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Return to sender: Lymphocyte trafficking mechanisms as contributors to primary sclerosing cholangitis

  • Manon de Krijger
    Affiliations
    Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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  • Manon E. Wildenberg
    Affiliations
    Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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  • Wouter J. de Jonge
    Affiliations
    Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Department of Surgery, University of Bonn, Bonn, Germany
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  • Cyriel Y. Ponsioen
    Correspondence
    Corresponding author. Address: Department of Gastroenterology and Hepatology, Amsterdam UMC, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. Tel.: +31 205666012.
    Affiliations
    Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands
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      Summary

      Primary sclerosing cholangitis (PSC) is an inflammatory disease of the biliary tree, characterised by stricturing bile duct disease and progression to liver fibrosis. The pathophysiology of PSC is still unknown. The concurrence with inflammatory bowel disease (IBD) in about 70% of cases has led to the hypothesis that gut-homing lymphocytes aberrantly traffic to the liver, contributing to disease pathogenesis in patients with both PSC and IBD (PSC-IBD). The discovery of mutual trafficking pathways of lymphocytes to target tissues, and expression of gut-specific adhesion molecules and chemokines in the liver has pointed in this direction. There is now increasing interest in using drugs that intervene with these trafficking pathways (e.g. vedolizumab, etrolizumab) for the treatment of PSC-IBD. In this review we discuss what is currently known about the immunological interactions between the gut and the liver in concomitant PSC and IBD, as well as potential therapeutic options for intervening in these mechanisms.

      Keywords

      Introduction

      Primary sclerosing cholangitis (PSC) is a rare, chronic liver disease, characterized by inflammation of the intra- and extrahepatic bile ducts, leading to destruction of the biliary epithelium and end-stage liver disease. There is an urgent clinical unmet need for treatment options for PSC as there is still no medical therapy with a proven effect on disease progression.
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      • Chapman R.W.
      New therapeutic strategies for primary sclerosing cholangitis.
      PSC is strongly associated with inflammatory bowel disease (IBD), giving rise to some intriguing and still unexplained questions regarding these disease entities. Approximately 70% of patients with PSC have or will develop concurrent IBD, of which the majority, about 80%, will suffer from ulcerative colitis (UC).
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      Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.
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      Patient age, sex and inflammatory bowel disease phenotype associate with course of primary sclerosing cholangitis.
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      Inflammatory bowel disease with primary sclerosing cholangitis: a Danish population-based cohort study 1977–2011..
      Conversely, the presence of PSC among the total population of patients with IBD is rare, with a prevalence varying between 1.7–3.8%.
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      It has been proposed that IBD in PSC represents a distinct phenotype, characterised by a higher frequency of pancolitis with involvement of the right colon and a relatively mild disease course, and a higher occurrence of pouchitis after colectomy, compared to IBD without PSC.
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      Primary sclerosing cholangitis is associated with a distinct phenotype of inflammatory bowel disease.
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      Pathologic features of ulcerative colitis in patients with primary sclerosing cholangitis: a case-control study.
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      Outcomes after ileal pouch anal anastomosis in patients with primary sclerosing cholangitis.
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      • Zinsmeister A.R.
      • et al.
      PSC-IBD: a unique form of inflammatory bowel disease associated with primary sclerosing cholangitis.
      This assumption is strengthened by genome-wide association studies showing a higher genetic correlation between UC and Crohn’s disease (CD) than between either of them and PSC-IBD.
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      • Mucha S.
      • Folseraas T.
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      • Melum E.
      • et al.
      Genome-wide association study of primary sclerosing cholangitis identifies new risk loci and quantifies the genetic relationship with inflammatory bowel disease.
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      • Bethune J.
      • Han B.
      • et al.
      Analysis of five chronic inflammatory diseases identifies 27 new associations and highlights disease-specific patterns at shared loci.
      Various clinical observations have led to the assumption that there is an interaction between the gut and the liver in patients with PSC. As for concomitant IBD, in the majority of cases clinical symptoms of IBD precede the diagnosis of PSC. However, IBD can also develop after PSC diagnosis or even years after liver transplantation.
      • Boonstra K.
      • Weersma R.K.
      • van Erpecum K.J.
      • Rauws E.A.
      • Spanier B.W.
      • Poen A.C.
      • et al.
      Population-based epidemiology, malignancy risk, and outcome of primary sclerosing cholangitis.
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      • Janse M.
      • Blokzijl H.
      • Weersma R.K.
      Distinctive inflammatory bowel disease phenotype in primary sclerosing cholangitis.
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      • Bruining D.H.
      • Lightner A.L.
      • Rosen C.B.
      • et al.
      Natural history of established and de novo inflammatory bowel disease after liver transplantation for primary sclerosing cholangitis.
      It is possible that microscopic abnormalities of IBD are already present at diagnosis of PSC, but do not result in clinical symptoms. Supporting this, Jorgensen et al. showed in a cohort of 184 patients with PSC that 89% had histopathological abnormalities compatible with IBD, whereas only 47.5% had endoscopic signs of inflammation.
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      • Grzyb K.
      • Lundin K.E.
      • Clausen O.P.
      • Aamodt G.
      • Schrumpf E.
      • et al.
      Inflammatory bowel disease in patients with primary sclerosing cholangitis: clinical characterization in liver transplanted and nontransplanted patients.
      In terms of disease activity, the correlation between IBD and the disease course of PSC is less clear. Patients with severe colitis tend to have less severe PSC in terms of need for liver transplantation, although a protective effect of IBD medication on progression to end-stage liver disease cannot be ruled out.
      • Navaneethan U.
      • Venkatesh P.G.
      • Lashner B.A.
      • Shen B.
      • Kiran R.P.
      The impact of ulcerative colitis on the long-term outcome of patients with primary sclerosing cholangitis.
      Furthermore, it has been reported that colectomy prior to the diagnosis of PSC confers a decreased risk of liver transplantation or death.
      • Nordenvall C.
      • Olen O.
      • Nilsson P.J.
      • von Seth E.
      • Ekbom A.
      • Bottai M.
      • et al.
      Colectomy prior to diagnosis of primary sclerosing cholangitis is associated with improved prognosis in a nationwide cohort study of 2594 PSC-IBD patients.
      Similarly, patients with PSC-UC and a more progressive form of PSC requiring liver transplantation seem to have a milder form of UC, less frequently requiring colectomy.
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      • Venkatesh P.G.
      • Mukewar S.
      • Lashner B.A.
      • Remzi F.H.
      • McCullough A.J.
      • et al.
      Progressive primary sclerosing cholangitis requiring liver transplantation is associated with reduced need for colectomy in patients with ulcerative colitis.
      • Marelli L.
      • Xirouchakis E.
      • Kalambokis G.
      • Cholongitas E.
      • Hamilton M.I.
      • Burroughs A.K.
      Does the severity of primary sclerosing cholangitis influence the clinical course of associated ulcerative colitis?.
      PSC is strongly associated with IBD, giving rise to the hypothesis that mature gut-homing lymphocytes aberrantly traffic to the liver to induce inflammation.
      Several hypotheses regarding the pathogenesis of PSC have been proposed, such as the toxic bile acid hypothesis and the hypothesis that translocation of microbiota from the gut to the liver triggers an aberrant cholangiocytic response.
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      • Beutler C.
      • Pico A.H.
      • Shibolet O.
      • Pratt D.S.
      • Pascher A.
      • et al.
      Enhanced innate immune responsiveness and intolerance to intestinal endotoxins in human biliary epithelial cells contributes to chronic cholangitis.
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      • Wagner M.
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      • Kaser A.
      • Tilg H.
      • et al.
      Regurgitation of bile acids from leaky bile ducts causes sclerosing cholangitis in Mdr2 (Abcb4) knockout mice.
      The prominent association between PSC and IBD has fuelled another hypothesis, which states that long-lived memory T lymphocytes expressing gut-homing markers, migrate into the liver via aberrantly expressed mucosal adhesion molecules and chemokines in the liver.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      The aim of this review is to present an overview of the current knowledge regarding lymphocyte recruitment and homing in the human liver and intestine in PSC-IBD.

      Lymphocyte homing to the gut and liver

      Recruitment of lymphocytes

      In 1990, Butcher and Springer described the lymphocyte homing paradigm.
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      • Terstappen L.W.
      • Rott L.S.
      • Streeter P.R.
      • Stein H.
      • Butcher E.C.
      Differential expression of homing-associated adhesion molecules by T cell subsets in man.
      • Springer T.A.
      Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm.
      After leaving the primary lymphoid organs, naïve lymphocytes circulate through secondary lymphoid tissues such as peripheral lymph nodes, spleen and gut-associated lymphoid tissues (GALTs). To trigger an immune response, these naïve T and B lymphocytes are primed in the secondary lymphoid tissues via interaction with antigen-presenting cells, dendritic cells (DCs) and follicular dendritic cells, respectively.
      • von Andrian U.H.
      • Mempel T.R.
      Homing and cellular traffic in lymph nodes.
      Subsequent expression of tissue-specific homing molecules, enables them to migrate back to their target tissues as mature effector T lymphocytes that can proliferate locally. Recruitment of lymphocytes from the blood into lymph nodes takes place via high endothelial venules. In order to be recruited from the circulation into tissue, a multistep process of lymphocyte-endothelial recognition has to take place.
      • Habtezion A.
      • Nguyen L.P.
      • Hadeiba H.
      • Butcher E.C.
      Leukocyte trafficking to the small intestine and colon.
      Fast flowing lymphocytes have to undergo a process of tethering, rolling and adhesion to the endothelium. For the initial step of tethering and rolling, interactions between selectins on the lymphocyte and glycosylated ligands on the endothelium are required.
      • Springer T.A.
      Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm.
      Together with chemokines, this will trigger lymphocyte activation and firm attachment to the endothelium via interactions between integrins and adhesion molecules such as vascular cell-adhesion molecule 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) on endothelial cells.
      • von Andrian U.H.
      • Mempel T.R.
      Homing and cellular traffic in lymph nodes.
      Chemoattractants can then mediate the transmigration of the cells through the endothelium into the specific microenvironments.

