Hepatitis B severity is associated with mitochondrial damage in T lymphocytes

doi:10.21203/rs.3.rs-2877811/v1

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Hepatitis B severity is associated with mitochondrial damage in T lymphocytes

https://doi.org/10.21203/rs.3.rs-2877811/v1

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Background

Hepatitis B infection remains a major cause of chronic liver disease worldwide, which exerts substantial pressure on global public health security. Recent studies have demonstrated that T cell-mediated cellular immune mechanisms are important in hepatitis B progression. Oxidative stress is also an important background of numerous liver disorders, but the connections between numbers and oxidative stress of T cells remain unclear in hepatitis B.

Purpose

To assess the characterizations and changes of peripheral blood T lymphocytes and their mitochondrial reactive oxygen species in hepatitis B development.

Methods

We recruited 432 patients with hepatitis B (144 with mild disease, 165 with moderate and severe disease, 90 with compensated cirrhosis, 33 with decompensated cirrhosis) and 65 healthy people (controls) to the study. Mitochondrial damage was detected by flow cytometry with a specific probe. The immune levels of specific immune cells and T cell mitochondrial functions were evaluated with the relative and absolute counts of T lymphocyte subsets.

Results

Patients with hepatitis B had higher mitochondrial damage indexes, which increased with disease progression. The patients also had lower absolute CD3⁺, CD4⁺, and CD8⁺ T lymphocyte counts compared with the controls (p < 0.05), where the counts decreased with disease progression. The absolute CD8⁺ T cell counts were negatively correlated with the mitochondrial damage indexes (p < 0.05, r = -0.11), but there were no correlations between the absolute CD4⁺ T cell counts and the mitochondrial damage indexes. Furthermore, the absolute T cell counts had a weakly positive correlation with the liver injury index, but the T cell mitochondrial damage indexes were not correlated with the liver injury index.

Conclusions

These data suggested that the mitochondrial damage frequencies and T lymphocyte subset levels differed between the different phases of chronic HBV infection, and decreased lymphocyte subsets might be related to the increased mitochondrial damage indexes in hepatitis B patients. The abnormal change in mitochondrial function and lymphocyte subsets might be important in hepatitis B development, but the underlying mechanisms remain ambiguous.

Mitochondrial mass

Absolute T lymphocyte counts

Hepatitis B

Hepatitis B virus (HBV) infection is one of the most prevalent chronic viral infections in the world and typically leads to cirrhosis and hepatocellular carcinoma. Several lines of evidence suggested that different viral loads can induce changes in the number of immune cells during chronic HBV infection (CHB). These immune cells secrete abundant pro-inflammatory and fibrogenic factors, which cause disease deterioration. Additionally, adaptive immune systems act through the expansion and functional maturation of discrete T cell subsets, which specifically recognize and directly attack infected hepatocytes, and subsequently recruit other immune system components, causing immunopathogenesis and further hepatic damage ¹. Jiang et al. reported that follicular cytotoxic T (Tfc) subsets enhanced the exhausted phenotype and led to a decrease in the numbers of Tfc subsets during CHB ². Briefly, the adaptive immune system causes immune-related pathologies in CHB, but the mechanism of T cell exhaustion in CHB remains unclear.

Mitochondria are the main source of cellular reactive oxygen species (ROS) within non-phagocytic human cells. The mitochondrial damage index refers to the flow cytometry results of T cell staining intensity after mitochondrial staining, where positive results indicate abnormal oxidative stress. Oxidative stress is involved in the course of inflammatory, metabolic, and proliferative liver diseases and constitutes an important background of numerous liver disorders ³. For example, Bhargava et al. reported increased ROS levels in lymphocytes from patients with chronic and occult hepatitis B ⁴. An increasing amount of evidence demonstrated that oxidative stress is involved in the pathogenesis of viral liver infection, especially hepatitis C virus (HCV) infection, but data on HBV infection are limited ^5,6. Therefore, characterizing the precise mechanisms by which ROS are involved in regulating T cell functions is important to improve understanding of the immune response in hepatitis B ⁷. In the present study, we investigated the characteristics and association of T lymphocyte subsets and mitochondrial oxidative stress in patients with different immune phases of CHB.

