scholarly journals Emerging Roles of T Cells in the Pathogenesis of Nonalcoholic Steatohepatitis and Hepatocellular Carcinoma

2021 ◽  
Vol 12 ◽  
Author(s):  
Petra Hirsova ◽  
Adebowale O. Bamidele ◽  
Haiguang Wang ◽  
Davide Povero ◽  
Xavier S. Revelo
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
Liver Disease ◽  
T Cell ◽  
Nonalcoholic Steatohepatitis ◽  
Immune Cell ◽  
Current Knowledge ◽  
Significant Proportion ◽  
Nonalcoholic Fatty Liver ◽  
Integral Role

Nonalcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. A significant proportion of patients with NAFLD develop a progressive inflammatory condition termed nonalcoholic steatohepatitis (NASH), which may eventually advance to cirrhosis and hepatocellular carcinoma (HCC). NASH is characterized by steatosis, hepatocyte ballooning, and lobular inflammation. Heightened immune cell infiltration is a hallmark of NASH, yet the mechanisms whereby hepatic inflammation occurs in NASH and how it contributes to disease initiation and progression remain incompletely understood. Emerging evidence indicates that intrahepatic T cell immune mechanisms play an integral role in the pathogenesis of NASH and its transition to HCC. In this review, we summarize the current knowledge regarding the T cell-mediated mechanisms of inflammation in NASH. We highlight recent preclinical and human studies implicating various subsets of conventional and innate-like T cells in the onset and progression of NASH and HCC. Finally, we discuss the potential therapeutic strategies targeting T cell-mediated responses for the treatment of NASH.

scholarly journals Immunological distinctions between nonalcoholic steatohepatitis and hepatocellular carcinoma

2020 ◽  
Vol 52 (8) ◽  
pp. 1209-1219 ◽  
Author(s):  
Seo-Young Koo ◽  
Eun-Ji Park ◽  
Chang-Woo Lee
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Immune Responses ◽  
Nonalcoholic Steatohepatitis ◽  
Immune Cell ◽  
Common Cause ◽  
Nonalcoholic Fatty Liver ◽  
Common Cancer ◽  
Aggressive Form ◽  
Immune Cell Subsets

Abstract Nonalcoholic fatty liver disease (NAFLD), the most common cause of chronic liver disease, ranges from simple hepatic steatosis to nonalcoholic steatohepatitis (NASH), which is a more aggressive form characterized by hepatocyte injury, inflammation, and fibrosis. Increasing evidence suggests that NASH is a risk factor for hepatocellular carcinoma (HCC), which is the fifth most common cancer worldwide and the second most common cause of cancer-related death. Recent studies support a strong mechanistic link between the NASH microenvironment and HCC development. The liver has a large capacity to remove circulating pathogens and gut-derived microbial compounds. Thus, the liver is a central player in immunoregulation. Altered immune responses are tightly associated with the development of NASH and HCC. The objective of this study was to differentiate the roles of specific immune cell subsets in NASH and HCC pathogenesis.

scholarly journals Inflammatory Mechanisms Underlying Nonalcoholic Steatohepatitis and the Transition to Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 730
Author(s):  
Moritz Peiseler ◽  
Frank Tacke
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Disease Progression ◽  
Immune Cells ◽  
Nonalcoholic Steatohepatitis ◽  
Adaptive Immune System ◽  
Nonalcoholic Fatty Liver ◽  
Inflammatory Processes ◽  
New Treatment ◽  
End Stage