      Recruitment of lymphocytes to the gut

      In the gut, a system of tissue-specific lymphocyte trafficking plays a key role in protecting the intestine from invading pathogens. The general concept in the field is that naïve lymphocytes recirculate through organised lymphoid tissue (e.g. Peyer’s patches and mesenteric lymph nodes), where they become activated. These activated effector cells will then seed the lamina propria. One of the key players in this lymphocyte trafficking mechanism is mucosal vascular addressin cell-adhesion molecule 1 (MAdCAM-1). MAdCAM-1 is an adhesion molecule, widely expressed in high endothelial venules of the gut-associated lymphoid tissue.
      • Briskin M.
      • Winsor-Hines D.
      • Shyjan A.
      • Cochran N.
      • Bloom S.
      • Wilson J.
      • et al.
      Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue.
      Pathogens penetrating the mucosal barrier are recognised by dendritic cells or microfold cells in the epithelial layer. High endothelial venules in gut-associated lymphoid tissue express CC-chemokine ligand 21 (CCL21), thereby attracting circulating naïve lymphocytes expressing its receptor, CC-chemokine receptor 7 (CCR7), as well as L-selectin (Fig. 1.1).
      • Trivedi P.J.
      • Adams D.H.
      Gut – liver immunity.
      • Jaensson E.
      • Uronen-Hansson H.
      • Pabst O.
      • Eksteen B.
      • Tian J.
      • Coombes J.L.
      • et al.
      Small intestinal CD103+ dendritic cells display unique functional properties that are conserved between mice and humans.
      Some DCs from the gut can produce retinal dehydrogenase-2, the rate-limiting enzyme for the conversion of retinal to retinoic acid (vitamin A metabolite). Retinoic acid is required to activate nuclear receptors that induce transcription of the genes that encode the gut-homing receptors integrin α4β7 and CCR9 on T lymphocytes.
      • Iwata M.
      • Hirakiyama A.
      • Eshima Y.
      • Kagechika H.
      • Kato C.
      • Song S.Y.
      Retinoic acid imprints gut-homing specificity on T cells.
      As a result, interaction between the antigen-expressing DCs and naïve lymphocytes results in a reduction in the expression of CCR7 and L-selectin, and upregulation of expression of integrin α4β7 and CCR9 (Fig. 1.2). These so-called gut-primed effector T cells (Teff) can enter the lamina propria through the interaction of integrin α4β7 with MAdCAM-1, which is expressed on endothelial cells (Fig. 1.3, Table 1).
      Figure thumbnail gr1
      Fig. 1Overview of aberrant homing in the gut and liver in primary sclerosing cholangitis. Naïve lymphocytes expressing CC-chemokine receptor 7 (CCR7) as well as L-selectin enter the gut-associated lymphoid tissue. Dendritic cells (DCs) which recognised pathogens penetrating the mucosal barrier, will migrate to the draining lymphoid structures to present their antigen to these naïve T cells (1). Via their production of retinal dehydrogenase to transform retinol into retinoic acid, the naïve T cells are imprinted with the gut-homing receptors integrin α4β7 and CC- chemokine receptor 9 (CCR9) (2). These so-called gut-primed T cells will re-circulate into the lamina propria via venules by binding to MAdCAM-1 on endothelium of the blood vessels as well as via interaction between CCR9 and CCL25 (3). Several chemoattractants (e.g. CCL25, CXCL12) can direct the lymphocytes into the lamina propria (4). In primary sclerosing cholangitis, it is hypothesised that gut-primed memory T cells expressing α4β7 and CCR9 could migrate to the liver via aberrantly expressed MAdCAM-1 and CCL25 by portal endothelial cells (5). Expression of CCL28 by biliary epithelial cells could provide a signal to attract CCR10 positive T cells to the portal tracts. Additionally, chemokines including CXCL12 could play a role in retaining CCR9+ lymphocytes around bile ducts. IL-17 stimulates CCL20 and CXCL9-11 expression by biliary epithelium, leading to recruitment of CCR6+ CXCR3+ Th17 cells to the bile ducts (6).
      Table 1Receptor-ligand pairs.
      Adhesion moleculeLigand
      MAdCAM-1α4β7, α4β1, L-selectin
      VAP-1 (AOC3)Siglec-9, Siglec-10
      E-cadherinαEβ7, α2β1
      ICAM-1αLβ2
      VCAM-1α4β1, α4β7
      Chemokine receptorLigand
      CCR6CCL20 (MIP-3α)
      CCR7CCL19, CCL21
      CCR9CCL25 (TECK)
      CCR10CCL27, CCL28
      CXCR4CXCL12 (SDF-1)
      Receptor-ligand pairs and alternative names. AOC3, amine oxidase copper containing 3; MIP-3α, macrophage inflammatory protein-3; TECK, thymus-expressed chemokine.
      In IBD, the concept of uncontrolled recruitment of lymphocytes is generally accepted and multiple drugs intervening in this trafficking pathway are currently being used. Although MAdCAM-1 is constitutively expressed in the small intestine and colon of patients with IBD, as well as healthy controls, during active inflammation, MAdCAM-1 expression is increased.
      • Briskin M.
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      • Shyjan A.
      • Cochran N.
      • Bloom S.
      • Wilson J.
      • et al.
      Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue.
      • Arihiro S.
      • Ohtani H.
      • Suzuki M.
      • Murata M.
      • Ejima C.
      • Oki M.
      • et al.
      Differential expression of mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in ulcerative colitis and Crohn's disease.
      Also VCAM-1, the endothelial ligand for both α4β1 and α4β7 (Table 1), is upregulated in IBD, supporting lymphocyte recruitment both to the small bowel and colon.
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      • King N.
      • Lobb R.
      • Benjamin C.
      • Podolsky D.K.
      Expression of vascular adhesion molecules in inflammatory bowel disease.
      The response triggered by interfering with α4β7-dependent homing is not yet fully clarified. In a humanised mouse model of CD, inhibition of α4β7-dependent homing of Teff cells was bypassed by homing to the ileum through integrin α4β1.
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      • Fischer A.
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      • et al.
      The alpha4beta1 homing pathway is essential for ileal homing of crohn's disease effector T cells in vivo.
      In a recent study, a role for innate immunity was proposed, consisting of a switch to wound-healing macrophages after inhibition of α4β7.
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      Vedolizumab is associated with changes in innate rather than adaptive immunity in patients with inflammatory bowel disease.
      As there are substantial anatomical and physiological distinctions between the small and large intestine, their immune compartments also contain differences. The small intestine contains a larger proportion of intra-epithelial lymphocytes compared to the colon, whereas proportions of Th1 and Th2 cells do not differ between the colon and ileum.
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      • Agace W.W.
      Regional specialization within the intestinal immune system.
      Furthermore, T cells with a regulatory phenotype (Tregs) seem to be more abundant in colonic tissue, at least in mice.
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      Regulatory T cells expressing interleukin 10 develop from Foxp3+ and Foxp3- precursor cells in the absence of interleukin 10.
      Since the majority of patients with PSC suffer from concomitant colonic disease, it may be of particular interest whether colonic homing requires different homing markers and mechanisms compared to the small intestine. In the small intestine, CCL25 and CCR9 seem to be key regulators. In non-inflammatory conditions, CCL25, the chemokine binding to CCR9 on intestinal lymphocytes, is expressed in the epithelium of the small intestine, especially in the crypts and lower villus epithelium.
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      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.
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      • et al.
      Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity.
      Additionally, expression on endothelial cells in the lamina propria was described in humans, albeit only by 1 group.
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      The role of thymus-expressed chemokine and its receptor CCR9 on lymphocytes in the regional specialization of the mucosal immune system.
      It has been postulated that CCL25, could diffuse to and be presented by the vascular endothelium, in order to facilitate transendothelial migration of α4β7+ CCR9+ lymphocytes.
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      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.
      Although it was long thought that CCL25 expression was restricted to the small bowel, Trivedi et al. recently identified the presence of CCL25 in colonic tissue in inflammatory conditions.
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      • Hirschfield G.M.
      • et al.
      Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity.
      They also observed significantly more T cells expressing its receptor CCR9 in the colonic tissue of patients with UC refractory to medical therapy compared to healthy controls.
      In contrast to the small intestine, in colonic tissue, recruitment of T cells predominantly takes place via CCR10 and G-protein coupled receptor 15 (GPR15) (Fig. 1.4).
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      • et al.
      Role and species-specific expression of colon T cell homing receptor GPR15 in colitis.
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      • et al.
      GPR15-mediated homing controls immune homeostasis in the large intestine mucosa.
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      CCR10 expression is a common feature of circulating and mucosal epithelial tissue IgA Ab-secreting cells.
      CCR10 is a chemokine receptor expressed by both T and B cells. Mucosal homing of CCR10+ lymphocytes in the colon is driven by binding to CCL28, a chemokine expressed by the epithelium, whose expression is upregulated during inflammation.
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      • Kagnoff M.F.
      Regulated production of the chemokine CCL28 in human colon epithelium.
      The orphan chemoattractant receptor GPR15 has recently been described as a homing receptor of Tregs to the colon, particularly in mice.
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      • O'Hara 3rd, E.
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      • et al.
      Role and species-specific expression of colon T cell homing receptor GPR15 in colitis.
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      • Yang Y.
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      • Ota M.
      • et al.
      GPR15-mediated homing controls immune homeostasis in the large intestine mucosa.
      However, in humans, GPR15 was found to be abundantly expressed on Th2 cells in the normal and inflamed colon, rather than on Tregs.
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      Role and species-specific expression of colon T cell homing receptor GPR15 in colitis.
      The recently described ligand for GPR15, GPR15L was found to be expressed by epithelia that are in close contact with a microbial environment, including the colon, skin and cervix.
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      • et al.
      A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia.
      Expression of GPR15L is only minimally influenced by inflammation in the context of UC, whereas no expression is seen in the liver.
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      • et al.
      A natural ligand for the orphan receptor GPR15 modulates lymphocyte recruitment to epithelia.
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      • Bscheider M.
      • et al.
      A Mucosal and cutaneous chemokine ligand for the lymphocyte chemoattractant receptor GPR15.
      It is thought that the GPR15/GPR15L interaction is involved in sustaining the inflammatory environment in UC, however a role for GPR15 in lymphocyte homing in patients with PSC-IBD has not been established yet.

