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Liver FOXP3 and PD1/PDL1 Expression is Down-Regulated in Chronic HBV Hepatitis on Maintained Remission Related to the Degree of Inflammation.

Germanidis G, Argentou N, Hytiroglou P, Vassiliadis T, Patsiaoura K, Germenis AE, Speletas M - Front Immunol (2013)

Bottom Line: T cell expression of PD1 and inhibition of T effector cells by Foxp3(+)-T regulatory cells are among the most powerful mechanisms for achieving a balanced immune response.The expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly down-regulated in the remission state.In contrast, liver expression of IL2 and IFNG, along with CD4, IL1B, TNFA, and FAS did not change significantly.

View Article: PubMed Central - PubMed

Affiliation: First Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki , Thessaloniki , Greece.

ABSTRACT

Background and aim: T cell expression of PD1 and inhibition of T effector cells by Foxp3(+)-T regulatory cells are among the most powerful mechanisms for achieving a balanced immune response. Our aim was to investigate, how liver FOXP3 and PD1/PDL1 expression is regulated in chronic HBV hepatitis (CHB) on maintained long-term remission in comparison with active disease, and whether they are correlated to the expression of pro- and anti-inflammatory cytokines and apoptosis mediators, along with the degree of histological inflammation and markers of T cell effector restoration.

Methods: Fifty-three HBeAg-negative CHB patients with both active (30) and completely remitted disease on long-term antiviral treatment (23) and four controls (submitted to liver biopsy due to a mild increase of aminotransferases but without liver necroinflammatory and architecture changes) were enrolled in the study. Liver mRNA levels of immunoregulatory genes (FOXP3, IL10, TGFB1, and those of PD1/PDL1/PDL2 pathway), major apoptosis mediators (FAS, FASL, TNFA, TRAIL), cytokines of effector T cell restoration (IL2, IFNG), and those of IL1B, CD4, and CD8, were evaluated by quantitative real-time reverse-transcriptase PCR and were correlated with each other, along with the intensity of liver inflammation and fibrosis staging. The expression and localization of FOXP3, PD1, PDL1, CD4, and CD8 were also assessed by immunohistochemistry.

Results: The expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly down-regulated in the remission state. In contrast, liver expression of IL2 and IFNG, along with CD4, IL1B, TNFA, and FAS did not change significantly. Moreover, FOXP3, PD1, PDL1, and CD8 transcripts were positively correlated to the intensity of liver inflammation.

Conclusion: Our data indicate that in the CHB disease model, the immunosuppressive liver environment is down-regulated in the maintained on-treatment long-term remission state and correlates with the intensity of liver inflammation, but not liver T cell restoration.

No MeSH data available.


Related in: MedlinePlus

Gene expressions with significant alteration of mRNA levels in the liver of CHB patients. Error bar diagrams presenting the expression of FOXP3 (A), PD1/PDCD1(B), PDL1/PDCD1LG1(C), CD8a(D), TGFB1(E), IL10(F), FASL(G), and TNFSF10/TRAIL(H) in the liver of patients in maintained on-treatment long-term remission as compared to CHB patients at diagnosis. The charts describe the algorithms for error bar computation of the mean ± 2 standard errors for the relative expression of each gene. p-Values in each diagram refers to Mann–Whitney U test.
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Figure 1: Gene expressions with significant alteration of mRNA levels in the liver of CHB patients. Error bar diagrams presenting the expression of FOXP3 (A), PD1/PDCD1(B), PDL1/PDCD1LG1(C), CD8a(D), TGFB1(E), IL10(F), FASL(G), and TNFSF10/TRAIL(H) in the liver of patients in maintained on-treatment long-term remission as compared to CHB patients at diagnosis. The charts describe the algorithms for error bar computation of the mean ± 2 standard errors for the relative expression of each gene. p-Values in each diagram refers to Mann–Whitney U test.

Mentions: As shown in Figure 1, patients maintained on-treatment at 5 years remission (virologic, biochemical, and histochemical) of CHB had significantly decreased mRNA levels of FOXP3, IL10, TGFB1, TNFSF6/FASL, PD1/PDCD1, PDL1/PDCD1LG1, and CD8a, as well as significantly increased levels of TNFSF10/TRAIL, as compared to patients at diagnosis with active disease. The expression levels of IL2 and IFNG were also decreased, but these alterations did not reach statistical significance (Table 4). Interestingly, the alteration of FOXP3 expression was not accompanied by a commensurate decrease of CD4 mRNA levels.


Liver FOXP3 and PD1/PDL1 Expression is Down-Regulated in Chronic HBV Hepatitis on Maintained Remission Related to the Degree of Inflammation.

