The mechanism underlying the differentiation of CD4+ T cells into functionally distinct subsets (Th1 and Th2) is incompletely understood, and hitherto unidentified cytokines may be required for the functional maturation of these cells. Here we report the cloning of a recently identified IFN-gamma-inducing factor (IGIF) that augments natural killer (NK) activity in spleen cells. The gene encodes a precursor protein of 192 amino acids and a mature protein of 157 amino acids, which have no obvious similarities to any peptide in the databases. Messenger RNAs for IGIF and interleukin-12 (IL-12) are readily detected in Kupffer cells and activated macrophages. Recombinant IGIF induces IFN-gamma more potently than does IL-12, apparently through a separate pathway. Administration of anti-IGIF antibodies prevents liver damage in mice inoculated with Propionibacterium acnes and challenged with lipopolysaccharide, which induces toxic shock. IGIF may be involved in the development of Th1 cells and also in mechanisms of tissue injury in inflammatory reactions.

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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.

The incidence of hepatocellular carcinoma (HCC) in patients with primary biliary cirrhosis (PBC) is not well known. The aims of this study are to determine HCC incidence and survival, and to identify risk factors associated with these outcomes in patients with PBC. We collected information on 396 patients with PBC at enrollment and followed-up from 6 to 271 months. They were all negative for hepatitis B and C virus markers. HCC was detected by scanning with ultrasonography, computed tomography, or both every 4 to 6 months. Life expectancy (LE) was approximated with the declining exponential approximation of LE. A total of 14 patients developed HCC. The cumulative appearance rate of HCC in patients with advanced-stage PBC (Scheuer's stage III or IV) was significantly higher than that for patients with early-stage (stage I or II) (12.3% and 7.7% by the tenth year, respectively. P ‫؍‬ .021). Proportional hazards analysis showed 3 factors are independently associated with the development of HCC: age at the time of diagnosis, male gender, and history of blood transfusion. Age, male gender, and advanced-stage PBC were associated with survival, but HCC development was not. The disease-specific annual mortality rate was estimated to be 0.008 for women and 0.028 for men with advanced-stage PBC. In conclusion, HCC develops in old patients with advanced-stage PBC, but HCC does not affect the patients' survival. P rimary biliary cirrhosis (PBC) is a chronic liver disease of unknown etiology presenting a variety of disease spectrum from asymptomatic disease state to full-blown cirrhosis. Patients with liver cirrhosis caused by chronic infection of hepatitis C virus (HCV) or hepatitis B virus (HBV) are at high risk of hepatocellular carcinoma (HCC); however, it is not known whether the HCC incidence is high in patients with PBC. Although there are 9 studies about HCC incidence in PBC, the results are not consistent. 1-9 Some studies 3,4 show that patients with PBC have no excess risk of developing HCC and others [5][6][7][8][9] show that the incidence of HCC is high in those patients. An Italian study indicated that HCC has a relatively high prevalence in PBC and HCV superinfection may play an important part in favoring HCC. 7 Even though without HBV or HCV infection, a study conducted in UK showed 5.9% of patients with PBC in precirrhotic or cirrhotic stage had developed HCC. 6 The authors of this large-scale cohort study concluded that men with advanced-stage PBC have a higher risk of developing HCC. A recent retrospective study in the Mayo Clinic also reported that patients with PBC 8 are at high risk of hepatobiliary malignancies but the authors did not mention risk factors for HCC development.The aims of the present study are to analyze the survival of patients with PBC, to quantify the incidence at which they develop HCC, and to identify HCC risk factors. In addition, we determined whether HCC affected the survival of patients with PBC. Therefore, we tested 2 hypotheses: (1) that the patients with advanced-stage PBC sur...

