<i>TIM3</i> gene polymorphisms in patients with chronic hepatitis B virus infection: impact on disease susceptibility and hepatocellular carcinoma traits

Li, Z.; Liu, Z.; Zhang, G.; Han, Qunying; Li, N.; Zhu, Qianqian; Lv, Yi; Chen, J.; Xing, Fanfan; Wang, Y.; Li, F.

doi:10.1111/j.1399-0039.2012.01898.x

Cited by 24 publications

(12 citation statements)

References 28 publications

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“…These results are consistent with previous findings, showing that the PD1 +8669 genotype AA and TIM3 −1516 genotypes GT+TT are associated with either increased PD-1 mRNA expression in peripheral blood nuclear cells and disease progression in chronic HBV infection [27,39] or higher tumor grade and more frequent lymph node metastasis in HBV-related HCC. [28] Furthermore, these genotypes have been shown to be related to the poor survival of HBV-related HCC patients. [30] Therefore, our findings in the present study provide further evidence linking the host genetic background and immune dysfunction, supporting the importance of host immunogenetic background in the development, progression, and prognosis of HBV-associated liver diseases.…”

Section: Discussionmentioning

confidence: 99%

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Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma

Zhu

et al. 2016

Medicine

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Immune checkpoint proteins programmed death-1 (PD-1) and T-cell immunoglobulin domain and mucin domain containing molecule-3 (TIM-3) expression and their gene polymorphisms have separately been shown to be associated with hepatitis B virus (HBV) infection and hepatocellular carcinoma (HCC). This study simultaneously examined PD-1 and TIM-3 expression in liver tissues and PD1 and TIM3 polymorphisms and analyzed their correlations in 171 patients with HBV-related HCC and 34 patients with HBV-related cirrhosis.PD-1 and TIM-3 expression in liver tissues were examined by immunohistochemistry and the genotypes of PD1 rs10204525 and TIM3 rs10053538 polymorphisms were determined using genomic DNA extracted from peripheral blood as template.Both PD-1 and TIM-3 expressions in liver infiltrating lymphocytes of HCC tumor tissues were significantly higher than those in tumor adjacent tissues or cirrhotic tissues. The elevated PD-1 and TIM-3 expressions were significantly associated with higher tumor grades. The levels between PD-1 and TIM-3 expression in tumor tissues and tumor adjacent tissues had a significant positive intercorrelation. The expressions of PD-1 and TIM-3 in tumor tissues, tumor adjacent tissues, and cirrhotic tissues were significantly associated with PD1 and TIM3 polymorphisms, with genotype AA of PD1 rs10204525 and genotypes GT+TT of TIM3 rs10053538 being associated with significantly increased PD-1 and TIM-3 expression, respectively.These findings support the potential to improve the efficiency of immune checkpoint-targeted therapy and reduce resistance to the therapy by blocking both PD-1 and TIM-3 and suggest the potential to apply the genotype determination of PD1 rs10204525 and TIM3 rs10053538 as biomarkers of immune checkpoint-directed therapies.

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Section: Discussionmentioning

confidence: 99%

“…Human genomic DNA was extracted from the whole blood and the genotyping of PD1 +8669 G/A (rs10204525) and TIM3 −1516 G/T (rs10053538) polymorphisms was carried out by using methods as described previously. [27,28] …”

Section: Methodsmentioning

confidence: 99%

Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma

Zhu

et al. 2016

Medicine

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“…Blocking Tim-3 signaling also increased the proliferation of tumor-infiltrating T cells in HBV-associated HCC patients, and the number of Tim-3+ tumor-infiltrating cells was negatively link with patients’ survival [ 111 ]. In addition, specific polymorphisms of the Tim-3 gene in patients with CHB seem to be associated with viral persistency and HCC development [ 112 ].…”

