|
|
|
|
|
|
|
|
|
|
The liver: a model of organ-specific lymphocyte recruitment
The
liver is constantly exposed to gut-derived antigens that enter via the portal
vein, and it must modulate immune responses so that harmful pathogens are cleared
but necessary food antigens are ignored. The liver contains a large resident
and migratory population of lymphocytes and macrophages that provide immune
surveillance against foreign antigen. This population of cells can be rapidly
expanded in response to infection or injury by recruiting leukocytes from the
circulation, a process that is dependent on the ability of lymphocytes to recognise,
bind to and migrate across the endothelial cells that line the vasculature.
Lymphocytes can enter the liver at several sites: the vascular endothelium in
the portal tracts (comprising the hepatic artery, portal vein and bile ductule),
the sinusoids (through which the blood percolates past the hepatocytes) or the
central hepatic veins (through which the blood exits). The requirements and
physical conditions at each site vary and there is evidence that different combinations
of adhesion proteins are involved at these different sites. This article discusses
the expression and function of adhesion molecules within the liver and demonstrates
how specific populations of effector lymphocytes can be selectively recruited
to the liver.
Expert Reviews
in Molecular Medicine © Cambridge University Press ISSN 1462-3994
The liver is responsible for the uptake, metabolism, detoxification and storage of macromolecules such as food products, as well as the clearance of pathogens and foreign antigens entering the body by the gastrointestinal tract. Mechanisms have evolved to ensure that the liver is patrolled by populations of lymphocytes that can respond rapidly upon detection of foreign antigen. In order to review these processes, this article begins with a brief summary of the structure and function of the liver before discussing the general principles of lymphocyte recruitment and the specific factors involved in the context of the liver microvasculature. Finally, the clinical implications of lymphocyte recruitment and the developments that might aid the clinician treating liver disease are discussed.
The
microanatomy of the liver
The functional
requirements of the liver have resulted in it developing a unique dual blood
supply, with oxygenated blood entering through the hepatic artery and blood
from the gut, which is rich in nutrients and bacterial endotoxin, entering through
the hepatic portal vein. Blood from both of these vessels percolates through
the sinusoids, which provide a large vascular bed that maximises exchange of
materials prior to exit of blood via the hepatic vein. The portal vein provides
a route through which infectious organisms can enter the liver, and mechanisms
have evolved to allow rapid and selective immune responses within this tissue.
The liver is composed of different cell populations with distinct functions (Fig. 1). Hepatocytes constitute the major cell type in the parenchyma, and are arranged into cell plates separated by narrow sinusoids lined with endothelial cells. The lumen of these channels is narrow, and is penetrated by resident macrophages called Kupffer cells and liver-associated natural killer lymphocytes or Pit cells that sit on the lumenal surface of the sinusoidal endothelial cells. The sinusoids allow oxygenated, nutrient-rich blood arriving from the portal tract (which is composed of a branch of the hepatic artery, a portal vessel and a bile duct) to percolate slowly past the hepatocyte cell plates, allowing maximal exchange of materials before the blood leaves the liver through the central vein branches that run to the hepatic vein (Fig. 1). Thus, leukocytes entering the liver can arrive through vascular endothelial cells lining the portal vein in the portal tract, or through the microvascular endothelial cells that line the sinusoids or through the terminal hepatic veins (Ref. 1).
Leukocyte
subpopulations
Normal human
blood contains 7.5 ± 3.5 X
109 leukocytes per litre, ~20–45% (1.5–4.0
X 109)
of which are lymphocytes. Lymphocytes are mobile immune cells that are able
to circulate within blood vessels and the lymphatic system, and to migrate through
tissue. Among leukocytes, they possess the unique ability to recognise and respond
to specific foreign antigens. There are two major classes of lymphocytes: T
cells and B cells.
When appropriately activated, B cells secrete antibodies that mediate humoral immune responses by binding antigen and activating effector functions. T cells respond to foreign antigen on the surface of other cells and, on activation, can regulate immune responses either by killing infected target cells or by secreting cytokines that regulate the function of other effector cells. T cells circulate continuously between blood and tissues and can be divided into naive or virgin cells that have not been exposed to antigen and primed cells that have been activated by specific antigen presented in lymphoid tissue. The primed cells consist of effector cells (or fully activated cells), which home to inflammatory sites to mediate immune responses, and memory cells, which are long-lived cells that have reverted to a less-activated phenotype and provide both immunological memory and the ability to respond rapidly to subsequent encounters with an antigen. These cells exhibit different migratory pathways dictated by changes in their cell-surface expression of adhesion receptors. Primed T cells are largely excluded from lymph nodes and instead migrate into non-lymphoid tissue; here they are retained or return to the circulation via lymphatics (Ref. 2). Thus, T cells activated in the gut acquire adhesion receptors that confer the ability to bind to MAdCAM-1 (mucosal addressin cell adhesion molecule 1). This ensures that they will recirculate as memory cells through this organ, thereby increasing the likelihood that they will re-encounter their cognate antigen (see later).
Lymphocyte
recirculation under physiological conditions
For a lymphocyte
to be recruited from the circulation it must first recognise and then bind to
adhesion molecules expressed on endothelial cells. A multi-step model of leukocyte
adhesion to vascular endothelium has been described (Refs 3,
4, 5) and is broadly applicable in different
tissues, although the details of the signals involved differ. According to this
generally accepted model, ‘tethering’ or rolling receptors expressed
on endothelial cells capture free-flowing leukocytes (Fig.
