The liver: a model of organ-specific lymphocyte recruitment

The liver is constantly exposed to gut-derived antigens that enter via the portal vein, and it must modulate immune responses so that harmful pathogens are cleared but necessary food antigens are ignored. The liver contains a large resident and migratory population of lymphocytes and macrophages that provide immune surveillance against foreign antigen. This population of cells can be rapidly expanded in response to infection or injury by recruiting leukocytes from the circulation, a process that is dependent on the ability of lymphocytes to recognise, bind to and migrate across the endothelial cells that line the vasculature. Lymphocytes can enter the liver at several sites: the vascular endothelium in the portal tracts (comprising the hepatic artery, portal vein and bile ductule), the sinusoids (through which the blood percolates past the hepatocytes) or the central hepatic veins (through which the blood exits). The requirements and physical conditions at each site vary and there is evidence that different combinations of adhesion proteins are involved at these different sites. This article discusses the expression and function of adhesion molecules within the liver and demonstrates how specific populations of effector lymphocytes can be selectively recruited to the liver.

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Interruption of thymic activity in adults improves responses to tumor immunotherapy

10.1101/2020.01.08.899484 ◽

2020 ◽

Author(s):

José Almeida-Santos ◽

Marie-Louise Bergman ◽

Inês Amendoeira Cabral ◽

Jocelyne Demengeot

Keyword(s):

Immune Responses ◽

Immune Surveillance ◽

Foxp3 Expression ◽

Treg Cells ◽

Adult Mice ◽

Cellular Analysis ◽

Cell Decline ◽

Specific Antigens ◽

And Function ◽

Different Origin

AbstractThe thymus produces precursors of both effectors and regulatory T cells (Tconv and Treg, respectively) whose interactions prevents autoimmunity while allowing efficient protective immune responses. Tumors express a composite of self- and tumor-specific antigens and engage both Tconv and Treg cells. Along the aging process, the thymus involutes, and tumor incidence increases, a correlation proposed previously to be causal and the result of effector cell decline. In this work, we directly tested whether interruption of thymic activity in adult mice affects Foxp3 expressing Treg composition and function, and alters tumor immune surveillance. Young adult mice, on two different genetic backgrounds, were surgically thymectomized (TxT) and analyzed or challenged 2 months later. Cellular analysis revealed a 10-fold decrease in both Tconv and Treg numbers and a bias for activated cells. The persisting Treg displayed reduced stability of Foxp3 expression and, as a population, showed compromised return to homeostasis upon induced perturbations. We next tested the growth of three tumor models from different origin and presenting distinct degrees of spontaneous immunogenicity. In none of these conditions adult TxT facilitated tumor growth. Rather TxT enhanced the efficacy of anti-tumor immunotherapies targeting Treg and/or the checkpoint CTLA4, as evidenced by increased frequency of responder mice and decreased intra-tumoral Treg to CD8+IFNγ+ cell ratio. Together, our findings point to a scenario where abrogation of thymic activities affects preferentially the regulatory over the ridding arm of the immune activities elicited by tumors, and argues that higher incidence of tumors with age cannot be solely attributed to thymic output decline.

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MicroRNAs and Multiple Sclerosis

Autoimmune Diseases ◽

10.4061/2011/807426 ◽

2011 ◽

Vol 2011 ◽

pp. 1-27 ◽

Cited By ~ 16

Author(s):

Kemal Ugur Tufekci ◽

Meryem Gulfem Oner ◽

Sermin Genc ◽

Kursad Genc

Keyword(s):

Multiple Sclerosis ◽

Immune Responses ◽

Inflammatory Responses ◽

Current Knowledge ◽

Expression Patterns ◽

Mirna Biogenesis ◽

Disease Marker ◽

Organ Specific ◽

And Function

MicroRNAs (miRNAs) have recently emerged as a new class of modulators of gene expression. miRNAs control protein synthesis by targeting mRNAs for translational repression or degradation at the posttranscriptional level. These noncoding RNAs are endogenous, single-stranded molecules approximately 22 nucleotides in length and have roles in multiple facets of immunity, from regulation of development of key cellular players to activation and function in immune responses. Recent studies have shown that dysregulation of miRNAs involved in immune responses leads to autoimmunity. Multiple sclerosis (MS) serves as an example of a chronic and organ-specific autoimmune disease in which miRNAs modulate immune responses in the peripheral immune compartment and the neuroinflammatory process in the brain. For MS, miRNAs have the potential to serve as modifying drugs. In this review, we summarize current knowledge of miRNA biogenesis and mode of action and the diverse roles of miRNAs in modulating the immune and inflammatory responses. We also review the role of miRNAs in autoimmunity, focusing on emerging data regarding miRNA expression patterns in MS. Finally, we discuss the potential of miRNAs as a disease marker and a novel therapeutic target in MS. Better understanding of the role of miRNAs in MS will improve our knowledge of the pathogenesis of this disease.

