Liver Immunology Research Articles (Page 1)

Liver diseases are of growing interest to clinicians and researchers due to their high prevalence, difficulty in early diagnosis, and limited treatment options. The liver is an important organ at the intersection of many metabolic and immune pathways. To this end, it contains a large number of immune cells of both the innate and adaptive immune system that perform multiple functions, detecting and destroying pathogens that enter the body through the intestine, as well as recognizing endogenous antigens. Immune cells in the liver have a complex regulation that can be impaired in various diseases such as metabolic dysfunction-associated steatotic liver disease (MASLD), liver cancer, and biliary diseases. A growing body of evidence reinforces the realization that not only impaired metabolism but also many immune mechanisms underlie MASLD. The liver has complex bilateral immune and metabolic links with the gut microbiota, and disruptions of these links underlie the development and progression of both gastrointestinal and other organ diseases. In this regard, acting on immune mechanisms is a promising therapeutic target for liver diseases.

Hepatic immune environment differences among common mouse strains in models of MASH and liver cancer

Background: While the liver’s hepatocytes and Kupffer cells are prominent foci of study, the distinct and relatively uncharted roles played by the natural killer cells in liver immunity provide fertile ground for exploration. In this review paper, we have tried to uncover the unique phenotypic and functional attributes of liver-resident natural killer cells, consequently establishing a profound connection between liver immunology and histopathology.Objective: This review aims to provide an overview of the phenotypic and functional properties of the liver-resident natural killer cells, giving insight on the immunological and histological repercussions of their interactions during liver infections, inflammation, and hepatocellular cancer. Methods: In this review, published papers in electronic databases comprising PubMed, Scopus, and Google Scholar were retrieved using search themes such as immunological cells, natural killer cell, liver inflammation, and liver cell were examined.Results: The liver-resident natural killer cells are potent producers of cytokines, including interferon-gamma (IFN-γ) and modulate the phenotype and function of hepatic macrophages, enhancing their antimicrobial activity, as well as influence the activation and cytotoxic function of CD8+ T cells, particularly during chronic liver inflammation.Conclusion: Our review underscores the undeniable significance of the natural killer cells in the liver defence and highlighted the challenges and constraints researchers encounter when studying the liver natural killer cells. Continued research endeavour are necessary to harness the full capabilities of the natural killer cells, ultimately leading to better insights, innovative therapies, and enhanced protection for the liver, and by extension, the entire body.International Journal of Human and Health Sciences Vol. 08 No. 03 Jul’24 Page: 231-240

The 2023 Joint Annual Congress of the International Liver Transplantation Society, European Liver and Intestine Transplant Association, and Liver Intensive Care Group of Europe were held in Rotterdam, the Netherlands, from May 3 to 6, 2023. This year, all speakers were invited to attend the Congress in person for the first time since the COVID-19 pandemic. The congress was attended by 1159 registered delegates from 54 countries representing 5 continents, with the 10 countries comprising the bulk of the delegates. Of the 647 abstracts initially submitted, 542 were eventually presented at the meeting, coming from 38 countries (mainly North America, Europe, and Asia) and 85% of them (462 abstracts) came from only 10 countries. Fifty-three (9.8%) abstracts, originated from 17 countries, were submitted under the Basic/Translational Scientific Research category, a similar percentage as in 2022. Abstracts presented at the meeting were classified as (1) ischemia and reperfusion injury, (2) machine perfusion, (3) bioengineering and liver regeneration, (4) transplant oncology, (5) novel biomarkers in liver transplantation, (6) liver immunology (rejection and tolerance), and (7) artificial intelligence and machine learning. Finally, we evaluated the number of abstracts commented in the Basic and Translational Research Committee-International Liver Transplantation Society annual reports over the past 5 y that resulted in publications in peer-reviewed journals to measure their scientific impact in the field of liver transplantation.

Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disease in the world. Most important contributors to its development are diet and obesity. Gut microbiome's importance for immune system and inflammatory pathways more widely accepted as an important component in NAFLD and other liver diseases' pathogenesis. In this article we review potential mechanisms of microbiome alteration of local and systemic immune responses leading to NAFLD's development, and how can modulate them for the treatment. Our review mentions different immune system pathways and microorganisms regulating metabolism, liver inflammation and fibrosis. We specifically point out TLR-4 as a potential key immune pathway activated by bacterial lipopolysaccharides producing pro-inflammatory cytokines in NAFLD. Also, we discuss three endotoxin-producing strains (Enterobacter cloacae B29, Escherichia coli PY102, Klebsiella pneumoniae A7) that can promote NAFLD development via TLR4-dependent immune response activation in animal models and how they potentially contribute to disease progression in humans. Additionally, we discuss their other immune and non-immune mechanisms contributing to NAFLD pathogenesis. In the end we point out gut microbiome researches' future perspective in NAFLD as a potential new target for both diagnostic and treatment.

The increased global prevalence of viral and noninfectious liver illnesses has coincided with a surge in scientific interest in gut microbiota (GM), a multispecies community of bacteria, fungi, archaea, and protozoans. Dietary nutrients that make up the host’s microbiome are responsible for maintaining intestinal homeostasis, whereas a disconnect between gut flora and nutrition might have serious consequences for digestive health. The risk of liver dysfunction was continuously elevated by changes in the commensal bacteria of the gut microbiome, which were carried to the liver via the portal vein. Insights into the role of gut microbiota in alcoholic liver disease, nonalcoholic liver disease, primary sclerosing cholangitis, and other liver disorders, as well as their link to liver cancer, continue to emerge. Systemic host defence against infections by the gut microbiota depends on the interplay between the microbiome, liver immunology, and liver disorders. Translocation of microbiota to the liver following injury and/or inflammation may mediate dysbiosis and the formation of gut microbial metabolite. This review discusses the role of the gut microbiota in connection to dysbiosis and how this knowledge might help us better understand the pathophysiology of various liver illnesses.

Impact of different processing mulberry leaf on growth, metabolism and liver immune function of largemouth bass (Micropterus salmoides)

Simultaneous liver and kidney (SLK) transplantation is considered the best treatment modality among selected patients with both chronic kidney disease (CKD) and end-stage liver disease (ESLD). Since the first SLK transplant in 1983, the number of SLK transplants has increased worldwide, and particularly in the United States since the implementation of the MELD system in 2002. SLK transplants are considered a relatively low immunological risk procedure evidenced by multiple studies displaying the immunomodulatory properties of the liver on the immune system of SLK recipients. SLK recipients demonstrate lower rates of both cellular and antibody-mediated rejection on the kidney allograft when compared to kidney transplant-alone recipients. Therefore, SLK transplants in the setting of preformed donor-specific HLA antibodies (DSA) are a common practice, at many centers. Acceptance and transplantation of SLKs are based solely on ABO compatibility without much consideration of crossmatch results or DSA levels. However, some studies suggest an increased risk for rejection for SLK recipients transplanted across high levels of pre-formed HLA DSA. Despite this, there is no consensus regarding acceptable levels of pre-formed DSA, the role of pre-transplant desensitization, splenectomy, or immunosuppressive management in this unique population. Also, the impact of post-transplant DSA monitoring on long-term outcomes is not well-studied in SLK recipients. In this article, we review recent and relevant past articles in this field with a focus on the immunological risk factors among SLK recipients, and strategies to mitigate the negative outcomes among them.

The complex immune system of the liver has a major role in tumor surveillance, but also partly explains why current immune therapies are poorly effective against liver cancers. Known primarily for its tolerogenic capacity, the hepatic immune repertoire also comprises diverse populations of armored immune cells with tumor surveillant roles. In healthy people, these work together to successfully identify malignant cells and prevent their proliferation, thus halting tumor formation. When frontline hepatic immune surveillance systems fail, compromised hepatic immunity, driven by obesity, infection, or other pathological factors, allows primary or secondary liver cancers to develop. Tumor growth promotes the normal tolerogenic immunological milieu of the liver, perhaps explaining why current immunotherapies fail to work. This review explores the complex local liver immune system with the hope of identifying potential therapeutic targets needed to best overcome immunological barriers in the liver to create an environment no longer hostile to immunotherapy for the treatment of liver cancer.