2). These receptors can be either selectins (Ref. 6), which
interact with carbohydrate epitopes, or, less commonly, members of the immunoglobulin
(Ig) superfamily, which bind leukocyte integrins (Refs 7, 8,
9). Once captured, the leukocyte can receive activating messages
presented by endothelial cells in the form of chemokines (see later section),
which activate specific G-protein-coupled receptors on the leukocyte surface
(Refs 10, 11) and trigger a cascade of intracellular
signals that result in presentation of high-affinity integrin receptors on the
leukocyte surface. These activated integrins promote arrest and firm adhesion
by binding their Ig-family ligands on the endothelium (Refs 12,
13). In the presence of the appropriate migratory signals
the leukocyte will then migrate across the endothelium into tissue, where it
follows a hierarchy of chemotactic signals towards the focus of inflammation
(Fig. 2; Movie 1, HTML
version only).
Adhesion of lymphocytes to endothelial cells within different tissues appears to follow this generalised pattern under both physiological and pathological conditions. Investigation of these physiological processes is a particularly fertile area of current research and several excellent reviews of the field have been published (Refs 3, 14). Of particular interest is the phenomenon of lymphocyte subset-specific recirculation – the observation that subsets of memory lymphocytes display tissue-specific homing properties. In effect, this means that, for example, a T cell that has been activated in lymphoid tissue draining the skin, will subsequently return or ‘home’ to the skin, thus providing a mechanism for maximising the chance that a particular antigen-specific T cell will re-encounter its antigen (Ref. 15). This process is facilitated by tissue-specific expression of components of the adhesion cascade on both endothelial cells in the target tissue and on the lymphocyte. For example, T cells that home to mucosal sites express the integrin molecule a4b1; this permits them to recognise and specifically bind to an adhesion molecule known as MAdCAM-1, which is expressed almost exclusively on mucosal blood vessels (Refs 16, 17).
The selectivity of this process can be further enhanced both by tissue-specific expression of chemokines required to activate integrin-mediated adhesion and by chemotactic gradients that guide adherent leukocytes into tissue. For example, the chemokine TECK (thymus-expressed chemokine) is largely restricted to the small intestine, where it acts to recruit lymphocytes bearing its receptor CCR9 (Ref. 18); by contrast, TARC (thymus- and activation-regulated chemokine) is concentrated in the skin where it promotes the recruitment of CCR4-expressing T cells (Ref. 19). This means that only those lymphocytes that express receptors allowing them to respond to the local chemokine profile will be activated and recruited to a specific site.
Thus, the patterns of lymphocyte recirculation will depend on the combinations of adhesion molecules and chemokine receptors expressed on the leukocyte, as well as on the chemokines and adhesion molecules that form the unique ‘address’ of a target tissue. How this might occur in the liver is discussed below.
Chemokines
and their receptors: essential players in conferring tissue specificity
Chemokines belong
to a large family of small chemotactic cytokines that currently has at least
50 members (Refs 11, 20, 21,
22). Members of this superfamily are subclassified according
to the sequence of cysteine residues that form conserved disulphide bonds within
the protein structure. There are two main subfamilies, termed CC and CXC, and
two smaller subfamilies, termed CX3C and C (Table
1). Chemokines are widely expressed and are involved in many biological
processes ranging from development of the haematopoietic system to angiogenesis
and inflammation.
Chemokines exert their biological effects by binding to complementary G-protein-coupled receptors expressed on the target cells (Table 1; Ref. 23). Chemokines secreted at a particular site can be concentrated on vessels in that tissue by sequestration on glycosaminoglycans (Refs 24, 25) on endothelial cells. This lumenal presentation of chemokines provides a mechanism for the presentation of locally secreted chemokines from several sources to the circulating leukocyte. However, the expression of chemokine receptors varies between different lymphocyte subsets and is particularly tightly regulated on resting cells (Table 1). Thus, under non-inflammatory conditions only a small subpopulation of lymphocytes that arrive in an organ will be able to respond to the limited number of chemokines present at that location. However, with inflammation, there is an increase in the number of activated lymphocytes expressing a broader range of chemokine receptors as well as increased local chemokine secretion, resulting in a broadening of lymphocyte recruitment (Ref. 20).
Activation of chemokine receptors on adherent leukocytes leads to phosphoinositide 3-kinase and Rho-dependent signalling and activation of integrins, as well as cytoskeletal reorganisation. This results in firm adhesion and diapedesis (leukocyte shape change and locomotion across the endothelial surface) of the adherent leukocyte (Refs 26, 27).
Lymphocyte
recruitment to the liver
The liver contains
a large population of lymphocytes, including CD4+ and
CD8+ T cells, natural killer (NK) cells and natural killer
T (NKT) cells (Refs 28, 29). These populations
can be rapidly expanded during inflammatory liver disease or in response to
viral infection (Ref. 30). It has been suggested that most
lymphocytes in the normal liver are activated, terminally differentiated, T
cells that are removed from the circulation by the liver where they are destined
to die by apoptosis (Refs 31, 32, 33)
However, although this is partly true, the liver also contains multiple lymphocyte
cells that provide protection against pathogens and tumour cells, and many of
these cells migrate through the liver as part of the process of continuing immune
surveillance (Ref. 34). Although the mechanisms that govern
lymphocyte adhesion to the liver have yet to be described in full, the current
understanding of this process is described in the following sections.
