Hyperactive Follicular Helper T Cells Contribute to Dysregulated Humoral Immunity in Patients With Liver Cirrhosis

Abstract

Objectives: Liver cirrhosis (LC) is usually accompanied by cirrhosis associated immune dysfunction (CAID), including reduced naïve T cells and memory B cells. However, little is known regarding on follicular helper T (Tfh) cell compartments in cirrhotic patients, especially in the secondary lymphoid organs such as spleen. This study characterizes splenic Tfh cells and explores its association with humoral immunity and disease progression in cirrhotic patients. Methods: Using flow cytometry and histological staining, we analyzed the frequency and cytokine production of splenic Tfh cells from LC patients and healthy controls (HCs). Co-culture experiments of sorted Tfh and B cells were performed for functional analysis in vitro . The correlations between Tfh cells and disease progression markers as well as B cell subset perturbations were also examined. Results: PD-1 high ICOS + CXCR5 + Tfh cells were preferentially enriched in the spleen of cirrhotic patients, where they expressed higher levels of CXCR3 and produced more interleukin (IL)-21. Histologically, more splenic Tfh cells occupied the B cell follicular structure in LC patients where they shaped more active germinal centers (GCs) than those in HC spleens. In vitro , splenic Tfh cells in cirrhotic patients robustly induce plasma cell differentiation through IL-21 dependent manner. Finally, increased Tfh cell frequency is positively correlated with the plasma cells and disease severity in LC patients. Conclusions: We conclude that hyperactive Tfh cells contribute to dysregulated humoral immunity in patients with liver cirrhosis.

Metabolic defects in splenic B cell compartments from patients with liver cirrhosis

“…1d–f ). In accordance with our previous study 26 , plasmablasts were found to be elevated in the spleens of cirrhotic patients. IgA memory B cells were found to be significantly decreased in peripheral blood; however, their counterpart in the spleen seemed to have largely remained at a level comparable to that of the healthy subjects (Fig.…”

“…A previous study showed that IgM + CD27 + B cells have a higher capacity to migrate toward CXCL13 49 , suggesting an ability of these cells to enter B cell follicles. Indeed, we observed a higher expression of CXCL13 in cirrhotic patients, and the increased splenic Tfh cells may facilitate the differentiation of plasma cells 26 . These data suggested that the increased engagement of MZB cells in GC reactions likely exhausts the splenic MZB cell pools during liver cirrhosis.…”

“…The persistent activation of splenic Tfh cells may enhance B cell maturation in cirrhotic patients 26 ; therefore, we analyzed the activation-associated markers (CD95, FcRL4, CD86, and CD71) and migration-associated markers (CD11c, CXCR3, and CCR6) on the B cell subsets in LC patients (Table 2 , panels 2 and 3). In these two panels, Trans&GC B cells, PBs, naïve B cells, and MZB cells were gated according to their phenotypes, while IgD − memory B cells within CD38 +/− CD10 − mature B cells were divided into CD27 + classical memory B cells (named cMBCs here) and CD27 − atypical memory B cells (named aMBCs here) 33 (Figs.…”

“…It is still unknown how CAID affects splenic immune cell compartments. Recently, we determined that an expanded hyperactive splenic Tfh cell population correlated with enhanced germinal center (GC) responses and hypergammaglobulinemia in cirrhotic patients 26 , showing the importance of investigating the regional immunity of the spleen in liver cirrhosis. Here, we comprehensively characterize the splenic B cell compartments from cirrhotic patients, investigate the underlying mechanisms of memory B cell depletion and functional impairment, and explore the consequences of these phenomena on the B cell repertoires and their potential clinical significance.…”

HEV and HBV Dual Infection: A Review

“…Additionally, patients with cirrhosis may have impaired cell-mediated and humoral immunity and so the presence of anti-HEV IgM may not be a reliable marker for active infection in this patient population. 24 , 25 HEV RNA may have been a more reliable marker of infection in these patients. Although the increased risk of poor prognosis in cirrhotics who become superinfected with HEV seems well supported, that is not surprising since the same risks have been shown with other viral superinfections, such as with hepatitis A virus (HAV) and hepatitis D virus (HDV).…”