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Liver Immunology

Dimitrios P. Bogdanos, Bin Gao, M. Eric Gershwin

10.1002/cphy.c120011

Source: Volume 3, Issue 2, April 2013

Published online: April 2013

Full Article on Wiley Online Library



Abstract

The liver is the largest organ in the body and is generally regarded by nonimmunologists as having little or no lymphoid function. However, such is far from accurate. This review highlights the importance of the liver as a lymphoid organ. Firstly, we discuss experimental data surrounding the role of liver as a lymphoid organ. The liver facilitates tolerance rather than immunoreactivity, which protects the host from antigenic overload of dietary components and drugs derived from the gut and it is instrumental to fetal immune tolerance. Loss of liver tolerance leads to autoaggressive phenomena, which if not controlled by regulatory lymphoid populations, may lead to the induction of autoimmune liver diseases. Liver‐related lymphoid subpopulations also act as critical antigen‐presenting cells. The study of the immunological properties of liver and delineation of the microenvironment of the intrahepatic milieu in normal and diseased livers provides a platform to understand the hierarchy of a series of detrimental events that lead to immune‐mediated destruction of the liver and the rejection of liver allografts. The majority of emphasis within this review will be on the normal mononuclear cell composition of the liver. However, within this context, we will discuss selected, but not all, immune‐mediated liver disease and attempt to place these data in the context of human autoimmunity. © 2013 American Physiological Society. Compr Physiol 3:567‐598, 2013.

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Figure 1. Figure 1.

Anatomical location and external appearance of the liver. The falciform ligament, on the surface of the diaphragm, splits the liver into right and left lobe. The anatomical relationship of the liver with organs such as the gallbladder, stomach, duodenum, and pancreas is illustrated.
Figure 2. Figure 2.

Cellular and extracellular composition of the liver.
Figure 3. Figure 3.

The morphological appearance of cells within the liver.
Figure 4. Figure 4.

The hepatic lobule is the structural unit of the liver. It consists of a hexagonal arrangement of hepatocyte plates with the central vein located in the center of the structure and the portal triads distributed at the vertices of the lobule. The portal triad consists of terminal branches of the portal vein and the hepatic artery and a bile duct.
Figure 5. Figure 5.

Illustration of the microanatomical localization of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. The space of Disse separates hepatocytes from the liver sinusoids. The endothelium of liver sinusoids is discontinued (fenestrated) as the liver sinusoidal cells are perforated by several clusters of pores forming sieve plates (420). These cells act as scavenger cells and form a physical filtering barrier between the sinusoidal blood and plasma (115,356). Kupffer cells are resident macrophages that are attached to the layer of liver sinusoidal endothelial cells. The hepatic stellate cells are located in the subendothelial space of Disse and play vital role in fibrogenesis.
Figure 6. Figure 6.

Cells comprising the liver including hepatocytes (HEP), liver sinusoidal ensothelial cells (LSEC), Kupffer cells (KC), hepatic stellate cells (HSC), and lymphoid cell subpopulations. NK, natural killer; NKT, natural killer T cells; DC, dendritic cell; Treg, T‐regulatory cell.
Figure 7. Figure 7.

Distribution of cell subpopulations within intrahepatic lymphocytes. A very wide range of these cell populations are reported in the liver, differs amongst species, and also varies by age. It is of note, that the highest proportion of intrahepatic human lymphocytes consists of natural killer T cell (NKT) and NK cells, a finding that in general contrasts what is found in the peripheral blood. Thus, NK cells account for approximately 20% to 30% of the total number of liver‐resident lymphocytes compared to less than 5% seen in peripheral blood (104).
Figure 8. Figure 8.

Flow cytometric analysis of peripheral blood reflects the relative proportion of bright and low natural killer (NK) (CD36+) cells, natural killer T cell (NKT) (CD3+CD56+), and T cells (CD3+CD56−) in a representative donor. Bright and low NK cells can be seen. Vertical axis (CD56); horizontal axis CD3.
Figure 9. Figure 9.