      Recruitment of lymphocytes to the liver

      Like the skin and gut, the liver is an important site of antigen exposure with its own response to invading pathogens. Several lymphocyte subsets including T cells, B cells, natural killer (NK) and natural killer T (NKT) cells commonly reside in the liver under homeostatic conditions. Whereas gut-activated T cells are primed in lymphoid structures (e.g. GALT), liver-activated T cells are primed in the liver itself. The adhesion of lymphocytes into the liver differs from the classical migration pathway as described earlier; firstly, extravasation of lymphocytes occurs mainly in the hepatic sinusoids instead of in the venules seen in most other tissues. Secondly, in the hepatic sinusoids this process is not dependent on selectins, at least not in mice, and often occurs independently of a rolling step.
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      • Beaudet A.L.
      • et al.
      A minimal role for selectins in the recruitment of leukocytes into the inflamed liver microvasculature.
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      • Wonigeit K.
      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.
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      • Kubes P.
      Leukocyte adhesion in the liver: distinct adhesion paradigm from other organs.
      However, there is an important role for lymphocyte adhesion molecules expressed by hepatic sinusoidal endothelial cells, including vascular adhesion protein 1 (VAP-1), ICAM-1 and the common lymphatic endothelial and vascular endothelial receptor-1 (CLEVER-1), also known as stabilin-1, which are constitutively expressed in the liver, but increased upon inflammation.
      • Steinhoff G.
      • Behrend M.
      • Schrader B.
      • Duijvestijn A.M.
      • Wonigeit K.
      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.
      • Lalor P.F.
      • Edwards S.
      • McNab G.
      • Salmi M.
      • Jalkanen S.
      • Adams D.H.
      Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells.
      CD8+ T cells have been shown to adhere to the sinusoidal endothelium via interactions between either VCAM-1 and integrin α4, or ICAM-1 and integrin αLβ2; adhesion can also take place independently of these molecules (Fig. 1.6).
      • Lee W.Y.
      • Kubes P.
      Leukocyte adhesion in the liver: distinct adhesion paradigm from other organs.
      • Guidotti L.G.
      • Inverso D.
      • Sironi L.
      • Di Lucia P.
      • Fioravanti J.
      • Ganzer L.
      • et al.
      Immunosurveillance of the liver by intravascular effector CD8(+) T cells.
      Involvement of secreted chemokines including CXC-chemokine ligand (CXCL)9, CXCL10 and CXCL11 attracts both regulatory and effector T cells, which express chemokine receptor CXCR3, to enter the liver via the sinusoidal endothelium (Fig. 1.6).
      • Eksteen B.
      • Miles A.
      • Curbishley S.M.
      • Tselepis C.
      • Grant A.J.
      • Walker L.S.
      • et al.
      Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.
      • Curbishley S.M.
      • Eksteen B.
      • Gladue R.P.
      • Lalor P.
      • Adams D.H.
      CXCR 3 activation promotes lymphocyte transendothelial migration across human hepatic endothelium under fluid flow.
      The biliary epithelium also plays a role in lymphocyte recruitment in response to inflammatory signals, whereupon cholangiocytes express VCAM-1 to support T-cell binding via α4β1.
      • Afford S.C.
      • Humphreys E.H.
      • Reid D.T.
      • Russell C.L.
      • Banz V.M.
      • Oo Y.
      • et al.
      Vascular cell adhesion molecule 1 expression by biliary epithelium promotes persistence of inflammation by inhibiting effector T-cell apoptosis.

      Evidence for a role for ‘gut-homing’ cells in PSC-IBD

      Gut-liver axis in PSC-IBD

      PSC is characterised by peribiliary infiltrates, mainly consisting of T lymphocytes. Interestingly, this infiltrate contains a subset of T lymphocytes expressing integrin α4β7, suggesting a gut origin whereas in normal liver, this is only occasionally the case.
      • Ponsioen C.Y.
      • Kuiper H.
      • Ten Kate F.J.
      • van Milligen de Wit M.
      • van Deventer S.J.
      • Tytgat G.N.
      Immunohistochemical analysis of inflammation in primary sclerosing cholangitis.
      This aberrant gut-homing lymphocyte hypothesis was further elaborated on by Adams et al. who proposed that long-lived mucosal T lymphocytes are recruited to the liver via aberrantly expressed mucosal adhesion molecules and chemokines in the liver that are normally restricted to the gut.
      • Adams D.H.
      • Eksteen B.
      Aberrant homing of mucosal T cells and extra-intestinal manifestations of inflammatory bowel disease.
      This gut origin is further supported by the finding that neither liver dendritic cells nor hepatic stellate cells (HSCs) are able to imprint gut trophism on CD8+ T cells.
      • Eksteen B.
      • Mora J.R.
      • Haughton E.L.
      • Henderson N.C.
      • Lee-Turner L.
      • Villablanca E.J.
      • et al.
      Gut homing receptors on CD8 T cells are retinoic acid dependent and not maintained by liver dendritic or stellate cells.
      Additionally, in a murine model, CD8+ T cells activated in GALT caused immune-mediated cholangitis in an antigen-dependent manner, and gut-primed CD8+ T cells activated in GALT could migrate to the liver, whereas liver-activated CD8+ T cells did not home to the intestine.
      • Seidel D.
      • Eickmeier I.
      • Kuhl A.A.
      • Hamann A.
      • Loddenkemper C.
      • Schott E.
      CD8 T cells primed in the gut-associated lymphoid tissue induce immune-mediated cholangitis in mice.
      • Eickmeier I.
      • Seidel D.
      • Grun J.R.
      • Derkow K.
      • Lehnardt S.
      • Kuhl A.A.
      • et al.
      Influence of CD8 T cell priming in liver and gut on the enterohepatic circulation.
      Conversely, one in vitro study showed that murine sinusoidal endothelium could induce gut trophism on CD4+ T cells.
      • Neumann K.
      • Kruse N.
      • Szilagyi B.
      • Erben U.
      • Rudolph C.
      • Flach A.
      • et al.
      Connecting liver and gut: murine liver sinusoidal endothelium induces gut tropism of CD4+ T cells via retinoic acid.
      In general, there are no differences in the amount of total circulating CD4+ and CD8+ T cells in the peripheral blood of patients with PSC-UC and UC compared to healthy controls.
      • Gwela A.
      • Siddhanathi P.
      • Oxford I.B.D.C.I.
      • Chapman R.W.
      • Travis S.
      • Powrie F.
      • et al.
      Th1 and innate lymphoid cells accumulate in primary sclerosing cholangitis-associated inflammatory bowel disease.
      • Schoknecht T.
      • Schwinge D.
      • Stein S.
      • Weiler-Normann C.
      • Sebode M.
      • Mucha S.
      • et al.
      CD4+ T cells from patients with primary sclerosing cholangitis exhibit reduced apoptosis and down-regulation of proapoptotic Bim in peripheral blood.
      However, patients with PSC-UC have increased frequencies of colonic Th1 cells as well as larger proportions of CXCR3-expressing CD8+ T cells in the colon and peripheral blood compared to patients with UC.
      • Gwela A.
      • Siddhanathi P.
      • Oxford I.B.D.C.I.
      • Chapman R.W.
      • Travis S.
      • Powrie F.
      • et al.
      Th1 and innate lymphoid cells accumulate in primary sclerosing cholangitis-associated inflammatory bowel disease.
      • Lampinen M.
      • Vessby J.
      • Fredricsson A.
      • Wanders A.
      • Rorsman F.
      • Carlson M.
      High serum sCD40 and a distinct colonic T-cell profile in ulcerative colitis associated with primary sclerosing cholangitis.
      Also, a role for innate lymphoid cells (ILCs) has been proposed, in that increased numbers of lineage- CD127+ ILCs were found in the colons of patients with PSC-UC compared to those with UC, giving rise to the idea that PSC-UC represents a distinct immunological phenotype compared to UC.
      • Gwela A.
      • Siddhanathi P.
      • Oxford I.B.D.C.I.
      • Chapman R.W.
      • Travis S.
      • Powrie F.
      • et al.
      Th1 and innate lymphoid cells accumulate in primary sclerosing cholangitis-associated inflammatory bowel disease.
      Lymphocyte homing to the intestine seems to be rather similar in patients with IBD and concomitant PSC, as for IBD in general.

      Contribution of various subsets of T cells in PSC liver pathology

      In PSC liver, increased numbers of intrahepatic CD4+ T cells negative for CD28, a costimulatory molecule required for T-cell activation and survival, localise close to the bile ducts.
      • Liaskou E.
      • Jeffery L.E.
      • Trivedi P.J.
      • Reynolds G.M.
      • Suresh S.
      • Bruns T.
      • et al.
      Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis.
      This increased frequency of CD28- T cells was not seen in the peripheral blood of patients with PSC compared to healthy controls.
      • Schoknecht T.
      • Schwinge D.
      • Stein S.
      • Weiler-Normann C.
      • Sebode M.
      • Mucha S.
      • et al.
      CD4+ T cells from patients with primary sclerosing cholangitis exhibit reduced apoptosis and down-regulation of proapoptotic Bim in peripheral blood.
      • Liaskou E.
      • Jeffery L.E.
      • Trivedi P.J.
      • Reynolds G.M.
      • Suresh S.
      • Bruns T.
      • et al.
      Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis.
      Downregulation of CD28 expression can be triggered by a tumor necrosis factor (TNF)-α rich environment, which could explain the locally increased numbers in PSC livers.
      • Liaskou E.
      • Jeffery L.E.
      • Trivedi P.J.
      • Reynolds G.M.
      • Suresh S.
      • Bruns T.
      • et al.
      Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis.
      • Bryl E.
      • Vallejo A.N.
      • Matteson E.L.
      • Witkowski J.M.
      • Weyand C.M.
      • Goronzy J.J.
      Modulation of CD28 expression with anti-tumor necrosis factor alpha therapy in rheumatoid arthritis.
      Liver infiltrating CD4+CD28- T cells express high levels of different chemokine receptors that play a role in tissue infiltration and localisation close to bile ducts, including CX3CR1, CCR10 and CCR9, compared to peripheral circulating cells.
      • Liaskou E.
      • Jeffery L.E.
      • Trivedi P.J.
      • Reynolds G.M.
      • Suresh S.
      • Bruns T.
      • et al.
      Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis.
      Upon activation, CD28- effector memory T cells can release high levels of the pro-inflammatory cytokines TNF-α and interferon-γ (IFN-γ), which further promotes inflammation, and triggers biliary epithelial cells to express adhesion and costimulatory molecules including ICAM-1, HLA-DR and CD40.
      • Liaskou E.
      • Jeffery L.E.
      • Trivedi P.J.
      • Reynolds G.M.
      • Suresh S.
      • Bruns T.
      • et al.
      Loss of CD28 expression by liver-infiltrating T cells contributes to pathogenesis of primary sclerosing cholangitis.
      The potential relevance of the cell surface molecule CD28 in PSC was strengthened by the identification of the CD28 locus as a risk factor in PSC development.
      • Liu J.Z.
      • Hov J.R.
      • Folseraas T.
      • Ellinghaus E.
      • Rushbrook S.M.
      • Doncheva N.T.
      • et al.
      Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.