Initial capture of lymphocytes
by hepatic endothelium
A minimal role for selectins
The hepatic sinusoids are lined by specialised endothelium that supports
lymphocyte adhesion and recruitment in a unique low-shear (i.e. low blood flow
velocity) environment (Refs 35, 36, 37).
Hepatic endothelium also has a distinct phenotype compared with endothelium
from other vascular beds (Table 2). Most strikingly,
sinusoidal endothelial cells in vivo fail to express selectins, even in the
presence of inflammation (Refs 38, 39),
and Wong et al. have used selectin-deficient mice to demonstrate that selectins
play a minimal role in leukocyte recruitment via the sinusoids in vivo (Ref.
40).
Other molecules that
mediate capture by sinusoidal endothelium
The lack of expression of these classical selectin ‘tethering’
or rolling receptors in the sinusoids, coupled with the low-shear environment
might indicate that primary capture receptors play only a minimal role at this
site. Thus, a lymphocyte moving slowly through the narrow, irregular sinusoids
might be able to interact directly by integrin-mediated interactions with vascular
cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 or intercellular
adhesion molecule 2 (ICAM-1 and ICAM-2, respectively) without the need for a
specialised capture phase. Furthermore, VCAM-1 itself can directly capture flowing
lymphocytes by supporting rolling adhesion, particularly under low-shear stress
(Refs 9, 16). VCAM-1-dependent rolling is
promoted at high concentrations of VCAM-1 (Ref. 9) and, although
hepatic endothelial cells express low basal levels of VCAM-1, these levels increase
considerably during inflammation (Refs 38, 41,
42) (Table 2). Moreover, VCAM-1
has been shown to mediate lymphocyte adhesion to hepatic endothelium in a tissue
binding assay (Ref. 43).
VAP-1
It is possible that molecules other than selectins or VCAM-1 act as
tethering receptors in the liver. One contender for this role is vascular adhesion
protein 1 (VAP-1), a homodimeric transmembrane protein that has been shown to
support lymphocyte adhesion to high endothelial vessels in lymph nodes (Refs
44, 45, 46, 47).
Interestingly, the human liver is one of the few extralymphoid sites where VAP-1
is constitutively expressed, suggesting that VAP-1 could act as a liver-specific
adhesion molecule. In support of this hypothesis several studies have demonstrated
that VAP-1 in human liver is functionally active and supports carbohydrate-dependent
adhesion. Because many of the tethering molecules use carbohydrate-dependent
binding, this latter observation suggests that VAP-1 might mediate capture.
Modelling of the structure of VAP-1 suggests that the sites for O- and N-linked
glycosylation are on the lumenal surface of the molecules, implying that the
carbohydrate chains will extend from the protein core into the vessel lumen,
where they would be ideally sited to capture flowing leukocytes (Refs 48,
49). Furthermore, VAP-1 can support adhesion to liver tissue
in a shear-dependent tissuesue ing adhesion assay (Refs 43,
50).
Further evidence for a specific role for VAP-1 in the liver comes from the recent observations that VAP-1, like many other endothelial adhesion proteins, can be released from endothelial cells in a soluble form (Ref. 51). Very high circulating levels of VAP-1 are present in patients with inflammatory liver disease but not in patients with other inflammatory conditions such as rheumatoid arthritis or inflammatory bowel disease (IBD) (Ref. 51). Moreover, soluble VAP-1 appears to be derived from the hepatic vascular bed (Ref. 52), further supporting the unique role of VAP-1 in the liver.
Does MAdCAM-1 have
a role in the liver?
MAdCAM-1 is generally considered to be a gut-specific adhesion molecule
and is absent from all other vascular beds, including the liver, under normal
conditions. However, recent studies suggest that it can be induced in the liver
under certain chronic inflammatory conditions that are associated with IBD (Refs
53, 54). Furthermore, when MAdCAM-1 is present
on hepatic endothelium it can support lymphocyte adhesion (Ref. 54).
This finding forms an interesting parallel with the observation that VAP-1 expression
can be induced in mucosal vessels in IBD (Ref. 45) and raises
the possibility that the gut and liver might share ‘addressins’ and
thus recirculation patterns of lymphocytes. However, the absence of MAdCAM-1
from the liver in most inflammatory conditions not associated with IBD argues
against this molecule acting as a liver- homing molecule under normal conditions.
Firm adhesion of lymphocytes
to hepatic endothelium
Do specific chemokines regulate recruitment to the liver? Some studies have
shown expression of many CC chemokines [macrophage inflammatory protein 1a
and b (MIP-1a and MIP-1b),
monocyte chemotactic protein 1 (MCP-1) and RANTES (‘regulated on activation,
normal T-cell expressed and secreted’)] and CXC chemokines [SexCkine (CXCL16/ligand
for the BONZO receptor), interferon g (IFN-g)-inducible
protein 10 (IP-10) and monokine induced by IFN-g
(MIG)] in the liver (Refs 55, 56). Furthermore,
other studies have shown that liver-infiltrating T cells possess the specific
receptors for these and other chemokines (Refs 15, 30,
56, 57). However there is little evidence
that any of the known chemokines provides a tissue-specific signal in the way
that TARC/CCR4 does for the skin (Ref. 19). Rather, these
chemokines appear to be involved in recruiting effector and memory T cells under
inflammatory conditions.