Administration of monoclonal anti-CD3 antibody to mice treated with Propionibacterium acnes induced secretion of a high level of gamma interferon (IFN-␥) into the circulation system, while it induced no significant release in untreated mice. In order to analyze this high-level induction of IFN-␥ in these bacterium-treated mice, we investigated the factors that might be involved. An activity that induces IFN-␥ in T cells was observed in the liver extracts of mice treated with P. acnes and subsequently challenged with lipopolysaccharide. Here, we purified an IFN-␥-inducing factor from the liver extract to homogeneity and characterized it. Its molecular mass was 18 to 19 kDa, and its pI was 4.9. The amino acid sequence of the NH 2-terminal portion was determined and shown to have no similarities to any protein in the EMBL, GenBank, and PIR data bases. The same molecule was also demonstrated in the serum factor that was previously reported to have an IFN-␥inducing activity and to have an apparent molecular mass of 75 kDa. Moreover, the activity of this serum factor was recovered in the fraction containing the 18-to 19-kDa protein under reducing conditions and was shown to have the same NH 2-terminal amino acid sequence as that of the factor from the liver extract. In addition to the ability to induce IFN-␥, this protein augmented T-cell proliferation and NK activity in the spleen cells. Thus, several of its biological activities were apparently similar to those of interleukin-12. These results indicated that this novel protein, which exhibited marked costimulatory activity on IFN-␥ production in vitro, was elevated in vivo in response to P. acnes treatment. This factor, probably released from the producing cells by lipopolysaccharide stimuli, may be involved in the high-level induction of IFN-␥ in the P. acnes-treated mice. Recently CD4 ϩ T (Th) cells were divided into distinct subsets according to the profiles of cytokine production (15, 22, 23, 25). This will help our understanding of the regulatory mechanism of immune responses caused by infections with a variety of pathogens. Accessory cells or cytokines produced in response to the initial contact with antigens were shown to exhibit important functions in the development of these cells, depending on the antigenic characteristics. Cells of the Th2 subset are thought to require interleukin-1 (IL-1) or IL-4 for their development (6, 9, 11, 12, 24), and it is shown that IL-12 induces the differentiation of Th1 cells from uncommitted T cells (7, 13, 21). Gamma interferon (IFN-␥), which is produced by activated CD4 ϩ T (Th1), CD8 ϩ T, or NK cells, has been demonstrated to play important roles in cell-mediated immunity. Each of these producer cells may be regulated in the same or different manners, when stimulated. IL-2 was shown to induce IFN-␥ production in NK cells (3, 8), and IL-12 was demonstrated to be involved in IFN-␥ induction in CD4 ϩ T cells or NK cells (7, 13, 21). However, the detailed mechanisms underlying IFN-␥ production as well as the mechanism of devel...

Background It is well known that the incidence of developing hepatocelluler carcinoma (HCC) is increased in liver cirrhosis of different etiologies. However, comparison of HCC incidence in various liver diseases has not yet been estimated. We surveyed this comparison. Methods The PubMed database was examined (1989‐2017) for studies published in English language regarding the prospective follow‐up results for the development of HCC in various liver diseases. A meta‐analysis was performed for each liver disease. Results The annual incidence (%) of HCC in the non‐cirrhotic stage and cirrhotic stage, and the ratio of HCC incidence in the cirrhotic stage/non‐cirrhotic stage were as follows. (a) hepatitis B virus liver disease: 0.37%→3.23% (8.73‐fold), (b) hepatitis C virus liver diseases: 0.68%→4.81% (7.07‐fold), (c) primary biliary cholangitis (0.26%→1.79%, 6.88‐fold), (d) autoimmune hepatitis (0.19%→0.53%, 2.79‐fold), and (e) NASH (0.03%→1.35%, 45.00‐fold). Regarding primary hemochromatosis and alcoholic liver diseases, only follow‐up studies in the cirrhotic stage were presented, 1.20% and 2.06%, respectively. Conclusions When the liver diseases advance to cirrhosis, the incidence of HCC is markedly increased. The development of HCC must be closely monitored by ultrasonography, magnetic resonance imaging, and computed tomography, irrespective of the different kinds of liver diseases.

Key Points Question Is the COVID-19 pandemic associated with the stage at which gastrointestinal cancer is diagnosed in Japan? Findings In this cohort study of 5167 patients, significant decreases were observed for the diagnosis of stage I gastric cancer and stage 0 to II colorectal cancer, whereas a significant increase was observed for the diagnosis of stage III colorectal cancer. Meaning These findings suggest that during the COVID-19 pandemic, there may have been fewer cases of screening-detected gastrointestinal cancer, and colorectal cancer may have been diagnosed at more advanced stages.

Recent studies have demonstrated that micro (mi)RNA molecules can be detected in the circulation and can serve as potential biomarkers of various diseases. This study used microarray analysis to identify aberrantly expressed circulating miRNAs in patients with type 1 autoimmune hepatitis (AIH) compared with healthy controls. Patients with well-documented and untreated AIH were selected from the National Hospital Organization (NHO)-AIH-liver-network database. They underwent blood sampling and liver biopsy with inflammation grading and fibrosis staging before receiving treatment. To further confirm the microarray data, circulating expression levels of miR-21 and miR-122 were quantified by real-time quantitative polymerase chain reaction in 46 AIH patients, 40 patients with chronic hepatitis C (CHC), and 13 healthy controls. Consistent with the microarray data, serum levels of miR-21 were significantly elevated in AIH patients compared with CHC patients and healthy controls. miR-21 and miR-122 serum levels correlated with alanine aminotransferase levels. Circulating levels of miR-21 and miR-122 were significantly reduced in AIH patients with liver cirrhosis, and were inversely correlated with increased stages of fibrosis. By contrast, levels of circulating miR-21 showed a significant correlation with the histological grades of inflammation in AIH. We postulate that aberrantly expressed serum miRNAs are potential biomarkers of AIH and could be implicated in AIH pathogenesis. Alternations of miR-21 and miR-122 serum levels could reflect their putative roles in the mediation of inflammatory processes in AIH.