Abstract
The liver is a very tolerogenic organ. It is continually exposed to a multitude of antigens and is able to promote an effective immune response against pathogens and simultaneously immune tolerance against self-antigens. In spite of strong peripheral and central tolerogenic mechanisms, loss of tolerance can occur in autoimmune liver diseases, such as autoimmune hepatitis (AIH) through a combination of genetic predisposition, environmental factors, and an imbalance in immunological regulatory mechanisms. The liver hosts several types of conventional resident antigen presenting cells (APCs) such as dendritic cells, B cells and macrophages (Kupffer cells), and unconventional APCs including liver sinusoidal endothelial cells, hepatic stellate cells and hepatocytes. By standard (direct presentation and cross-presentation) and alternative mechanisms (cross-dressing and MHC class II-dressing), liver APCs presents self-antigen to naive T cells in the presence of costimulation leading to an altered immune response that results in liver injury and inflammation. Additionally, the transport of antigens and antigen:MHC complexes by trogocytosis and extracellular vesicles between different cells in the liver contributes to enhance antigen presentation and amplify autoimmune response. Here, we focus on the impact of antigen presentation on the immune response in the liver and on the functional role of the immune cells in the induction of liver inflammation. A better understanding of these key pathogenic aspects could facilitate the establishment of novel therapeutic strategies in AIH.
Highlights
The liver is an important immunological organ with the unique capacity to mount effective immune responses against hepatotropic pathogens on one hand and maintain a local and systemic immune tolerance to self and foreign antigens on the other [1]
The liver’s immune function is strongly influenced by its exclusive anatomy and by its cell composition [1]. The liver hosts both conventional such as dendritic cells (DCs), B cells and macrophages (Kupffer cells, KCs), and unconventional antigen presenting cells (APCs) including liver sinusoidal endothelial cells (LSECs), Antigen Presentation in Autoimmune Hepatitis hepatic stellate cells (HSCs), and hepatocytes (HCs) which uptake antigens, process and present them to CD4+ and CD8+ T cells by canonical and noncanonical mechanisms resulting in initiation and amplification of immune responses or in induction of immune tolerance [1, 2]
The majority of clones obtained from the peripheral blood are CD4+ T cells bearing the ab T cell receptor, while the largest numbers of clones generated from liver biopsies of the same patients are CD4-CD8- cells bearing the gd TCR or CD8+ ab T cells [91]. gd T-cell clones obtained from the peripheral blood and the portal areas of pediatric autoimmune hepatitis (AIH) patients show cytolytic activity against hepatocytes [91, 92]
Summary
The liver is an important immunological organ with the unique capacity to mount effective immune responses against hepatotropic pathogens on one hand and maintain a local and systemic immune tolerance to self and foreign antigens on the other [1]. The liver’s immune function is strongly influenced by its exclusive anatomy and by its cell composition [1] The liver hosts both conventional such as dendritic cells (DCs), B cells and macrophages (Kupffer cells, KCs), and unconventional antigen presenting cells (APCs) including liver sinusoidal endothelial cells (LSECs), Antigen Presentation in Autoimmune Hepatitis hepatic stellate cells (HSCs), and hepatocytes (HCs) which uptake antigens, process and present them to CD4+ and CD8+ T cells by canonical and noncanonical mechanisms resulting in initiation and amplification of immune responses or in induction of immune tolerance [1, 2].
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