Schematic illustration of natural killer (NK) cell receptors and killing of viral hepatitis infected cells. (A) Under normal conditions, noninfected cells are not killed because inhibitory signals from HLA class I molecules prevail over activating signals. (B) Virus‐infected cells are characterized by altered expression of HLA class I molecules. This disrupts the inhibitory signals and allows activation of NK cells and subsequent lysis of the infected hepatocytes. NK‐mediated killing of infected hepatocytes is not efficient in viral hepatitides
Figure 10. Figure 10.

Cell‐cell interaction which can lead to activation of naïve T lymphocytes within the liver include contact with Kupffer cells (KC) (A), liver sinusoidal endothelial cells (LSEC) (B), or hepatocytes (C) (indicated by the respective arrows).
Figure 11. Figure 11.

Hepatic dendritic subsets in mouse.
Figure 12. Figure 12.

Cell‐Cell interaction of biliary epithelial cells (BECs) as antigen presenting cells, effector and regulatory T cells determines the outcome of BEC‐specific immune responses. In the case of primary biliary cirrhosis, an autoimmune cholestatic disease characterized by an immune response against mitochondrial antigens, the close interplay between proinflammatory (IFN‐γ, TGF‐β) and immunoregulatory (IL‐10) cytokines greatly influences the outcome of the antigen‐specific immune response, especially in the absence of regulatory T cells.
Figure 13. Figure 13.

Cytochrome P450 (CYP)2D6, CYP1A2, and CYP2D6 amino acid homology. The three cytochromes appear highly conserved but autoantibody responses against the one do not invoke cross‐reactive immunity targeting the other. Amino acid analysis has been performed using the T‐coffee software. Highlights of red, yellow, and green correspond to areas of good, average, and bad degree of homology; cons, conservation of amino acids (* indicate identical amino acids, “:” conserved and, and “.” semiconservative substitutions).
Figure 14. Figure 14.

Three‐dimensional‐prediction model of the three major linear epitopic regions of human cytochrome P450IID6 (CYP2D6). The B‐cell epitopes of anti‐CYP2D6 antibodies (also known as antiliver kidney microsomal type 1 antibodies (anti‐LKM1) (176) has been studied and the three main epitopic regions recognized span CYP2D6254‐271, CYP2D6193‐212, and CYP2D6321‐351 sequences, being targeted by more than 95% of the patients with CYP2D6 autoantibodies (97,206,265,272). The antigenicity of this area may in part been explained by the exposure of these sequences to the surface of the molecule as it is illustrated in Figure 7. Aminoacids of the autoepitopic regions are presented in the form of space fill in different colors and the remaining in a wire worm backbone (gray); in red and yellow are the dominant CYP2D6254‐271 and CYP2D6193‐212 epitopes. Prediction analysis anticipates that the epitopes are exposed on the surface of the molecule. The structure was analyzed with the Cn3D visualization tool.
Figure 15. Figure 15.

Hepatitis B and C viruses are considered noncytopathic. The prevailing notion is that the ultimate clearance of intracellular viruses by host's immune system largely depends on the endogenous efficiency for the destruction of the infected cells by components of the innate and the adaptive immune system (cytolytic control). It has become apparent that innate and adaptive immune cells can exert their antiviral effects through the effect induced by the production of IFN‐γ and other cytokines at the site of inflammation (the liver in the case of hepatotropic viruses). IFN‐γ can eradicate the pathogen from the viral‐infected hepatocytes in a noncytopathic manner. These cytokines exert immunomodulatory effects in an attempt to control the virus and regulate at least in part antigen processing and the induction, amplification, recruitment, and effector functions of the immune responses. This may explain why viruses establish evasion mechanisms based on the inhibition of the antiviral potential of cytokines
Figure 16. Figure 16.

The tetraspin CD81 is used by hepatitis C virus to entry the hepatocyte. Expression of CD81 by NK suppresses the induction of proinflammatory cytokines such as interferon‐γ and inhibits the cytotoxic capability of these cells allowing for the persistence of the virus. Other HCV coreceptors (for further details, see main text), expressed by cells of the innate immune system resident within the sinusoids, may participate in a similar fashion by facilitating the inability of the host to clear the virus.
Figure 17. Figure 17.