Germanidis G, Argentou N, Hytiroglou P, Vassiliadis T, Patsiaoura K, Germenis AE, Speletas M - Front Immunol (2013)

Gene expressions with significant alteration of mRNA levels in the liver of CHB patients. Error bar diagrams presenting the expression of FOXP3 (A), PD1/PDCD1(B), PDL1/PDCD1LG1(C), CD8a(D), TGFB1(E), IL10(F), FASL(G), and TNFSF10/TRAIL(H) in the liver of patients in maintained on-treatment long-term remission as compared to CHB patients at diagnosis. The charts describe the algorithms for error bar computation of the mean ± 2 standard errors for the relative expression of each gene. p-Values in each diagram refers to Mann–Whitney U test.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3722555&req=5

Figure 1: Gene expressions with significant alteration of mRNA levels in the liver of CHB patients. Error bar diagrams presenting the expression of FOXP3 (A), PD1/PDCD1(B), PDL1/PDCD1LG1(C), CD8a(D), TGFB1(E), IL10(F), FASL(G), and TNFSF10/TRAIL(H) in the liver of patients in maintained on-treatment long-term remission as compared to CHB patients at diagnosis. The charts describe the algorithms for error bar computation of the mean ± 2 standard errors for the relative expression of each gene. p-Values in each diagram refers to Mann–Whitney U test.
Mentions: As shown in Figure 1, patients maintained on-treatment at 5 years remission (virologic, biochemical, and histochemical) of CHB had significantly decreased mRNA levels of FOXP3, IL10, TGFB1, TNFSF6/FASL, PD1/PDCD1, PDL1/PDCD1LG1, and CD8a, as well as significantly increased levels of TNFSF10/TRAIL, as compared to patients at diagnosis with active disease. The expression levels of IL2 and IFNG were also decreased, but these alterations did not reach statistical significance (Table 4). Interestingly, the alteration of FOXP3 expression was not accompanied by a commensurate decrease of CD4 mRNA levels.

Bottom Line: T cell expression of PD1 and inhibition of T effector cells by Foxp3(+)-T regulatory cells are among the most powerful mechanisms for achieving a balanced immune response.The expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly down-regulated in the remission state.In contrast, liver expression of IL2 and IFNG, along with CD4, IL1B, TNFA, and FAS did not change significantly.

View Article: PubMed Central - PubMed

Affiliation: First Department of Internal Medicine, AHEPA Hospital, School of Medicine, Aristotle University of Thessaloniki , Thessaloniki , Greece.

ABSTRACT

Background and aim: T cell expression of PD1 and inhibition of T effector cells by Foxp3(+)-T regulatory cells are among the most powerful mechanisms for achieving a balanced immune response. Our aim was to investigate, how liver FOXP3 and PD1/PDL1 expression is regulated in chronic HBV hepatitis (CHB) on maintained long-term remission in comparison with active disease, and whether they are correlated to the expression of pro- and anti-inflammatory cytokines and apoptosis mediators, along with the degree of histological inflammation and markers of T cell effector restoration.

Methods: Fifty-three HBeAg-negative CHB patients with both active (30) and completely remitted disease on long-term antiviral treatment (23) and four controls (submitted to liver biopsy due to a mild increase of aminotransferases but without liver necroinflammatory and architecture changes) were enrolled in the study. Liver mRNA levels of immunoregulatory genes (FOXP3, IL10, TGFB1, and those of PD1/PDL1/PDL2 pathway), major apoptosis mediators (FAS, FASL, TNFA, TRAIL), cytokines of effector T cell restoration (IL2, IFNG), and those of IL1B, CD4, and CD8, were evaluated by quantitative real-time reverse-transcriptase PCR and were correlated with each other, along with the intensity of liver inflammation and fibrosis staging. The expression and localization of FOXP3, PD1, PDL1, CD4, and CD8 were also assessed by immunohistochemistry.

Results: The expression of FOXP3, IL10, TGFB1, PD1, PDL1, FASL, and CD8 was significantly down-regulated in the remission state. In contrast, liver expression of IL2 and IFNG, along with CD4, IL1B, TNFA, and FAS did not change significantly. Moreover, FOXP3, PD1, PDL1, and CD8 transcripts were positively correlated to the intensity of liver inflammation.

Conclusion: Our data indicate that in the CHB disease model, the immunosuppressive liver environment is down-regulated in the maintained on-treatment long-term remission state and correlates with the intensity of liver inflammation, but not liver T cell restoration.

No MeSH data available.


Related in: MedlinePlus