In recent years, immune-based therapies have emerged as novel pillars for hepatocellular carcinoma (HCC). The rationale of immune-checkpoint inhibitors (ICIs) trial in HCC originated from the fact that the tumor cells and the infiltrating stromal and immune cells promote an immunosuppressive tumor microenvironment, including the up-regulation of immune checkpoint molecules on their surface. Antibody-based blockage targeting inhibitory checkpoint molecules on cytotoxic T cells, including programmed cell death-1 (PD-1) or its counterpart on antigen-presenting cells has shown strong anti-tumor activity in a subset of HCC patients. Single nucleotide polymorphisms (SNP) of PD-1 gene may affect the PD-1 expression or function, which eventually can cause dysfunctionality of immune balance. Based on the inhibitory role of PD-1 in anti-tumor responses, it has been investigated in several studies as a candidate to test for genetic susceptibility of individuals to HCC. The present paper highlights the knowledge on cross-talks for liver immunology and HCC course, recent studies investigating the role of functional SNPs of PD-1 gene in Turkish HCC population, and the data on already investigated PD-1 inhibitor molecules in clinical trials.

Background.Liver diseases associated with pregnancy are recorded in 0.73% of pregnant women, often accompanied by the development of hepatic dysfunction/insufficiency, and are the cause of increased morbidity and mortality in both mother and child. A pathomorphological study helps to understand the pathophysiology of severe liver damage in preeclampsia, and to optimize the management of such patients.Aims to study the clinical, morphological and immunohistochemical features of liver tissue lesions in the most severe forms of preeclampsia and eclampsia, which ended in death.Methods.Autopsy material analysis of 10 patients who died from preeclampsia, eclampsia and their complications (main group) and 3 patients who died from other causes (comparison group). Pathomorphological and immunohistochemical studies of organs and tissues (in particular, liver tissue) were performed using a marker of neurons and neuroendocrine cells -NSE and a marker of endotheliocytes CD-34.Results.An immunohistochemical study with a CD-34 endotheliocyte marker in the main group revealed a vascularization deficiency in the 2nd and 3rd zone of hepatic acini, there were also foci of necrosis. Such changes indicate deep and prolonged hypoperfusion. The use of the NSE marker in the group of patients who died from preeclampsia/eclampsia revealed a sharp increase in Kupffer cells in the first and second zones of acini with pronounced immunoexpression of NSE in the nuclei and cytoplasm of these cells, which indicates severe hepatic dysfunction (in particular, impaired detoxification and elimination functions of the liver). At the same time, only 3 out of 10 women in the main group are clinically registered with HELLP syndrome, while the rest had signs of multiple organ (including acute liver) failure.Conclusions.The clinical symptoms of liver damage, including those with severe preeclampsia, arise, as a rule, already against the background of severe morphological changes in its tissue and, as a rule, indicate functional decompensation. Liver immunology remains little studied, which requires further research on this problem.

The gut microbiota is a complex and plastic consortium of microorganisms that are intricately connected with human physiology. The liver is a central immunological organ that is particularly enriched in innate immune cells and constantly exposed to circulating nutrients and endotoxins derived from the gut microbiota. The delicate interaction between the gut and liver prevents accidental immune activation against otherwise harmless antigens. Work on the interplay between the gut microbiota and liver has assisted in understanding the pathophysiology of various liver diseases. Of immense importance is the step from high-throughput sequencing (correlation) to mechanistic studies (causality) and therapeutic intervention. Here, we review the gut microbiota, liver immunology, and the interaction between the gut and liver. In addition, the impairment in the gut-liver axis found in various liver diseases is reviewed here, with an emphasis on alcohol-associated liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and autoimmune liver disease (AILD). On the basis of growing evidence from these preclinical studies, we propose that the gut-liver axis paves the way for targeted therapeutic modalities for liver diseases.

