Natural killer (NK) cells are abundant in the liver and serve as a major innate immune component against microbial infection. Although NK cells have been implicated in inducing hepatocellular damage in patients with chronic hepatitis virus infections, the roles that hepatic NK cells play in chronic hepatitis B virus (HBV) infections remain obscure. In this study, we comprehensively characterized intrahepatic and peripheral NK cells and investigated their impact on liver pathology in a cohort of HBV-infected individuals; this cohort included 51 immune-activated (IA) patients, 27 immune-tolerant (IT) carriers, and 26 healthy subjects. We found that NK cells expressing NK receptors (activation receptors) preferentially accumulated in the livers of IA patients, in which they were activated and skewed toward cytolytic activity but without a concomitant increase in interferon-γ production, in comparison with those of IT carriers and healthy subjects. Further analysis showed that the livers of IA patients, in comparison with those of IT and healthy subjects, expressed higher levels of interleukin-12 (IL-12), IL-15, and IL-18 in situ and lower levels of IL-10, which in vitro can induce the activation and degranulation of NK cells from healthy individuals. Finally, hepatic NK cells displayed more cytolytic activity than peripheral NK cells, and this was found to be positively correlated with the liver histological activity index and serum alanine aminotransferase levels in these IA patients. Conclusion In IA patients, hepatic NK cells are activated and preferentially skew toward cytolytic activity, which depends on an imbalanced cytokine milieu and correlates with liver injury during chronic HBV infection.
BackgroundExtensive mononuclear cell infiltration is strongly correlated with liver damage in patients with chronic hepatitis B virus (CHB) infection. Macrophages and infiltrating monocytes also participate in the development of liver damage and fibrosis in animal models. However, little is known regarding the immunopathogenic role of peripheral blood monocytes and intrahepatic macrophages.Methodology/Principal FindingsThe frequencies, phenotypes, and functions of peripheral blood and intrahepatic monocyte/macrophage subsets were analyzed in 110 HBeAg positive CHB patients, including 32 immune tolerant (IT) carriers and 78 immune activated (IA) patients. Liver biopsies from 20 IA patients undergoing diagnosis were collected for immunohistochemical analysis. IA patients displayed significant increases in peripheral blood monocytes and intrahepatic macrophages as well as CD16+ subsets, which were closely associated with serum alanine aminotransferase (ALT) levels and the liver histological activity index (HAI) scores. In addition, the increased CD16+ monocytes/macrophages expressed higher levels of the activation marker HLA-DR compared with CD16− monocytes/macrophages. Furthermore, peripheral blood CD16+ monocytes preferentially released inflammatory cytokines and hold higher potency in inducing the expansion of Th17 cells. Of note, hepatic neutrophils also positively correlated with HAI scores.ConclusionsThese distinct properties of monocyte/macrophage subpopulations participate in fostering the inflammatory microenvironment and liver damage in CHB patients and further represent a collaborative scenario among different cell types contributing to the pathogenesis of HBV-induced liver disease.
The normal expression of human  globin is critically dependent upon the constitutively high stability of its encoding mRNA. Unlike with ␣-globin mRNA, the specific cis-acting determinants and trans-acting factors that participate in stabilizing -globin mRNA are poorly described. The current work uses a linker-scanning strategy to identify a previously unknown determinant of mRNA stability within the -globin 3 untranslated region (3UTR). The new determinant is positioned on an mRNA half-stem opposite a pyrimidine-rich sequence targeted by ␣CP/hnRNP-E, a factor that plays a critical role in stabilizing human ␣-globin mRNA. Mutations within the new determinant destabilize -globin mRNA in intact cells while also ablating its 3UTR-specific interaction with the polyfunctional RNA-binding factor nucleolin. We speculate that 3UTR-bound nucleolin enhances mRNA stability by optimizing ␣CP access to its functional binding site. This model is favored by in vitro evidence that ␣CP binding is enhanced both by cis-acting stem-destabilizing mutations and by the trans-acting effects of supplemental nucleolin. These studies suggest a mechanism for -globin mRNA stability that is related to, but distinct from, the mechanism that stabilizes human ␣-globin mRNA.Erythroid cells accumulate hemoglobin through a process that is critically dependent upon the high stabilities of mRNAs that encode their constituent ␣-and -globin subunits (10, 64). In vivo analyses estimate a half-life for human ␣-globin mRNA of between 24 and 60 h (47,62,63,74), while similar studies with cultured NIH 3T3 and murine erythroleukemia (MEL) cells (2, 36, 42), primary mouse hematopoietic cells (4), and human erythroid progenitors (62, 63) suggest a half-life value for human -globin mRNA that exceeds 16 to 20 h. Globin mRNAs survive, and continue to translate at high levels, for as long as a week following nuclear condensation and extrusion in transcriptionally silent erythroid progenitor cells. As might be anticipated, mutations that impair the normal stabilities of globin mRNAs can severely impact the levels of their encoded proteins. For example, an mRNA-destabilizing mutation reduces the expression of ␣ Constant Spring to less than 2% of normal levels (45,51,80), resulting in a clinically important form of thalassemia characterized by a substantial imbalance in ␣-and -globin chain accumulation (10, 64).The cis-acting determinants and trans-acting factors that participate in regulating ␣-globin mRNA stability have recently been identified, and the relevant molecular mechanisms have been described in detail. Mutational analyses carried out with cultured cells (80, 81) and with animal models (52, 66) clearly demonstrate the importance of the 3Ј untranslated region (3ЈUTR) to the constitutively high stability of ␣-globin mRNA (45). Other studies have mapped this characteristic to a phylogenically conserved, 16-nucleotide (nt) C/U-rich element in this region (39,75,76). The cis-acting pyrimidine-rich element (PRE) assembles an mRNP "␣-complex" that compri...
There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5+CD4+ Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for one year. We report herein several key observations. Firstly, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (p < 0.05) and HC (p < 0.01). Second, the function of circulating Tfh cells from PBC patients, including IL-21 production (p < 0.05), the ability to promote B cell maturation and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in UDCA responders compared to UDCA-treated non-responders, in both cross-sectional (p = 0.023) and longitudinal studies (p = 0.036),respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. In conclusion, these results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches.
B cells play an important role in the clearance of hepatitis B virus (HBV) and protection against reinfection. However, the functional characteristics of these cells that are associated with the outcome of chronic HBV infection remain unknown. We comprehensively investigated the frequency, phenotype, and function of peripheral B-cell subsets from CHB patients in different phases: immune tolerance (IT), immune activation (IA), immune clearance (IC), responders with HBsAg seroconversion (resolved patients, RP), and healthy controls (HC). IA patients displayed lower percentages of peripheral blood memory B cells compared with the other groups. Overall polyclonal activation of B cells, indicated by higher levels of activation markers and secretion of IgG and IgM, was observed in IA patients. This B-cell hyperactivation could be induced by increased IFN-a and soluble CD40 ligands in IA patients. Notably, the expression of the co-stimulator molecule CD80 and serum HBsAb and the frequency of HBsAg-specific B cells were significantly decreased in IT, IA, and IC patients compared with HC subjects. More importantly, the B-cell hyperactivation, co-stimulatory molecule downregulation and HBsAg-specific B-cell impairment were reversed in RP patients. The reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
hi@scite.ai
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
Copyright © 2024 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.