Carlo Selmi

M. Eric Gershwin

Mauro Podda

PubMed

C. Selmi

M. Podda

M. E. Gershwin

AIR Universita degli studi di Milano

Old and rising stars in the lymphoid liver

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INTRODUCTION
Old and rising stars in the lymphoid liver
Carlo Selmi & Mauro Podda & M. Eric Gershwin
Received: 11 May 2009 /Accepted: 12 June 2009 /Published online: 15 July 2009
# The Author(s) 2009. This article is published with open access at Springerlink.com
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 repre-
sented 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 transplanta-
tion 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 patho-
gens. Furthermore, the mechanisms by which hepatitis
viruses cause a liver injury also involve the liver immuno-
logical milieu which ultimately constitutes per se an
important element in the pathogenesis of chronic inflam-
matory 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
C. Selmi :M. Podda
Department of Internal Medicine,
IRCCS Istituto Clinico Humanitas, University of Milan,
Milan, Italy
C. Selmi :M. E. Gershwin (*)
Division of Rheumatology, Allergy, and Clinical Immunology,
University of California at Davis School of Medicine,
451 Health Sciences Drive, Suite 6510,
Davis, CA 95616, USA
e-mail: megershwin@ucdavis.edu
Semin Immunopathol (2009) 31:279–282
DOI 10.1007/s00281-009-0175-2
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 develop-
ments [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 conjunc-
tion 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]
Prevalence [47] Expenditures
(US$ million) [47]
Liver transplantations
(% of total) [48]
Adult disease
Alcoholic liver disease 7.4% 26,400 18%a
Non-alcoholic fatty liver disease 20% – 11%b
Hepatitis C 1.8% 1,300 29%a
Hepatitis B 4.9% – 2%
Primary biliary cirrhosis 0.04% 115 9%c
Primary sclerosing cholangitis 0.004% – –
Autoimmune hepatitis 2%
Hepatocellular carcinoma 0.004% 1,300 13%
Pediatric disease
Biliary atresia – – 3%
Wilson disease 0.003% – –
Table 1 Prevalence, yearly
economic cost, and liver trans-
plantation of adult and pediatric
liver diseases in the US
Of note, several data are
currently missing due to the lack
of solid population-based
studies while in some cases
multiple etiologies coexist
a Patients with mixed etiology
(alcohol and HCV) are included
in both categories
b Cases include also cryptogenic
cirrhosis
c The percentage refers to cases
of cholestatic liver disease
(PBC and PSC)
280 Semin Immunopathol (2009) 31:279–282
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.
Open Access This article is distributed under the terms of the Crea-
tive Commons Attribution Noncommercial License which permits any
noncommercial use, distribution, and reproduction in any medium,
provided the original author(s) and source are credited.
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282 Semin Immunopathol (2009) 31:279–282