Study participants

A total of 432 patients with hepatitis B (144 with mild disease, 165 with moderate and severe disease, 90 with compensated cirrhosis, 33 with decompensated cirrhosis) and 65 healthy people (controls) were enrolled in this study. The patients were selected from the hepatitis outpatient service of Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University from January 2019 to October 2022. Patients were excluded if they met any of the following criteria: (1) received immunosuppressive treatment within the previous 6 months; (2) infected with other hepatitis viruses, including HCV, HAV, HDV, and HEV; (3) had other well-known liver diseases such as metabolic or autoimmune disorders, alcoholic liver disease, non-alcoholic steatohepatitis, and drug-induced hepatitis; or (4) had acute-phase hepatitis B infection. All selected patients with CHB were categorized into four groups according to the Diagnostic Criteria for Viral Hepatitis B in the People’s Republic of China, WS 299–2008: (1) mild hepatitis B (n = 144), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) three times below the lower normal limit, bilirubin two times below the lower normal limit, and albumin/globulin ≥ 1.4; (2) moderate and severe hepatitis B (n = 165), ALT and AST three times above the upper normal limit, bilirubin two times above the upper normal limit, and A/G < 1.4; (3) hepatitis B compensated cirrhosis (n = 90), diffuse fibrosis and pseudolobule formation, but no obvious decompensation of liver function; (4) hepatitis B decompensated cirrhosis (n = 33), serum albumin < 35 g/L, bilirubin > 35 µmol/L, and prothrombin activity < 60%. The Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University ethics committee approved this study.

Virological and biochemical assessments

The hepatitis B surface antigen (HBsAg) and hepatitis B e antigen (HBeAg) levels were measured using chemiluminescent immunoassay (Architect System, Abbott, North Chicago, IL, USA). Serum HBV DNA loads were determined using quantitative real-time PCR (ABI 7500, Thermo Fisher Scientific, Waltham, MA, USA) according to the manufacturer’s instructions. The lower detection limit of HBV DNA was 30 IU/mL. The serum ALT and AST levels were measured with a Beckman Biochemical Autoanalyzer (AU5800, Beckman Coulter, Brea, CA, USA).

Flow cytometry

For the immunophenotyping and absolute count detection of T cell subtypes with mitochondrial metabolic characteristics, whole blood was stained for the following anti-human monoclonal antibodies: CD3⁺ (clone UCHT1, FITC-conjugated), CD8⁺ (clone SK1, PE-conjugated), and CD4⁺ (clone SK3, PE-Cyanine7-conjugated; all from UB Biotechnology [Zhejiang] Co., Ltd., Zhejiang, China) and incubated at room temperature for 15 minutes. MitoDye [UB Biotechnology (Zhejiang) Co., Ltd.] was used for monoclonal antibody staining to analyze mitochondrial quality, and samples were analyzed using an Agilent NovoCell flow cytometer and NovoExpress software (both from Agilent Technology, California, USA). Immune cells were gated with different cell lineage-specific markers for analysis: CD3⁺ for total T cells, CD4⁺ for helper T cells, and CD8⁺ for cytotoxic T cells. The absolute number of target cells in the sample (cells/µL) was determined by comparing cell and absolute counting bead (BD Biosciences) events. The flow cytometry demonstrated that different immune cell subpopulations emitted different levels of MitoDye fluorescence intensity.

Statistical analysis

All data were analyzed using SPSS 22 (IBM, Armonk, NY, USA). Groups were compared with the Mann-Whitney U test. Categorical data were analyzed by Pearson’s chi-square or Fisher’s exact tests. Variance between groups was compared by analysis of variance or the Kruskal-Wallis H test. Correlations between variables were determined by Spearman’s correlation analysis. P < 0.05 was considered statistically significant.

Clinical and demographic data of CHB patients

Among the 432 CHB patients, 144 were in the mild phase, 165 were in the moderate and severe phases, 90 were in the compensated cirrhosis phase, and 33 were in decompensated cirrhosis phase. The control participants were negative for HBsAg, HBeAg, and HBV DNA, and had normal ALT, AST, total bilirubin, and albumin levels. There were more male than female patients and the liver cirrhosis patients were significantly older than the hepatitis patients. Univariate regression analysis demonstrated no association between the patients’ age, sex, and mitochondrial mass (p > 0.05). Furthermore, the patients had significantly higher AST and ALT levels than the controls. There was no significant difference in HBeAg among the patients, but the decompensated cirrhosis patients had significantly lower HBsAg levels than the patients with mild, moderate, and severe hepatitis B. Moreover, the decompensated cirrhosis patients had the lowest HBV DNA detection rate (Table 1).