      Th17 cells

      Biliary epithelial cells can express the IL-17 receptor IL-17RA, and can therefore react on locally secreted IL-17 by Th17 cells.
      • Oo Y.H.
      • Banz V.
      • Kavanagh D.
      • Liaskou E.
      • Withers D.R.
      • Humphreys E.
      • et al.
      CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.
      The cytokine IL-17A has profibrotic properties, leading to hypersensitivity of HSCs to transforming growth factor (TGF)-β.
      • Fabre T.
      • Kared H.
      • Friedman S.L.
      • Shoukry N.H.
      IL-17A enhances the expression of profibrotic genes through upregulation of the TGF-beta receptor on hepatic stellate cells in a JNK-dependent manner.
      In the acute phase, this could be beneficial for liver wound healing, but in cases of chronic liver disease like PSC, this could cause enhanced fibrogenesis. The contribution of IL-17 to PSC has been described in different studies. IL-17 stimulates CCL20 and CXCL9-11 expression by the biliary epithelium, leading to recruitment of CCR6+ CXCR3+ Th17 cells to the bile ducts (Fig. 1.6).
      • Oo Y.H.
      • Banz V.
      • Kavanagh D.
      • Liaskou E.
      • Withers D.R.
      • Humphreys E.
      • et al.
      CXCR3-dependent recruitment and CCR6-mediated positioning of Th-17 cells in the inflamed liver.
      An increased response of Th17 and Th1/Th17 cells after pathogen stimulation was found in the peripheral blood of patients with PSC, as well as an accumulation of IL-17A expressing T cells around bile ducts and areas of neoductular proliferation.
      • Katt J.
      • Schwinge D.
      • Schoknecht T.
      • Quaas A.
      • Sobottka I.
      • Burandt E.
      • et al.
      Increased T helper type 17 response to pathogen stimulation in patients with primary sclerosing cholangitis.
      Furthermore, a selective enrichment of γδT cells capable of producing both IL-17 and IFNy was present in PSC livers, compared to hepatitis C virus (HCV) livers where mainly IFNy secretion was seen.
      • Martins E.B.
      • Graham A.K.
      • Chapman R.W.
      • Fleming K.A.
      Elevation of gamma delta T lymphocytes in peripheral blood and livers of patients with primary sclerosing cholangitis and other autoimmune liver diseases.
      • Tedesco D.
      • Thapa M.
      • Chin C.Y.
      • Ge Y.
      • Gong M.
      • Li J.
      • et al.
      Alterations in intestinal microbiota lead to production of interleukin 17 by intrahepatic gammadelta T-cell receptor-positive cells and pathogenesis of cholestatic liver disease.
      Overall, infiltrating Th17 cells seem to play a role in sustaining inflammation in PSC.
      The pro-inflammatory and pro-fibrotic cytokine IL-17 also plays a role in recruitment of Th17 cells in the inflamed PSC liver.

      Regulatory T cells

      The role Tregs play in PSC remains unclear. Tregs are thought to limit local damage resulting from infectious challenges to a host and have critical functions in maintaining tolerance against autoantigens. Genetic studies revealed single nucleotide polymorphisms within the IL-2 receptor alpha (IL-2RA) locus and the IL-2/IL-21 locus that were associated with PSC.
      • Liu J.Z.
      • Hov J.R.
      • Folseraas T.
      • Ellinghaus E.
      • Rushbrook S.M.
      • Doncheva N.T.
      • et al.
      Dense genotyping of immune-related disease regions identifies nine new risk loci for primary sclerosing cholangitis.
      • Melum E.
      • Franke A.
      • Schramm C.
      • Weismuller T.J.
      • Gotthardt D.N.
      • Offner F.A.
      • et al.
      Genome-wide association analysis in primary sclerosing cholangitis identifies two non-HLA susceptibility loci.
      IL-2RA (CD25) is a type 1 transmembrane protein constitutively expressed by Tregs, whereas IL-2, the ligand for IL-2R, is required for expansion of Tregs and induction of their suppressive function.
      • Thornton A.M.
      • Donovan E.E.
      • Piccirillo C.A.
      • Shevach E.M.
      Cutting edge: IL-2 is critically required for the in vitro activation of CD4+CD25+ T cell suppressor function.
      Interestingly, Il2ra−/− mice spontaneously develop both intestinal and biliary inflammation, and in a T-cell mediated colitis model with low abundance of Tregs, mice developed liver inflammation and fibrotic signs.
      • Hsu W.
      • Zhang W.
      • Tsuneyama K.
      • Moritoki Y.
      • Ridgway W.M.
      • Ansari A.A.
      • et al.
      Differential mechanisms in the pathogenesis of autoimmune cholangitis versus inflammatory bowel disease in interleukin-2Ralpha(-/-) mice.
      • Mathies F.
      • Steffens N.
      • Kleinschmidt D.
      • Stuhlmann F.
      • Huber F.J.
      • Roy U.
      • et al.
      Colitis promotes a pathological condition of the liver in the absence of Foxp3(+) regulatory T cells.
      A significantly lower number of Tregs were found in peripheral blood from patients with PSC than from patients with primary biliary cholangitis (PBC) or healthy controls. The lower number of Tregs was not associated with concomitant IBD.
      • Sebode M.
      • Peiseler M.
      • Franke B.
      • Schwinge D.
      • Schoknecht T.
      • Wortmann F.
      • et al.
      Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms.
      Also, the proportion of Tregs in the liver was reported to be significantly reduced in patients with PSC, at the time of diagnosis as well as at the time of end-stage disease.
      • Sebode M.
      • Peiseler M.
      • Franke B.
      • Schwinge D.
      • Schoknecht T.
      • Wortmann F.
      • et al.
      Reduced FOXP3(+) regulatory T cells in patients with primary sclerosing cholangitis are associated with IL2RA gene polymorphisms.
      • Koyabu M.
      • Uchida K.
      • Miyoshi H.
      • Sakaguchi Y.
      • Fukui T.
      • Ikeda H.
      • et al.
      Analysis of regulatory T cells and IgG4-positive plasma cells among patients of IgG4-related sclerosing cholangitis and autoimmune liver diseases.
      This finding suggests that impaired production or recruitment of Tregs, which reduce inflammation, may play a causal role in PSC. Conversely, another study reported a marked increase in FoxP3+ cells around heavily inflamed portal tracts in chronically inflamed livers of patients with PSC, PBC and alcohol-related liver disease (ALD), suggesting that interactions between CCL28 and CCR10 on Tregs could play a role.
      • Eksteen B.
      • Miles A.
      • Curbishley S.M.
      • Tselepis C.
      • Grant A.J.
      • Walker L.S.
      • et al.
      Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.

      Evidence for gut-homing molecules in PSC liver

      The fact that not all patients with IBD develop liver disease suggests that there should also be a trigger in the liver, which could attract circulating lymphocytes into the liver tissue.
      A recent study looking at shared clonotypes of the T-cell receptors of matched colon, liver and blood samples, showed a higher level of overlap between paired PSC-IBD samples than normal gut and liver samples, suggesting that memory T cells in the gut and liver of patients with PSC-IBD react to shared antigens.
      • Henriksen E.K.
      • Jorgensen K.K.
      • Kaveh F.
      • Holm K.
      • Hamm D.
      • Olweus J.
      • et al.
      Gut and liver T cells of common clonal origin in primary sclerosing cholangitis-inflammatory bowel disease.
      Furthermore, there is also evidence that certain adhesion molecules and chemokines are aberrantly expressed in PSC livers. Thus far, transcriptomic analysis of non-end-stage PSC livers is still lacking. This may provide more insight into which trafficking molecules are involved in PSC.

