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Chronic hepatitis E mostly occurs in organ transplant recipients and can lead to rapid liver fibrosis and cirrhosis. Previous studies found that the development of chronic hepatitis E virus (HEV) infection is linked to the type of immunosuppressant used. Animal models are crucial for the study of pathogenesis of chronic hepatitis E. We previously established a stable chronic HEV infection rabbit model using cyclosporine A (CsA), a calcineurin inhibitor (CNI)-based immunosuppressant. However, the immunosuppression strategy and timing may be optimized, and how different types of immunosuppressants affect the establishment of chronic HEV infection in this model is still unknown. Here, we showed that chronic HEV infection can be established in 100% of rabbits when CsA treatment was started at HEV challenge or even 4 weeks after. Tacrolimus or prednisolone treatment alone also contributed to chronic HEV infection, resulting in 100% and 77.8% chronicity rates, respectively, while mycophenolate mofetil (MMF) only led to a 28.6% chronicity rate. Chronic HEV infection was accompanied with a persistent activation of innate immune response evidenced by transcriptome analysis. The suppressed adaptive immune response evidenced by low expression of genes related to cytotoxicity (like perforin and FasL ) and low anti-HEV seroconversion rates may play important roles in causing chronic HEV infection. By analyzing HEV antigen concentrations with different infection outcomes, we also found that HEV antigen levels could indicate chronic HEV infection development. This study optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits and highlighted the potential association between the development of chronic HEV infection and immunosuppressants.IMPORTANCEOrgan transplant recipients are at high risk of chronic hepatitis E and generally receive a CNI-based immunosuppression regimen containing CNI (tacrolimus or CsA), MMF, and/or corticosteroids. Previously, we established stable chronic HEV infection in a rabbit model by using CsA before HEV challenge. In this study, we further optimized the immunosuppression strategies for establishing chronic HEV infection in rabbits. Chronic HEV infection can also be established when CsA treatment was started at the same time or even 4 weeks after HEV challenge, clearly indicating the risk of progression to chronic infection under these circumstances and the necessity of HEV screening for both the recipient and the donor preoperatively. CsA, tacrolimus, or prednisolone instead of MMF significantly contributed to chronic HEV infection. HEV antigen in acute infection phase indicates the development of chronic infection. Our results have important implications for understanding the potential association between chronic HEV infection and immunosuppressants., Competing Interests: The authors declare no conflict of interest.

Immune regulation has an important role in cancer development, particularly in organs with continuous exposure to environmental pathogens, such as the liver and gastrointestinal tract. Chronic liver inflammation can lead to the development of hepatobiliary cancers, namely hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (iCCA), or combined HCC (cHCC)-CCA. In this review, we discuss the link between oxidative stress and the hepatic immune compartments, as well as how these factors trigger hepatocyte damage, proliferation, and eventually cancer initiation and its sustainment. We further give an overview of new anticancer therapies based on immunomodulation., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Neutrophils, the most abundant type of leukocyte in human blood, play a major role in host defense against invading pathogens and in sterile injury. Neutrophil infiltration is characteristic of inflammation because of its antimicrobial and cytotoxic activities. Neutrophils also actively participate in the resolution of inflammation and subsequent tissue repair by acting as a critical mediator between the inflammation and resolution phases of tissue damage. However, neutrophils that are consistently exposed to inflammatory conditions lose their self-resolving capabilities and maintain an inflammatory phenotype, further exacerbating tissue damage. The current review describes how neutrophils interact with tissue microenvironments and acquire disease-specific phenotypes under chronic inflammatory conditions. Here, we aim to provide a better understanding of neutrophil-mediated pathogenesis of various liver diseases., (© 2021 by the American Association for the Study of Liver Diseases.)

Histopathology is essential for the diagnosis and evaluation of disease activity of autoimmune hepatitis (AIH). We aimed to elucidate the characteristics of AIH from the localization of inflammation. We re-evaluated a nationwide survey that was performed in Japan in 2018 of AIH patients diagnosed between 2014 and 2017. A total of 303 patients were enrolled, and the clinical and treatment characteristics were compared between the patients with predominantly portal inflammation (230 patients) or lobular inflammation (73 patients). AIH patients with lobular inflammation had a higher probability of being diagnosed with acute hepatitis than those with portal inflammation. Liver enzyme levels were higher in patients with lobular inflammation, whereas immunoglobulin G levels were higher in patients with portal inflammation. The prevalence of an alanine aminotransferase level < 30 U/L after 6 months of treatment was significantly higher in patients with lobular inflammation than in those with portal inflammation (81.7% vs. 67.3%, P = 0.046). The localization of inflammation may be useful for evaluating the onset of AIH.

Natural killer T (NKT) cells are a key component of innate immunity. Importantly, a growing body of evidence indicates that NKT cells play an integral role in various acute and chronic liver injuries. NKT cells participate in the progression of an injury through the secretion of cytokines, which promote neutrophil infiltration and enhance Fas ligand (FasL) and granzyme-mediated NKT cytotoxic activity. Therefore, examining the role of NKT cells in hepatic disease is critical for a comprehensive understanding of disease pathogenesis and may provide insight into novel approaches for treatment. For more than a century, mouse models that imitate the physiopathological conditions of human disease have served as a critical tool in biological and medical basic research, including studies of liver disease. Here, we review the role of NKT cells in various mouse models of hepatitis., Competing Interests: The authors declare no potential conflicts of interest., (Copyright © 2021 Jun Guan et al.)

Here, we discuss how the tendency of a liver infection to chronify can be seen as an evolutionary advantage for infected individuals. For this purpose, we present a set of reaction-diffusion equations as a mathematical model of viral liver infections, which allows chronic and acute courses of the liver infection. We introduce a cumulative wealth function, and finally, we show that an immune response favoring the chronification is evolutionary advantageous at the same time.