Selmi, Carlo

Podda, Mauro

Gershwin, M. Eric

eScholarship - University of California

UC DavisUC Davis Previously Published WorksTitleOld and rising stars in the lymphoid liverPermalinkhttps://escholarship.org/uc/item/5cd937krJournalSeminars in Immunopathology, 31(3)ISSN1863-2300AuthorsSelmi, CarloPodda, MauroGershwin, M. EricPublication Date2009-09-01DOI10.1007/s00281-009-0175-2 Peer reviewedeScholarship.org Powered by the California Digital LibraryUniversity of CaliforniaINTRODUCTIONOld and rising stars in the lymphoid liverCarlo Selmi & Mauro Podda & M. Eric GershwinReceived: 11 May 2009 /Accepted: 12 June 2009 /Published online: 15 July 2009# The Author(s) 2009. This article is published with open access at Springerlink.comRegardless of the etiology or pathogenesis, chronic liverdisease remains a major health issue worldwide and asignificant cause of morbidity and mortality particularlywhen its common outcomes, i.e., liver cirrhosis and primaryliver cancer, are observed. As a result, liver diseasescumulatively account for enormous costs, as well repre-sented by health-state utilities and subsequent cost-utilityanalysis [1]. Table 1 illustrates the available data on diseaseprevalence, economic costs, and need for liver transplanta-tion in the US. From a clinical standpoint, the majority ofconditions remain asymptomatic until advanced stages areestablished. From a pathogenetic standpoint, all chronicliver diseases manifest one common trait, that is theinvolvement of the immune system, and over the pastdecade the role of the liver as a critical immunologicalcenter has been established thus overcoming the classicalview of this organ as a mere target of the autoimmune orimmune-mediated injury.Indeed, the liver is a unique lymphoid organ being thecrossroad at which the majority of antigens enter theorganism. The liver is located between the gastrointestinalsystem and the systemic venous circulation, and everyminute approximately one third of the total blood volumepasses through the liver delivering over 100 millionlymphocytes in 1 day. As a result, the liver must providean accurate balance between generating tolerance to self aswell as to non-pathogenic molecules and microorganisms,and producing an appropriate immune response to patho-gens. Furthermore, the mechanisms by which hepatitisviruses cause a liver injury also involve the liver immuno-logical milieu which ultimately constitutes per se animportant element in the pathogenesis of chronic inflam-matory liver diseases, either infectious or autoimmune. Thehistory of the existence of mechanisms capable to induceliver tolerance well illustrates this scenario starting with thefirst data on the tolerogenic properties of the liver in 1969when the liver allograft acceptance across an MHCmismatch in the pig was reported [2]. Following theseearlier studies, numerous authors have suggested over thedecades possible mechanisms underlying hepatic toleranceto intestinally derived antigens or the mechanisms of virus-induced liver injury, yet none of the hypotheses has gainedsufficient support for universal acceptance.As previously mentioned, the lymphoid liver is expectedto act in two separate yet closely correlated ways as the firstline of defense against invasion by intestinally derivedinfectious agents or as a site of tolerance. This questionbecomes particularly relevant in clinical conditions whereinthe machinery does not function properly, as in cases ofchronic hepatitis virus infections in which an effectorimmune response is directed unsuccessfully against virallyinfected hepatocytes, or in liver autoimmunity whereintolerance to self molecules is inefficient. The present issueof the Seminars in Immunopathology will attempt toprovide a comprehensive overview of what we currentlyknow on these complex mechanisms. This issue will notdiscuss the enormous field of the immunology of viralhepatitis; this has been a difficult editorial choice and doesnot imply a lack of interest in the field. Indeed, new andexciting observations in chronic viral hepatitis C have beenC. Selmi :M. PoddaDepartment of Internal Medicine,IRCCS Istituto Clinico Humanitas, University of Milan,Milan, ItalyC. Selmi :M. E. Gershwin (*)Division of Rheumatology, Allergy, and Clinical Immunology,University of California at Davis School of Medicine,451 Health Sciences Drive, Suite 6510,Davis, CA 95616, USAe-mail: megershwin@ucdavis.eduSemin Immunopathol (2009) 31:279–282DOI 10.1007/s00281-009-0175-2most recently reported in both disease mechanisms [3–6]and therapeutic applications [7, 8] while data on hepatitis Bvirus also appear promising for novel therapeutic develop-ments [9–11]. On the other hand, we have decided todedicate the first part of the issue to general issues such asliver microanatomy and architecture. The role of specificcell populations such as the bile duct and the hematopoieticstem cells will be also discussed in dedicated articles toreflect the importance of these cells supported by the mostrecent data [12–22]. Further, the development of fibrosis isthe common outcome of all chronic liver diseases and Dr.Marra and colleagues will illustrate the current knowledgeon the role of mononuclear immune cells in determininginflammation and fibrosis, as suggested by the most recentliterature [23]. The second part of this issue will bededicated to specific clinical entities, including biliaryatresia, chronic autoimmune hepatitis, primary