Table 1

Clinical features of patients with different stages of CHB
	M	MS	CC	DC	HC
Age	43(35-52.8)	43(35–42)	53(45.8–60)	59(54-66.5)	36(33–46)
Sex (m/f)	86/58	109/56	62/28	22/11	20/45
ALT(U/L)	27.0(18.0-40.5)	32.0(22.0-64.3)	44.0(20.0–94.0)	21.0(18.0–31.0)	18(12.5–27.5)
AST(U/L)	25.0(21.5–35.5)	29.5(23.0-44.8)	37.0(27.0-124.0)	35.0(28.0-40.1)	22(18-27.5)
TBIL (µmol/L)	14.9(10.7–19.6)	15.9(12.3–20.1)	22.9(12.2–38.4)	20.3(14.6–37.7)	11.9(9.6–15.7)
ALB (g/L)	44.8(43.0-46.4)	44.3(40.9–46.5)	37.9(31.0-43.1)	36.2(28.6–41.4)	44.1(42.3–45.6)
HBsAg (IU/mL)	873(76.2-15825.2)	1627.3(222.9-3273.5)	1410.3(386.5-3007.4)	160.3(1.0-578.8)	0(0–0)
HBeAg (IU/mL)	0.4(0.36-1024.8)	0.43(0.37–27.1)	2.3(0.4–53.0)	0.41(0.37–1.1)	0(0–0)
HBV DNA D/U (%)	68/76 47.2%	69/96 41.8%	23/67 25.6%	2/31 6.1%	0
Abbreviations: M, mild hepatitis B; MS, moderate and severe hepatitis B; CC, compensated cirrhosis; DC, decompensated cirrhosis; HC, healthy control; m/f, male/female; TBIL, total bilirubin; ALB, albumin; D/U, detectable/undetectable.

Absolute T cell counts in CHB patients

Using flow cytometry, we determined the absolute T cell counts in peripheral blood lymphocytes to investigate the differential absolute CD4⁺ and CD8⁺ T cell counts in peripheral blood from the CHB patients. The patients had lower absolute CD4⁺ and CD8⁺ T cell counts as compared to the controls (all, p < 0.05). Furthermore, the total T cells were mainly increased in the patients with mild hepatitis B than in the hepatitis B patients with compensated and decompensated cirrhosis. The patients with moderate and severe hepatitis B also had higher absolute total T cell counts than the decompensated cirrhosis patients, while there were no significant differences in the absolute CD4⁺ and CD8⁺ T cell counts between the patients with compensated and decompensated cirrhosis. Additionally, the CD4⁺ and CD8⁺ T cell counts of the decompensated cirrhosis patients were significantly lower than those of the patients with mild, moderate, and severe hepatitis B. Lastly, the compensated cirrhosis patients had lower CD8⁺ T cell counts than the patients with moderate and severe hepatitis B (Fig. 1).

T cell mitochondrial mass of CHB patients

Comparison of the CD4⁺ and CD8⁺ T cell mitochondrial masses in the CHB patients indicated that the patients with mild hepatitis B had lower frequencies of CD4⁺ and CD8⁺ T cells with mitochondrial damage than the patients with compensated and decompensated cirrhosis. The patients with decompensated cirrhosis had a higher frequency of CD8⁺ T cells with mitochondrial damage than the patients with compensated cirrhosis and the moderate and severe hepatitis B patients. However, there were no differences in the frequencies of CD4⁺ cells with mitochondrial damage between the patients with moderate and severe hepatitis B and the patients with decompensated cirrhosis (Fig. 2). The mitochondrial damage indexes of the CD4⁺ and CD8⁺ T cells increased with disease progression, where the patients with mild hepatitis B had significantly lower CD3⁺ and CD4⁺ T lymphocyte mitochondrial damage indexes than the cirrhosis patients (p < 0.05) (Fig. 3).