Background and Aims: Sporadic hepatitis E is an emerging indigenous disease in Europe induced by genotype 3 of the virus. While the disease takes an acute self-limited course in immunocompetent individuals, under immunocompromised conditions chronic hepatitis E might develop. The histology of chronic hepatitis E has not been described in detail systematically., Methods: Liver biopsies from 19 immunosuppressed patients with chronic hepatitis E were collected: 17 were organ transplant recipients, one had a CD4-deficiency and one had received steroid therapy because of ulcerative colitis. Biopsies were processed with standard stains. Evaluation of histologic activity and fibrosis was performed according to Ishak. Additionally, immunohistochemistry with antibodies directed against open reading frame 2 and 3 of the virus was performed and liver biopsies were tested for hepatitis E virus RNA., Results: Biochemical data showed an increase in alanine transaminase, aspartate transaminase, gamma-glutamyl transferase and total bilirubin. Histopathology displayed typical features of chronic hepatitis with mild to moderate activity. The number of polymorphonuclear leucocytes was considerably increased and all patients had a florid cholangitis that presented as a destructive form in five of them. Hepatocytes and bile duct epithelia stained positive for hepatitis E virus by immunohistochemistry., Conclusions: Chronic hepatitis E in immunocompromised individuals runs a similar course as hepatitis B and C and shows similar histopathology. However, the presence of destructive cholangitis in some cases accompanied by an increased number of polymorphonuclear leucocytes is markedly different. Immunohistochemically the virus is present in bile duct epithelia, seemingly the cause for cholangitis., (© 2019 The Authors. Liver International published by John Wiley & Sons Ltd.)

Background & Aims: Immunosuppressed patients with chronic hepatitis E virus infection (cHEV), who are ineligible or have failed current treatment with off-label ribavirin, are a potential target population for T cell-based therapy. T cell responses are important for viral control. Herein, we aimed to identify human leukocyte antigen (HLA)-A2 restricted HEV-specific CD8+ T cell epitopes and T cell receptors (TCR) targeting these epitopes, as the basis for a redirected TCR treatment approach for patients with cHEV., Methods: HEV genotype 3 overlapping peptide pools were used to screen HEV-specific CD8+ T cell immune responses in HLA-A2+ patients with acute HEV infection and healthy donors, by intracellular cytokine staining. CD8+ T cells targeting the identified epitopes were sorted for sequencing of the TCR repertoires by next generation sequencing. Messenger RNA encoding these TCRs were introduced into lymphocytes of healthy donors and patients with cHEV through TCR redirection. TCR-engineered lymphocytes were evaluated for Dextramer®-binding capacity, target sensitivity and cytotoxicity against peptide-loaded T2 cells., Results: HEV-specific responses were observed across open reading frame (ORF)1 and ORF2 of the HEV genome in patients with acute resolving HEV infection. HLA-A2-restricted HEV-specific CD8+ T cell epitopes targeting the HEV RNA helicase and RNA-dependent RNA polymerase were selected for functional studies. Introduction of HEV-specific TCRs into lymphocytes of immunocompetent donors and patients with chronic hepatitis E enabled the lymphocytes to bind HEV Dextramers, secrete multiple cytokines and exert cytotoxicity in a target-specific manner., Conclusion: We identified TCRs that target HEV-specific CD8+ T cell epitopes, and characterized their immune properties, which may have clinical potential in future T cell-based therapy., Lay Summary: Patients who are immunosuppressed are vulnerable to developing chronic liver disease following infection with hepatitis E virus (HEV). To-date, there is no approved therapy for chronic hepatitis E. Interferon-α and ribavirin are off-label treatment options, but their applications are limited by side effects. Thus, immunotherapy, more specifically T cell-based therapy, may be an alternative approach. We designed T cell receptor-engineered T cells that effectively conferred immune cells, taken from patients with chronic hepatitis E, with the ability to recognize virus-specific epitopes and mediate killing of target cells in vitro., (Copyright © 2019 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Background: To investigate the effects of dual plasma molecular adsorption system (DPMAS) on the liver function, electrolytes, inflammation, and immunity in patients with chronic severe hepatitis (CSH)., Methods: Total of 162 patients with CSH treated in our hospital from March 2016 to December 2018 were enrolled and equally randomly divided into control group (n = 81) and observation group (n = 81). The patients in control group were treated with plasma exchange, while those in observation group were additionally treated with DPMAS based on the treatment in control group. The liver function, electrolytes, inflammation, and immunity were evaluated and compared between the two groups., Results: After treatment, the liver function indexes in observation group were significantly favorable compared with those in control group, with the reduction in TBIL, DBIL, ALT, and rise of CHE levels (P < 0.05). The levels of K + , Na + , Cl - , and Ca 2+ in both groups were significantly improved after treatment (P < 0.05), although there were no significant differences between the two groups (P > 0.05). The levels of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) in both groups declined after treatment compared with those before treatment, and those levels in observation group were higher than that in control group (P < 0.05). After treatment, the levels of cluster of differentiation 3 + (CD3 + ), CD4 + , and CD4 + /CD8 + were higher in observation group than those in control group, with decreasing level of CD8 + (P < 0.05)., Conclusion: Dual plasma molecular adsorption system can effectively improve the liver function, effectively correct the electrolyte disorders, reduce the inflammatory response, and adjust the immunity in patients with CSH., (© 2019 The Authors Journal of Clinical Laboratory Analysis Published by Wiley Periodicals, Inc.)

Hepatitis E virus (HEV) has traditionally been associated with an acute, self-limiting hepatitis and is not known to have any chronic sequelae. HEV genotypes 1 and 2, which are human pathogens, have been associated with this self-limiting presentation, in both sporadic and epidemic settings. HEV genotype 3, which is zoonotically transmitted, is increasingly being reported as a cause of chronic infection in immunocompromised patients. These include patients with solid organ transplants, patients receiving chemotherapy for haematologic malignancies and patients infected with HIV. Chronic infection is associated with rapidly progressing liver disease and extrahepatic manifestations including neurologic disorders. We review the clinical manifestations of chronic HEV infection and discuss factors determining persistence and chronicity of HEV., (© 2019 John Wiley & Sons Ltd.)