sclerosingcholangitis, and primary biliary cirrhosis. Finally, a specialcontribution will be dedicated to the condition that is expectedto constitute the major chronic liver disease challenge in thenext future, that is, non-alcoholic fatty liver disease and itsprogressing subtype steatohepatitis. Of note, the pathogenesisof this condition has been subject to a tremendous researcheffort over the past months [6, 23–39] and we foresee thatsuch interest will increase in the future.Some outlines from the present days are to provide asnapshot of the several peculiarities of the lymphoid liver.As an example, the liver exhibits unique cytoarchitecturalfeatures; there is consignment of proliferating T cells toactivation-induced cell death; and there are placatingactivities in the liver of cell populations such as NKT,Treg, and others. Considering effector activities, there isinput from elements of the innate system, neutralizingantibodies, and the well-studied CD4+ helper and CD8+cytolytic T cell populations that normally provide sturdyresponses to intruders ranging from hepatitis viruses tomulticellular parasites. However, the necessarily fineimmunotuning in the liver may constitute a risk foroccurrence of autoreactivity or the occupancy of liver cellsby hepatitis B and C viruses and metabolic disturbancessuch as lipid deposition that alter the normal liver cellstructure to provoke profound cytokine and chemokineactivation.The example of primary biliary cirrhosis may wellillustrate these concepts as data on the disease pathogenesisare becoming more convincing [40]. The presence of serumautoantibodies and autoreactive T and B cells, in conjunc-tion with the coexistence of other autoimmune diseases,implies an autoimmune pathogenesis for primary biliarycirrhosis while experimental data suggest an important rolefor the bile duct cell in mediating or facilitating theautoimmune injury. However, the mechanisms for diseaseonset remain to be determined with putative contributorssuch as innate immunity or microRNA being studied onlyrecently [41–43].Another important issue in liver immunology is relatedto liver transplantation, the only therapeutic option in end-stage liver diseases. Clinical practice has witnessed severaladvancements in this field, yet legislation and regulationshave often failed to keep the pace with the advances inhealthcare technology [44]. Current estimates suggest thatover 15,000 people in the US await for a liver transplantand this number has been steadily increasing over the pastfew years while it has been estimated that nearly 4,000patients are added to the list each month. Conversely, organdonation and transplantation rates recently decreased in theUS as 27,958 organ transplant procedures were performedin 2008 (declined by 1.42% from 2007) according toUNOS data. The lymphoid liver is obviously central to theissue of liver transplantation in terms of donor liver andrecipient graft tolerance. Two major examples come fromthe recent observation of occult hepatitis B infection [45]Prevalence [47] Expenditures(US$ million) [47]Liver transplantations(% of total) [48]Adult diseaseAlcoholic liver disease 7.4% 26,400 18%aNon-alcoholic fatty liver disease 20% – 11%bHepatitis C 1.8% 1,300 29%aHepatitis B 4.9% – 2%Primary biliary cirrhosis 0.04% 115 9%cPrimary sclerosing cholangitis 0.004% – –Autoimmune hepatitis 2%Hepatocellular carcinoma 0.004% 1,300 13%Pediatric diseaseBiliary atresia – – 3%Wilson disease 0.003% – –Table 1 Prevalence, yearlyeconomic cost, and liver trans-plantation of adult and pediatricliver diseases in the USOf note, several data arecurrently missing due to the lackof solid population-basedstudies while in some casesmultiple etiologies coexista Patients with mixed etiology(alcohol and HCV) are includedin both categoriesb Cases include also cryptogeniccirrhosisc The percentage refers to casesof cholestatic liver disease(PBC and PSC)280 Semin Immunopathol (2009) 31:279–282which has significantly mined the concept of ‘healthy’organ donor and the most recent data suggesting that liverimmunology is critical to graft tolerance or rejection [46].Indeed, we hope that the answers to the numerous openquestions in liver immunology will be closer following thisSeminars issue.Open Access This article is distributed under the terms of the Crea-tive Commons Attribution Noncommercial License which permits anynoncommercial use, distribution, and reproduction in any medium,provided the original author(s) and source are credited.References1. McLernon DJ, Dillon J, Donnan PT (2008) Health-state utilities inliver disease: a systematic review. Med Decis Mak 28:582–5922. Calne RY, Sells RA, Pena JR, Davis DR, Millard PR, HerbertsonBM, Binns RM, Davies DA (1969) Induction of immunologicaltolerance by porcine liver allografts. Nature 223:472–4763. 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 toTRAIL-induced apoptosis in a caspase 9-dependent manner. JImmunol 181:4926–49354. Lukens JR, Cruise MW, Lassen MG, Hahn YS (2008) Blockade ofPD-1/B7-H1 interaction restores effector CD8+ T cell responses in ahepatitis C virus core murine model. J Immunol 180:4875–48845. Saito T, Owen DM, Jiang F, Marcotrigiano J, Gale M Jr (2008)Innate immunity induced by composition-dependent RIG-I recog-nition of hepatitis C virus RNA. Nature 454:523–5276. 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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.