Nonalcoholic fatty liver disease (NAFLD) is a rising chronic liver disease and comprises a spectrum from simple steatosis to nonalcoholic steatohepatitis (NASH) to end-stage cirrhosis and risk of hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is multifactorial, but inflammation is considered the key element of disease progression. The liver harbors an abundance of resident immune cells, that in concert with recruited immune cells, orchestrate steatohepatitis. While inflammatory processes drive fibrosis and disease progression in NASH, fueling the ground for HCC development, immunity also exerts antitumor activities. Furthermore, immunotherapy is a promising new treatment of HCC, warranting a more detailed understanding of inflammatory mechanisms underlying the progression of NASH and transition to HCC. Novel methodologies such as single-cell sequencing, genetic fate mapping, and intravital microscopy have unraveled complex mechanisms behind immune-mediated liver injury. In this review, we highlight some of the emerging paradigms, including macrophage heterogeneity, contributions of nonclassical immune cells, the role of the adaptive immune system, interorgan crosstalk with adipose tissue and gut microbiota. Furthermore, we summarize recent advances in preclinical and clinical studies aimed at modulating the inflammatory cascade and discuss how these novel therapeutic avenues may help in preventing or combating NAFLD-associated HCC.

scholarly journals Pathogenesis of Nonalcoholic Steatohepatitis: Interactions between Liver Parenchymal and Nonparenchymal Cells

2016 ◽  
Vol 2016 ◽  
pp. 1-11 ◽  
Author(s):  
Nancy Magee ◽  
An Zou ◽  
Yuxia Zhang
Keyword(s):  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Steatohepatitis ◽  
Fatty Liver Disease ◽  
Immune Cell ◽  
Health Concern ◽  
Nonalcoholic Fatty Liver ◽  
Liver Parenchymal ◽  
Nonparenchymal Cells ◽  
The Metabolic Syndrome

Nonalcoholic fatty liver disease (NAFLD) is the most common type of chronic liver disease in the Western countries, affecting up to 25% of the general population and becoming a major health concern in both adults and children. NAFLD encompasses the entire spectrum of fatty liver disease in individuals without significant alcohol consumption, ranging from nonalcoholic fatty liver (NAFL) to nonalcoholic steatohepatitis (NASH) and cirrhosis. NASH is a manifestation of the metabolic syndrome and hepatic disorders with the presence of steatosis, hepatocyte injury (ballooning), inflammation, and, in some patients, progressive fibrosis leading to cirrhosis. The pathogenesis of NASH is a complex process and implicates cell interactions between liver parenchymal and nonparenchymal cells as well as crosstalk between various immune cell populations in liver. Lipotoxicity appears to be the central driver of hepatic cellular injury via oxidative stress and endoplasmic reticulum (ER) stress. This review focuses on the contributions of hepatocytes and nonparenchymal cells to NASH, assessing their potential applications to the development of novel therapeutic agents. Currently, there are limited pharmacological treatments for NASH; therefore, an increased understanding of NASH pathogenesis is pertinent to improve disease interventions in the future.

scholarly journals Global immune characterization of HBV/HCV-related hepatocellular carcinoma identifies macrophage and T-cell subsets associated with disease progression

2020 ◽  
Vol 6 (1) ◽  
Author(s):  
Guohe Song ◽  
Yang Shi ◽  
Meiying Zhang ◽  
Shyamal Goswami ◽  
Saifullah Afridi ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Single Cell ◽  
Immune Cells ◽  
Immune Cell ◽  
T Cell Subsets ◽  
M2 Macrophage ◽  
Advanced Hcc ◽  
Immune Cell Subsets

AbstractDiverse immune cells in the tumor microenvironment form a complex ecosystem, but our knowledge of their heterogeneity and dynamics within hepatocellular carcinoma (HCC) still remains limited. To assess the plasticity and phenotypes of immune cells within HBV/HCV-related HCC microenvironment at single-cell level, we performed single-cell RNA sequencing on 41,698 immune cells from seven pairs of HBV/HCV-related HCC tumors and non-tumor liver tissues. We combined bio-informatic analyses, flow cytometry, and multiplex immunohistochemistry to assess the heterogeneity of different immune cell subsets in functional characteristics, transcriptional regulation, phenotypic switching, and interactions. We identified 29 immune cell subsets of myeloid cells, NK cells, and lymphocytes with unique transcriptomic profiles in HCC. A highly complex immunological network was shaped by diverse immune cell subsets that can transit among different states and mutually interact. Notably, we identified a subset of M2 macrophage with high expression of CCL18 and transcription factor CREM that was enriched in advanced HCC patients, and potentially participated in tumor progression. We also detected a new subset of activated CD8+ T cells highly expressing XCL1 that correlated with better patient survival rates. Meanwhile, distinct transcriptomic signatures, cytotoxic phenotypes, and evolution trajectory of effector CD8+ T cells from early-stage to advanced HCC were also identified. Our study provides insight into the immune microenvironment in HBV/HCV-related HCC and highlights novel macrophage and T-cell subsets that could be further exploited in future immunotherapy.