However, if normal immune surveillance of the non-inflamed liver is to occur, chemokines need to be constitutively expressed in the absence of inflammation. Some of the chemokines mentioned above have been detected in the non-inflamed liver and studies suggest that lymphocytes infiltrating non-diseased liver express similar chemokine receptors to those entering the inflamed liver, indicating that recruitment under physiological conditions is likely to be equivalent to a state of mild or controlled inflammation (Ref. 30). Other constitutively expressed chemokines include liver-expressed chemokine (LEC; Ref. 58) and the CC chemokine MIP-5, which is chemotactic for T cells and monocytes (Ref. 59).
As mentioned above, lymphocyte recruitment to the liver can occur at several sites, and there is evidence that the pattern of chemokine secretion in the liver will determine the distribution and severity of T-cell infiltration (Table 3). Indeed, whereas the CC chemokines MIP-1a and MIP-1b are expressed predominantly by vascular endothelium within portal tracts in both normal and inflamed liver, the CXC chemokines MIG, ITAC (interferon-inducible T-cell alpha chemoattractant) and IP-10 are preferentially expressed by sinusoidal endothelium (Ref. 30). Although MIG can be detected in normal liver, its expression is increased greatly in inflammation, and both ITAC and IP-10 are detected on sinusoidal endothelium in the inflamed liver. In vitro, IP-10 secretion by sinusoidal endothelial cells is stimulated by IFN-g and tumour necrosis factor a (TNF-a). Since IP-10 expression in vivo is associated with local production of TNF (Refs 30, 60, 61, 62), it seems likely that such CXC chemokines might play a specific role in the recruitment of T cells to the hepatic parenchyma via the sinusoids.
Liver-infiltrating T cells express much higher levels of CXCR3 (the receptor for IP-10 and MIG) and CCR5 (the receptor for MIP-1a, MIP-1b and RANTES) when compared with circulating memory T cells (Refs 30, 59). This provides further evidence that these receptors are involved in leukocyte adhesion in liver tissue.
The different patterns of chemokine expression within portal tracts and the liver parenchyma provide further evidence for specific pathways of lymphocyte recruitment to the liver (Refs 34, 63, 64). Portal inflammation is a frequent finding in many inflammatory liver diseases and the portal tract is the main site at which lymphocytes are found in the normal liver (Refs 34, 63, 64). The interaction between the CC chemokines MIP-1a and MIP-1b and their receptor CCR5 might be involved in the recruitment of T cells to portal areas. Because these CCR5 ligands are constitutively expressed on portal vessels, they provide a mechanism for the recruitment of CCR5high memory T cells to portal areas in normal liver during immune surveillance, as well as for recruiting T cells to portal areas in inflammatory liver diseases. Cases of chronic hepatitis in which inflammation is confined to portal areas are generally associated with a favourable outcome, whereas extension of the inflammatory process into the adjacent liver parenchyma is associated with destruction of periportal hepatocytes and progressive fibrosis. Very few lymphocytes are detected in the parenchyma of normal liver, and if CXCR3 ligands IP-10 and MIG on sinusoidal endothelium are required for the direct recruitment of CXCR3high T cells to the liver parenchyma, their absence in non-inflamed liver might exclude memory T cells from the parenchyma in non-inflamed conditions.
Firm adhesion and arrest
Once chemokine signals have been received by adherent lymphocytes, newly
expressed or activated integrin molecules can bind to their Ig counter-receptors
on the endothelium. To date, no liver-specific Ig molecule has been described,
and it appears that firm adhesion in this organ is mediated by ICAM-1 and VCAM-1
(see Table 2 and Table 3)
as is the case in other organs. ICAM-1 is constitutively expressed on both the
vascular and sinusoidal endothelial cells in the liver (Refs 65,
66, 67, 68) and is considerably
upregulated in inflammation (Ref. 42). Functional studies
in animal models and in vitro suggest that, out of ICAM-1 and ICAM-2, ICAM-1-dependent
mechanisms are the most important, particularly in recruitment via sinusoids
(Refs 40, 43).
Transendothelial migration
Although the molecules implicated in firm adhesion of lymphocytes to hepatic
vessels are not unique to the liver, the mechanisms underlying transendothelial
migration of adherent lymphocytes might differ from those described in other
tissues. In many tissues, lymphocyte transit through vascular endothelial junctions
appears to be aided by interactions with CD31 (Ref. 69). This
Ig-superfamily member is expressed on vascular endothelium and concentrated
at cell–cell junctions, and is also used by neutrophils to migrate into
the liver (Refs 69, 70, 71,
72, 73). However, hepatic sinusoidal endothelial
cells form a discontinuous barrier lacking tightly regulated junctions, and
they express much lower levels of CD31 than other vascular endothelium, suggesting
that factors other than CD31 might be involved in leukocyte transmigration in
the liver.