      MAdCAM-1 - α4β7

      One of the key findings supporting the hypothesis that long-lived memory T cells primed in the gut could migrate to liver tissue in patients with PSC, is the presence of mucosal adhesion molecule MAdCAM-1 in PSC livers (Fig. 1.5). In humans, MAdCAM-1 is widely expressed during early foetal development, whereas it gradually becomes polarised to mucosal vessels and downregulated in other tissues after birth.
      • Salmi M.
      • Alanen K.
      • Grenman S.
      • Briskin M.
      • Butcher E.C.
      • Jalkanen S.
      Immune cell trafficking in uterus and early life is dominated by the mucosal addressin MAdCAM-1 in humans.
      Its expression is then restricted to endothelial cells lining blood vessels of only a few distinct tissues, including the gastrointestinal (GI) tract (colon and small intestine), mucosal associated lymphoid tissues of the GI tract, and to a lesser extent pancreas, gallbladder and spleen.
      • Briskin M.
      • Winsor-Hines D.
      • Shyjan A.
      • Cochran N.
      • Bloom S.
      • Wilson J.
      • et al.
      Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue.
      • Salmi M.
      • Alanen K.
      • Grenman S.
      • Briskin M.
      • Butcher E.C.
      • Jalkanen S.
      Immune cell trafficking in uterus and early life is dominated by the mucosal addressin MAdCAM-1 in humans.
      • Hillan K.J.
      • Hagler K.E.
      • MacSween R.N.
      • Ryan A.M.
      • Renz M.E.
      • Chiu H.H.
      • et al.
      Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.
      Only a few studies have looked into MAdCAM-1 expression in liver tissue. While at least 4 studies showed that the MAdCAM-1 protein is not present in normal liver tissue, 3 studies have shown aberrant expression of MAdCAM-1 on large and small portal vein endothelium in several inflammatory liver diseases.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      • Briskin M.
      • Winsor-Hines D.
      • Shyjan A.
      • Cochran N.
      • Bloom S.
      • Wilson J.
      • et al.
      Human mucosal addressin cell adhesion molecule-1 is preferentially expressed in intestinal tract and associated lymphoid tissue.
      • Hillan K.J.
      • Hagler K.E.
      • MacSween R.N.
      • Ryan A.M.
      • Renz M.E.
      • Chiu H.H.
      • et al.
      Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.
      • Ala A.
      • Brown D.
      • Khan K.
      • Standish R.
      • Odin J.A.
      • Fiel M.I.
      • et al.
      Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates.
      Under inflammatory conditions, MAdCAM-1 expression was shown on portal vein endothelium, portal tract venules and vessels of the peribiliary capillary plexus (Table 2). The presence appeared focal, in which only a proportion of portal tracts stained positive.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      • Hillan K.J.
      • Hagler K.E.
      • MacSween R.N.
      • Ryan A.M.
      • Renz M.E.
      • Chiu H.H.
      • et al.
      Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.
      Moreover, MAdCAM-1 expression was also seen in association with lymphoid aggregate and follicle formation, where cells were negative for CD34, a marker of vascular endothelium.
      • Hillan K.J.
      • Hagler K.E.
      • MacSween R.N.
      • Ryan A.M.
      • Renz M.E.
      • Chiu H.H.
      • et al.
      Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.
      • Ala A.
      • Brown D.
      • Khan K.
      • Standish R.
      • Odin J.A.
      • Fiel M.I.
      • et al.
      Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates.
      The presence of MAdCAM-1 was more prominent in PSC and autoimmune hepatitis (AIH) livers than in PBC and HCV livers, suggesting a correlation with IBD.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      Table 2Adhesion molecules and their protein expression in normal and PSC liver.
      AdhesionNormal liverPSC liver
      MADCAM-1Not expressed
      Low levels of mRNA expression found in normal liver by Ala et al.81
      Inflamed portal vein/sinusoidal endothelium

      Peribiliary capillary plexus
      VAP-1Portal endothelium

      Sinusoidal endothelium
      Increased sinusoidal expression

      Fibrous septa
      E-CADHERINBiliary epithelium

      Hepatocytes
      Loss of expression in biliary epithelial cells

      No changes in hepatocytes
      ICAM-1Portal endothelium

      Sinusoidal endothelium
      Increased endothelial expression

      Biliary epithelial cells
      VCAM-1Portal endotheliumIncrease endothelial expression

      Biliary epithelial cells
      PSC, primary sclerosing cholangitis.
      * Low levels of mRNA expression found in normal liver by Ala et al.
      • Ala A.
      • Brown D.
      • Khan K.
      • Standish R.
      • Odin J.A.
      • Fiel M.I.
      • et al.
      Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates.
      Aberrant expression of adhesion molecule MAdCAM-1 could cause adhesion of effector memory T cells expressing integrin α4β7 into the liver.
      There is a lot of variability in the presence of MAdCAM-1 in PSC livers between different studies. In needle biopsies of non-end-stage PSC livers, Ala et al. failed to detect MAdCAM-1, whereas Hillan et al. did detect MAdCAM-1 staining in 20% of specimens.
      • Hillan K.J.
      • Hagler K.E.
      • MacSween R.N.
      • Ryan A.M.
      • Renz M.E.
      • Chiu H.H.
      • et al.
      Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.
      • Ala A.
      • Brown D.
      • Khan K.
      • Standish R.
      • Odin J.A.
      • Fiel M.I.
      • et al.
      Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates.
      In explanted PSC livers, these numbers were much higher, with MAdCAM-1 present in 69–100% of liver sections.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      • Hillan K.J.
      • Hagler K.E.
      • MacSween R.N.
      • Ryan A.M.
      • Renz M.E.
      • Chiu H.H.
      • et al.
      Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.
      • Ala A.
      • Brown D.
      • Khan K.
      • Standish R.
      • Odin J.A.
      • Fiel M.I.
      • et al.
      Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates.
      This discrepancy may in part be explained by the focal nature of expression, especially in small liver biopsies containing little portal tracts, leading to an underestimation. However, in the study of Hillan et al., both needle biopsies and autopsy specimens of patients with HCV showed the same percentage of cases expressing MAdCAM-1, suggesting that the observed difference between PSC and HCV could also be disease specific. Another explanation for the variability of the results may be the different detection techniques used. For example, Ala et al. showed in normal liver tissue there is no protein expression of MAdCAM-1, but MAdCAM-1 mRNA is constitutively expressed, albeit only in small amounts.
      • Ala A.
      • Brown D.
      • Khan K.
      • Standish R.
      • Odin J.A.
      • Fiel M.I.
      • et al.
      Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates.
      In addition, the differences in disease stage or grade could cause variability. It has been shown that MAdCAM-1 mRNA expression is significantly upregulated in cirrhotic livers compared to normal liver, however it is not known how this relates to different disease stages.
      • Ala A.
      • Brown D.
      • Khan K.
      • Standish R.
      • Odin J.A.
      • Fiel M.I.
      • et al.
      Mucosal addressin cell adhesion molecule (MAdCAM-1) expression is upregulated in the cirrhotic liver and immunolocalises to the peribiliary plexus and lymphoid aggregates.
      There does seem to be a positive correlation between histologic grade (degree of inflammation) and MAdCAM-1 presence in HCV needle biopsies, however this has not yet been evaluated for PSC.
      • Hillan K.J.
      • Hagler K.E.
      • MacSween R.N.
      • Ryan A.M.
      • Renz M.E.
      • Chiu H.H.
      • et al.
      Expression of the mucosal vascular addressin, MAdCAM-1, in inflammatory liver disease.
      Whether MAdCAM-1 upregulation is a critical event in the pathogenesis of inflammatory liver diseases or whether it is more a secondary epiphenomenon is still under debate. Possibly, the foetal downregulated MAdCAM-1 cannot be suppressed in inflammatory conditions. Both in mice and in humans, expression of MAdCAM-1 can be induced by TNF-α and IL-1, which is regulated through the nuclear factor (NF)-kappa B pathway.
      • Liaskou E.
      • Karikoski M.
      • Reynolds G.M.
      • Lalor P.F.
      • Weston C.J.
      • Pullen N.
      • et al.
      Regulation of mucosal addressin cell adhesion molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity.
      • Oshima T.
      • Pavlick K.P.
      • Laroux F.S.
      • Verma S.K.
      • Jordan P.
      • Grisham M.B.
      • et al.
      Regulation and distribution of MAdCAM-1 in endothelial cells in vitro.
      • Takeuchi M.
      • Baichwal V.R.
      Induction of the gene encoding mucosal vascular addressin cell adhesion molecule 1 by tumor necrosis factor alpha is mediated by NF-kappa B proteins.
      Integrin α4β7 is present on approximately 50% of circulating T cells in the peripheral blood of healthy individuals.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      • Meenan J.
      • Spaans J.
      • Grool T.A.
      • Pals S.T.
      • Tytgat G.N.
      • van Deventer S.J.
      Altered expression of alpha 4 beta 7, a gut homing integrin, by circulating and mucosal T cells in colonic mucosal inflammation.
      This proportion is the same in the peripheral blood of patients with PSC, whereas about 10–30% of CD3+ liver infiltrating T cells of patients with PSC are α4β7 positive.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      Integrin α4β7 is expressed on a wide range of leukocytes, including naïve and memory CD4+ and CD8+ T cells, B cells, eosinophils, NK cells, and to a lesser extent monocytes (Table 3).
      • Meenan J.
      • Spaans J.
      • Grool T.A.
      • Pals S.T.
      • Tytgat G.N.
      • van Deventer S.J.
      Altered expression of alpha 4 beta 7, a gut homing integrin, by circulating and mucosal T cells in colonic mucosal inflammation.
      • Soler D.
      • Chapman T.
      • Yang L.L.
      • Wyant T.
      • Egan R.
      • Fedyk E.R.
      The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
      The chemokines CXCL12, CCL21, CCL25 and CCL28 all promote binding of α4β7+ lymphocytes to MAdCAM-1, of which CXCL12 appears to have the most potent effect (Table 3).
      • Koizumi M.
      • King N.
      • Lobb R.
      • Benjamin C.
      • Podolsky D.K.
      Expression of vascular adhesion molecules in inflammatory bowel disease.
      Expression of CCL21, the ligand of CCR7, was found to be increased in portal tracts of patients with PSC, which could have the additional effect of attracting CCR7+ α4β7+ lymphocytes into the liver.
      • Grant A.J.
      • Goddard S.
      • Ahmed-Choudhury J.
      • Reynolds G.
      • Jackson D.G.
      • Briskin M.
      • et al.
      Hepatic expression of secondary lymphoid chemokine (CCL21) promotes the development of portal-associated lymphoid tissue in chronic inflammatory liver disease.
      • Langeneckert A.E.
      • Lunemann S.
      • Martrus G.
      • Salzberger W.
      • Hess L.U.
      • Ziegler A.E.
      • et al.
      CCL21-expression and accumulation of CCR7(+) NK cells in livers of patients with primary sclerosing cholangitis.
      It could be that in the situation of inflammation, local release of TNF-α could induce expression of MAdCAM-1, which together with stimulatory chemokines could promote the influx of integrin-expressing leukocytes.
      Table 3Overview of cells expressing integrin α4β7, αEβ7 or α4β1.
      Cell expressionActivating chemokine(s)
      α4β7Naïve T cells

