br Conflicts of interest br Introduction Hepatitis

Conflicts of interest

Hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF) refers to an acute deterioration of liver function due to a precipitating event such as microbial infection, reactivation of viral hepatitis, hepatotoxic drugs, surgical procedures, or variceal bleeding occurring in patients with any form of underlying chronic HBV infection. In China, HBV infection constitutes >80% of all etiologies of ACLF owing to a high carriage rate of HBV. HBV-related ACLF exhibits relatively high mortalities and liver transplantation is the most promising treatment.
Recent studies have shed light on CD4+CD25+ regulatory T cells (Treg) that are actively engaged in the maintenance of immune tolerance to both self and nonself dhpg by suppressing aggressive T-cell response. This specialized subpopulation of CD4+ T cells constitutively expresses interleukin (IL)-2 receptor α-chain (CD25), and represents approximately 2–4% of peripheral CD4+ T cells. The forkhead-winged helix transcription factor (Foxp3) has been demonstrated to be a unique molecule for the development and functions of CD4+CD25+ Treg.
Accumulating evidence indicates that increased Treg numbers are associated with persistence of HBV infection by downregulating HBV-specific effector T cell responses. Depletion of this proportion of cells in vitro can enhance proliferation of effector cells and secretion of interferon-γ (IFN-γ) against HBV antigens in a dose-dependent manner. By contrast, the suppressive role of Treg may prevent excessive immunopathological damages induced by sustained immune activation and inflammation. ACLF often represents a complicated state of host immune dysregulation, in which exacerbated innate immune responses and aberrant adaptive immune responses may mediate hepatic inflammation. However, it is still controversial whether Treg is increased or decreased in HBV-related ACLF due to discrepant results.
In this study, we examined the frequency of peripheral CD4+CD25+ Treg and the distribution of liver-infiltrating Foxp3+ cells in patients with HBV-related ACLF. We also investigated inhibitory functions of Treg, as well as its association with short-term prognosis in HBV-related ACLF.

Patients and methods


HBV infection remains a serious public health problem, worldwide affecting 350–400 million people. A small proportion of patients with chronic HBV infection may develop ACLF which exhibits high mortalities and poor prognosis. Although pathogenesis of HBV-related ACLF is extremely complex and still remains unclear, dysregulation of host immune responses induced by host-HBV interactions is proposed to be the most contributing factor. It has been suggested that Treg may play a crucial role in controlling immunopathological damage, but it may also contribute to hyporesponsiveness against infection.
The relationship between Treg and HBV-related ACLF is poorly understood. We observed that ACLF patients had a markedly higher peripheral CD4+CD25+ Treg, as well as increased inhibitory activity against CD4+CD25− responder cells, than healthy controls. Our data are identical to those observed by Xu et al, who showed that patients with chronic severe hepatitis B (i.e., HBV-related ACLF) had the highest circulating CD4+CD25high Treg among patients with different phases of HBV infections. These results support the notion that upregulation of Treg in ACLF may suppress immune responses, thereby limiting liver injuries and inflammation caused by necrosis or apoptosis of hepatocytes. However, Wang et al demonstrated the opposite finding that decreased peripheral CD4+CD25+CD127low Treg could aggravate liver injuries by enhancing immunological responsiveness to HBV in HBV-related ACLF. The discrepancies between these studies may be largely attributed to differences in the molecular markers selected for identifying Treg. Previous studies have confirmed that early-stage ACLF are usually characterized by immune activation, but “sepsis-like” immune paralysis usually accompanies late-stage ACLF. Thus, we propose that host immune status in different phases of ACLF may also be responsible for numbers and functions of Treg. Although higher Treg were observed in patients with severe complications with no statistical significance, a larger sample size may lead to a statistical significance.