Background & Aims: Chronic inflammatory liver diseases are frequently associated with neuropsychiatric and cognitive dysfunctions. We hypothesized that symptomatic patients may show altered levels of soluble inflammatory mediators (SIMs) as well as changes in immune cell phenotypes., Methods: A comprehensive immune-phenotyping including investigation of 50 SIMs as well as ex-vivo phenotypes of NK-cells, CD3+, CD4+, CD8+ and regulatory T cells in 40 patients with viral and autoimmune chronic liver diseases was performed. The patients' cognitive functions were assessed using an extensive battery of neuropsychological testing., Results and Conclusion: Overall, our data indicate that while SIMs are significantly up-regulated, NK- and T-cells are less-activated in patients with neuropsychiatric symptoms accompanying chronic inflammatory liver diseases compared to patients without these symptoms. Moreover, HCV patients showed a unique pattern of immune alterations as compared to patients with HBV, autoimmune hepatitis and primary biliary cirrhosis. These findings hint towards potential mechanisms explaining these symptoms in patients with chronic liver diseases., (© 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Hepatitis B virus (HBV) infection is a major cause of hepatic inflammation. Successful HBV clearance in patients is associated with sustained viral control by effector T cells. Compared with acute hepatitis B, chronic HBV infection is associated with the depletion of T cells, resulting in weak or absent virus‑specific T cells reactivity, which is described as 'exhaustion'. This exhaustion is characterized by impaired cytokine production and sustained expression of multiple coinhibitory molecules. Cytotoxic T lymphocyte‑associated antigen‑4 (CTLA‑4) is one of many coinhibitory molecules that can attenuate T cell activation by inhibiting costimulation and transmitting inhibitory signals to T cells. Persistent HBV infection results in the upregulation of CTLA‑4 on hepatic CD8+ T cells. This prompts CD8+ T cell apoptosis, and the activation of cytotoxic T lymphocytes is blocked. Similar to CD8+ T cells, CD4+ T helper (Th) cell proliferation is hindered following CTLA‑4 upregulation. In addition, the differentiation of CD4+ Th is polarized toward the Th2/peripherally‑inducible T regulatory cell types, increasing the levels of anti‑inflammatory cytokines. Conversely, the activation of proinflammatory cells (Th1 and follicular helper T) is blocked, and the levels of proinflammatory cytokines decline. This review summarizes the current literature relevant to T cell exhaustion in patients with HBV‑related chronic hepatitis, and discusses the roles of CTLA‑4 in T cell exhaustion.

Aim: To assess the levels of different immune modulators in patients with hepatocellular carcinoma (HCC), in relation to other hepatic diseases., Methods: Eighty-eight patients were included in the current study and represented patients with HCC (20), liver cirrhosis (28) and chronic hepatitis (CH; 25), and normal controls (NC; 15). Peripheral blood was isolated for immunophenotyping of active myeloid dendritic cells (mDCs; CD1c and CD40), mature inactive myeloid cells (CD1c and HLA), active plasmacytoid cells (pDCs; CD303 and CD40), mature inactive pDCs (CD30 and HLA), active natural killer (NK) cells (CD56 and CD161), active NK cells (CD56 and CD314) and inactive NK cells (CD56 and CD158) was done by flow cytometry. Serum levels of interleukin (IL)-2, IL-10, IL-12, IL-1β, interferon (IFN)-α, IFN-γ and tumor necrosis factor (TNF)-αR2 were assessed by ELISA., Results: Active mDCs (CD1C+/CD40+) and inactive mDCs (CD1c+/HLA+) were significantly decreased in HCC patients in relation to NC ( P < 0.001). CD40+ expression on active pDCs was decreased in HCC patients ( P < 0.001), and its level was not significantly changed among other groups. Inactive pDCs (CD303+/HLA+), inactive NKs (CD56+/CD158+) and active NKs (CD56+/CD161+) were not statistically changed among the four groups studied; however, the latter was increased in CH ( P < 0.05). NKG2D was statistically decreased in HCC, CH and cirrhosis ( P < 0.001), and it was not expressed in 63% (12/20) of HCC patients. There was significant decrease of IL-2, IFN-α and IFN-γ ( P < 0.001), and a significant increase in IL-10, IL-1β, and TNF-αR2 ( P <0.01, P < 0.001 and P < 0.001; respectively) in HCC patients. There was inverted correlation between IL-12 and IL-1β in HCC ( r = -0.565, P < 0.01), with a strong correlation between pDCs (CD303+/CD40+) and NKs (CD56+/CD161+; r = 0.512, P < 0.05) as well as inactive mDCs (CD1c+/HLA+) and inactive NK cells (CD56+/CD158+; r = 0.945, P < 0.001)., Conclusion: NKG2D, CD40, IL-2 and IL-10 are important modulators in the development and progression of HCC., Competing Interests: Conflict-of-interest statement: All the authors have no conflict of interest related to the manuscript.

We present a 38-year-old white British man who was taking long-term immunosuppressive medication following kidney transplantation. On routine review, he was noted to have an isolated and asymptomatic rise in alanine aminotransferase. After thorough investigation, he was found to have positive IgM and IgG serology to hepatitis E virus-and given the duration of his transaminitis, he was determined to have chronic hepatitis E infection. Treatment options were complicated by the presence of his kidney transplant, by chronic anaemia and by his wish for concomitant fertility treatment. Ribavirin therapy was instituted with a dramatic and immediate drop in serum viral load, although stool viraemia persisted. No clear protocols guide duration of treatment in chronic hepatitis E infection, but protracted faecal virus shedding predicts viral recrudescence, and treatment should continue at least until the stool is clear of virus., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The broadening field of microbiome research has led to a substantial reappraisal of the gut-liver axis and its role in chronic liver disease. The liver is a central immunologic organ that is continuously exposed to food and microbial-derived antigens from the gastrointestinal tract. Mucosal-associated invariant T (MAIT) cells are enriched in the human liver and can be activated by inflammatory cytokines and microbial antigens. In chronic inflammatory liver disease, MAIT cells are depleted suggesting an impaired MAIT cell-dependent protection against bacterial infections., Competing Interests: Disclosure The authors report no conflicts of interest in this work., (Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.)