Adipocyte/macrophage fatty acidbinding proteins contribute to metabolic deterioration through actions in both macrophages and adipocytes in mice.

Aggravation of viral hepatitis by platelet-derived serotonin.

Autoantibodies to glutathione S-transferase theta 1 in patients with primary sclerosing cholangitis and other autoimmune diseases.

Blockade of PD-1/B7-H1 interaction restores effector CD8+ Tcell responses in a hepatitis C virus core murine model.

Burden of liver disease in the United States: summary of a workshop.

ChREBP, but not LXRs, is required for the induction of glucose-regulated genes in mouse liver.

Combination of ursodeoxycholic acid and glucocorticoids upregulates the AE2 alternate promoter in human liver cells.

Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance: lessons from genetically engineered mice.

Crispe IN (2008) E2F4 modulates differentiation and gene expression in hematopoietic progenitor cells during commitment to the lymphoid lineage.

Endothelial cell O-glycan deficiency causes blood/lymphatic misconnections and consequent fatty liver disease in mice.

Fox RI et al (2008) Broadly neutralizing antibodies protect against hepatitis C virus quasispecies challenge.

From fatty streak to fatty liver: 33 years of joint publications in the JCI.

Generation and regeneration of cells of the liver and pancreas.

Genome-wide hepatitis C virus amino acid covariance networks can predict response to antiviral therapy in humans.

Health-state utilities in liver disease: a systematic review. Med Decis Mak

Hedgehog signaling in biliary fibrosis.

Hepatic IL-17 responses in human and murine primary biliary cirrhosis.

IL-4R alpha expression by bone marrow-derived cells is necessary and sufficient for host protection against acute schistosomiasis.

Induction of immunological tolerance by porcine liver allografts.

Inhibition of apolipoprotein B100 secretion by lipid-induced hepatic endoplasmic reticulum stress in rodents.

Innate immunity induced by composition-dependent RIG-I recognition of hepatitis C virus RNA.

Insulin sensitivity: modulation by nutrients and inflammation.

Integration of metabolism and inflammation by lipid-activated nuclear receptors.

IR et al (2008) CD4 T-cell autoreactivity to the mitochondrial autoantigen PDC-E2 in AMA-negative primary biliary cirrhosis.

Lymphocytes support oval cell-dependent liver regeneration.

Metabolism: food alert.

MicroRNA15a modulates expression of the cellcycle regulator Cdc25A and affects hepatic cystogenesis in a rat model of polycystic kidney disease.

Monosodium glutamate (MSG): a villain and promoter of liver inflammation and dysplasia.

Novel role of IL-13 in fibrosis induced by nonalcoholic steatohepatitis and its amelioration byIL-13R-directed cytotoxinin a rat model.

Occult hepatitis B virus in liver tissue of individuals without hepatic disease.

OdinJA(2008)Anti-CD16autoantibodiesanddelayedphagocytosis of apoptotic cells in primary biliary cirrhosis.

Overindulgence and metabolic syndrome: is FoxO1 a missing link?

Physiology. Unfolding lipid metabolism.

Plunkett FJ et al (2008) Functional skewing of the global CD8 Tcell population in chronic hepatitis B virus infection.

Polyautoimmunity and familial autoimmunity in systemic sclerosis.

PPARalpha activation is essential for HCV core protein-induced hepatic steatosis and hepatocellular carcinoma in mice.

Regulation of hepatic lipogenesis by the transcription factor XBP1.

Schmitt-Graeff A et al (2008) Hepatitis C virus infection sensitizes human hepatocytes to TRAIL-induced apoptosis in a caspase 9-dependent manner.

The level of hepatitis B virus replication is not affected by protein ISG15 modification but is reduced by inhibition of UBP43 (USP18) expression.

TRIF and IRF-3 binding to the TNF promoter results in macrophage TNF dysregulation and steatosis induced by chronic ethanol.

Unique aspects of rejection and tolerance in liver transplantation.

Upper intestinal lipids trigger a gut–brain–liver axis to regulate glucose production.

Vandongen HM et al (2008) Hedgehog signaling regulates epithelial–mesenchymal transition during biliary fibrosis in rodents and humans.

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Old and rising stars in the lymphoid liver

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