Immune surveillance of the liver by T cells

2020 ◽  
Vol 5 (51) ◽  
pp. eaba2351
Author(s):  
Xenia Ficht ◽  
Matteo Iannacone
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cross Talk ◽  
Immune Cell ◽  
Current Knowledge ◽  
Immune Surveillance ◽  
Neoplastic Diseases ◽  
Cell Responses ◽  
Immune Cell Subsets ◽  
Invariant T Cells

The liver is the target of several infectious, inflammatory, and neoplastic diseases, which affect hundreds of millions of people worldwide and cause an estimated death toll of more than 2 million people each year. Dysregulation of T cell responses has been implicated in the pathogenesis of these diseases; hence, it is critically important to understand the function and fate of T cells in the liver. Here, we provide an overview of the current knowledge on liver immune surveillance by conventional and invariant T cells and explore the complex cross-talk between immune cell subsets that determines the balance between hepatic immunity and tolerance.

scholarly journals Hepatic Immune Microenvironment in Alcoholic and Nonalcoholic Liver Disease

2017 ◽  
Vol 2017 ◽  
pp. 1-12 ◽  
Author(s):  
Jin-Seok Byun ◽  
Hyon-Seung Yi
Keyword(s):  
T Cells ◽  
Liver Disease ◽  
Fatty Liver ◽  
Nonalcoholic Fatty Liver Disease ◽  
Natural Killer ◽  
Alcoholic Liver Disease ◽  
Immune Cells ◽  
Nonalcoholic Steatohepatitis ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver

Many types of innate (natural killer cells, natural killer T cells, and Kupffer cells/macrophages) and adaptive (T cells and B cells) immune cells are enriched within the liver and function in liver physiology and pathology. Liver pathology is generally induced by two types of immunologic insults: failure to eliminate antigens derived from the gastrointestinal tract which are important for host defense and an impaired tissue protective tolerance mechanism that helps reduce the negative outcomes of immunopathology. Accumulating evidence from the last several decades suggests that hepatic immune cells play an important role in the pathogenesis of alcoholic and nonalcoholic liver injury and inflammation in humans and mice. Here, we focus on the roles of innate and adaptive immune cells in the development and maintenance of alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis. Additionally, the pathogenesis of liver disease and new therapeutic targets for preventing and treating alcoholic liver disease and nonalcoholic fatty liver disease/nonalcoholic steatohepatitis are discussed.

Hepatocellular Carcinoma in Nonalcoholic Steatohepatitis

2017 ◽  
Vol 01 (02) ◽  
pp. 066-073
Author(s):  
Sean Koppe ◽  
Hafiz Arshad
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Nonalcoholic Steatohepatitis ◽  
The United States ◽  
Nuclear Factor ◽  
Obese Patients ◽  
Nonalcoholic Fatty Liver ◽  
Potential Risk Factors ◽  
Factor Α ◽  
Necrosis Factor

AbstractNonalcoholic fatty liver disease (NAFLD) has become the most common cause of chronic liver disease in the United States. Approximately 10 to 20% of patients with NAFLD progress to nonalcoholic steatohepatitis (NASH). NASH can progress to cirrhosis, which, in turn, can lead to hepatocellular carcinoma (HCC). However, evidence also supports that HCC can develop in patients with NASH who do not have cirrhosis or advanced fibrosis. Obesity, diabetes mellitus, hepatic iron deposition, and insulin resistance are potential risk factors for HCC in NASH. Mechanisms proposed include a role for tumor necrosis factor-α, interleukin-6, insulinlike growth factor, and nuclear factor κβ activation in progression of NASH to HCC. Polymorphisms in patatin-like phospholipase domain-containing 3 also support a genetic influence in NASH-related HCC. Surgical resection, liver directed therapy, and liver transplant remain the mainstay of therapy. Ultrasound has reduced sensitivity for surveillance of HCC in obese patients and alpha fetoprotein may have more value for HCC surveillance in the NASH patient as compared with the HCV patient. Although HCC can develop in noncirrhotic NASH, currently there are no guidelines to recommend surveillance in noncirrhotic NASH patients.