The Mutational and Transcriptional Landscapes of Hepatocarcinogenesis in a Rat Model.

It is a well-documented event that fibroblast growth factors (FGFs) regulate liver development and homeostasis in autocrine, paracrine, and endocrine manners via binding and activating FGF receptors (FGFRs) tyrosine kinase in hepatocytes. Recent research reveals that hepatic stellate cells (HSCs) play a fundamental role in liver immunology. However, how FGF signaling in HSCs regulates liver inflammation remains unclear. Here, we report that FGF promoted NF-κB signaling, an inflammatory pathway, in human HSCs, which was associated with FGFR1 expression. Both FGF and NF-κB signaling in HSCs were compromised by FGFR1 tyrosine kinase inhibitor. After stimulating HSCs with proinflammatory cytokines, expression of multiple FGF ligands was significantly increased. However, disruption of FGF signaling with FGFR inhibitors prominently reduced the apoptosis, inflammatory response, NF-κB nuclear translocation, and expression of matrix metalloproteinase-9 (MMP-9) induced by TNFα in HSCs. Interestingly, FGF21 significantly alleviated the inflammation responses in the concanavalin A (Con A)-induced acutely injured liver. Unlike canonic FGFs that elicit signals through activating the FGFR–heparan sulfate complex, FGF21 activates the FGFR–KLB complex and elicits a different set of signals. Therefore, the finding here indicates the urgency of developing pathway-specific inhibitors that only suppress canonical FGF, but not non-canonical FGF21, signaling for alleviating inflammation in the liver, which is presented in all stages of diseased liver.

Top Papers in Liver Transplantation 2017-2018

The mechanism of innate and adaptive immune responses to chronic infections with hepatotropic viruses (HBV, HCV) was studied in 2018. Its mechanism elucidated the dysregulation of natural killer (NK) cells, monocytes, B cells and T cells. In addition, a new target for immune regulation of HBV infection (TLR3/OX40L) was introduced. The discovery of new NK cell immune checkpoints, the involvement of mononuclear macrophages in liver failure and inflammation, sex hormone affecting intrahepatic-resistant bacterial infection through the regulation of humoral immunity, and the communication mechanism between liver and other immune organs have enriched people's understanding of liver immunology and its clinical significance.

The aim of the study was to investigate the prevalence of renal function and liver enzyme abnormalities among HIV-infected children, changes in prevalence with time on combination antiretroviral therapy (cART), and the factors associated with these abnormalities. A prospective cohort study was conducted among HIV-infected children < 18 years old (n = 705) who were on first-line cART. Liver enzymes, renal function, haematology, immunology and virological response were assessed at enrolment and followed bi-annually for 18 months. Liver fibrosis and cirrhosis were assessed using noninvasive markers including the aspartate aminotransferase (AST) to platelet ratio index (APRI) and fibrosis score (FIB-4). The median age was 12 [interquartile range (IQR) 8-14] years; 53.3% of patients were male. At enrolment, the median cART duration was 3.3 (IQR 1.1-6.1) years; 177 (25.1%) and 83 (11.8%) patients had elevated AST and alanine aminotransferase (ALT), respectively. A tenth of the children had an APRI score > 0.5, suggesting liver fibrosis. Being on a zidovudine (ZDV)- or nevirapine (NVP)-based regimen and having a viral load > 1000 HIV-1 RNA copies/mL were significantly associated with elevated ALT. Twenty-four (3.4%) and 84 (12.1%) patients had elevated creatinine and blood urea nitrogen (BUN), respectively. As cART duration increased by 6 months, median BUN increased by 1.6 [95% confidence interval (CI) 0.4-2.7] mg/dL (P = 0.01); the glomerular filtration rate (GFR) decreased by 35.6 (95% CI 17.7-53.4) mL/min/1.73 m2 (P < 0.0001); and AST and ALT decreased by 1.4 (95% CI 0.4-2.5) IU/L (P = 0.01) and 1.4 (95% CI 0.2-2.6) IU/L (P = 0.01), respectively. A high prevalence of liver enzyme and renal function abnormalities was observed at enrolment. Decreasing liver enzyme levels during follow-up are possibly reassuring, while the progressive reduction in GFR and the increase in BUN are worrisome and require further study.

