Regardless of the etiology or pathogenesis, chronic liver disease remains a major health issue worldwide and a significant cause of morbidity and mortality particularly when its common outcomes, i.e., liver cirrhosis and primary liver cancer, are observed. As a result, liver diseases cumulatively account for enormous costs, as well represented by health-state utilities and subsequent cost-utility analysis [1]. Table 1 illustrates the available data on disease prevalence, economic costs, and need for liver transplantation in the US. From a clinical standpoint, the majority of conditions remain asymptomatic until advanced stages are established. From a pathogenetic standpoint, all chronic liver diseases manifest one common trait, that is the involvement of the immune system, and over the past decade the role of the liver as a critical immunological center has been established thus overcoming the classical view of this organ as a mere target of the autoimmune or immune-mediated injury.
Indeed, the liver is a unique lymphoid organ being the crossroad at which the majority of antigens enter the organism. The liver is located between the gastrointestinal system and the systemic venous circulation, and every minute approximately one third of the total blood volume passes through the liver delivering over 100 million lymphocytes in 1 day. As a result, the liver must provide an accurate balance between generating tolerance to self as well as to non-pathogenic molecules and microorganisms, and producing an appropriate immune response to pathogens. Furthermore, the mechanisms by which hepatitis viruses cause a liver injury also involve the liver immunological milieu which ultimately constitutes per se an important element in the pathogenesis of chronic inflammatory liver diseases, either infectious or autoimmune. The history of the existence of mechanisms capable to induce liver tolerance well illustrates this scenario starting with the first data on the tolerogenic properties of the liver in 1969 when the liver allograft acceptance across an MHC mismatch in the pig was reported [2]. Following these earlier studies, numerous authors have suggested over the decades possible mechanisms underlying hepatic tolerance to intestinally derived antigens or the mechanisms of virus-induced liver injury, yet none of the hypotheses has gained sufficient support for universal acceptance.
As previously mentioned, the lymphoid liver is expected to act in two separate yet closely correlated ways as the first line of defense against invasion by intestinally derived infectious agents or as a site of tolerance. This question becomes particularly relevant in clinical conditions wherein the machinery does not function properly, as in cases of chronic hepatitis virus infections in which an effector immune response is directed unsuccessfully against virally infected hepatocytes, or in liver autoimmunity wherein tolerance to self molecules is inefficient. The present issue of the Seminars in Immunopathology will attempt to provide a comprehensive overview of what we currently know on these complex mechanisms. This issue will not discuss the enormous field of the immunology of viral hepatitis; this has been a difficult editorial choice and does not imply a lack of interest in the field. Indeed, new and exciting observations in chronic viral hepatitis C have been most recently reported in both disease mechanisms [3–6] and therapeutic applications [7, 8] while data on hepatitis B virus also appear promising for novel therapeutic developments [9–11]. On the other hand, we have decided to dedicate the first part of the issue to general issues such as liver microanatomy and architecture. The role of specific cell populations such as the bile duct and the hematopoietic stem cells will be also discussed in dedicated articles to reflect the importance of these cells supported by the most recent data [12–22]. Further, the development of fibrosis is the common outcome of all chronic liver diseases and Dr. Marra and colleagues will illustrate the current knowledge on the role of mononuclear immune cells in determining inflammation and fibrosis, as suggested by the most recent literature [23]. The second part of this issue will be dedicated to specific clinical entities, including biliary atresia, chronic autoimmune hepatitis, primary sclerosing cholangitis, and primary biliary cirrhosis. Finally, a special contribution will be dedicated to the condition that is expected to constitute the major chronic liver disease challenge in the next future, that is, non-alcoholic fatty liver disease and its progressing subtype steatohepatitis. Of note, the pathogenesis of this condition has been subject to a tremendous research effort over the past months [6, 23–39] and we foresee that such interest will increase in the future.