scholarly journals T Cell Subsets and Natural Killer Cells in the Pathogenesis of Nonalcoholic Fatty Liver Disease

2021 ◽  
Vol 22 (22) ◽  
pp. 12190
Author(s):  
Yoseph Asmelash Gebru ◽  
Haripriya Gupta ◽  
Hyeong Seop Kim ◽  
Jung A. Eom ◽  
Goo Hyun Kwon ◽  
...  
Keyword(s):  
T Cells ◽  
Liver Disease ◽  
T Cell ◽  
Fatty Liver ◽  
Nk Cells ◽  
Nonalcoholic Fatty Liver Disease ◽  
Natural Killer ◽  
Fatty Liver Disease ◽  
T Cell Subsets ◽  
Nonalcoholic Fatty Liver

Nonalcoholic fatty liver disease (NAFLD) is a condition characterized by hepatic accumulation of excess lipids. T cells are commonly classified into various subsets based on their surface markers including T cell receptors, type of antigen presentation and pathophysiological functions. Several studies have implicated various T cell subsets and natural killer (NK) cells in the progression of NAFLD. While NK cells are mainly components of the innate hepatic immune system, the majority of T cell subsets can be part of both the adaptive and innate systems. Several studies have reported that various stages of NAFLD are accompanied by the accumulation of distinct T cell subsets and NK cells with different functions and phenotypes observed usually resulting in proinflammatory effects. More importantly, the overall stimulation of the intrahepatic T cell subsets is directly influenced by the homeostasis of the gut microbiota. Similarly, NK cells have been found to accumulate in the liver in response to pathogens and tumors. In this review, we discussed the nature and pathophysiological roles of T cell subsets including γδ T cells, NKT cells, Mucosal-associated invariant T (MAIT) cells as well as NK cells in NAFLD.

scholarly journals Advances and challenges in the management of advanced fibrosis in nonalcoholic steatohepatitis

2018 ◽  
Vol 11 ◽  
pp. 175628481881150 ◽  
Author(s):  
Mehmet Sayiner ◽  
Brian Lam ◽  
Pegah Golabi ◽  
Zobair M. Younossi
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Disease ◽  
Nonalcoholic Steatohepatitis ◽  
Metabolic Diseases ◽  
Lifestyle Modification ◽  
Visceral Obesity ◽  
Nonalcoholic Fatty Liver ◽  
Risk Of Mortality ◽  
Increased Risk ◽  
Risk Of Progression

Nonalcoholic fatty liver disease (NAFLD) is rapidly becoming the most common type of chronic liver disease worldwide. From the spectrum of NAFLD, it is nonalcoholic steatohepatitis (NASH) that predominantly predisposes patients to higher risk for development of cirrhosis and hepatocellular carcinoma. There is growing evidence that the risk of progression to cirrhosis and hepatocellular carcinoma is not uniform among all patients with NASH. In fact, NASH patients with increasing numbers of metabolic diseases such as diabetes, hypertension, visceral obesity and dyslipidemia are at a higher risk of mortality. Additionally, patients with higher stage of liver fibrosis are also at increased risk of mortality. In this context, NASH patients with fibrosis are in the most urgent need of treatment. Also, the first line of treatment for NASH is lifestyle modification with diet and exercise. Nevertheless, the efficacy of lifestyle modification is quite limited. Additionally, vitamin E and pioglitazone may be considered for subset of patients with NASH. There are various medications targeting one or more steps in the pathogenesis of NASH being developed. These drug regimens either alone or in combination, may provide potential treatment option for patients with NASH.

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