Section: The Role Of Pd-1 and Ctla-4 In Viral Hepatitismentioning

confidence: 99%

Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis

Cho

Kang

Lee

et al. 2017

IJMS

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Virus-specific cluster of differentiation 8 (CD8+) cytotoxic T cells (CTL) recognize viral antigens presented on major histocompatibility complex (MHC) class I chains on infected hepatocytes, with help from CD4+ T cells. However, this CTL response is frequently weak or undetectable in patients with chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection. Programmed cell death 1 (PD-1) and cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) are receptors in the CD28 family of costimulatory molecules, providing inhibitory signals to T cells. The overexpressions of PD-1 and CTLA-4 in patients with viral infection have been shown to associate with functional impairment of virus-specific T cells. In acute viral hepatitis, PD-1 and CTLA-4 are up-regulated during the symptomatic phase, and then down-regulated after recovery. These findings suggest that PD-1 and CTLA-4 have protective effects as inhibitory molecules to suppress cytotoxic T cells which induce harmful destruction of viral infected hepatocytes in self-limited viral hepatitis. In chronic viral hepatitis, the extended upregulations of PD-1 and CTLA-4 are associated with T cell exhaustion and persistent viral infection, suggesting positive correlations between expression of immune inhibitory factors and the chronicity of viral disease. In this review, we summarize recent literature relating to PD-1, CTLA-4, and other inhibitory receptors in antigen-specific T cell exhaustion in viral hepatitis, including hepatitis A, B, C, and others.

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“…The Tim-3-1541C/T, -1516G/T, -882C/T, -574G/T and +4259T/G polymorphisms were examined and analyzed, and the results showed that allele T-containing genotypes (GT+ TT), allele T and the allele T-containing haplotype (CTCGT) of the -1516G/T polymorphism occur more often in patients with CHB. The allele T-containing genotypes and allele T of -1516G/T are also associated with lymph node metastasis and tumor grade of HCC [67] . Other researchers have identified 2 other single nucleotide polymorphisms, rs31223 and rs246871, which correlate with the progression of HBV-induced liver disease.…”

Section: Infectionmentioning

confidence: 99%

Role of Tim-3 in hepatitis B virus infection: An overview

Liu

Gao

Liang

et al. 2016

WJG

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Hepatitis B virus (HBV) infection has received increasing public attention. hBV is the prototypical member of hepadnaviruses, which naturally infect only humans and great apes and induce the acute and persistent chronic infection of hepatocytes. A large body of evidence has demonstrated that dysfunction of the host anti-viral immune response is responsible for persistent HBV replication, unresolved inflammation and disease progression. Many regulatory factors are involved in immune dysfunction. Among these, T cell immunoglobulin domain and mucin domain-3 (Tim-3), one of the immune checkpoint proteins, has attracted increasing attention due to its critical role in regulating both adaptive and innate immune cells. In chronic HBV infection, Tim-3 expression is elevated in many types of immune cells, such as T helper cells, cytotoxic T lymphocytes, dendritic cells, macrophages and natural killer cells. Tim-3 over-expression is often accompanied by impaired function of the abovementioned immunocytes, and Tim-3 inhibition can at least partially rescue impaired immune function and thus promote viral clearance. A better understanding of the regulatory role of Tim-3 in host immunity during HBV infection will shed new light on the mechanisms of hBV-related liver disease and suggest new therapeutic methods for intervention.

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TIM3 gene polymorphisms in patients with chronic hepatitis B virus infection: impact on disease susceptibility and hepatocellular carcinoma traits

Cited by 24 publications

References 28 publications

Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma

Immune checkpoint proteins PD-1 and TIM-3 are both highly expressed in liver tissues and correlate with their gene polymorphisms in patients with HBV-related hepatocellular carcinoma

Programmed Cell Death 1 (PD-1) and Cytotoxic T Lymphocyte-Associated Antigen 4 (CTLA-4) in Viral Hepatitis

Role of Tim-3 in hepatitis B virus infection: An overview

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