Background: The idea that changes to the host immune system are critical for cancer progression was proposed a century ago and recently regained experimental support., Results: Herein, the hypothesis that hepatocellular carcinoma (HCC) leaves a molecular signature in the host peripheral immune system was tested by profiling DNA methylation in peripheral blood mononuclear cells (PBMC) and T cells from a discovery cohort ( n  = 69) of healthy controls, chronic hepatitis, and HCC using Illumina 450K platform and was validated in two validation sets ( n  = 80 and n  = 48) using pyrosequencing., Conclusions: The study reveals a broad signature of hepatocellular carcinoma in PBMC and T cells DNA methylation which discriminates early HCC stage from chronic hepatitis B and C and healthy controls, intensifies with progression of HCC, and is highly enriched in immune function-related genes such as PD-1 , a current cancer immunotherapy target. These data also support the feasibility of using these profiles for early detection of HCC., Competing Interests: Informed consent has been obtained from all participants and the study received ethical approval from The Capital Medical School in Beijing and McGill University (IRB Study Number A02-M34-13B).Participants/patients have given their consent for their data to be published in the report.The authors declare that MS, YZ, SP, and NL have applied for patent protection, MS has equity in HKG epitherapeutics and Montreal epiterapia, and DC has equity in Montreal epiterapia.Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Hepatocellular carcinoma (HCC) is one of the most deadly and rapidly evolving cancers worldwide. The current systemic treatment strategies in advanced tumor stages remain limited despite promising preclinical and early-phase clinical results for some compounds, highlighting an unmet clinical need. Since the majority of HCCs evolve in the background of a chronic inflammatory liver damage, HCCs can be considered a paradigm for inflammation-induced cancers, which renders immunotherapeutic strategies particularly promising for this tumor entity. Consequently, an improved understanding of key oncogenic and immune response signaling pathways as well as increasing appreciation of the diseased microenvironment for HCC initiation and progression has led to the development of a diverse range of immune-oncological interventions during the last decade. Besides oncolytic viruses, vaccines, or immune cell infusions, first results from early-phase clinical trials particularly encourage the use of immune checkpoint inhibitors against PD-1/PD-L1 and CTLA-4 for HCC. In this review, we delineate the current clinical and preclinical landscape of immunotherapies in HCC, critically discuss recent findings from clinical trials and outline future perspectives in the field of liver cancer., (© 2018 S. Karger GmbH, Freiburg.)

There is a well-established link between biliary tract cancers (BTC) and chronic inflammatory conditions such as primary sclerosing cholangitis, chronic cholecystitis, chronic cholelithiasis, liver fluke-associated infestations, and chronic viral hepatic infections. These associated risk factors highlight the potential for development of immune-modulatory agents in this poor-prognostic disease group with limited treatment options. Clinical trials have evaluated the role of immune cells, inflammatory biomarkers, vaccines, cytokines, adoptive cell therapy, and immune checkpoint inhibitors in patients with BTC. Although these have demonstrated the importance of the immune environment in BTC, currently none of the immune-based therapies have been approved for use in this disease group. The role of immunomodulatory agents is a developing field and has yet to find its way 'from bench to bedside' in BTC., (© 2018 S. Karger GmbH, Freiburg.)

Competing Interests: Competing interests: None declared.

Rationale: Acute hepatitis E virus (HEV) infections are usually self-limiting in immunocompetent patients. HEV persistence has been described only in immunosuppressed patients such as solid-organ transplant recipients, patients with hematological diseases, or patients with human immunodeficiency virus (HIV) infection., Patient Concerns: A 61-year-old patient was admitted in hospital for jaundice and asthenia., Diagnoses: The patient had underlying cirrhosis and developed a chronic HEV infection., Intervention: Ribavirin therapy was initiated., Outcomes: Ribavirin therapy for 12 months allowed the clearance of the virus and HEV viral load remained undetectable thereafter. This patient had taken no immunosuppressive drugs, was not suffering from any autoimmune disease and was not infected with HIV. We studied the patient's anti-HEV immune response months after the viral clearance. His peripheral blood mononuclear cells (PBMC) were stimulated in vitro by HEV peptides. The patient had a mild T lymphopenia, but polyclonal stimulation of PBMC showed a robust T cell response. The response of his anti-HEV specific interferon-γ producing T cells was low., Lessons: Other studies are now needed to identify the population with a chronic evolution of HEV infection despite no apparent immunodepression.

Hepatitis E virus (HEV) infection is increasingly being reported in immunocompromised patients and particularly organ transplant recipients. In this context, HEV infection frequently evolves to chronic infection with a rapid progression of fibrosis to cirrhosis. Ribavirin monotherapy and a minimization of immunosuppression represent the treatment of choice, with a good response rate. However, no data are available on whether treatment can achieve a regression of liver fibrosis in chronic HEV patients. A 57-year-old male patient received a liver transplant for alcoholic cirrhosis and, 6 years later, developed biopsy-proven chronic HEV infection. The patient received different antiviral therapy regimens (pegylated interferon alpha 2b and ribavirin different dosages, and long-term treatment with ribavirin monotherapy still ongoing) but without achieving a sustained virological response. Liver function parameters normalized after 1 month of treatment but without the clearance of HEV. Hepatitis E virus RNA levels also remained detectable in the serum and stools throughout ribavirin monotherapy. No serious adverse events were reported. A gradual regression of liver fibrosis was reported (Metavir A0/F1 in 2015 versus A3/F4 in 2008). Long-term treatment with ribavirin is safe in liver transplant recipients, without achieving HEV sustained virological response, and may induce a biopsy-proven regression of liver fibrosis in a liver transplant recipient with cirrhosis after chronic HEV infection.

Background & Aims: During liver inflammation, triggering fibrogenesis and carcinogenesis immune cells play a pivotal role. In the present study we investigated the role of CCL5 in human and in murine models of chronic liver inflammation leading to hepatocellular carcinoma (HCC) development., Methods: CCL5 expression and its receptors were studied in well-defined patients with chronic liver disease (CLD) and in two murine inflammation based HCC models. The role of CCL5 in inflammation, fibrosis, tumor initiation and progression was analyzed in different cell populations of NEMO Δhepa /CCL5 -/- animals and after bone marrow transplantation (BMT). For therapeutic intervention Evasin-4 was injected for 24h or 8weeks., Results: In CLD patients, CCL5 and its receptor CCR5 are overexpressed - an observation confirmed in the Mdr2 -/- and NEMO Δhepa model. CCL5 deletion in NEMO Δhepa mice diminished hepatocyte apoptosis, compensatory proliferation and fibrogenesis due to reduced immune cell infiltration. Especially, CD45 + /Ly6G + granulocytes, CD45 + /CD11b + /Gr1.1 + /F4/80 + pro-inflammatory monocytes, CD4 + and CD8 + T cells were decreased. One year old NEMO Δhepa /CCL5 -/- mice displayed smaller and less malignant tumors, characterized by reduced proliferative capacity and less pronounced angiogenesis. We identified hematopoietic cells as the main source of CCL5, while CCL5 deficiency did not sensitise NEMO Δhepa hepatocytes towards TNFα induced apoptosis. Finally, therapeutic intervention with Evasin-4 over a period of 8weeks ameliorated liver disease progression., Conclusion: We identified an important role of CCL5 in human and functionally in mice with disease progression, especially HCC development. A novel approach to inhibit CCL5 in vivo thus appears encouraging for patients with CLD., Lay Summary: Our present study identifies the essential role of the chemoattractive cytokine CCL5 for liver disease progression and especially hepatocellular carcinoma development in men and mice. Finally, the inhibition of CCL5 appears to be encouraging for therapy of human chronic liver disease., (Copyright © 2016 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Advanced hepatocellular carcinoma (HCC) carries a dismal prognosis and the current treatment is limited to sorafenib, an agent with modest benefit. Preclinical data have indicated that several immunologic mechanisms are at play to promote HCC development and growth while impairing effective antitumor immune surveillance. Several novel approaches geared toward manipulating the immune response to HCC have suggested a therapeutic benefit in early-stage clinical trials, indicating a real potential to augment tumor-specific immunity and improve outcomes in patients with this disease. In the current study, the authors reviewed the barriers to an effective immune response against HCC and contemporary clinical investigations that may be "primed" to alter the natural history of HCC., (© 2015 American Cancer Society.)

