This is the first study to demonstrate the clinical features and response to therapy of NAFLD patients comorbid with MDD. The comorbid state of MDD was associated with more severe histological liver steatosis and worse treatment outcomes in patients with NAFLD. Further investigations are required to develop new lifestyle modification programs that enable NAFLD patients with MDD to achieve the treatment goal.

We have identified a novel association between Alaska specific core mutations and HCC development in AN people infected with genotype F1b. Accumulation of these core mutations during the course of chronic infection with genotype F1b would contribute to HCC development in AN people earlier in life. This article is protected by copyright. All rights reserved.

Hepatitis B virus (HBV) remains a leading cause of liver-related morbidity and mortality through chronic hepatitis that may progress to liver cirrhosis and cancer. The central role played by HBV-specific CD8+ T cells in the clearance of acute HBV infection, and HBV-related liver injury is now well established. Vigorous, multifunctional CD8+ T cell responses are usually induced in most adult-onset HBV infections, while chronic hepatitis B (CHB) is characterized by quantitatively and qualitatively weak HBV-specific CD8+ T cell responses. The molecular basis of this dichotomy is poorly understood. Genomic analysis of dysfunctional HBV-specific CD8+ T cells in CHB patients and various mouse models suggest that multifaceted mechanisms including negative signaling and metabolic abnormalities cooperatively establish CD8+ T cell dysfunction. Immunoregulatory cell populations in the liver, including liver resident dendritic cells (DCs), hepatic stellate cells (HSCs), myeloid-derived suppressor cells (MDSCs), may contribute to intrahepatic CD8+ T cell dysfunction through the production of soluble mediators, such as arginase, indoleamine 2,3-dioxygenase (IDO) and suppressive cytokines and the expression of co-inhibitory molecules. A series of recent studies with mouse models of HBV infection suggest that genetic and epigenetic changes in dysfunctional CD8+ T cells are the manifestation of prolonged antigenic stimulation, as well as the absence of co-stimulatory or cytokine signaling. These new findings may provide potential new targets for immunotherapy aiming at invigorating HBV-specific CD8+ T cells, which hopefully cures CHB.

CD8 T cells are the key cellular effectors mediating the clearance of hepatitis B virus (HBV) infections. However, early immunological events surrounding the priming of HBV-specific CD8 T cell responses remain poorly understood. This study examined the importance of priming location and the relative contribution of endogenous antigen presentation by hepatocytes versus cross-presentation by bone marrow-derived cells to the induction of functional HBV-specific CD8 T cell responses using the animal models of acute and chronic HBV infection. Functional HBV-specific CD8 T cell responses could be induced to intrahepatically expressed HBV even when T cell homing to the lymphoid tissues was severely suppressed, suggesting that functional priming could occur in the liver. The expansion of HBV-specific CD8 T cells was significantly reduced in the mice whose major histocompatibility complex (MHC) class I expression was mostly restricted to nonhematopoietic cells, suggesting the importance of cross-presentation by hematopoietic cells in the induction of HBV-specific CD8 T cells. Strikingly, the expansion and cytolytic differentiation of HBV-specific CD8 T cells were reduced even more severely in the mice whose MHC class I expression was restricted to hematopoietic cells. Collectively, these results indicate that cross-presentation is required but relatively inefficient in terms of inducing the cytolytic differentiation of HBV-specific CD8 T cells by itself. Instead, the expansion and functional differentiation of HBV-specific CD8 T cells are primarily dependent on hepatocellular antigen presentation. Hepatitis B virus (HBV) causes acute and chronic hepatitis. Approximately 260 million people are chronically infected with HBV and under an increased risk of developing cirrhosis and hepatocellular carcinoma. Host immune responses, particularly HBV-specific CD8 T cell responses, largely determine the outcome of HBV infection. It is widely accepted that antigen inexperienced CD8 T cells should be initially activated by professional antigen-presenting cells (pAPCs) in lymphoid tissues to differentiate into effector CD8 T cells. However, this notion has not been tested for HBV-specific CD8 T cells. In this study, we show that HBV-specific CD8 T cell responses can be induced in the liver. Surprisingly, antigen presentation by hepatocytes is more important than cross-presentation by hematopoietic cells for the induction of HBV-specific CD8 T cell responses. These results revealed a previously unappreciated role of antigen presentation by hepatocytes in the induction of HBV-specific CD8 T cell responses.