Migration through hepatic
endothelium and retention within liver tissue
The presence of lymphocytes in tissue and the establishment of an inflammatory
infiltrate depend upon not only the recruitment of cells but also their retention
and survival in the tissue. Once they have undergone endothelial transmigration,
leukocytes migrate through tissue in response to a hierarchy of chemotactic
signals until they reach their target cell (Refs 10, 74).
These chemokines might be secreted by other infiltrating cells and also by stromal
and epithelial cells within the tissue. In the liver, chemokines can be derived
from hepatocytes, cholangiocytes, Kupffer cells and stellate cells, and the
retention and presentation of these multiple chemokines in the proteoglycan-rich
extracellular matrix provides the substrate for migration through the tissue
(Refs 75, 76, 77). If
tissue cells express specific chemokines that are able to activate leukocyte
integrins they might also be able to regulate the retention of cells at specific
sites. An example of this type of retention is provided by cholangiocytes of
the bile duct. These cells are frequent targets for inflammatory damage in several
liver diseases, but in normal liver lymphocytes are found in association with
portal tract bile ducts where they presumably provide immune survelliance. Human
cholangiocytes express the chemokine SDF (stromal-cell-derived factor) constitutively
and can secrete many other chemokines when stimulated (Refs 78,
79). SDF in particular has the ability to activate leukocyte
integrins, suggesting that it could act to trigger adhesion of CXCR4 lymphocytes
to inflamed bile ducts that express the integrin ligands ICAM-1 and VCAM-1 at
high levels in inflammatory liver disease, and it might also have a role in
maintaining lymphocytes within portal tracts as part of the so-called portal-associated
liver tissue (Refs 79, 80, 81).
Conclusions
Major advances
in our understanding of the broad molecular regulation of lymphocyte–endothelial-cell
interactions have been made during the past ten years. However, relatively little
work has focused on tissue-specific recruitment mechanisms and, although it
is likely that generic mechanisms apply in different vascular beds, tissue-specific
factors will be crucial in regulating the control of local immune microenvironments.
The liver is particularly interesting in this respect given both its unique
immunological role and its distinct vascular supply. There is already good evidence
for the involvement of novel mechanisms in lymphocyte recruitment via the sinusoids,
and understanding the nature and function of the molecules involved in the liver
has important implications for understanding disease pathogenesis. Such mechanisms
might, for example, explain why some diseases show progressive inflammatory
damage whereas others resolve spontaneously. Understanding of the recruitment
of leukocytes might also aid the clinician treating liver disease. For example,
in the context of liver transplantation, it is likely that the endothelium within
vascularised allografts will behave like any other acute inflammatory tissue
and express molecules that promote lymphocyte recruitment during graft rejection.
In the future it might be possible to modify the endothelium within the graft
by genetic manipulation to prevent expression of molecules such as ICAM-1 and
VCAM-1 that appear to be critical for lymphocyte entry (Ref. 82).
The future development of drugs or biological agents that inhibit adhesion molecule
function might add to the armamentarium of immunosuppressive therapy. One problem
with the latter approaches is that targeting widely expressed adhesion molecules
will also inhibit lymphocyte recirculation to host tissues. If specific molecules
regulate lymphocyte recruitment to particular tissues the inhibition of these
molecules might deliver tissue-specific immunosuppression and leave generalised
lymphocyte recirculation intact. Potentially the most exciting approach is to
modulate the nature of the lymphocyte subsets recruited to the graft so that
harmful cells are excluded and beneficial subsets preferentially recruited.
For example, understanding the signals, that control the recruitment of T helper
1 (Th1) versus T helper 2 (Th2) cells to tissue raises the possibility of therapeutic
strategies in which the recruitment of Th1 cells is promoted when there is a
need to clear virus (e.g. in chronic hepatitis), or the recruitment of immunomodulatory
Th2 cells is promoted in inflammatory disorders where control of inflammation
is required.
Acknowledgements
and funding
We are grateful
to Dr Gerard Nash (Department of Physiology, Department of Medicine, University
of Birmingham, UK) and Dr Ken Simpson (Scottish Liver Transplant Unit, Royal
Infirmary, Edinburgh, UK) for peer review of this manuscript. Studies in our
laboratory were supported by The Wellcome Trust, The European Union, Pfizer
UK, and the MRC.