A case is described of severe acute hepatitis in 47-year-old woman with chronic psoriasis and psoriatic arthritis treated with infliximab. Although clinical, serological and laboratory results were compatible with acute EBV hepatitis, it was difficult to differentiate between EBV infection and other non-infectious causes of hepatitis. The patient gradually developed chronic hepatitis with liver steatosis and efficient treatment with adalimumab had to be stopped. This case presents an uncommon complication that may arise from the use of biologic therapy and calls for caution in long-term management of psoriatic patients with internal comorbidities., (© 2015 Wiley Periodicals, Inc.)

Autoimmune hepatitis lacks an identifiable cause, and its diagnosis requires the exclusion of etiologically defined diseases that resemble it. Insights into its pathogenesis are moving autoimmune hepatitis from an idiopathic to explainable disease, and the goal of this review is to describe the insights that are hastening this transition. Two types of autoimmune hepatitis are justified by serological markers, but they also have distinctive genetic associations (DRB1 and DQB1 genes) and autoantigens. DRB1 alleles are the principal susceptibility factors in white adults, and a six amino acid sequence encoded in the antigen-binding groove of class II molecules of the major histocompatibility complex can influence the selection of autoantigens. Polymorphisms, including variants of SH2B3 and CARD10 genes, may affect immune reactivity and disease severity. The cytochrome mono-oxygenase, CYP2D6, is the autoantigen associated with type 2 autoimmune hepatitis, and it shares homologies with multiple viruses that might promote self-intolerance by molecular mimicry. Chemokines, especially CXCL9 and CXCL10, orchestrate the migration of effector cells to sites of injury and are associated with disease severity. Cells of the innate and adaptive immune responses promote tissue damage, and possible deficiencies in the number and function of regulatory T cells may facilitate the injurious process. Receptor-mediated apoptosis is the principal mechanism of hepatocyte loss, and cell-mediated and antibody-dependent mechanisms of cytotoxicity also contribute. Insights that explain autoimmune hepatitis will allow triggering exogenous antigens to be characterized, risk management to be improved, prognostic indices to be refined, and site-specific therapeutic interventions to emerge.

Objectives: Hepatitis E virus infection is increasingly reported as a cause of chronic hepatitis in organ transplant recipients. Besides reduction of immunosuppressive therapy or pegylated-interferon therapy, promising results have been reported for ribavirin monotherapy of hepatitis E virus after kidney transplant. To our knowledge, this is the first report of a successful ribavirin monotherapy for chronic hepatitis E virus infection after and orthotopic liver transplant., Materials and Methods: This is a case report of a 55-year-old man with a diagnosis of chronic hepatitis E (genotype 3f) 26 months after an orthotopic liver transplant. A reduction of immunosuppressive therapy was not tolerated, and the patient did not qualify for pegylated-interferon therapy. Because of progressively elevated liver transaminases accompanied by histologic changes in the liver allograft, ribavirin monotherapy was undertaken for 16 weeks., Results: We saw a decrease in liver enzymes after 1 week of ribavirin monotherapy. Hepatitis E virus RNA anti-HEV-IgM were tested after 8 weeks of ribavirin therapy, and were both negative. Antiviral therapy was continued for 16 weeks, and hepatitis E virus RNA remained undetectable; there also was a significant decrease in liver transaminases levels to normal values. In the 8-week and 8-month follow-ups at the end of antiviral therapy, the patient presented with normal liver enzymes and no detectable hepatitis E virus RNA., Conclusions: In conclusion, successful therapy of chronic hepatitis E after an orthotopic liver transplant may be achieved by ribavirin monotherapy and should be considered in patients who are sensitive to a reduction of immunosuppressive therapy or pegylated-interferon therapy.

Aim: To investigate the serovirological prevalence and clinical features of hepatitis E virus (HEV) infection in end-stage renal failure patients and in the healthy population., Methods: HEV infection is a viral disease that can cause sporadic and epidemic hepatitis. Previous studies unexpectedly showed a high prevalence of HEV antibodies in immunosuppressed subjects, including hemodialysis (HD) patients and patients who had undergone kidney transplant. A cohort/case-control study was carried out from January 2012 to August 2013 in two hospitals in southern Italy (Foggia and S. Giovanni Rotondo, Apulia). The seroprevalence of HEV was determined in 801 subjects; 231 HD patients, 120 renal transplant recipients, and 450 health individuals. All HD patients and the recipients of renal transplants were attending the Departments of Nephrology and Dialysis at two hospitals located in Southern Italy, and were included progressively in this study. Serum samples were tested for HEV antibodies (IgG/IgM); in the case of positivity they were confirmed by a Western blot assay and were also tested for HEV-RNA, and the HEV genotypes were determined., Results: A total of 30/801 (3.7%) patients were positive for anti-HEV Ig (IgG and/or IgM) and by Western blot. The healthy population presented with a prevalence of 2.7%, HD patients had a prevalence of 6.0%, and transplant recipients had a prevalence of 3.3%. The overall combined HEV-positive prevalence in the two groups with chronic renal failure was 5.1%. The rates of exposure to HEV (positivity of HEV-IgG/M in the early samples) were lower in the healthy controls, but the difference among the three groups was not statistically significant (P > 0.05). Positivity for anti-HEV/IgM was detected in 4/30 (13.33%) anti-HEV Ig positive individuals, in 2/14 HD patients, in 1/4 transplant individuals, and in 1/12 of the healthy population. The relative risk of being HEV-IgM-positive was significantly higher among transplant recipients compared to the other two groups (OR = 65.4, 95%CI: 7.2-592.7, P < 0.001), but the subjects with HEV-IgM positivity were numerically too few to calculate a significant difference. No patient presented with chronic hepatitis from HEV infection alone., Conclusion: This study indicated a higher, but not significant, circulation of HEV in hemodialysis patients vs the healthy population. Chronic hepatitis due to the HEV virus was not observed.

