(MHC) restriction and, especially, discussion of maternal–fetal immune homeostasis. These omissions are easily forgiven when it is realized that the tools used by immunologists in the 1960s had not changed significantly in over three decades and relied particularly on diffusion and electrophoresis.
This issue of maternal–fetal immune homeostasis is critical in the introduction of liver autoimmunity. Whether it is a human or a mouse, the fetus is a privileged site and spared from any immune attack from the mother. The basis for this tolerance resides in the liver. The liver was known even in ancient Greek mythology to be an organ capable of regeneration. Prometheus stole from the Gods, giving it away to mortals. As a result, he was chained to a rock by Zeus, where each day an eagle pecked out his liver. Presumably, Prometheus survived because of liver regeneration. However, with that singular exception, and the use of liver in the everyday kitchen, the liver as an organ responsible for immunity was ignored. Indeed, a major basis for maternal–fetal tolerance is the portal circulation. It is therefore ironic that the organ which is most important for the critical element of immune tolerance can itself become a victim of autoimmunity, manifest in such diseases as autoimmune hepatitis, primary biliary cholangitis, primary sclerosing cholangitis and IgG4‐associated disease.
In this volume, Neuberger and Hirschfield have taken up the challenge of providing the scientific basis for liver autoimmunity. Liver autoimmunity has often been a stepchild compared with other autoimmune diseases. The pharmaceutical industry has made enormous efforts in helping patients with rheumatoid arthritis, with psoriasis, and of course with human viral hepatitis, but the commitment to liver autoimmunity, not only in industry but in academia, has been modest at best. And yet the same generic factors that lead to both organ‐specific and systemic autoimmune diseases are at play in the liver autoimmune syndromes, since the development of disease requires a genetic predisposition and an environmental stimulus. This is a feature that I have coined “bad genes and bad luck.” However, this volume goes beyond descriptive immunobiology. It provides a rigorous analysis of multiple critical areas of why patients become susceptible and why their natural history of disease may vary, including for example the roles of genetics and epigenetics, environmental exposures, the specific and usual clinical challenges faced by patients with liver disease, and of course helping the particularly difficult and challenging patient (i.e. liver disease during pregnancy). This volume also fills a major void in explaining the role of liver transplantation by placing not only its scientific significance in perspective, but also tackling the difficult subject of disease recurrence following liver transplant. There remain many controversies and multiple unanswered questions, and the book ends with an attempt to make sense of overlap and crossover syndromes, and the relationship to extrahepatic abnormalities in patients with autoimmune liver disease. Finally, it focuses on the most important element, which is clinical management and how we may help our patients. At the end of the day, whatever the scientific interest may be, the only fundamental question of value is whether our work and our publications will have a positive impact on the health of people. This volume should fill such a need.
1 Introduction to the Physiology, Immunology and Pathology of the Liver and Biliary Tree
Marco Carbone1 and Mario Strazzabosco2
1 Division of Gastroenterology, University of Milan Bicocca, Milan, Italy
2 Digestive Disease Section, Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA
Abstract
The liver has many functions including metabolic homeostasis, disposal of endotoxins and xenotoxins, metabolism of bilirubin and urea, and bile formation and secretion. The process of bile formation depends on the liver synthesis and the canalicular secretion of bile acids. Besides their roles in dietary lipid absorption and cholesterol homeostasis, bile acids also play a key role as signaling molecules in the regulation of hepatic metabolism and energy homeostasis. The regenerative ability of the liver lies in the multiple niches of biliary tree stem cells.
Keywords bile formation; carbohydrate metabolism; hepatocyte; cholangiocytes lipid metabolism; metabolic zonation; protein metabolism; bile acid.
Key Points
The liver is largely composed of hepatocytes and biliary epithelial cells or cholangiocytes; both hepatocytes and intrahepatic cholangiocytes differentiate from bipotent liver progenitors, the hepatoblasts.
The liver has many functions, among which metabolic homeostasis, disposal of endotoxins and xenotoxins, metabolism of bilirubin and urea, and bile formation and secretion are just examples. The liver also produces fundamental circulating proteins and clotting factors and hormones. In addition, the liver receives and processes the blood coming from the intestine and has a fundamental role in innate immunity.
Besides their roles in dietary lipid absorption and cholesterol homeostasis, bile acids (BAs) also play a key role as signaling molecules in the regulation of hepatic metabolism and energy homeostasis.
BAs also have hormonal signaling functions and interact with dedicated receptors such as the nuclear receptor farnesoid X receptor and G protein‐coupled receptors, which regulate BA homeostasis and BA‐induced injury and/or inflammation.
Multiple niches of biliary tree stem/progenitor cells reside in different locations along the human biliary tree and within the liver parenchyma and have a key role in regeneration of the liver.
Cholangiocytes modify the primary bile by secretion of chloride and bicarbonate fluid. This is a major protective mechanism for the biliary tree.
Cholangiocytes, a barrier and secretory epithelium in normal conditions, activate and/or proliferate following a liver insult and give rise to the ductular reaction, a major driver of the progression of hepatic fibrosis.
Cholangiocytes also contribute to the immune response through antigen presentation to immune cells, being a target of immune‐mediated aggression or being the initiators of an inflammatory reaction that then progresses to adaptive immune activation.
Liver Cell Types and Organization
Liver cells can be classified into the following groups:
parenchymal cells, which include hepatocytes and biliary epithelial cells (BECs);
sinusoidal cells, which include hepatic sinusoidal endothelial cells and Kupffer cells; and
perisinusoidal cells, which include the hepatic stellate cells (HSCs) and the pit cells [1].
The hepatocytes, which comprise approximately 60% of the liver cell mass, are epithelial cells with two distinct domains on their plasma membrane: (i) the sinusoidal (or basolateral) surface, facing the sinusoids, in contact with plasma through the fenestrated endothelium of the sinusoids, which allows a bidirectional flow of liquids and solutes though the space of Disse; and (ii) the canalicular (or apical) surface, which encloses the bile ductules and represents the beginning of the biliary drainage system.
The BECs (or cholangiocytes) are the epithelial cells lining the biliary tree. The biliary epithelium shows a morphologic heterogeneity that is associated with a variety of functions performed