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Structure and function of the liver, biliary tract, and pancreas

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.1519 ◽

2010 ◽

pp. 2435-2443

Author(s):

Alexander Gimson ◽

Simon M. Rushbrook

Keyword(s):

Endothelial Cells ◽

Single Cell ◽

Biliary Tract ◽

Structural Unit ◽

Structure And Function ◽

Hepatic Veins ◽

Canalicular Membrane ◽

The Right ◽

And Function ◽

Portal Tracts

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Structure and function of the liver, biliary tract, and pancreas

Oxford Textbook of Medicine ◽

10.1093/med/9780198746690.003.0315 ◽

2020 ◽

pp. 3032-3042

Author(s):

William Gelson ◽

Alexander Gimson

Keyword(s):

Biliary Tract ◽

Serine Proteases ◽

Digestive Enzymes ◽

Structural Unit ◽

Hepatic Veins ◽

Principal Mechanism ◽

Alkaline Secretion ◽

The Right ◽

And Function ◽

Portal Tracts

The liver, sited in the right upper quadrant of the abdomen, comprises eight segments, each of which is a complete functional unit with a single portal pedicle and a hepatic vein. Within the functional segments, the structural unit is the hepatic lobule, a polyhedron surrounded by four to six portal tracts containing hepatic arterial and portal venous branches from which blood perfuses through sinusoids, surrounded by walls of hepatocytes that are a single cell thick and lined by specialized endothelial cells with ‘windows’ (fenestrae), to the centrilobular region and the central hepatic veins. Bile secreted through the canalicular membrane of the hepatocyte collects in biliary canaliculi, from which it passes through the biliary tract into the gut. The liver secretes bile, which aids digestion by emulsifying lipids, and has a central role in metabolism of (1) bilirubin, from haem; (2) bile salts, the principal mechanism for clearance of cholesterol; (3) carbohydrates; (4) amino acids and ammonia; (5) proteins, most circulating plasma proteins being produced by hepatocytes; and (6) lipid and lipoproteins. The pancreas lies in the retroperitoneum and is composed of (1) an exocrine portion centred on acini, producing an alkaline secretion containing digestive enzymes including serine proteases, exopeptidases, and lipolytic enzymes, draining through a ductal system into the duodenum; and (2) the islets of Langerhans, which secrete insulin (also glucagon, somatostatin, and pancreatic polypeptide).

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A Mathematical Model of Blood Circulation in the Liver Lobule

ASME 2010 Summer Bioengineering Conference, Parts A and B ◽

10.1115/sbc2010-19237 ◽

2010 ◽

Author(s):

Andrea Bonfiglio ◽

Kritsada Leungchavaphongse ◽

Rodolfo Repetto ◽

Jennifer H. Siggers

Keyword(s):

Portal Vein ◽

Hepatic Artery ◽

Portal Tract ◽

Hepatic Veins ◽

Central Vein ◽

Hexagonal Prism ◽

Hepatic Portal Vein ◽

Hepatic Portal ◽

Portal Tracts ◽

Sinusoidal Space

The liver has a specialized circulation. It is supplied by two main vessels: the hepatic portal vein, carrying nutrient-rich deoxygenated blood, and the hepatic artery, carrying oxygenated blood. The hepatic portal vein supplies up to 80% of the blood. Within the liver, both the portal vein and the hepatic artery undergo a series of successive bifurcations, which end at the portal tracts. Each portal tract contains three vessels: a portal vein, an artery and a bile duct. Blood drains out from the portal tracts into the sinusoidal space and from there into the central veins. The central veins, after a series of converging bifurcations, end at the hepatic veins, which carry blood out of the liver. The sinusoidal space consists of a network of tortuous, interconnected channels called sinusoids. One of the most common and widely accepted descriptions of the primitive units of the liver is the “classic lobule”. A diagram of an idealized arrangement of liver lobules is shown in Figure 1. Each lobule has the shape of a hexagonal prism with a portal tract running along each of the parallel edges and a central vein on the central axis. The remainder of the space is made up of sinusoids.

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Matrix Metalloproteinases in Invertebrates

Protein and Peptide Letters ◽

10.2174/0929866527666200429110945 ◽

2020 ◽

Vol 27 (11) ◽

pp. 1068-1081

Author(s):

Xi Liu ◽

Dongwu Liu ◽

Yangyang Shen ◽

Mujie Huang ◽

Lili Gao ◽

...