Kinetics of hepatitis B antigens and antibodies in serum from patients who successfully resolved the virus.
Figure 18. Figure 18.

After initial exposure to Hepatitis C virus (HCV), a significant proportion of the infected individuals will develop chronic infection, and subsequent cirrhosis. Chronic HCV infection can lead to the development of hepatocellular carcinoma. They will die from the complications of cirrhosis, liver failure and hepatocellular carcinoma. What determines the outcome of the original exposure to the virus is not clear. So far, most studies (see text for more) have concluded that those infected individuals who show a vigorous, persistent and multispecific immune response to HCV can clear the virus, while most of those with persistent infection mount an immune response that fails to clear the virus.


Figure 1.

Anatomical location and external appearance of the liver. The falciform ligament, on the surface of the diaphragm, splits the liver into right and left lobe. The anatomical relationship of the liver with organs such as the gallbladder, stomach, duodenum, and pancreas is illustrated.



Figure 2.

Cellular and extracellular composition of the liver.



Figure 3.

The morphological appearance of cells within the liver.



Figure 4.

The hepatic lobule is the structural unit of the liver. It consists of a hexagonal arrangement of hepatocyte plates with the central vein located in the center of the structure and the portal triads distributed at the vertices of the lobule. The portal triad consists of terminal branches of the portal vein and the hepatic artery and a bile duct.



Figure 5.

Illustration of the microanatomical localization of hepatocytes, liver sinusoidal endothelial cells, Kupffer cells, and hepatic stellate cells. The space of Disse separates hepatocytes from the liver sinusoids. The endothelium of liver sinusoids is discontinued (fenestrated) as the liver sinusoidal cells are perforated by several clusters of pores forming sieve plates (420). These cells act as scavenger cells and form a physical filtering barrier between the sinusoidal blood and plasma (115,356). Kupffer cells are resident macrophages that are attached to the layer of liver sinusoidal endothelial cells. The hepatic stellate cells are located in the subendothelial space of Disse and play vital role in fibrogenesis.



Figure 6.

Cells comprising the liver including hepatocytes (HEP), liver sinusoidal ensothelial cells (LSEC), Kupffer cells (KC), hepatic stellate cells (HSC), and lymphoid cell subpopulations. NK, natural killer; NKT, natural killer T cells; DC, dendritic cell; Treg, T‐regulatory cell.



Figure 7.

Distribution of cell subpopulations within intrahepatic lymphocytes. A very wide range of these cell populations are reported in the liver, differs amongst species, and also varies by age. It is of note, that the highest proportion of intrahepatic human lymphocytes consists of natural killer T cell (NKT) and NK cells, a finding that in general contrasts what is found in the peripheral blood. Thus, NK cells account for approximately 20% to 30% of the total number of liver‐resident lymphocytes compared to less than 5% seen in peripheral blood (104).



Figure 8.

Flow cytometric analysis of peripheral blood reflects the relative proportion of bright and low natural killer (NK) (CD36+) cells, natural killer T cell (NKT) (CD3+CD56+), and T cells (CD3+CD56−) in a representative donor. Bright and low NK cells can be seen. Vertical axis (CD56); horizontal axis CD3.



Figure 9.

Schematic illustration of natural killer (NK) cell receptors and killing of viral hepatitis infected cells. (A) Under normal conditions, noninfected cells are not killed because inhibitory signals from HLA class I molecules prevail over activating signals. (B) Virus‐infected cells are characterized by altered expression of HLA class I molecules. This disrupts the inhibitory signals and allows activation of NK cells and subsequent lysis of the infected hepatocytes. NK‐mediated killing of infected hepatocytes is not efficient in viral hepatitides



Figure 10.

Cell‐cell interaction which can lead to activation of naïve T lymphocytes within the liver include contact with Kupffer cells (KC) (A), liver sinusoidal endothelial cells (LSEC) (B), or hepatocytes (C) (indicated by the respective arrows).



Figure 11.

Hepatic dendritic subsets in mouse.



Figure 12.