Hepatitis C virus (HCV) infection is a major cause of chronic liver disease, usually resulting in persistent infection involving hepatic steatosis, cirrhosis, and hepatocellular carcinoma via escape of the host's immune response. Set7 is a lysine-specific methyltransferase that is involved in gene regulation and virus replication. However, the mechanism underlying the immune evasion between HCV and Set7 is not well understood. In this study, we observed that the expression of Set7 in Huh7.5.1 cells was upregulated by HCV infection, and high levels of Set7 expression were also found in the sera, PBMCs, and liver tissue of HCV patients relative to healthy individuals. Further investigation showed that Set7 enhanced HCV replication in an enzymatic activity-dependent manner. Moreover, our data showed that Set7 decreased the expression of virus-induced IFN and IFN-related effectors, such as dsRNA-activated protein kinase and 2',5'-oligoadenylate synthetase. Further investigation suggested that Set7 suppressed the endogenous IFN expression by reducing the nuclear translocation of IFN regulatory factor 3/7 and the p65 subunit of NF-κB and reduced IFN-induced dsRNA-activated protein kinase and 2',5'-oligoadenylate synthetase via attenuation of the phosphorylation of STAT1 and STAT2. Additionally, IFN receptors, including IFNAR1 and IFNAR2, which are located upstream of the JAK/STAT pathway, were reduced by Set7. Taken together, our results reveal that Set7 facilitates HCV replication through the attenuation of IFN signaling pathways and IFN-related effectors., (Copyright © 2015 by The American Association of Immunologists, Inc.)

Background: Inflammatory gene expression in peripheral blood mononuclear cells (PBMCs) is altered in chronic Hepatitis C Virus (HCV) infection. Duration of changes after pegylated interferon- (peg-IFN-) based HCV treatment is unclear., Methods: PBMC mRNA expression of 184 inflammatory response genes was analyzed (nCounter GX Human Inflammation Kit, Nanostring) from peg-IFN treatment nonresponders (NR, n = 18), sustained virologic responders (SVR, n = 22), and spontaneous clearers (SC, n = 15). Logistic regression was used for comparison., Results: Median time from last treatment was 2 and 2.7 years in SVR and NR, respectively (p = NS). Mean mRNA counts were significantly different for 42 and 29 genes comparing SVR to SC patients and NR to SC, respectively, and no genes comparing SVR to NR. Differential expression of 24 genes was significantly different in both SVR and NR groups compared to SC. Among these 24 acute and chronic inflammatory cascade genes, significant upregulation was noted for proinflammatory transcription regulators Fos, CEBPB, and MyD88 in SVR and NR compared to SC. HDAC4 was significantly downregulated in SVR and NR compared to the SC group., Conclusions: PBMC inflammatory gene expression patterns in SVR resemble NR more than SC patients. A generalized inflammatory response persists in PBMCs long after successful peg-IFN treatment for HCV infection.

Background: Hepatitis E virus (HEV) infection represents an emerging infection in developed countries and is thought to be a zoonotic infection. It has recently been described as a new causative agent of acute and chronic hepatitis in immunosuppressed subjects, including HIV-infected patients. The aim of this study was to assess the sero-virological prevalence of HEV in HIV patients and in the general population as control group., Methods: A prospective and observational cohort study was carried out in two hospitals in southern Italy. The seroprevalence of HEV was determined in a cohort of 959 subjects, 509 (53%) of whom were HIV-positive patients and 450 were from the general population. Serum samples were tested for anti-HEV antibodies; repeatedly positive results were confirmed by a Western blot assay. In positive patients HEV RNA and genotypes were also determined., Results: A total of 46 (4.8%) of the 959 serum samples examined were reactive to anti-HEV Ig and confirmed by Western blotting. The prevalence of HEV antibodies (IgG and/or IgM) was 2.7% in the control group and 6.7% in HIV-infected patients. Anti-HEV IgM was found in 6/46 (13.0%) of the anti-HEV Ig-positive serum samples, in 5/34 HIV patients and in 1/12 of the general population. No HIV-infected patient presented chronic hepatitis with HEV infection alone., Conclusions: This study indicates a higher circulation of HEV in HIV-infected patients, whereas a low prevalence of HEV antibodies in the general Italian population was shown. Chronic hepatitis with HEV alone was absent, while it was present in subjects with HIV-HEV, co-infected with hepatitis B virus (HBV) and/or hepatitis C virus (HCV).

Background:  Natural killer (NK) cells are an integral part of the innate immune system. They have been suggested to play an important role in both defense against viral hepatitis and the pathogenesis of other liver diseases., Methods:  NK cells from 134 individuals including patients with acute hepatitis B and C as well as chronic hepatitis B, C, and delta (D) patients were studied., Results:  Infection with viral hepatitis was associated with increased frequencies of NK cells in the peripheral blood; that NK cells showed a less activated phenotype and were compromised in cytolotytic function and cytokine production in all viral hepatitis infections: Hepatitis virus infections did not alter NK cell differentiation, and the activity and severity of liver disease were reflected by alterations of NK cell surface receptors as demonstrated by principal component analysis., Conclusion:  NK cell phenotypic and functional alterations can equally be observed in HBV, HCV, and HDV infections. Instead, patterns of NK cell alterations differ in acute and chronic infections. Thus, our data suggest a common mechanism in the alteration of NK cell phenotype and function with unique variations that depend on disease activity rather than virus-specific factors.

