Reduced Energy Metabolism Impairs T Cell-Dependent B Cell Responses in Patients With Advanced HBV-Related Cirrhosis

Abstract

Background and AimsPatients with decompensated HBV-related liver cirrhosis (HBV D-LC) showed compromised immune responses, which manifested as a proneness to develop infections and hyporesponsiveness to vaccines, resulting in accelerated disease progression. The alterations in T cell-dependent B cell responses in this pathophysiological process were not well understood. This study aimed to investigate T cell-dependent B cell responses in this process and discuss the mechanism from the perspective of metabolism.MethodsChanges in phenotypes and subsets of peripheral B cells between HBV D-LC patients and healthy controls (HCs) were compared by flow cytometry. Isolated B cells were activated by coculture with circulating T follicular (cTfh) cells. After coculture, the frequencies of plasmablasts and plasma cells and immunoglobin levels were analyzed. Oxidative phosphorylation (OXPHOS) and glycolysis were analyzed by a Seahorse analyzer. Mitochondrial function and the AKT/mTOR pathway were analyzed by flow cytometry.ResultsThe proliferation and differentiation capacities of B cells after T cell stimulation were impaired in D-LC. Furthermore, we found that B cells from D-LC patients showed reductions in OXPHOS and glycolysis after activation, which may result from reduced glucose uptake, mitochondrial dysfunction and attenuated activation of the AKT/mTOR pathway.ConclusionsB cells from HBV D-LC patients showed dysfunctional energy metabolism after T cell-dependent activation. Understanding the regulations of B cell metabolic pathway and their changes may provide a new direction to rescue B cell hyporesponsiveness in patients with HBV D-LC, preventing these patients be infected and improving sensitivity to vaccines.

CD5L-associated gene analyses highlight the dysregulations, prognostic effects, immune associations, and drug-sensitivity predicative potentials of LCAT and CDC20 in hepatocellular carcinoma

“…A signature of six metabolic genes including G6PD, AKR1B15, HMMR, CSPG5, ELOVL3 and FABP6 was shown to be predictive for HCC prognosis [10]. The associations between metabolism dysregulation and immune response were presented in many studies [11]. In HCC, reprogramming of lipid metabolism was confirmed to be involved in HCC development and immunoregulation [12][13][14].…”

The glucose metabolic reprogramming in hepatitis B virus infection and hepatitis B virus associated diseases

“…It has been verified that normally HBV could active mTOR pathway of B cell and promote its glycolysis 44 . But a comparative clinical study showed decreased glycolysis and OXPHOS in patients with decompensated HBV‐related liver cirrhosis (HBV D‐LC) patients 26 . It may be due to reduced glucose uptake, impaired mitochondrial function, or weak activation of the AKT–mTOR pathway.…”

“…Notably, lactate, a “waste product” of aerobic glycolysis, is used by HBV and other viruses to inhibit the innate immune response 24,65 . Furthermore, HBV‐induced metabolic alterations may be linked to peripheral immune cell suppression 26–28 …”

“…24,65 Furthermore, HBV-induced metabolic alterations may be linked to peripheral immune cell suppression. [26][27][28] Until now, interferon and nucleotide analogs are the two main drugs used to treat HBV infection. There are no clinical trials on the addition of glucose metabolism modifying drugs during HBV treatment.…”

Mitochondrial stress in advanced fibrosis and cirrhosis associated with chronic hepatitis B, chronic hepatitis C, or nonalcoholic steatohepatitis

“…In vitro and in vivo studies have shown that hepatitis B virus (HBV) or Hepatitis B virus X protein (HBx) cause oxidative stress and alter mitochondrial dynamics and homeostasis (9,10,13,(28)(29)(30)(31)(32)(33)(34)(35). HBV-induced oxidative stress might speed up the oxidative damage to mtDNA in patients with CHB.…”