Keyword(s):

Matrix Metalloproteinases ◽

Immune Responses ◽

Theoretical Basis ◽

Regulatory Mechanism ◽

Structure And Function ◽

Catalytic Domains ◽

Physiological Processes ◽

Disease Occurrence ◽

Complex Functions ◽

And Function

Matrix Metalloproteinases (MMPs) belong to a family of metal-dependent endopeptidases which contain a series of conserved pro-peptide domains and catalytic domains. MMPs have been widely found in plants, animals, and microorganisms. MMPs are involved in regulating numerous physiological processes, pathological processes, and immune responses. In addition, MMPs play a key role in disease occurrence, including tumors, cardiovascular diseases, and other diseases. Compared with invertebrate MMPs, vertebrate MMPs have diverse subtypes and complex functions. Therefore, it is difficult to study the function of MMPs in vertebrates. However, it is relatively easy to study invertebrate MMPs because there are fewer subtypes of MMPs in invertebrates. In the present review, the structure and function of MMPs in invertebrates were summarized, which will provide a theoretical basis for investigating the regulatory mechanism of MMPs in invertebrates.

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Vascular Involvements in Cholangiocarcinoma: Tips and Tricks

Cancers ◽

10.3390/cancers13153735 ◽

2021 ◽

Vol 13 (15) ◽

pp. 3735

Author(s):

Roberta Angelico ◽

Bruno Sensi ◽

Alessandro Parente ◽

Leandro Siragusa ◽

Carlo Gazia ◽

...

Keyword(s):

Portal Vein ◽

Hepatic Artery ◽

Vena Cava ◽

High Volume ◽

Vascular Reconstruction ◽

Ex Situ ◽

Vascular Involvement ◽

Hepatic Veins ◽

Hepatic Artery Resection ◽

Artery Resection

Cholangiocarcinoma (CCA) is an aggressive malignancy of the biliary tract. To date, surgical treatment remains the only hope for definitive cure of CCA patients. Involvement of major vascular structures was traditionally considered a contraindication for resection. Nowadays, selected cases of CCA with vascular involvement can be successfully approached. Intrahepatic CCA often involves the major hepatic veins or the inferior vena cava and might necessitate complete vascular exclusion, in situ hypothermic perfusion, ex situ surgery and reconstruction with autologous, heterologous or synthetic grafts. Hilar CCA more frequently involves the portal vein and hepatic artery. Resection and reconstruction of the portal vein is now considered a relatively safe and beneficial technique, and it is accepted as a standard option either with direct anastomosis or jump grafts. However, hepatic artery resection remains controversial; despite accumulating positive reports, the procedure remains technically challenging with increased rates of morbidity. When arterial reconstruction is not possible, arterio-portal shunting may offer salvage, while sometimes an efficient collateral system could bypass the need for arterial reconstructions. Keys to achieve success are represented by accurate selection of patients in high-volume referral centres, adequate technical skills and eclectic knowledge of the various possibilities for vascular reconstruction.

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Transsplenic portal vein recanalization and direct intrahepatic portosystemic shunt placement to optimize liver transplantation

CVIR Endovascular ◽

10.1186/s42155-019-0096-7 ◽

2020 ◽

Vol 3 (1) ◽

Author(s):

Osman Ahmed ◽

Abhijit L. Salaskar ◽

Steven Zangan ◽

Anjana Pillai ◽

Talia Baker

Keyword(s):