Aim: To evaluate liver necro-inflammation and function by using gadoxetic acid-enhanced dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), with histological analysis as the reference standard., Materials and Methods: Seventy-nine subjects (21 healthy subjects; 58 chronic hepatitis patients) who received gadoxetic acid-enhanced DCE-MRI were divided into three subgroups: no (A0, n = 31), mild (A1, n = 27), and moderate-severe (A2-A3, n = 21) activities. Two DCE-MRI models were measured: (1) a dual-input single-compartment model to obtain absolute arterial, portal venous, and total blood flow, arterial fraction (ART), distribution volume, and mean transit time; (2) a curve analysis method to obtain peak, slope, and AUC (area under curve). The serum alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels also obtained. Statistical testing included Kruskal-Wallis tests for continuous data, Pearson's correlation tests, and multiple linear regression analyses., Results: Hepatic necro-inflammatory activity grades were significantly correlated with fibrotic stages, serum ALT level, ART and AUC. ART was helpful to predict the mild activity (≤ A1 versus >A1; Az = 0.728), whereas AUC could differentiate no activity from any activity (A0 versus >A0; Az = 0.703). Peak, slope and AUC were all associated with AST and ALT (p < 0.05)., Conclusion: Gadoxetic acid-enhanced DCE-MRI parameters may be used to evaluate the severity of hepatic necro-inflammation and function., (Copyright © 2013 The Royal College of Radiologists. Published by Elsevier Ltd. All rights reserved.)

To explore the possibility of using a mini-array of multiple tumor-associated antigens (TAAs) as an approach to the diagnosis of hepatocellular carcinoma (HCC), 14 TAAs were selected to examine autoantibodies in sera from patients with chronic hepatitis, liver cirrhosis and HCC by immunoassays. Antibody frequency to any individual TAA in HCC varied from 6.6% to 21.1%. With the successive addition of TAAs to the panel of TAAs, there was a stepwise increase of positive antibody reactions. The sensitivity and specificity of 14 TAAs for immunodiagnosis of HCC was 69.7% and 83.0%, respectively. This TAA mini-array also identified 43.8% of HCC patients who had normal alpha-fetoprotein (AFP) levels in serum. In summary, this study further supports the hypothesis that a customized TAA array used for detecting anti-TAA autoantibodies can constitute a promising and powerful tool for immunodiagnosis of HCC and may be especially useful in patients with normal AFP levels., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Unlabelled: The rationale for screening inflammatory serum biomarkers of the hepatic vein pressure gradient (HVPG) is based on the fact that portal hypertension is pathogenically related to liver injury and fibrosis, and that in turn these are associated with the activation of inflammatory pathways. This was a nested cohort study in the setting of a randomized, clinical trial to assess the development of gastroesophageal varices (GEV) (N Engl J Med 2005;353:2254). Patients had cirrhosis and portal hypertension but did not have GEV. A total of 90 patients who had baseline day-1 sera available were enrolled in the present study. The objective of this study was to determine whether inflammatory biomarkers in conjunction with clinical parameters could be used to develop a predictive paradigm for HVPG. The correlations between HVPG and interleukin (IL)-1β (P=0.0052); IL-1R-α (P=0.0085); Fas-R (P=0.0354), and serum VCAM-1 (P=0.0007) were highly significant. By using multivariate logistic regression analysis and selected parameters (transforming growth factor beta [TGFβ]; heat shock protein [HSP]-70; at-risk alcohol use; and Child class B) we could exclude HVPG ≥ 12 mmHg with 86% accuracy (95% confidence interval [CI]: 67.78 to 96.16%) and the sensitivity was 87.01% (95% CI: 69.68 to 96.34%). Therefore, the composite test could identify 86% of compensated cirrhosis patients with HVPG below 12 mmHg and prevent unnecessary esophagogastroduodenoscopy with its associated morbidity and costs in these patients. Our diagnostic test was not efficient in predicting HVPG ≥ 12 mmHg., Conclusion: A blood test for HVPG could be performed in cirrhosis patients to prevent unnecessary esophagogastroduodenoscopy., (© 2014 by the American Association for the Study of Liver Diseases.)

This article presents an analysis of a recently published study of the survival experience among a group of patients treated for hepatitis C with advanced hepatic fibrosis/cirrhosis, divided into groups based on whether or not sustained virological response was achieved. The purpose is to evaluate the magnitude of excess mortality relative to a comparison population. The potential errors inherent in generating mock age/sex distributions from limited published data are also highlighted.

Persistent inflammation is known to promote and exacerbate malignancy. Primary liver cancer, mostly hepatocellular carcinoma (HCC), is a clear example of inflammation-related cancer as more than 90 % of HCCs arise in the context of hepatic injury and inflammation. HCC represents the fifth most common malignancy and the third leading cause of cancer-related death worldwide with about one million new cases diagnosed every year with almost an equal number of deaths. Chronic unresolved inflammation is associated with persistent hepatic injury and concurrent regeneration, leading to sequential development of fibrosis, cirrhosis, and eventually HCC. Irrespective of the intrinsic differences among various etiological factors, a common denominator at the origin of HCC is the perpetuation of a wound-healing response activated by parenchymal cell death and the resulting inflammatory cascade. Hence, the identification of fundamental inflammatory signaling pathways causing transition from chronic liver injury to dysplasia and HCC could depict new predictive biomarkers and targets to identify and treat patients with chronic liver inflammation. This chapter critically discusses the roles of several major cytokines, chemokines, growth factors, transcription factors, and enzymes as well as a distinct network of inflammatory signaling pathways in the development and progression of HCC. It also highlights and analyzes preclinical animal studies showing innovative approaches of targeting inflammatory mediators and signaling by a variety of natural compounds and synthetic agents to achieve effective therapy as well as prevention of hepatic malignancy. Additionally, current limitations and potential challenges associated with the inhibition of inflammatory signaling as well as future directions of research to accelerate clinical development of anti-inflammatory agents to prevent and treat liver cancer are presented.

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infections account for 57% of cases of liver cirrhosis and 78% of cases of primary liver cancer worldwide and cause a million deaths per year. Although HBV and HCV differ in their genome structures, replication strategies and life cycles, they have common features, including their noncytopathic nature and their capacity to induce chronic liver disease, which is thought to be immune mediated. However, the rate of disease progression from chronic hepatitis to cirrhosis varies greatly among infected individuals, and the factors that regulate it are largely unknown. This review summarizes our current understanding of the roles of antigen-specific and nonspecific immune cells in the pathogenesis of chronic hepatitis B and C and discusses recent findings that identify natural killer cells as regulators of T cell function and liver inflammation.

Dupuytren's contracture--a pathology that should not be seen as an isolated lesion tendon-aponeurotic structures of the palmar surface of the hand, but as a disease that requires careful research and a comprehensive, differentiated approach to treatment. The aim of the study was to investigate the functional activity of the phagocytic system of Dupuytren's contracture patients with chronic hepatitis and liver fibrosis in liquidators of the CHNPP accident consequences. The resulting study 188 patients aged 45-65 years showed the correlation of the data of the functional activity of phagocytic system with degree of liver fibrosis, thus objectively assess the patient's condition and make the appropriate correction in the diagnostic criteria as well as in medical and rehabilitative programs.