Some outlines from the present days are to provide a snapshot of the several peculiarities of the lymphoid liver. As an example, the liver exhibits unique cytoarchitectural features; there is consignment of proliferating T cells to activation-induced cell death; and there are placating activities in the liver of cell populations such as NKT, Treg, and others. Considering effector activities, there is input from elements of the innate system, neutralizing antibodies, and the well-studied CD4+ helper and CD8+ cytolytic T cell populations that normally provide sturdy responses to intruders ranging from hepatitis viruses to multicellular parasites. However, the necessarily fine immunotuning in the liver may constitute a risk for occurrence of autoreactivity or the occupancy of liver cells by hepatitis B and C viruses and metabolic disturbances such as lipid deposition that alter the normal liver cell structure to provoke profound cytokine and chemokine activation.
The example of primary biliary cirrhosis may well illustrate these concepts as data on the disease pathogenesis are becoming more convincing [40]. The presence of serum autoantibodies and autoreactive T and B cells, in conjunction with the coexistence of other autoimmune diseases, implies an autoimmune pathogenesis for primary biliary cirrhosis while experimental data suggest an important role for the bile duct cell in mediating or facilitating the autoimmune injury. However, the mechanisms for disease onset remain to be determined with putative contributors such as innate immunity or microRNA being studied only recently [41–43].
Another important issue in liver immunology is related to liver transplantation, the only therapeutic option in end-stage liver diseases. Clinical practice has witnessed several advancements in this field, yet legislation and regulations have often failed to keep the pace with the advances in healthcare technology [44]. Current estimates suggest that over 15,000 people in the US await for a liver transplant and this number has been steadily increasing over the past few years while it has been estimated that nearly 4,000 patients are added to the list each month. Conversely, organ donation and transplantation rates recently decreased in the US as 27,958 organ transplant procedures were performed in 2008 (declined by 1.42% from 2007) according to UNOS data. The lymphoid liver is obviously central to the issue of liver transplantation in terms of donor liver and recipient graft tolerance. Two major examples come from the recent observation of occult hepatitis B infection [45] which has significantly mined the concept of ‘healthy’ organ donor and the most recent data suggesting that liver immunology is critical to graft tolerance or rejection [46]. Indeed, we hope that the answers to the numerous open questions in liver immunology will be closer following this Seminars issue.
References
McLernon DJ, Dillon J, Donnan PT (2008) Health-state utilities in liver disease: a systematic review. Med Decis Mak 28:582–592
Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, Herbertson BM, Binns RM, Davies DA (1969) Induction of immunological tolerance by porcine liver allografts. Nature 223:472–476
Lan L, Gorke S, Rau SJ, Zeisel MB, Hildt E, Himmelsbach K, Carvajal-Yepes M, Huber R, Wakita T, Schmitt-Graeff A et al (2008) Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner. J Immunol 181:4926–4935
Lukens JR, Cruise MW, Lassen MG, Hahn YS (2008) Blockade of PD-1/B7-H1 interaction restores effector CD8+ T cell responses in a hepatitis C virus core murine model. J Immunol 180:4875–4884
Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr (2008) Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA. Nature 454:523–527
Tanaka N, Moriya K, Kiyosawa K, Koike K, Gonzalez FJ, Aoyama T (2008) PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice. J Clin Invest 118:683–694