      Memory T cells

      Regulatory T cells

      B cells

      Eosinophils

      Natural killer cells

      Monocytes
      CXCL12, CCL21,

      CCL25, CCL28
      αEβ7Memory T cells

      Regulatory T cells

      Dendritic cells

      Mast cells
      CCL25
      α4β1Memory T cells

      B cells

      Eosinophils

      Natural killer cells

      Monocytes

      Neutrophils
      CXCL12

      CCL25 - CCR9

      In explanted PSC livers, CCL25 was found to be expressed on hepatic sinusoidal endothelium at areas of interface hepatitis and in portal macrophages, whereas it was not present in non-diseased livers or other chronic inflammatory liver diseases (Table 4).
      • Eksteen B.
      • Grant A.J.
      • Miles A.
      • Curbishley S.M.
      • Lalor P.F.
      • Hubscher S.G.
      • et al.
      Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.
      Approximately 20% of liver infiltrating lymphocytes express CCR9, compared to less than 2% in the livers of organ donors or patients with other chronic inflammatory liver diseases.
      • Eksteen B.
      • Grant A.J.
      • Miles A.
      • Curbishley S.M.
      • Lalor P.F.
      • Hubscher S.G.
      • et al.
      Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.
      Cells expressing both α4β7 and CCR9 adhere significantly better to hepatic sinusoidal endothelial cells than α4β7+CCR9- cells under flow,
      • Trivedi P.J.
      • Bruns T.
      • Ward S.
      • Mai M.
      • Schmidt C.
      • Hirschfield G.M.
      • et al.
      Intestinal CCL25 expression is increased in colitis and correlates with inflammatory activity.
      indicating a specific role for these ‘gut-homing’ markers. Because both CCL25 and CCR9 are not present in livers of other chronic inflammatory diseases, including PBC and AIH, it is thought that this mechanism could be specific to PSC.
      Table 4Chemokines and their expression in normal and PSC liver.
      ChemokineNormal liverPSC liver
      CXCL12Bile ducts in portal tractsEnhanced expression in interlobular and septal bile ducts
      CCL20Biliary epithelial cellsIncreased in biliary epithelial cells
      CCL21Portal endothelium, Dendritic cellsIncreased on portal endothelium and small vascular channels
      CCL25Not expressedHepatic sinusoidal endothelium
      CCL28Low amountsBile ducts

      Reactive bile ducts

      Portal and sinusoidal endothelium

      Macrophages
      PSC, primary sclerosing cholangitis.

      CCL28 - CCR10

      CCL28 expression is low in normal liver, but enhanced considerably in patients with PSC or other chronic liver diseases (PBC, HCV and ALD), especially in the presence of the ductular reaction (i.e. cholangiocyte, hepatocyte or hepatic progenitor cell proliferation into reactive bile ducts in response to liver injury).
      • Govaere O.
      • Cockell S.
      • Van Haele M.
      • Wouters J.
      • Van Delm W.
      • Van den Eynde K.
      • et al.
      High-throughput sequencing identifies aetiology-dependent differences in ductular reaction in human chronic liver disease.
      Expression is most abundant on biliary epithelial cells, but also on portal endothelial cells and to a lesser extent on sinusoidal endothelium (Table 4).
      • Eksteen B.
      • Miles A.
      • Curbishley S.M.
      • Tselepis C.
      • Grant A.J.
      • Walker L.S.
      • et al.
      Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.
      A subset of liver infiltrating T cells expressing its receptor CCR10, co-expresses integrin αEβ7 (encoded by ITGAE and ITGB7), which allows them to position in the intra-epithelial compartment via binding to E-cadherin expressed at epithelial adherens junctions.
      • Eksteen B.
      • Miles A.
      • Curbishley S.M.
      • Tselepis C.
      • Grant A.J.
      • Walker L.S.
      • et al.
      Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.
      Apart from the aforementioned pro-inflammatory mechanisms, CCL28 expression by biliary epithelial cells could also provide a signal to attract CCR10 positive Tregs to the inflamed portal tracts in order to dampen inflammation.
      • Eksteen B.
      • Miles A.
      • Curbishley S.M.
      • Tselepis C.
      • Grant A.J.
      • Walker L.S.
      • et al.
      Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.
      Although a small proportion of CCR10+ T cells that infiltrate the liver in PSC co-express gut-homing integrin α4β7, and CCL28 is also able to trigger α4β7-dependent lymphocyte arrest on MAdCAM-1, CCL28’s specific role in PSC-IBD still remains to be determined.
      • Miles A.
      • Liaskou E.
      • Eksteen B.
      • Lalor P.F.
      • Adams D.H.
      CCL25 and CCL28 promote alpha4 beta7-integrin-dependent adhesion of lymphocytes to MAdCAM-1 under shear flow.

      CXCL12 - CXCR4

      CXCL12, also called stromal cell-derived factor 1 (SDF-1), is a chemokine that binds to its specific receptor CXCR4 as well as to atypical chemokine receptor 3 (ACKR3). In normal liver, CXCL12 is expressed on bile ducts in portal tracts, whereas this expression is greatly enhanced and also present in interlobular and septal bile ducts in different liver diseases, including PSC, PBC and AIH.
      • Terada R.
      • Yamamoto K.
      • Hakoda T.
      • Shimada N.
      • Okano N.
      • Baba N.
      • et al.
      Stromal cell-derived factor-1 from biliary epithelial cells recruits CXCR4-positive cells: implications for inflammatory liver diseases.
      Migration and adhesion assays showed that CCR9+ liver infiltrating lymphocytes preferentially migrate to CCL25 rather than CCL5 or CXCL12, but CXCL12 did elicit chemotaxis of PSC liver-derived lymphocytes.
      • Eksteen B.
      • Grant A.J.
      • Miles A.
      • Curbishley S.M.
      • Lalor P.F.
      • Hubscher S.G.
      • et al.
      Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.
      This suggests that CXCL12 may play a role in retaining CCR9+ lymphocytes around bile ducts via co-expression of CXCR4, rather than in recruiting these lymphocytes into the liver.
      • Eksteen B.
      • Grant A.J.
      • Miles A.
      • Curbishley S.M.
      • Lalor P.F.
      • Hubscher S.G.
      • et al.
      Hepatic endothelial CCL25 mediates the recruitment of CCR9+ gut-homing lymphocytes to the liver in primary sclerosing cholangitis.
      Chemokines CCL25, CCL28 and CXCL12 are present in PSC livers, contributing to infiltration and positioning of T cells in the liver.

      VAP-1

      VAP-1 is an adhesion molecule expressed by endothelial cells in the liver with dual properties: it has amine oxidase activity and supports leukocyte recruitment to sites of inflammation.
      • Lalor P.F.
      • Edwards S.
      • McNab G.
      • Salmi M.
      • Jalkanen S.
      • Adams D.H.
      Vascular adhesion protein-1 mediates adhesion and transmigration of lymphocytes on human hepatic endothelial cells.
      Two ligands have been described for VAP-1; Siglec-9, expressed on granulocytes and monocytes, and Siglec-10, expressed on B cells, monocytes and eosinophils (Table 1).
      • Aalto K.
      • Autio A.
      • Kiss E.A.
      • Elima K.
      • Nymalm Y.
      • Veres T.Z.
      • et al.
      Siglec-9 is a novel leukocyte ligand for vascular adhesion protein-1 and can be used in PET imaging of inflammation and cancer.
      • Kivi E.
      • Elima K.
      • Aalto K.
      • Nymalm Y.
      • Auvinen K.
      • Koivunen E.
      • et al.
      Human Siglec-10 can bind to vascular adhesion protein-1 and serves as its substrate.
      In the absence of inflammation, VAP-1 is expressed in extrahepatic vessels throughout the body, however during inflammation, it is upregulated in the large and small intestine where it mediates T-cell binding to mucosal vessels.
      • Salmi M.
      • Kalimo K.
      • Jalkanen S.
      Induction and function of vascular adhesion protein-1 at sites of inflammation.
      Enzymatic activity of VAP-1 generates products including aldehyde, ammonia and H2O2 that can induce NF-κB-dependent expression of different adhesion molecules in the gut and liver including VCAM-1 and ICAM-1, and more specifically, MAdCAM-1 expression on endothelial cells in vitro and ex vivo in human samples and in vivo in mice.
      • Liaskou E.
      • Karikoski M.
      • Reynolds G.M.
      • Lalor P.F.
      • Weston C.J.
      • Pullen N.
      • et al.
      Regulation of mucosal addressin cell adhesion molecule 1 expression in human and mice by vascular adhesion protein 1 amine oxidase activity.
      • Lalor P.F.
      • Sun P.J.
      • Weston C.J.
      • Martin-Santos A.
      • Wakelam M.J.
      • Adams D.H.
      Activation of vascular adhesion protein-1 on liver endothelium results in an NF-kappaB-dependent increase in lymphocyte adhesion.
      • Trivedi P.J.
      • Tickle J.
      • Vesterhus M.N.
      • Eddowes P.J.
      • Bruns T.
      • Vainio J.
      • et al.
      Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner.
      In PSC livers, as well as in other immune-mediated liver diseases, VAP-1 is highly expressed compared to non-diseased liver, most prominently on the endothelial lining of the sinusoids (Table 2).
      • Eksteen B.
      • Miles A.
      • Curbishley S.M.
      • Tselepis C.
      • Grant A.J.
      • Walker L.S.
      • et al.
      Epithelial inflammation is associated with CCL28 production and the recruitment of regulatory T cells expressing CCR10.
      • Trivedi P.J.
      • Tickle J.
      • Vesterhus M.N.
      • Eddowes P.J.
      • Bruns T.
      • Vainio J.
      • et al.
      Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner.
      Additionally, VAP-1 expression is markedly present on fibrotic septa and the walls of portal/septal vessels of cirrhotic livers from patients with PSC, co-localising with α-smooth muscle actin (αSMA) and stromal cells within fibrous septa.
      • Trivedi P.J.
      • Tickle J.
      • Vesterhus M.N.
      • Eddowes P.J.
      • Bruns T.
      • Vainio J.
      • et al.
      Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner.
      It has been proposed that in patients in the early stages of PSC-IBD, colonic inflammation leads to an increased burden of amine release from both bacteria and inflamed epithelium via the portal circulation to the liver. This would lead to an increase in amine oxidase activity via VAP-1, driving upregulation of adhesion molecules including MAdCAM-1, which causes recruitment of α4β7+ mucosal T cells leading to a pro-inflammatory response.
      • Trivedi P.J.
      • Tickle J.
      • Vesterhus M.N.
      • Eddowes P.J.
      • Bruns T.
      • Vainio J.
      • et al.
      Vascular adhesion protein-1 is elevated in primary sclerosing cholangitis, is predictive of clinical outcome and facilitates recruitment of gut-tropic lymphocytes to liver in a substrate-dependent manner.
      However, the increased expression in fibrous septa and αSMA-positive cells in various cirrhotic liver diseases could indicate that this is not disease specific, but has a more general role in influencing tissue fibrogenesis.
      • Weston C.J.
      • Shepherd E.L.
      • Claridge L.C.
      • Rantakari P.
      • Curbishley S.M.
      • Tomlinson J.W.
      • et al.
      Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis.

