The frequency and skewed T-cell receptor beta-chain variable patterns of peripheral CD4(+)CD25(+) regulatory T-cells are associated with hepatitis B e antigen seroconversion of chronic hepatitis B patients during antiviral treatment - PubMed (original) (raw)

The frequency and skewed T-cell receptor beta-chain variable patterns of peripheral CD4(+)CD25(+) regulatory T-cells are associated with hepatitis B e antigen seroconversion of chronic hepatitis B patients during antiviral treatment

Jiezuan Yang et al. Cell Mol Immunol. 2016 Sep.

Abstract

The frequency and T-cell receptor beta-chain variable (TCRBV) patterns of peripheral CD4(+)CD25(+) regulatory T-cells (Tregs) are ambiguously altered in chronic hepatitis B (CHB) patients following tenofovir disoproxil fumarate (TDF) treatment. Moreover, the clinical significance of these parameters in relation to hepatitis B e antigen (HBeAg) seroconversion (SC) is largely unknown. In this study, the circulation of Tregs in HBeAg-positive CHB patients was determined by flow cytometry, and the molecular profiles of frequent TCRBV patterns of Tregs were analyzed using a gene melting spectral pattern. The parameters, such as Treg frequency, the number of skewed TCRBV patterns, hepatitis B virus (HBV) DNA levels, and alanine aminotransferase (ALT) levels, were analyzed by comparing their associations in seroconverting and non-seroconverting patients following TDF treatment. The Treg frequency was significantly correlated with the ALT level in seroconverting but not in non-seroconverting patients. Similarly, skewed TCRBV patterns were remarkably associated with HBV DNA levels in the SC group. Six TCRBV families (BV3, BV11, BV12, BV14, BV20, and BV24) were more prevalent than other TCRBV members in seroconverting patients pretreated with TDF, while BV12, BV15, and BV22 were predominant in non-seroconverting patients during TDF treatment. Taken together, the preferential TCRBV patterns may be associated with immune responses related to SC. The dynamic frequency and skewed TCRBV patterns of peripheral Tregs could contribute to predicting SC in CHB patients. Moreover, the conserved TCRBV complementarity-determining region (CDR3) motif may be targeted to develop personalized immunotherapy for CHB patients.

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Figures

Figure 1

Longitudinal study of serum HBV DNA levels in seroconverting and non-seroconverting patients during TDF treatment. (a) The baseline (0 week) HBV DNA levels (log10 copies/ml) in seroconverting and non-seroconverting patients are shown in a scatter diagram. (b) Changes in mean HBV DNA levels for patients during treatment. HBV DNA could not be detected after week 72 in all seroconverting patients, but HBV DNA could be detected throughout the entire treatment in the non-SC group. *P < 0.05; **P = 0.01; #P = 0.02 for the HBV DNA level of seroconverting patients relative to that of the non-SC group.

Figure 2

Dynamic profile of the percentage of circulating CD4+CD25+ Tregs in SC or non-SC patients following TDF treatment and the proportion of Treg normalization in these patients. Comparison of the CD4+CD25+ Treg percentages between seroconverting and non-seroconverting patients during TDF treatment (a); Changing percentages of CD4+CD25+ Tregs for each subject with SC (b) and non-SC (c); Proportion of patients with normalization of Treg frequency during TDF treatment (d). The horizontal lines indicate the mean for each time point from the SC and non-SC groups during treatment (b and c); Treg frequency that is within the range of normal levels (from HDs) is classified as normalization of Treg frequency (d). *P < 0.05 and **P < 0.01 when comparing the Treg frequency between non-seroconverting and seroconverting patients at the same time point, respectively; ***P < 0.001 when comparing the Treg frequency of the non-SC group at each time point during treatment with that of the HD group.

Figure 3

Association between circulating Tregs and HBV DNA or ALT levels in HBeAg seroconverting or non-seroconverting patients during TDF treatment. The relationship between the HBV DNA level (log10 copies/ml) and the Treg percentage in seroconverting (a) and non-seroconverting patients (b). The relationship between the ALT level (U/l) and the Treg percentage is shown for seroconverting (c) and non-seroconverting patients (d). The _x_-axis indicates the different treatment time points; a and b on the _y_-axis show the HBV DNA levels; c and d on the _y_-axis show the ALT levels; and the right portion of the _y_-axis shows the Treg percentage. Correlations were analyzed using a Spearman correlation analysis.

Figure 4

Association between the number of skewed TCRBV families and the HBV DNA or ALT levels in HBeAg seroconverting or non-seroconverting patients during TDF treatment. The relationship between the HBV DNA level (log10 copies/ml) and the number of skewed TCRBV families is shown for seroconverting (a) and non-seroconverting patients (b). The relationship between the ALT level (U/l) and the number of skewed TCRBV families is shown for seroconverting (c) and non-seroconverting patients (d). The _x_-axis indicates the different treatment time points; a and b on the _y_-axis show the HBV DNA levels; c and d on the _y_-axis show the ALT levels; and the right portion of the _y_-axis shows the number of skewed TCRBV families. Correlations were analyzed using a Spearman correlation analysis.

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The frequency and skewed T-cell receptor beta-chain variable patterns of peripheral CD4(+)CD25(+) regulatory T-cells are associated with hepatitis B e antigen seroconversion of chronic hepatitis B patients during antiviral treatment - PubMed (original) (raw)