References
1 Takasaki,
S. and Hano, H. (2001) Three-dimensional observations of the human hepatic artery
(Arterial system in the liver). J Hepatol 34, 455-466, PubMed
2 Faint, J.M. et al. (2001) Memory T cells constitute a subset of the human CD8+CD45RA+ pool with distinct phenotypic and migratory characteristics. J Immunol 167, 212-220, PubMed
3 Butcher, E.C. and Picker, L.J. (1996) Lymphocyte homing and homeostasis. Science 272, 60-66, PubMed
4 Adams, D.H. and Shaw, S. (1994) Leucocyte-endothelial interactions and regulation of leucocyte migration. Lancet 343, 831-836, PubMed
5 Springer, T.A. (1994) Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 76, 301-314, PubMed
6 Tedder, T.F. et al. (1995) The selectins: vascular adhesion molecules. Faseb J 9, 866-873, PubMed
7 Alon, R. et al. (1995) The integrin VLA-4 supports tethering and rolling in flow on VCAM-1. J Cell Biol 128, 1243-1253, PubMed
8 Berlin, C. et al. (1995) alpha 4 integrins mediate lymphocyte attachment and rolling under physiologic flow. Cell 80, 413-422, PubMed
9 Lalor, P.F. et al. (1997) Association between receptor density, cellular activation, and transformation of adhesive behavior of flowing lymphocytes binding to VCAM-1. Eur J Immunol 27, 1422-1426, PubMed
10 Campbell, J.J. et al. (1996) Biology of chemokine and classical chemoattractant receptors: differential requirements for adhesion-triggering versus chemotactic responses in lymphoid cells. J Cell Biol 134, 255-266, PubMed
11 Luster, A.D. (1998) Chemokines – chemotactic cytokines that mediate inflammation. N Engl J Med 338, 436-445, PubMed
12 Campbell, J.J. and Butcher, E.C. (2000) Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. Curr Opin Immunol 12, 336-341, PubMed
13 Campbell, J.J. et al. (1998) Chemokines and the arrest of lymphocytes rolling under flow conditions. Science 279, 381-384, PubMed
14 Salmi, M. and Jalkanen, S. (1997) How do lymphocytes know where to go: current concepts and enigmas of lymphocyte homing. Adv Immunol 64, 139-218, PubMed
15 Warnock, R.A. et al. (2000) The role of chemokines in the microenvironmental control of T versus B cell arrest in Peyer’s patch high endothelial venules. J Exp Med 191, 77-88, PubMed
16 Berlin, C. et al. (1993) Alpha 4 beta 7 integrin mediates lymphocyte binding to the mucosal vascular addressin MAdCAM-1. Cell 74, 185-185, PubMed
17 Briskin, M. et al. (1997) Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue. Am J Pathol 151, 97-110, PubMed
18 Kunkel, E.J. et al. (2000) Lymphocyte CC chemokine receptor 9 and epithelial thymus-expressed chemokine (TECK) expression distinguish the small intestinal immune compartment: Epithelial expression of tissue-specific chemokines as an organizing principle in regional immunity. J Exp Med 192, 761-768, PubMed
19 Campbell, J.J. et al. (1999) The chemokine receptor CCR4 in vascular recognition by cutaneous but not intestinal memory T cells. Nature 400, 776-780, PubMed
20 Moser, B. and Loetscher, P. (2001) Lymphocyte traffic control by chemokines. Nat Immunol 2, 123-128, PubMed
21 Lukacs, N.W. et al. (1999) Chemokines: function, regulation and alteration of inflammatory responses. Chem Immunol 72, 102-120, PubMed
22 Murdoch, C. and Finn, A. (2000) Chemokine receptors and their role in inflammation and infectious diseases. Blood 95, 3032-3043, PubMed
23 Hancock, W.W. et al. (2000) Chemokines and their receptors in allograft rejection. Curr Opin Immunol 12, 511-516, PubMed
24 Tanaka, Y. et al. (1993) T-cell adhesion induced by proteoglycan-immobilized cytokine MIP-1 beta. Nature 361, 79-82, PubMed
25 Tanaka, Y. et al. (1998) Modulation of cytokine function by heparan sulfate proteoglycans: sophisticated models for the regulation of cellular responses to cytokines. Proc Assoc Am Physicians 110, 118-125, PubMed
26 Sotsios, Y. and Ward, S.G. (2000) Phosphoinositide 3-kinase: a key biochemical signal for cell migration in response to chemokines. Immunol Rev 177, 217-235, PubMed
27 Ward, S.G., Bacon, K. and Westwick, J. (1998) Chemokines and T lymphocytes: more than an attraction. Immunity 9, 1-11, PubMed
28 Doherty, D.G. et al. (1999) The human liver contains multiple populations of NK cells, T cells, and CD3+CD56+ natural T cells with distinct cytotoxic activities and Th1, Th2, and Th0 cytokine secretion patterns. J Immunol 163, 2314-2321, PubMed
29 Doherty, D.G. and O’Farrelly, C. (2000) Innate and adaptive lymphoid cells in the human liver. Immunol Rev 174, 5-20, PubMed
30 Shields, P.L. et al. (1999) Chemokine and chemokine receptor interactions provide a mechanism for selective T cell recruitment to specific liver compartments within hepatitis C-infected liver. J Immunol 163, 6236-6243, PubMed
31 Crispe, I.N. et al. (2000) The liver as a site of T-cell apoptosis: graveyard, or killing field? Immunol Rev 174, 47-62, PubMed
32 Mehal, W.Z., Juedes, A.E. and Crispe, I.N. (1999) Selective retention of activated CD8+ T cells by the normal liver. J Immunol 163, 3202-3210, PubMed