Liver Transplantation ◽

Portal Vein ◽

Splenic Vein ◽

Portosystemic Shunt ◽

Refractory Ascites ◽

Hepatic Veins ◽

Sonographic Guidance ◽

Portosystemic Shunts ◽

Intrahepatic Portosystemic Shunt ◽

End To End

Abstract Background Percutaneous trans-splenic portal vein recanalization (PVR) has been reported for facilitation of transjugular intrahepatic portosystemic shunts (TIPS), however has not been applied to patients undergoing direct intrahepatic portosystemic shunt (DIPS). We report the utilization of trans-splenic-PVR with DIPS creation in a patient with chronic portal and hepatic vein occlusions undergoing liver transplantation evaluation. Case presentation A 48-year-old male with decompensated alcoholic cirrhosis complicated by refractory ascites, hepatic encephalopathy, and variceal bleeding underwent CT that demonstrated chronic occlusion of the hepatic veins (HV), extrahepatic portal vein (PV), and superior mesenteric vein (SMV). Due to failed attempts at TIPS at outside institutions, interventional radiology was consulted for portal vein recanalization (PVR) with TIPS to treat the portal hypertension and ascites and also facilitate an end-to-end PV anastomosis at transplantation. After an initial hepatic venogram confirmed chronic HV occlusion, a DIPS with trans-splenic PVR was planned. The splenic vein was accessed under sonographic guidance using a micropuncture set and subsequently upsized to a 6 French sheath over a stiff guidewire. A splenic venogram via this access confirmed occlusion of the PV with drainage of the splenic vein (SV) through gastric varices. The thrombosed PV was then recanalized and angioplastied to restore PV flow via the transsplenic approach. A transjugular liver access kit with a modified 21-gauge needle was advanced into the IVC through the internal jugular vein (IJV) sheath and directed towards the target snare in PV. The needle was used to subsequently puncture the PV through the caudate lobe and facilitate placement of a wire into the SV. The initial portosystemic gradient (PSG) was 20 mmHg. The IJV sheath was advanced through the hepatic parenchymal tract into the main-PV and a stent-graft was placed across the main PV and into the IVC. A portal venogram demonstrated brisk blood flow through the DIPS, resolution of varices and a PSG of 8 mmHg. One month after the procedure, the patient had a significant reduction in ascites and MELD-NA score. Patient is currently listed and awaiting transplantation. Conclusions In the setting of chronically occluded portal and hepatic veins, trans-splenic PVR DIPS may serve as an effective bridge to liver transplantation by facilitating an end to end portal vein anastomosis.

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How Changes in the Nutritional Landscape Shape Gut Immunometabolism

Nutrients ◽

10.3390/nu13030823 ◽

2021 ◽

Vol 13 (3) ◽

pp. 823

Author(s):

Jian Tan ◽

Duan Ni ◽

Rosilene V. Ribeiro ◽

Gabriela V. Pinget ◽

Laurence Macia

Keyword(s):

Immune Cells ◽

Metabolic Pathways ◽

Immune Cell ◽

Food Additives ◽

Cell Activity ◽

Inflammatory Cells ◽

Therapeutic Approaches ◽

Food Antigens ◽

And Function ◽

Micro Organisms

Cell survival, proliferation and function are energy-demanding processes, fuelled by different metabolic pathways. Immune cells like any other cells will adapt their energy production to their function with specific metabolic pathways characteristic of resting, inflammatory or anti-inflammatory cells. This concept of immunometabolism is revolutionising the field of immunology, opening the gates for novel therapeutic approaches aimed at altering immune responses through immune metabolic manipulations. The first part of this review will give an extensive overview on the metabolic pathways used by immune cells. Diet is a major source of energy, providing substrates to fuel these different metabolic pathways. Protein, lipid and carbohydrate composition as well as food additives can thus shape the immune response particularly in the gut, the first immune point of contact with food antigens and gastrointestinal tract pathogens. How diet composition might affect gut immunometabolism and its impact on diseases will also be discussed. Finally, the food ingested by the host is also a source of energy for the micro-organisms inhabiting the gut lumen particularly in the colon. The by-products released through the processing of specific nutrients by gut bacteria also influence immune cell activity and differentiation. How bacterial metabolites influence gut immunometabolism will be covered in the third part of this review. This notion of immunometabolism and immune function is recent and a deeper understanding of how lifestyle might influence gut immunometabolism is key to prevent or treat diseases.

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Contribution of Infectious Agents to the Development of Celiac Disease

Microorganisms ◽

10.3390/microorganisms9030547 ◽

2021 ◽

Vol 9 (3) ◽

pp. 547

Author(s):

Daniel Sánchez ◽

Iva Hoffmanová ◽

Adéla Szczepanková ◽

Věra Hábová ◽

Helena Tlaskalová-Hogenová

Keyword(s):

Celiac Disease ◽

Intestinal Mucosa ◽

Wheat Gluten ◽

Small Intestinal Mucosa ◽

Beneficial Effects ◽

Immune Mediated ◽

Healthy State ◽

Food Antigens ◽

Small Intestinal ◽

And Function

The ingestion of wheat gliadin (alcohol-soluble proteins, an integral part of wheat gluten) and related proteins induce, in genetically predisposed individuals, celiac disease (CD), which is characterized by immune-mediated impairment of the small intestinal mucosa. The lifelong omission of gluten and related grain proteins, i.e., a gluten-free diet (GFD), is at present the only therapy for CD. Although a GFD usually reduces CD symptoms, it does not entirely restore the small intestinal mucosa to a fully healthy state. Recently, the participation of microbial components in pathogenetic mechanisms of celiac disease was suggested. The present review provides information on infectious diseases associated with CD and the putative role of infections in CD development. Moreover, the involvement of the microbiota as a factor contributing to pathological changes in the intestine is discussed. Attention is paid to the mechanisms by which microbes and their components affect mucosal immunity, including tolerance to food antigens. Modulation of microbiota composition and function and the potential beneficial effects of probiotics in celiac disease are discussed.

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