Aurora R, Donlin MJ, Cannon NA, Tavis JE (2009) Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans. J Clin Invest 119:225–236
Law M, Maruyama T, Lewis J, Giang E, Tarr AW, Stamataki Z, Gastaminza P, Chisari FV, Jones IM, Fox RI et al (2008) Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge. Nat Med 14:25–27
Das A, Hoare M, Davies N, Lopes AR, Dunn C, Kennedy PT, Alexander G, Finney H, Lawson A, Plunkett FJ et al (2008) Functional skewing of the global CD8 T cell population in chronic hepatitis B virus infection. J Exp Med 205:2111–2124
Kim JH, Luo JK, Zhang DE (2008) The level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression. J Immunol 181:6467–6472
Lang PA, Contaldo C, Georgiev P, El-Badry AM, Recher M, Kurrer M, Cervantes-Barragan L, Ludewig B, Calzascia T, Bolinger B et al (2008) Aggravation of viral hepatitis by platelet-derived serotonin. Nat Med 14:756–761
Herbert DR, Orekov T, Perkins C, Rothenberg ME, Finkelman FD (2008) IL-4R alpha expression by bone marrow-derived cells is necessary and sufficient for host protection against acute schistosomiasis. J Immunol 180:4948–4955
Enos ME, Bancos SA, Bushnell T, Crispe IN (2008) E2F4 modulates differentiation and gene expression in hematopoietic progenitor cells during commitment to the lymphoid lineage. J Immunol 180:3699–3707
Zaret KS, Grompe M (2008) Generation and regeneration of cells of the liver and pancreas. Science 322:1490–1494
Allina J, Stanca CM, Garber J, Hu B, Sautes-Fridman C, Bach N, Odin JA (2008) Anti-CD16 autoantibodies and delayed phagocytosis of apoptotic cells in primary biliary cirrhosis. J Autoimmun 30:238–245
Greenbaum LE (2008) Hedgehog signaling in biliary fibrosis. J Clin Invest 118:3263–3265
Lan RY, Salunga TL, Tsuneyama K, Lian ZX, Yang GX, Hsu W, Moritoki Y, Ansari AA, Kemper C, Price J et al (2009) Hepatic IL-17 responses in human and murine primary biliary cirrhosis. J Autoimmun 32:43–51
Lee SO, Masyuk T, Splinter P, Banales JM, Masyuk A, Stroope A, Larusso N (2008) MicroRNA15a modulates expression of the cell-cycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease. J Clin Invest 118:3714–3724
Omenetti A, Porrello A, Jung Y, Yang L, Popov Y, Choi SS, Witek RP, Alpini G, Venter J, Vandongen HM et al (2008) Hedgehog signaling regulates epithelial–mesenchymal transition during biliary fibrosis in rodents and humans. J Clin Invest 118:3331–3342
Sasaki M, Ikeda H, Nakanuma Y (2008) Activation of ATM signaling pathway is involved in oxidative stress-induced expression of mito-inhibitory p21WAF1/Cip1 in chronic non-suppurative destructive cholangitis in primary biliary cirrhosis: an immunohistochemical study. J Autoimmun 31:73–78
Strick-Marchand H, Masse GX, Weiss MC, Di Santo JP (2008) Lymphocytes support oval cell-dependent liver regeneration. J Immunol 181:2764–2771
Arenas F, Hervias I, Uriz M, Joplin R, Prieto J, Medina JF (2008) Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells. J Clin Invest 118:695–709
Shimamura T, Fujisawa T, Husain SR, Kioi M, Nakajima A, Puri RK (2008) Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration by IL-13R-directed cytotoxin in a rat model. J Immunol 181:4656–4665
Bensinger SJ, Tontonoz P (2008) Integration of metabolism and inflammation by lipid-activated nuclear receptors. Nature 454:470–477
Denechaud PD, Bossard P, Lobaccaro JM, Millatt L, Staels B, Girard J, Postic C (2008) ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver. J Clin Invest 118:956–964
Fu J, Gerhardt H, McDaniel JM, Xia B, Liu X, Ivanciu L, Ny A, Hermans K, Silasi-Mansat R, McGee S et al (2008) Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice. J Clin Invest 118:3725–3737
Furuhashi M, Fucho R, Gorgun CZ, Tuncman G, Cao H, Hotamisligil GS (2008) Adipocyte/macrophage fatty acid-binding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice. J Clin Invest 118:2640–2650