33 Hamann, A. et al. (2000) Activation induces rapid and profound alterations in the trafficking of T cells. Eur J Immunol 30, 3207-3218, PubMed
34 Salmi, M., Adams, D. and Jalkanen, S. (1998) Cell adhesion and migration. IV. Lymphocyte trafficking in the intestine and liver. Am J Physiol 274, G1-6, PubMed
35 Lalor, P.F. and Adams, D.H. (1999) Adhesion of lymphocytes to hepatic endothelium. Mol Pathol 52, 214-219, PubMed
36 Knolle, P.A. and Gerken, G. (2000) Local control of the immune response in the liver. Immunol Rev 174, 21-34, PubMed
37 Jaeschke, H. and Smith, C.W. (1997) Cell adhesion and migration. III. Leukocyte adhesion and transmigration in the liver vasculature. Am J Physiol 273, G1169-1173, PubMed
38 Steinhoff, G. et al. (1993) Expression patterns of leukocyte adhesion ligand molecules on human liver endothelia. Lack of ELAM-1 and CD62 inducibility on sinusoidal endothelia and distinct distribution of VCAM-1, ICAM-1, ICAM-2, and LFA- 3. Am J Pathol 142, 481-488, PubMed
39 Adams, D.H. et al. (1996) Expression of E-selectin and E-selectin ligands in human liver inflammation. Hepatology 24, 533-538, PubMed
40 Wong, J. et al. (1997) A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature. J Clin Invest 99, 2782-2790, PubMed
41 Steinhoff, G. et al. (1993) Intercellular immune adhesion molecules in human liver transplants: overview on expression patterns of leukocyte receptor and ligand molecules. Hepatology 18, 440-453, PubMed
42 Adams, D.H. et al. (1994) Endothelial activation and circulating vascular adhesion molecules in alcoholic liver disease. Hepatology 19, 588-594, PubMed
43 Yoong, K.F. et al. (1998) Vascular adhesion protein-1 and ICAM-1 support the adhesion of tumor- infiltrating lymphocytes to tumor endothelium in human hepatocellular carcinoma. J Immunol 160, 3978-3988, PubMed
44 Salmi, M. and Jalkanen, S. (1992) A 90-kilodalton endothelial cell molecule mediating lymphocyte binding in humans. Science 257, 1407-1409, PubMed
45 Salmi, M., Kalimo, K. and Jalkanen, S. (1993) Induction and function of vascular adhesion protein-1 at sites of inflammation. J Exp Med 178, 2255-2260, PubMed
46 Salmi, M. and Jalkanen, S. (1996) Human vascular adhesion protein 1 (VAP-1) is a unique sialoglycoprotein that mediates carbohydrate-dependent binding of lymphocytes to endothelial cells. J Exp Med 183, 569-579, PubMed
47 Salmi, M. et al. (1997) Vascular adhesion protein 1 (VAP-1) mediates lymphocyte subtype- specific, selectin-independent recognition of vascular endothelium in human lymph nodes. J Exp Med 186, 589-600, PubMed
48 Salminen, T.A. et al. (1999) Production, crystallization and preliminary X-ray analysis of the human integrin alpha1 I domain. Acta Crystallogr D Biol Crystallogr 55, 1365-1367, PubMed
49 Salminen, T.A. et al. (1998) Structural model of the catalytic domain of an enzyme with cell adhesion activity: human vascular adhesion protein-1 (HVAP-1) D4 domain is an amine oxidase. Protein Eng 11, 1195-1204, PubMed
50 McNab, G. et al. (1996) Vascular adhesion protein 1 mediates binding of T cells to human hepatic endothelium. Gastroenterology 110, 522-528, PubMed
51 Kurkijarvi, R. et al. (1998) Circulating form of human vascular adhesion protein-1 (VAP-1): increased serum levels in inflammatory liver diseases. J Immunol 161, 1549-1557, PubMed
52 Kurkijarvi, R. et al. (2000) Circulating soluble vascular adhesion protein 1 accounts for the increased serum monoamine oxidase activity in chronic liver disease. Gastroenterology 119, 1096-1103, PubMed
53 Hillan, K.J. et al. (1999) Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease. Liver 19, 509-518, PubMed
54 Grant, A.J. et al. (2001) MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease). Hepatology 33, 1065-1072, PubMed
55 Maltby, J. et al. (1996) Chemokine levels in human liver homogenates: associations between GRO alpha and histopathological evidence of alcoholic hepatitis. Hepatology 24, 1156-1160, PubMed
56 Yoong, K.F. et al. (1999) Expression and function of CXC and CC chemokines in human malignant liver tumors: a role for human monokine induced by gamma-interferon in lymphocyte recruitment to hepatocellular carcinoma. Hepatology 30, 100-111, PubMed
57 Kim, C.H. et al. (2001) Bonzo/CXCR6 expression defines type 1-polarized T-cell subsets with extralymphoid tissue homing potential. J Clin Invest 107, 595-601., PubMed
58 Shoudai, K. et al. (1998) Isolation of cDNA encoding a novel human CC chemokine NCC-4/LEC. Biochim Biophys Acta 1396, 273-277, PubMed
59 Coulin, F. et al. (1997) Characterisation of macrophage inflammatory protein-5/human CC cytokine- 2, a member of the macrophage-inflammatory-protein family of chemokines. Eur J Biochem 248, 507-515, PubMed
60 Narumi, S. et al. (1997) Expression of IFN-inducible protein-10 in chronic hepatitis. J Immunol 158, 5536-5544, PubMed
61 Narumi, S. et al. (2000) TNF-alpha is a potent inducer for IFN-inducible protein-10 in hepatocytes and unaffected by GM-CSF in vivo, in contrast to IL-1beta and IFN-gamma. Cytokine 12, 1007-1016, PubMed