The liver is a multifunctional organ responsible for complex metabolic and immune functions. Although not a classic lymphoid organ, the liver is enriched with traditional immune cells as well as parenchymal and nonparenchymal cells that play a key role in immune homeostasis. Due to its location and unique anatomic structure, the liver must finely balance immunity and tolerance to avoid undue inflammation in the setting of constant antigenic exposure from portal blood flow while maintaining appropriate immunity against pathogens. Since the first successful liver transplantation in humans in 1967 at the University of Colorado, our knowledge of hepatic immunity and tolerance, in the context of both liver disease and liver transplantation, has evolved dramatically. With these advancements, therapeutic modalities have been developed that have revolutionized the care of liver transplant recipients. In Part 2: Application to Liver Allograft Immunity, we apply the basic principles of liver immunology and allorecognition to our current management of liver transplant recipients in the context of both immunosuppression and the holy grail of transplantation, operational tolerance. This review contains 4 figures, 3 tables, and 32 references Key Words: adaptive immunity; allograft rejection; allograft tolerance; allorecognition; antigen presenting cells; immunosuppression; innate immunity; liver transplantation; T lymphocytes

The liver is a multifunctional organ responsible for complex metabolic and immune functions. Although not a classic lymphoid organ, the liver is enriched with traditional immune cells as well as parenchymal and nonparenchymal cells that play a key role in immune homeostasis. Due to its location and unique anatomic structure, the liver must finely balance immunity and tolerance to avoid undue inflammation in the setting of constant antigenic exposure from portal blood flow while maintaining appropriate immunity against pathogens. Since the first successful liver transplantation in humans in 1967 at the University of Colorado, our knowledge of hepatic immunity and tolerance, in the context of both liver disease and liver transplantation, has evolved dramatically. With these advancements, therapeutic modalities have been developed that have revolutionized the care of liver transplant recipients. In Part 1: Fundamentals of Liver Immunology and Allorecognition, we review current knowledge of hepatic immunity, including anatomic features and cellular components that give the liver its unique properties. In addition, we describe critical concepts of innate and adaptive immune function to provide a context for understanding allograft injury and rejection. This review contains 4 figures, 4 tables and 26 references. Key Words: adaptive immunity; allorecognition; antigen presenting cells; innate immunity; liver transplantation; T lymphocytes

Innate lymphocytes are selectively enriched in the liver where they have important roles in liver immunology. Murine studies have shown that type I NKTcells can promote liver inflammation, whereas type II NKTcells have an anti-inflammatory role. In humans, type II NKTcells were found to accumulate in the gut during inflammation and IL13Rα2 was proposed as a marker for these cells. In the human liver, less is known about type I and II NKTcells. Here, we studied the phenotype and function of human liver Tcells expressing IL13Rα2. We found that IL13Rα2 was expressed by around 1% of liver-resident memory Tcells but not on circulating Tcells. In support of their innate-like T-cell character, the IL13Rα2+ Tcells had higher expression of promyelocytic leukaemia zinc finger (PLZF) compared to IL13Rα2- Tcells and possessed the capacity to produce IL-22. However, only a minority of human liver sulfatide-reactive type II NKTcells expressed IL13Rα2. Collectively, these findings suggest that IL13Rα2 identifies tissue-resident intrahepatic Tcells with innate characteristics and the capacity to produce IL-22.