Correlations between absolute T cell count and mitochondrial mass with ALT and AST levels

The correlations between the absolute T cell counts, mitochondrial mass, and serum levels of ALT, AST, HBV DNA, HBsAg, and HBeAg in the CHB patients were analyzed (Fig. 4, Fig. 5), as were the correlations between the absolute T cell counts and the mitochondrial damage indexes (Fig. 6). The absolute CD4⁺ and CD8⁺ T cell counts had a weakly positive correlation with serum AST levels (p < 0.001, r = -0.178 and p < 0.001, r = -0.171, respectively) (Fig. 4), while the absolute CD4⁺ T cell counts had a weakly positive correlation with HBsAg (p < 0.05, r = -0.129) and HBeAg (p < 0.001, r = -0.192) levels (Fig. 4). However, there were no correlations between the T cell counts and the other indicators. Additionally, the mitochondrial damage indexes of the CD3⁺, CD4⁺, and CD8⁺ T lymphocytes were not correlated with the serum ALT and AST levels (Fig. 6). The absolute CD8⁺ T cell count was negatively correlated with the mitochondrial damage indexes (p < 0.05, r = -0.11) (Fig. 6). However, there were no correlations between the absolute CD4⁺ T cell counts and the mitochondrial damage indexes.

CD4⁺ and CD8⁺ T cells have long been considered the subjects of the cellular immune response to eliminate infected cells. Hodgson et al. reported that disturbance of immunoregulatory T lymphocyte numbers or functions might be a primary pathogenetic determinant in ongoing liver cell injury in CHB patients ⁸. In the present study, we investigated the characteristics of T lymphocytes, including the absolute counts and mitochondrial mass, in different CHB statuses. We determined that the CHB patients had lower absolute T cell counts than the controls, but had higher T cell mitochondrial damage frequencies, which agreed with the studies of Bhargava et al. ⁴ and Jiang et al. ⁹. Further analysis indicated that the T cell mitochondrial damage frequencies were significantly elevated in the decompensated cirrhosis phase. Furthermore, the T cell mitochondrial damage frequencies increased with disease progression. In contrast, the absolute T cell counts were significantly decreased in the decompensated cirrhosis phase, where the absolute T cell counts decreased with disease progression. The absolute CD8⁺ T cell counts were negatively correlated with the mitochondrial damage indexes. The absolute CD4⁺ and CD8⁺ T cells counts had a weakly positive correlation with AST levels, while the absolute CD4⁺ T cell counts had a weakly positive correlation with HBsAg and HBeAg levels. However, the T lymphocyte mitochondrial damage indexes were not correlated with serum ALT and AST levels, and there were no correlations between the T cells and other indicators.

The immune mechanism of HBV infection has been widely studied in recent years. Hepatitis B patients have disordered cellular immunity, with imbalanced T cell subsets and decreased T cell numbers ¹⁰, which might be caused by virus-specific T cells overexpressing co-inhibitory molecules. The constant overexpression of such molecules leads to T cell apoptosis, such as PD-1 overexpression, which obstructs T cell receptor-mediated signaling and induces functional exhaustion in T cells ^11–13. Additionally, virus-specific T cells also express higher levels of the apoptosis gene BIM, which induces apoptosis and contributes to CD8⁺ T cell exhaustion ¹⁴. Furthermore, targeted mitochondrial oxidation in T cells causes mitochondrial dysfunction, and this injury accelerates and promotes T cell senescence, dysfunction, and apoptosis ¹⁵. Briefly, as a complex mechanism of energetic and metabolic impairment, mitochondrial dysfunction can lead to cell injury ¹⁶. However, it remains unclear whether the characteristics of lymphocyte subsets and mitochondrial mass differ between the CHB disease stages, and few studies have reported whether decreased T cell numbers are associated with mitochondrial mass functional defects. Accordingly, we detected the mitochondrial damage indexes in patients with different stages of CHB and demonstrated that the patients, particularly patients in the decompensated cirrhosis phase, had decreased absolute total T cell counts as compared with the controls and that the T cell counts decreased with disease progression. However, the patients had higher mitochondrial damage indexes and T cell frequencies, which were comparable to previous results ^17,18. We also determined that there was a correlation between the mitochondrial damage indexes and the absolute T cell counts, and the CD8⁺ T cells were negatively correlated with mitochondrial damage indexes, which agreed with the results of Fisicaro et al. ¹⁹.

