information

Correlation between TLR2, TLR3, TLR4, and TLR9 polymorphisms and susceptibility to and prognosis of severe hepatitis among the newborns.

Publications

Correlation between TLR2, TLR3, TLR4, and TLR9 polymorphisms and susceptibility to and prognosis of severe hepatitis among the newborns.

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