Nephronectin (Npnt) is an extracellular matrix protein known to play a critical role in kidney development; however, its physiological role in the liver remains elusive. Here we show that Npnt expression is upregulated in mouse models of both acute and chronic hepatitis induced by Concanavalin A (Con A) and 3,5-diethocarbonyl-1,4-dihydrocollidine (DDC), respectively. In both models, Npnt was localized in inflammatory foci and was mainly secreted from mesenchymal cells and in part by cholangiocytes. Interestingly, ectopic expression of Npnt in hepatocytes induced the development of granuloma-like cell clusters mainly composed of CD4(+) T cells or NKT cells but did not induce apparent hepatitis. Furthermore, we found that Npnt exacerbated the Con A-induced acute hepatitis. These results indicate that Npnt plays an important role in the initiation of hepatitis by recruiting CD4(+) T cells or NKT cells into the foci of inflammation. In addition, we reveal that Npnt expression is also upregulated in human hepatitis. Therefore, Npnt may be a potential therapeutic target for acute and chronic hepatitis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Hepatitis E virus (HEV) is a new causative agent of chronic hepatitis in solid organ transplant recipients. Clinical studies suggest that the occurrence and persistence of chronic HEV infection are related to the immunological status of patients., Methods: We used whole-genome microarray and quantitative reverse transcription polymerase chain reaction (qRT-PCR) to compare the transcriptional profiles of whole blood from 8 kidney transplant recipients with chronic HEV infection and 8 matched kidney transplant recipients without HEV infection., Results: We found that 30 genes in HEV-infected patients were upregulated, compared with those in control patients, as determined by microarray analysis. In contrast, no genes were downregulated. The 30 upregulated genes included 25 interferon-stimulated genes. Increased expression of the genes that encode IFIT1, IFI44L, RSAD2, EPSTI1, and ISG15 was confirmed by qRT-PCR. Interestingly, the expression levels of these genes were associated with the persistence of HEV infection., Conclusions: Increased expression of interferon-stimulated genes may favor the persistence of an HEV infection. Whether the expression of interferon-stimulated genes is a marker of ongoing viremia or independent prognostic marker of HEV clearance needs further investigations., Clinical Trials Registration: NCT01090232.

Viral hepatitis remains the most common cause of liver disease and a major public health problem. Here, we focus on the role of CD4 CD8 double negative T (DN T) cells involved in the mechanisms of viral persistence in hepatitis. C3H/HeJ mice infected with murine hepatitis virus strain 3 (MHV-3) were used to display chronic viral hepatitis. DN T cells dramatically increased in MHV-3 infected mice. Adoptive transfer of DN T cells from MHV-3 infected mice led to a significant increase in mice survival. The DN T cells with production of IFN-γ and IL-2 are able to kill virus-specific CD8(+) T cells via the Fas/FasL dependent pathway. The delicate balance of multiple effects of DN T cells may lead to viral persistence in MHV-3 induced hepatitis. In short, our study identified DN T cells contributing to viral persistence in MHV-3 induced hepatitis in C3H/HeJ mice, which provides a rationale for modulating DN T cells for the management of viral hepatitis., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Sustained hepatic inflammation, driven by alcohol consumption, nonalcoholic fatty liver disease, and/or chronic viral hepatitis (hepatitis B and C), results in damage to parenchyma, oxidative stress, and compensatory regeneration/proliferation. There is substantial evidence linking these inflammation-associated events with the increased incidence of hepatocellular carcinogenesis. Although acute liver inflammation can play a vital and beneficial role in response to liver damage or acute infection, the effects of chronic liver inflammation, including liver fibrosis and cirrhosis, are sufficient in a fraction of individuals to initiate the process of transformation and the development of hepatocellular carcinoma. This review highlights immune-dependent mechanisms that may be associated with hepatocellular oncogenesis, including critical transformative events/pathways in the context of chronic inflammation and subverted tolerogenesis., (Copyright © 2012 American Association for the Study of Liver Diseases.)

Hepatocellular carcinoma (HCC) is a type of cancer with a very poor prognosis. Although α-fetoprotein (AFP) is the most effective marker available to detect HCC, the sensitivity and specificity are not optimal. Therefore, there is a need for the development of more sensitive and specific methods that can supplement AFP in the early detection of this cancer. In this study, autoantibody responses to glucose-regulated protein 78 (GRP78) were evaluated by enzyme-linked immunosorbent assay (ELISA), western blotting and indirect immunofluorescence assay in sera from patients with HCC, liver cirrhosis (LC) and chronic hepatitis (CH), as well as from normal human individuals. Immunohistochemistry (IHC) with tissue array slides was also preformed to analyze protein expression profiles of GRP78 in HCC and control tissues. The prevalence of autoantibodies against GRP78 was 35.5% (27/76) in HCC, which was significantly higher than that in LC, CH and normal human sera (NHS; P<0.01). The average titer of autoantibodies against GRP78 in HCC sera was higher compared to that in LC, CH and NHS(P<0.01). When both autoantibodies against GRP78 and AFP were used simultaneously as diagnostic markers, sensitivity reached 71.4%. Our data indicate that anti-GRP78 autoantibodies may be potential diagnostic markers for HCC, especially in conjunction with AFP.

'Alarmins' are a group of proteins or molecules that are released from cells during cellular demise to alert the host immune system. Two of them, Interleukin-33 (IL-33) and high-mobility group box-1 (HMGB1), share many similarities of cellular localization, functions and involvement in various inflammatory pathologies including hepatitis. The expressions of IL-33 and HMGB1, and their receptors ST2 and receptor for advanced glycation end products (RAGE), are substantially up-regulated during acute and chronic hepatitis. Recent data evidence a possible protective role of IL-33/ST2 axis during liver injury. A contrast in expression of IL-33 and HMGB1 alarmins were associated with type of hepatocellular death mediated by immune cells or hepato-toxic agents. The massive release of active form of IL-33 from hepatocytes may affect the recruitment and activation of its ST2-positive target immune cells in the liver to confer its alarmin functions. This review highlights the emerging roles of alarmin proteins in various liver pathologies, by focusing on classical HMGB1 and a newly discovered alarmin, the IL-33., (© 2012 John Wiley & Sons A/S.)