These characteristic mechanisms of FC accumulation in HSCs are potential targets to treat liver fibrosis in liver diseases including NASH.

For the identification of susceptibility loci for primary biliary cirrhosis (PBC), a genome-wide association study (GWAS) was performed in 963 Japanese individuals (487 PBC cases and 476 healthy controls) and in a subsequent replication study that included 1,402 other Japanese individuals (787 cases and 615 controls). In addition to the most significant susceptibility region, human leukocyte antigen (HLA), we identified two significant susceptibility loci, TNFSF15 (rs4979462) and POU2AF1 (rs4938534) (combined odds ratio [OR] = 1.56, p = 2.84 × 10(-14) for rs4979462, and combined OR = 1.39, p = 2.38 × 10(-8) for rs4938534). Among 21 non-HLA susceptibility loci for PBC identified in GWASs of individuals of European descent, three loci (IL7R, IKZF3, and CD80) showed significant associations (combined p = 3.66 × 10(-8), 3.66 × 10(-9), and 3.04 × 10(-9), respectively) and STAT4 and NFKB1 loci showed suggestive association with PBC (combined p = 1.11 × 10(-6) and 1.42 × 10(-7), respectively) in the Japanese population. These observations indicated the existence of ethnic differences in genetic susceptibility loci to PBC and the importance of TNF signaling and B cell differentiation for the development of PBC in individuals of European descent and Japanese individuals.

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CD4؉ CD25 ؉ regulatory T cells (CD25 ؉ Tregs) play a key role in immune regulation. Since hepatitis C virus (HCV) persists with increased circulating CD4 ؉ CD25 ؉ T cells and virus-specific effector T-cell dysfunction, we asked if CD4 ؉ CD25 ؉ T cells in HCV-infected individuals are similar to natural Tregs in uninfected individuals and if they include HCV-specific Tregs using the specific Treg marker FoxP3 at the single-cell level. We report that HCV-infected patients display increased circulating FoxP3 ؉ Tregs that are phenotypically and functionally indistinguishable from FoxP3 ؉ Tregs in uninfected subjects. Furthermore, HCV-specific FoxP3 ؉ Tregs were detected in HCV-seropositive persons with antigen-specific expansion, major histocompatibility complex class II/peptide tetramer binding affinity, and preferential suppression of HCV-specific CD8 T cells. Transforming growth factor ␤ contributed to antigen-specific Treg expansion in vitro, suggesting that it may contribute to antigen-specific Treg expansion in vivo. Interestingly, FoxP3 expression was also detected in influenza virus-specific CD4 T cells. In conclusion, functionally active and virus-specific FoxP3 ؉ Tregs are induced in HCV infection, thus providing targeted immune regulation in vivo. Detection of FoxP3 expression in non-HCV-specific CD4 T cells suggests that immune regulation through antigen-specific Treg induction extends beyond HCV.Hepatitis C virus (HCV) is a highly persistent human pathogen that causes chronic necroinflammatory liver disease with progression to liver failure and cancer (25, 31). While T cells play a critical role in HCV clearance (24, 53), the virus generally persists, along with impaired antiviral effector T-cell responses (13,59,63,69). While the precise underlying mechanisms for HCV persistence and disease pathogenesis are not fully defined, a role for CD4 ϩ CD25 ϩ regulatory T cells (CD25 ϩ Tregs) has been proposed based on increased circulating CD4 ϩ CD25 ϩ T cells that can suppress HCV-specific T cells in HCV-infected patients (10,12,48,54). CD25ϩ Tregs are a subset of naturally occurring, thymus-derived CD4 ϩ regulatory T cells that highly express CD25 (the interleukin-2 [IL-2] receptor alpha chain) and play a critical role in immune tolerance to self and nonself antigens (27,44,49,51). The role of CD25 ϩ Tregs in immune regulation has been demonstrated in animal models of organ-specific autoimmune diseases, in which pathology is precipitated by their depletion and ameliorated by their reconstitution (52). The key marker of CD25 ϩ Tregs is the forkhead/winged helix family transcription factor FoxP3 (70). Impaired FoxP3 gene expression results in severe autoimmunity in human immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome (8, 67) and in Scurfy mice (11); furthermore, forced FoxP3 expression in FoxP3 Ϫ T cells confers regulatory properties in vitro (21, 65). CD25 ϩ Tregs may also contribute to pathogen-specific immune regulation in viral infections, including those with hepatitis B and C, her...