Cell‐Cell interaction of biliary epithelial cells (BECs) as antigen presenting cells, effector and regulatory T cells determines the outcome of BEC‐specific immune responses. In the case of primary biliary cirrhosis, an autoimmune cholestatic disease characterized by an immune response against mitochondrial antigens, the close interplay between proinflammatory (IFN‐γ, TGF‐β) and immunoregulatory (IL‐10) cytokines greatly influences the outcome of the antigen‐specific immune response, especially in the absence of regulatory T cells.



Figure 13.

Cytochrome P450 (CYP)2D6, CYP1A2, and CYP2D6 amino acid homology. The three cytochromes appear highly conserved but autoantibody responses against the one do not invoke cross‐reactive immunity targeting the other. Amino acid analysis has been performed using the T‐coffee software. Highlights of red, yellow, and green correspond to areas of good, average, and bad degree of homology; cons, conservation of amino acids (* indicate identical amino acids, “:” conserved and, and “.” semiconservative substitutions).



Figure 14.

Three‐dimensional‐prediction model of the three major linear epitopic regions of human cytochrome P450IID6 (CYP2D6). The B‐cell epitopes of anti‐CYP2D6 antibodies (also known as antiliver kidney microsomal type 1 antibodies (anti‐LKM1) (176) has been studied and the three main epitopic regions recognized span CYP2D6254‐271, CYP2D6193‐212, and CYP2D6321‐351 sequences, being targeted by more than 95% of the patients with CYP2D6 autoantibodies (97,206,265,272). The antigenicity of this area may in part been explained by the exposure of these sequences to the surface of the molecule as it is illustrated in Figure 7. Aminoacids of the autoepitopic regions are presented in the form of space fill in different colors and the remaining in a wire worm backbone (gray); in red and yellow are the dominant CYP2D6254‐271 and CYP2D6193‐212 epitopes. Prediction analysis anticipates that the epitopes are exposed on the surface of the molecule. The structure was analyzed with the Cn3D visualization tool.



Figure 15.

Hepatitis B and C viruses are considered noncytopathic. The prevailing notion is that the ultimate clearance of intracellular viruses by host's immune system largely depends on the endogenous efficiency for the destruction of the infected cells by components of the innate and the adaptive immune system (cytolytic control). It has become apparent that innate and adaptive immune cells can exert their antiviral effects through the effect induced by the production of IFN‐γ and other cytokines at the site of inflammation (the liver in the case of hepatotropic viruses). IFN‐γ can eradicate the pathogen from the viral‐infected hepatocytes in a noncytopathic manner. These cytokines exert immunomodulatory effects in an attempt to control the virus and regulate at least in part antigen processing and the induction, amplification, recruitment, and effector functions of the immune responses. This may explain why viruses establish evasion mechanisms based on the inhibition of the antiviral potential of cytokines



Figure 16.

The tetraspin CD81 is used by hepatitis C virus to entry the hepatocyte. Expression of CD81 by NK suppresses the induction of proinflammatory cytokines such as interferon‐γ and inhibits the cytotoxic capability of these cells allowing for the persistence of the virus. Other HCV coreceptors (for further details, see main text), expressed by cells of the innate immune system resident within the sinusoids, may participate in a similar fashion by facilitating the inability of the host to clear the virus.



Figure 17.

Kinetics of hepatitis B antigens and antibodies in serum from patients who successfully resolved the virus.



Figure 18.

After initial exposure to Hepatitis C virus (HCV), a significant proportion of the infected individuals will develop chronic infection, and subsequent cirrhosis. Chronic HCV infection can lead to the development of hepatocellular carcinoma. They will die from the complications of cirrhosis, liver failure and hepatocellular carcinoma. What determines the outcome of the original exposure to the virus is not clear. So far, most studies (see text for more) have concluded that those infected individuals who show a vigorous, persistent and multispecific immune response to HCV can clear the virus, while most of those with persistent infection mount an immune response that fails to clear the virus.

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Article Title: Liver Immunology
 

How to Cite

Dimitrios P. Bogdanos, Bin Gao, M. Eric Gershwin. Liver Immunology. Compr Physiol 2013, 3: 567-598. doi: 10.1002/cphy.c120011