Goldstein JL, Brown MS (2008) From fatty streak to fatty liver: 33 years of joint publications in the JCI. J Clin Invest 118:1220–1222
Horton JD (2008) Physiology. Unfolding lipid metabolism. Science 320:1433–1434
Lee AH, Scapa EF, Cohen DE, Glimcher LH (2008) Regulation of hepatic lipogenesis by the transcription factor XBP1. Science 320:1492–1496
Nakanishi Y, Tsuneyama K, Fujimoto M, Salunga TL, Nomoto K, An JL, Takano Y, Iizuka S, Nagata M, Suzuki W et al (2008) Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia. J Autoimmun 30:42–50
Osei-Hyiaman D, Liu J, Zhou L, Godlewski G, Harvey-White J, Jeong WI, Batkai S, Marsicano G, Lutz B, Buettner C et al (2008) Hepatic CB1 receptor is required for development of diet-induced steatosis, dyslipidemia, and insulin and leptin resistance in mice. J Clin Invest 118:3160–3169
Ota T, Gayet C, Ginsberg HN (2008) Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents. J Clin Invest 118:316–332
Postic C, Girard J (2008) Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice. J Clin Invest 118:829–838
Schenk S, Saberi M, Olefsky JM (2008) Insulin sensitivity: modulation by nutrients and inflammation. J Clin Invest 118:2992–3002
Sparks JD, Sparks CE (2008) Overindulgence and metabolic syndrome: is FoxO1 a missing link? J Clin Invest 118:2012–2015
Thaler JP, Cummings DE (2008) Metabolism: food alert. Nature 452:941–942
Wang PY, Caspi L, Lam CK, Chari M, Li X, Light PE, Gutierrez-Juarez R, Ang M, Schwartz GJ, Lam TK (2008) Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production. Nature 452:1012–1016
Zhao XJ, Dong Q, Bindas J, Piganelli JD, Magill A, Reiser J, Kolls JK (2008) TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol. J Immunol 181:3049–3056
Shimoda S, Miyakawa H, Nakamura M, Ishibashi H, Kikuchi K, Kita H, Niiro H, Arinobu Y, Ono N, Mackay IR et al (2008) CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis. J Autoimmun 31:110–115
Hudson M, Rojas-Villarraga A, Coral-Alvarado P, Lopez-Guzman S, Mantilla RD, Chalem P, Baron M, Anaya JM (2008) Polyautoimmunity and familial autoimmunity in systemic sclerosis. J Autoimmun 31:156–159
Ardesjo B, Hansson CM, Bruder CE, Rorsman F, Betterle C, Dumanski JP, Kampe O, Ekwall O (2008) Autoantibodies to glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases. J Autoimmun 30:273–282
Joyce S, Van Kaer L (2008) Invariant natural killer T cells trigger adaptive lymphocytes to churn up bile. Cell Host Microbe 3:275–277
Rhee J, Kern B, Cooper J, Freeman RB (2009) Organ donation. Semin Liver Dis 29:19–39
Raimondo G, Navarra G, Mondello S, Costantino L, Colloredo G, Cucinotta E, Di Vita G, Scisca C, Squadrito G, Pollicino T (2008) Occult hepatitis B virus in liver tissue of individuals without hepatic disease. J Hepatol 48:743–746
Knechtle SJ, Kwun J (2009) Unique aspects of rejection and tolerance in liver transplantation. Semin Liver Dis 29:91–101
Kim WR, Brown RS Jr, Terrault NA, El-Serag H (2002) Burden of liver disease in the United States: summary of a workshop. Hepatology 36:227–242
Berg CL, Steffick DE, Edwards EB, Heimbach JK, Magee JC, Washburn WK, Mazariegos GV (2009) Liver and intestine transplantation in the United States 1998–2007. Am J Transplant 9:907–931
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Open Access This is an open access article distributed under the terms of the Creative Commons Attribution Noncommercial License (https://creativecommons.org/licenses/by-nc/2.0), which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
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Selmi, C., Podda, M. & Gershwin, M.E. Old and rising stars in the lymphoid liver. Semin Immunopathol 31, 279–282 (2009). https://doi.org/10.1007/s00281-009-0175-2
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DOI: https://doi.org/10.1007/s00281-009-0175-2