      E-cadherin - αEβ7

      Cell-adhesion molecule E-cadherin is constitutively expressed by hepatocytes and biliary epithelial cells (Table 2).
      • Nakagawa H.
      • Hikiba Y.
      • Hirata Y.
      • Font-Burgada J.
      • Sakamoto K.
      • Hayakawa Y.
      • et al.
      Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis.
      Nakagawa et al. identified a loss of E-cadherin expression in biliary epithelial cells from PSC livers compared to normal livers, and demonstrated that E-cadherin loss in the biliary epithelium favours periportal inflammation in mice.
      • Nakagawa H.
      • Hikiba Y.
      • Hirata Y.
      • Font-Burgada J.
      • Sakamoto K.
      • Hayakawa Y.
      • et al.
      Loss of liver E-cadherin induces sclerosing cholangitis and promotes carcinogenesis.
      The β7 integrin is only present in 2 heterodimeric integrins, α4β7 and αEβ7.
      • Gorfu G.
      • Rivera-Nieves J.
      • Ley K.
      Role of beta7 integrins in intestinal lymphocyte homing and retention.
      The heterodimer integrin αEβ7 is predominantly expressed on mucosal T lymphocytes and dendritic cells, where it mediates retention of lymphocytes in or near the epithelium via interactions with E-cadherin expressed on epithelial cell membranes (Table 2).
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      As expected, a higher proportion of liver-derived CD3+ lymphocytes than peripheral blood CD3+ T cells were αEβ7 positive in patients with PSC.
      • Grant A.J.
      • Lalor P.F.
      • Hubscher S.G.
      • Briskin M.
      • Adams D.H.
      MAdCAM-1 expressed in chronic inflammatory liver disease supports mucosal lymphocyte adhesion to hepatic endothelium (MAdCAM-1 in chronic inflammatory liver disease).
      TGF-β, which is highly present in fibrotic tissue, has been shown to increase the expression of ITGAE and ITGB7 mRNA, whereas it decreases ITGA4 (gene encoding for α4) mRNA levels.
      • Lim S.P.
      • Leung E.
      • Krissansen G.W.
      The beta7 integrin gene (Itgb-7) promoter is responsive to TGF-beta1: defining control regions.
      This has led to the hypothesis that α4β7+ T cells could differentiate into αEβ7+ T cells within the liver tissue under the influence of TGF-β, which is locally secreted by epithelial cells.
      • Lim S.P.
      • Leung E.
      • Krissansen G.W.
      The beta7 integrin gene (Itgb-7) promoter is responsive to TGF-beta1: defining control regions.
      In murine small intestine, adhesion of αE to epithelial E-cadherin is promoted by CCL25, suggesting that the interaction between CCR9 and CCL25 plays a role.
      • Ericsson A.
      • Svensson M.
      • Arya A.
      • Agace W.W.
      CCL25/CCR9 promotes the induction and function of CD103 on intestinal intraepithelial lymphocytes.
      In PSC livers, where CCL25 is aberrantly expressed, this interaction could also be present.

      Therapeutic options using lymphocyte trafficking mechanisms

      Thus far, there is still no recommended medical therapy for PSC according to European and American guidelines.
      • Liver. EAftSot
      EASL clinical practice guidelines: management of cholestatic liver diseases.
      • Chapman R.
      • Fevery J.
      • Kalloo A.
      • Nagorney D.M.
      • Boberg K.M.
      • Shneider B.
      • et al.
      Diagnosis and management of primary sclerosing cholangitis.
      Ursodeoxycholic acid is widely prescribed, but despite more than 20 years of research has not been proven to modify the disease course.
      • Ponsioen C.Y.
      • Chapman R.W.
      • Chazouilleres O.
      • Hirschfield G.M.
      • Karlsen T.H.
      • Lohse A.W.
      • et al.
      Surrogate endpoints for clinical trials in primary sclerosing cholangitis: review and results from an International PSC Study Group consensus process.
      Currently, therapy is in fact limited to treatment of complications such as dilatation of dominant strictures and liver transplantation in case of end-stage liver failure. Therefore, finding a medical treatment for PSC is an urgent unmet need. In the past decade, several novel agents interfering with gut-homing immune cells have emerged. However, to date, studies have mainly focused on IBD. Blocking lymphocyte trafficking to the bile ducts could be a potential mechanism to reduce inflammation and halt disease progression in PSC.

      Vedolizumab

      Vedolizumab is a humanised monoclonal antibody that specifically targets integrin α4β7. When vedolizumab binds to integrin α4β7, the antibody-integrin complex is internalised into the cell within 24 hours, rendering binding to MAdCAM-1 and fibronectin impossible.
      • Soler D.
      • Chapman T.
      • Yang L.L.
      • Wyant T.
      • Egan R.
      • Fedyk E.R.
      The binding specificity and selective antagonism of vedolizumab, an anti-alpha4beta7 integrin therapeutic antibody in development for inflammatory bowel diseases.
      • Wyant T.
      • Yang L.
      • Fedyk E.
      In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes.
      The efficacy of vedolizumab in IBD was demonstrated in several placebo-controlled phase II and III clinical trials of patients with moderately active UC as well as moderately active CD, and it has also been shown to be effective during long-term follow-up.
      • Feagan B.G.
      • Rutgeerts P.
      • Sands B.E.
      • Hanauer S.
      • Colombel J.F.
      • Sandborn W.J.
      • et al.
      Vedolizumab as induction and maintenance therapy for ulcerative colitis.
      • Loftus Jr., E.V.
      • Colombel J.F.
      • Feagan B.G.
      • Vermeire S.
      • Sandborn W.J.
      • Sands B.E.
      • et al.
      Long-term efficacy of vedolizumab for ulcerative colitis.
      • Sandborn W.J.
      • Feagan B.G.
      • Rutgeerts P.
      • Hanauer S.
      • Colombel J.F.
      • Sands B.E.
      • et al.
      Vedolizumab as induction and maintenance therapy for Crohn's disease.
      • Vermeire S.
      • Loftus Jr., E.V.
      • Colombel J.F.
      • Feagan B.G.
      • Sandborn W.J.
      • Sands B.E.
      • et al.
      Long-term efficacy of vedolizumab for Crohn's disease.
      Vedolizumab was licensed for the treatment of CD and UC in 2014. The potential efficacy and safety of vedolizumab for the treatment of PSC-IBD has only been evaluated in small, retrospective studies and case reports (Table 5). Treatment with vedolizumab was shown to be efficient with regard to the intestinal inflammation in patients with PSC-IBD.
      • Christensen B.
      • Micic D.
      • Gibson P.R.
      • Yarur A.
      • Bellaguarda E.
      • Corsello P.
      • et al.
      Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease.
      • Lim T.Y.
      • Pavlidis P.
      • Gulati S.
      • Pirani T.
      • Samaan M.
      • Chung-Faye G.
      • et al.
      Vedolizumab in inflammatory bowel disease associated with autoimmune liver disease pre- and postliver transplantation: a case series.
      However, these series showed conflicting results regarding changes in alkaline phosphatase levels as a surrogate endpoint for liver disease activity.
      • Christensen B.
      • Micic D.
      • Gibson P.R.
      • Yarur A.
      • Bellaguarda E.
      • Corsello P.
      • et al.
      Vedolizumab in patients with concurrent primary sclerosing cholangitis and inflammatory bowel disease does not improve liver biochemistry but is safe and effective for the bowel disease.
      • Lynch K.D.
      • Chapman R.W.
      • Keshav S.
      • Montano-Loza A.J.
      • Mason A.L.
      • Kremer A.E.
      • et al.
      Effects of Vedolizumab in Patients with Primary Sclerosing Cholangitis and Inflammatory Bowel Diseases.
      • Westerveld D.
      • Grajo J.
      • Beattie L.
      • Glover S.
      Vedolizumab: a novel medical intervention in the treatment of primary sclerosing cholangitis.

      Caron LP-B, Nachury M, Bouhnik Y, Seksik P, Bouguen G, Caillo L, Laharie D, Carbonnel F, Altwegg R, Reenaers C, Serrero M, Boureille A, Nancey S, Filippi J, Abitbol V, Savoye G, Vuitton L, Viennot S, Fumery M, Reymond M, Bronowicki JP, Reimund J-M, Amiot A. Vedolizumab for primary sclerosing cholangitis associated with inflammatory bowel disease: A multicentre cohort study from the GETAID. Concres abstract, ECCO 2018. 2018.

