Abstract
ObjectivesT Follicular helper (Tfh) cells, recognized as a distinct CD4+ T cell subset, mediate the development of long-lived humoral immunity via B cell activation/differentiation. Tfh cells play an important role during hepatic viral infection, but its role in hepatitis B virus-related acute on chronic liver failure (HBV-ACLF) remains to be explored.Materials and MethodsThe frequency of Tfh cells, serum pro-inflammatory cytokine (IL-12, IL-21, IL-17 and TNF) levels and IgG/M levels were investigated in HBV-ACLF (n = 36), serious chronic hepatitis B (n = 21), moderate chronic hepatitis B patients (n = 32) and healthy control (HC) subjects (n = 10).ResultsCirculating Tfh cells were significantly increased in HBV-ACLF patients compared to other groups, correlating well with MELD score. However, the frequency of Tfh cells decreased in ameliorated HBV-ACLF patients. Furthermore, serum IL-12 and IL-21 levels were higher in HBV-ACLF patients, compared to other groups. Naïve CD4+ T cells from HC subjects differentiate into Tfh cells following treatment with HBV-ACLF patients’ serum, a process that can be blocked by IL-12/21 neutralizing antibodies. Tfh cells induced by HBV-ACLF patient’s serum promoted the proliferation and IgG production of B cells in vitro. Moreover, circulating CD19+ B cells, serum and liver IgG/M levels were significantly higher in HBV-ACLF patients, compared to other groups.ConclusionsOur data demonstrated that there was a high frequency of Tfh cells and high levels of serum IL-12/21 in HBV-ACLF patients. Naïve CD4+ T cells differentiate into Tfh cells in the presence of HBV-ACLF patients’ serum rich in IL-12/21, which can be blocked by neutralizing IL-12/21 antibodies. These data may provide useful insights for both clinical and basic research in the treatment of HBV-ACLF.
Highlights
Hepatitis B virus-related acute on chronic liver failure (HBVACLF) has recently been characterized as an acute hepatic insult, manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously chronic hepatitis B virus (HBV) infection [1]
Peripheral blood was collected from HBV-ACLF (n = 36), SCHB (n = 21), M-chronic hepatitis B (CHB) (n = 32) and healthy controls (HC) subjects (n = 10) subjects
Peripheral blood mononuclear cells (PBMCs) were gated on CD4+ T lymphocyte cells and identified CD4+CXCR5+, CD4+CXCR5+PD-1+, and CD4+CXCR5+ICOS+ T follicular helper (Tfh) cell subsets in the peripheral blood
Summary
Hepatitis B virus-related acute on chronic liver failure (HBVACLF) has recently been characterized as an acute hepatic insult, manifesting as jaundice and coagulopathy, complicated within 4 weeks by ascites and/or encephalopathy in a patient with previously chronic hepatitis B virus (HBV) infection [1]. A new class of T cells, specializing in promoting B cell differentiation in the lymphoid follicles, was characterized, and named T follicular helper (Tfh) cells [5]. Tfh cells can be distinguished from other CD4+ T cell lineages by their expression of a unique combination of effector molecules, including high levels of CXCR5, ICOS, PD-1, IL-21 and Bcl-6 [6, 7]. Circulating CD4+CXCR5+ T cells have been found in recent studies to have functional characteristics similar to Tfh. circulating CD4+CXCR5+ T cells promote survival, proliferation and differentiation of B cells into plasma cells as Tfh cells are present in germinal centers. The phenotype of circulating Tfh differs from “conventional” tissue-specific Tfh cells that express high levels of PD-1 and ICOS. The definition of circulating Tfh cells differs in various studies [8, 9]
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