The mitochondria are the main source of intracellular ROS and are the regulatory center of apoptosis ²⁰. Some studies reported that depleted HBV-specific CD8⁺ T cells with high ROS levels demonstrated extensive downregulation of mitochondrial function ¹⁹. Furthermore, previous studies demonstrated that hepatitis B pathogenesis involved mitochondrial dysfunction in immune cells, and hepatitis B patients typically have increased ROS levels ^21,22. Therefore, we hypothesized that mitochondrial dysfunction might trigger the decrease in immune cells as a mechanism of chronic liver disease development, which consequently leads to immunosuppression and the persistent existence of viruses. In the present study, the absolute T cell counts were not correlated with HBV DNA levels, which was inconsistent with the results of Ferrari ²³ and might be related to the control of the virus after the use of antiviral drugs. However, the absolute T cell counts were correlated with the mitochondrial damage indexes. These results indicated that the reduction of T cells in CHB might be associated with mitochondrial dysfunction severity rather than the viral load. Nevertheless, determining which of these hypotheses is correct clearly requires further studies. Regardless, the causal relationship between mitochondrial dysfunction and decreased T cells counts remains unclear. Although mitochondrial dysfunction is considered the significant cause of T lymphocyte depletion, various other causes, such chronic antigen stimulation, might also lead to T cell dysfunction ²⁴. Therefore, the association between mitochondrial and T cell dysfunction in CHB and whether mitochondrial damage leads to cell reduction requires further investigation in vivo and in vitro.

Some studies demonstrated that the considerable ROS reactivity can disrupt the integrity of hepatic cell functions and structures ^25,26. However, few studies discussed the relation between the T cell mitochondrial damage index and liver injury indicators such as AST and ALT. Most studies focused on the relationship between hepatitis B markers and AST and ALT, possibly because of the known relationship with hepatitis B severity ²⁷. Our results suggested that the mitochondrial damage index and liver injury markers are not related, which contradicted the results of some studies ²⁸. We speculated that this might be related to the fact that we detected the T cell mitochondrial damage index rather than that of liver cells.

In summary, there is strong evidence that patients with HBV infection, especially patients with decompensated cirrhosis, have higher CD4⁺ and CD8⁺ T cell mitochondrial damage frequencies and indexes than healthy controls, and have lower absolute CD4⁺ and CD8⁺ T cell counts, which might be caused by mitochondrial damage and which may contribute to viral persistence. However, there is no relationship between the mitochondrial damage index and liver injury markers. It was not possible to state that CD4⁺ and CD8⁺ T cell mitochondrial damage was the proximate cause of hepatic cell injury in the CHB patients, and the decreased CD4⁺ and CD8⁺ T cells caused by mitochondrial damage could represent an important arm in disease progression in this group of patients.

More detailed knowledge about the exact interplay of T cell mitochondrial damage and the immune response in HBV infection is needed. Future studies should focus on the longitudinal changes of T cells during anti-HBV treatment of CHB. Moreover, only CD4⁺ and CD8⁺ cells were evaluated in this study. Mitochondrial damage in other cells, such as B cells and natural killer cells, should also be evaluated in CHB patients. Finally, the relation between T cell mitochondrial damage and absolute T cell counts requires confirmation by larger-scale studies with different patient profiles.

ALT, alanine aminotransferase; AST, aspartate aminotransferase; CHB, chronic HBV infection; HBeAg, hepatitis B e antigen; HBsAg, hepatitis B surface antigen; HBV, hepatitis B virus; HCV, hepatitis C virus; ROS, reactive oxygen species.

Acknowledgments

We thank all the patients and their families who participated in this study.

Declaration of interest statement

The authors have no conflicts of interest to declare.

Ethics Approval and Informed Consent

This study was approved by the ethics committee of Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University. The study was carried out in accordance with the principles of the Declaration of Helsinki. Waiving of informed consent was given by the ethics committee of Hangzhou Xixi Hospital Affiliated to Zhejiang Chinese Medical University due to the retrospective, non-interventional study design. All patient data were collected anonymously and ensured about the confidentiality of their information.

Consent for publication

Not applicable.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Data availability statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Funding

This work was supported by the Hangzhou Health Science and Technology Plan [grant ZD20220040] and the Hangzhou Biomedical and Health Industry Development Support Plan [grant 2021WJCY363].

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No competing interests reported.

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Hepatitis B severity is associated with mitochondrial damage in T lymphocytes

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Abstract

Figures

Background

Materials and methods

Study participants

Virological and biochemical assessments

Flow cytometry

Statistical analysis

Results

Clinical and demographic data of CHB patients

Absolute T cell counts in CHB patients

T cell mitochondrial mass of CHB patients

Correlations between absolute T cell count and mitochondrial mass with ALT and AST levels

Discussion

Abbreviations

Declarations

References

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