      It must be noted that there were different limitations in these studies. The studies consisted of small numbers and heterogeneous groups, including both patients with and without ursodeoxycholic acid treatment, which could dampen the effect of changes in alkaline phosphatase. Furthermore, both pre- and post-transplant patients were included, as well as patients with different disease stages. More detailed analysis of these preliminary data as well as prospective trials using sufficient numbers and follow-up time are warranted.
      Table 5Current studies investigating vedolizumab treatment for PSC.
      Ref.Study typePatients, nPrimary outcomePopulationResults
      Lim et al. Inflamm Bowel Dis 2016Case series10Clinical and biochemical intestinal response after 7 monthsPSC-IBD, AISC-IBD, Pre- and post-LT
      • Clinical response in 40%, significant decrease in fecal calprotectin (p = 0.03) and QOL (p = 0.03)
      • FU too short to comment on effect on pre-LT flares or post-LT recurrence
      Westerveld et al. BMJ Case reports 2017Case report1Changes in liver biochemistry and MRCP imaging after 13 monthsPSC-UC
      • Improvement of stricturing on MRCP
      • Decrease in ALP (225 IU/L to 127 IU/L), ALT (121 IU/L to 64 IU/L) and AST (69 IU/L to 42 IU/L)
      Christensen et al. Al Pharmacol Ther 2018Retrospective cohort study34Change in serum ALP at week 14 and week 30PSC-IBD Pre- and post-LT
      • No -overall change in ALP levels at week 14 or week 30 (p = 0.35 and p = 0.99, respectively)
      Caron et al. ECCO 2018Retrospective cohort study
      Data from abstracts presented at international congresses, no full manuscript available yet.
      54Decrease ≥ 50% serum ALP at week 30PSC-IBD
      • Decrease of at least 50% from baseline to week 30 in 4 patients (7.4%)
      Doherty et al. ECCO 2018Retrospective cohort study
      Data from abstracts presented at international congresses, no full manuscript available yet.
      44Changes in liver biochemistry at 8, 24 and 36 weeksPSC-IBD Pre- and post-LT
      • Significant rise in ALP levels at week 8, 24 and 36 in PSC-IBD patients (p = 0.033, p = 0.005, p = 0.028 respectively)
      Tse et al. Al Pharmacol Ther 2018Retrospective cohort study27Changes in hepatic biochemistries and radiographic changes after 14 monthsPSC-IBD
      • No significant change of ALP levels after 14 months (p = 0.24)
      • No significant decreases in AST, ALT, bilirubin or radiographic changes (p = 0.98, p = 0.99, and p = 0.70, respectively)
      Lynch et al. Clin Gastroenterol Hepatol 2019Retrospective cohort study102Changes in liver biochemistry at day 42 and last follow-upPSC-IBD
      • ALP drop by > 20% in 20.6% of patients at last FU
      • Rise in mean ALP, ALT and bilirubin from baseline to last FU (p ≤ 0.05, p ≤ 0.01 and p ≤ 0.001 respectively)
      AISC, autoimmune sclerosing cholangitis; ALP, alkaline phosphatase; ALT, alanine aminotransferase; AST, aspartate transaminase; FU, follow-up; IBD, inflammatory bowel disease; LT, liver transplantation; PSC, primary sclerosing cholangitis; QoL, quality of life; MRCP, magnetic resonance cholangiopancreatography; QoL, quality of life; UC, ulcerative colitis.
      * Data from abstracts presented at international congresses, no full manuscript available yet.
      Vedolizumab as a treatment option for patients with PSC-IBD has thus far only been evaluated in retrospective series, showing conflicting results regarding changes in alkaline phosphatase levels (used as a surrogate for liver disease activity).

      Abrilumab

      Abrilumab (AMG181/MEDI7183), which is a fully human monoclonal antibody against α4β7, has been investigated for the treatment of moderate to severe CD, where it showed moderate beneficial effects for remission and response.
      • Sandborn W.
      • Cyrille M.
      • Hansen M.B.
      • Feagan B.G.
      • Loftus E.
      • Vermeire S.
      • et al.
      Efficacy and safety of abrilumab (AMG 181/MEDI 7183) therapy for moderate to severe Crohn’s disease.
      A phase IIb trial for moderate to severe UC demonstrated a favourable safety and efficacy profile in patients with UC,
      • Sandborn W.J.
      • Cyrille M.
      • Hansen M.B.
      • Feagan B.G.
      • Loftus Jr., E.V.
      • Rogler G.
      • et al.
      Efficacy and Safety of Abrilumab in a Randomized, Placebo-Controlled Trial for Moderate-to-Severe Ulcerative Colitis.
      however, to date, there has been no data reported on patients with co-existent PSC.

      Etrolizumab

      Etrolizumab is a monoclonal antibody against β7, selectively blocking both binding of integrin α4β7 to MAdCAM-1 as well as αEβ7 to E-cadherin. It has been investigated in a randomised phase II trial for UC, where it showed potential beneficial results, and phase III trials are currently underway.
      • Vermeire S.
      • O'Byrne S.
      • Keir M.
      • Williams M.
      • Lu T.T.
      • Mansfield J.C.
      • et al.
      Etrolizumab as induction therapy for ulcerative colitis: a randomised, controlled, phase 2 trial.
      Inhibition of β7 could be less gut-specific than inhibition of α4β7, since αEβ7 is expressed in different tissues throughout the body. It is not yet clear whether αE-expressing dendritic cells are blocked by etrolizumab, which could also affect priming of gut-homing T cells. Whether etrolizumab could influence liver infiltrating T cells in patients with PSC has not been investigated yet.

      Anti-MAdCAM-1

      Recently, 2 phase II randomised, double-blind, placebo-controlled trials investigating the efficacy and safety of an anti-MAdCAM-1 antibody (ontamalimab, SHP647, PF-00547659) for the treatment of UC and CD have been completed. It showed that ontamalimab was safe and well tolerated, as well as superior to placebo for induction and remission in patients with moderate to severe UC.
      • Vermeire S.
      • Sandborn W.J.
      • Danese S.
      • Hebuterne X.
      • Salzberg B.A.
      • Klopocka M.
      • et al.
      Anti-MAdCAM antibody (PF-00547659) for ulcerative colitis (TURANDOT): a phase 2, randomised, double-blind, placebo-controlled trial.
      In CD no significant differences between study drug and placebo were found.
      • Sandborn W.J.
      • Lee S.D.
      • Tarabar D.
      • Louis E.
      • Klopocka M.
      • Klaus J.
      • et al.
      Phase II evaluation of anti-MAdCAM antibody PF-00547659 in the treatment of Crohn's disease: report of the OPERA study.
      Given the finding that MAdCAM-1 is aberrantly expressed in PSC livers, treatment with this compound could have potential benefit for patients with PSC. In the previous studies, patients with liver disease were excluded from the programme, so no data on PSC-IBD are available.

      VAP-1 inhibition

      In 4 different animal models of liver injury, inhibition of VAP-1 reduced recruitment of leukocytes and improved fibrosis.
      • Weston C.J.
      • Shepherd E.L.
      • Claridge L.C.
      • Rantakari P.
      • Curbishley S.M.
      • Tomlinson J.W.
      • et al.
      Vascular adhesion protein-1 promotes liver inflammation and drives hepatic fibrosis.
      Currently, a single-arm, 2-stage, open-label, multicentre phase II clinical trial is being conducted, in which the safety and activity of timolumab (BTT1023), a fully human, monoclonal antibody against VAP-1, is being investigated in patients with PSC.
      • Arndtz K.
      • Corrigan M.
      • Rowe A.
      • Kirkham A.
      • Barton D.
      • Fox R.P.
      • et al.
      Investigating the safety and activity of the use of BTT1023 (Timolumab), in the treatment of patients with primary sclerosing cholangitis (BUTEO): a single-arm, two-stage, open-label, multi-centre, phase II clinical trial protocol.
      To date, no data on efficacy are available.

      Other compounds

      Natalizumab was the first antibody developed to interfere with gut-homing. It targets the α4 integrin, thereby blocking both binding of α4β7 to MAdCAM-1, as well as α4β1 to VCAM-1. After approval of natalizumab for CD, a report of progressive multifocal leukoencephalopathy due to activation of the JC virus (human polyomavirus 2) was published, which was attributed to inhibition of α4β1 dependent homing via VCAM-1 in the central nervous system.
      • Van Assche G.
      • Van Ranst M.
      • Sciot R.
      • Dubois B.
      • Vermeire S.
      • Noman M.
      • et al.
      Progressive multifocal leukoencephalopathy after natalizumab therapy for Crohn's disease.
      The use of natalizumab for CD is only registered in the US. Cilofexor, a non-steroidal farnesoid X receptor (FXR) agonist, has recently been tested for the treatment of PSC in a phase II study, in which it led to significant improvement in liver biochemistries and markers of cholestasis.
      • Trauner M.
      • Gulamhusein A.
      • Hameed B.
      • Caldwell S.
      • Shiffman M.L.
      • Landis C.
      • et al.
      The nonsteroidal farnesoid X receptor agonist cilofexor (GS-9674) improves markers of cholestasis and liver injury in patients with primary sclerosing cholangitis.
      Its potential interference with lymphocyte trafficking was shown in mice, in which treatment with obeticholic acid, another FXR agonist, showed a reduction of α4β1 expression on both T and B cells in the spleen.
      • Ho P.P.
      • Steinman L.
      Obeticholic acid, a synthetic bile acid agonist of the farnesoid X receptor, attenuates experimental autoimmune encephalomyelitis.
      Another homing-interfering small molecule, which has been studied in IBD was vercirnon (CCX282-B), a CCR9 antagonist. Clinical studies for the treatment of CD did not demonstrate efficacy.
      • Feagan B.G.
      • Sandborn W.J.
      • D'Haens G.
      • Lee S.D.
      • Allez M.
      • Fedorak R.N.
      • et al.
      Randomised clinical trial: vercirnon, an oral CCR9 antagonist, vs. placebo as induction therapy in active Crohn's disease.
      There are no data on natalizumab, nor vercinon, for patients with PSC.

      Conclusions

      In the past decade, gradual steps towards unravelling the aberrant gut-homing hypothesis have been taken. The proposed mechanism involving recruitment of gut-primed T cells expressing integrin α4β7 towards the liver in PSC is influenced by expression and upregulation of several adhesion molecules and chemokine receptors. Although there are some differences in lymphocyte subsets present in the small intestine and colon of patients with PSC-IBD, no significant differences involving chemokines or adhesion molecules have been observed in the gut, specifically for PSC-IBD compared to IBD in general. This suggests that the origins of the aberrant gut-homing in PSC should likely be sought in the liver. Fig. 1 presents a putative overview of which factors may play a role in this aberrant homing.
      It must be noted that virtually all of the data comes from observational studies. In order to advance our understanding, given the lack of a proper inflammatory animal model of PSC, clinical trials of compounds that interfere with these homing mechanisms are warranted to really tease out which pathways/cell types matter in causing and/or maintaining portal inflammation in PSC.

      Financial support

      WJDJ received research grants from Glaxo Smith Kline , Gut Research Services BV , Reckitt Benckiser , GenDX , and Galvani Bioelectronics BV . CYP received research grants form Takeda , speaker’s fees from Takeda, Tillotts , and Abbvie , and consultancy fees form Takeda and Pliant . MEW received grants from Glaxo Smith Kline, grants and personal fees from Tillotts Pharma, and personal fees from Takeda.

      Conflict of interest

      The authors declare no conflicts of interest that pertain to this work.
      Please refer to the accompanying ICMJE disclosure forms for further details.

      Supplementary data

      The following are the Supplementary data to this article:

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