62 Tamaru, M. et al. (2000) Liver-infiltrating T lymphocytes are attracted selectively by IFN- inducible protein-10. Cytokine 12, 299-308, PubMed
63 Adams, D.H. (1996) Lymphocyte-endothelial cell interactions in hepatic inflammation. Hepatogastroenterology 43, 32-43, PubMed
64 Hubscher, S.G. (1998) Histological grading and staging in chronic hepatitis: clinical applications and problems. J Hepatol 29, 1015-1022, PubMed
65 Scoazec, J.Y. et al. (1994) Expression of cytokine-dependent adhesion molecules in postreperfusion biopsy specimens of liver allografts. Gastroenterology 107, 1094-1102, PubMed
66 Scoazec, J.Y. and Feldmann, G. (1994) The cell adhesion molecules of hepatic sinusoidal endothelial cells. J Hepatol 20, 296-300, PubMed
67 Scoazec, J.Y. et al. (1995) Focal nodular hyperplasia of the liver: composition of the extracellular matrix and expression of cell-cell and cell-matrix adhesion molecules. Hum Pathol 26, 1114-1125, PubMed
68 Scoazec, J.Y. et al. (1994) Endothelial cell heterogeneity in the normal human liver acinus: in situ immunohistochemical demonstration. Liver 14, 113-123, PubMed
69 Bird, I.N. et al. (1993) Studies of lymphocyte transendothelial migration: analysis of migrated cell phenotypes with regard to CD31 (PECAM-1), CD45RA and CD45RO. Immunology 80, 553-560, PubMed
70 Berman, M.E., Xie, Y. and Muller, W.A. (1996) Roles of platelet/endothelial cell adhesion molecule-1 (PECAM-1, CD31) in natural killer cell transendothelial migration and beta 2 integrin activation. J Immunol 156, 1515-1524, PubMed
71 Bogen, S.A. et al. (1992) Association of murine CD31 with transmigrating lymphocytes following antigenic stimulation. Am J Pathol 141, 843-854, PubMed
72 Muller, W.A. (1995) The role of PECAM-1 (CD31) in leukocyte emigration: studies in vitro and in vivo. J Leukoc Biol 57, 523-528, PubMed
73 Tanaka, Y. et al. (1992) CD31/PECAM-1 is an adhesion amplifier on unique T cell subsets (abstract). FASEB J 6, A1125
74 Butcher, E.C. et al. (1999) Lymphocyte trafficking and regional immunity. Adv Immunol 72, 209-253, PubMed
75 Ohkubo, K. et al. (1998) Induction of CINC (interleukin-8) production in rat liver by non- parenchymal cells. J Gastroenterol Hepatol 13, 696-702, PubMed
76 Rowell, D.L. et al. (1997) Human hepatocytes express an array of proinflammatory cytokines after agonist stimulation or bacterial invasion. Am J Physiol 273, G322-332, PubMed
77 Wang, H. et al. (1999) Differential expression and regulation of chemokines JE, KC, and IP-10 gene in primary cultured murine hepatocytes. J Cell Physiol 181, 361-370, PubMed
78 Morland, C.M. et al. (1997) Promotion of leukocyte transendothelial cell migration by chemokines derived from human biliary epithelial cells in vitro. Proceedings of the Association of American Physicians 109, 372-382
79 Goddard, S. et al. (2001) Differential expression of chemokines and chemokine receptors in rejecting human liver transplants. Transplantation 72, 1957-67
80 Buckley, C.D. et al. (2000) Persistent induction of the chemokine receptor CXCR4 by TGF-beta 1 on synovial T cells contributes to their accumulation within the rheumatoid synovium. J Immunol 165, 3423-3429, PubMed
81 Yoneyama, H. et al. (2001) Regulation by chemokines of circulating dendritic cell precursors, and the formation of portal tract-associated lymphoid tissue, in a granulomatous liver disease. J Exp Med 193, 35-49, PubMed
82 Dragun, D. and Haller, H. (1999) Diapedesis of leukocytes: antisense oligonucleotides for rescue. Exp Nephrol 7, 185-192, PubMed
|
Further resources, reading and contacts Sherlock, S. and Dooley, J., eds (1993) Diseases of the Liver and Biliary System (9th edn), Blackwell Scientific Publications, Oxford, UK O’Grady, J.G., Lake, J.R. and Howdle, P.D., eds (2000) Comprehensive Clinical Hepatology (1st edn), Harcourt Publishers, Sidcup, Kent, UK The Canadian Liver Foundation provides patient support and research funding. The British Association for the Study of the Liver promotes research and education activities of scientists and clinicians interested in liver physiology and pathophysiology. The website of the British Transplantation Society provides useful information on transplantation for clinicians and patients. The website of the European Liver Transplant Registry provides data on all transplant operations carried out in Europe. The website of the Transplant Pathology Internet Services provides a useful online liver pathology textbook. A website of the Department of Biomedical Engineering, University of Virginia, Charlottesville, USA, provides a useful summary of leukocyte adhesion and migration.
|
|
Features
associated with this article Figures Figure 1. Diagrammatic representation of the ultrastructure of the human liver Web, Reprint/PDF version Figure 2. Adhesion of leukocytes to endothelial cells under conditions
of blood flow Tables Table 2. Hepatic
expression of endothelial cell adhesion molecules Table 3. Molecules
implicated in lymphocyte adhesion to endothelial and epithelial cells
within different compartments of the human liver Movie |