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Pathology International 2015; 65: 344–354
doi:10.1111/pin.12294
Review Article
Lymphocyte ‘homing’ and chronic inflammation
Yasuhiro Sakai and Motohiro Kobayashi Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV-like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV-like vessel-mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others. Key words: autoimmune pancreatitis, chronic inflammation, Helicobacter pylori gastritis, high endothelial venule (HEV), inflammatory bowel disease (IBD), lymphocyte homing, MALT lymphoma, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), peripheral lymph node addressin (PNAd), tertiary lymphoid tissue.
Correspondence: Motohiro Kobayashi, MD, PhD, Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui 910-1193, Japan. Email: [email protected] Received 28 October 2014. Accepted for publication 4 March 2015. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
It is well-established that inflammatory disorders have their roots in infiltration of tissue by inflammatory cells, and lymphocyte infiltration is a critical step in tissue damage resulting from chronic inflammation. Thus, it is important to clarify how lymphocytes emigrate from the bloodstream to inflamed tissues in order to understand any chronic inflammatory disorder. Extravascular lymphocyte migration is not an unusual event: even in non-inflammatory states, lymphocytes are mobilized to lymph nodes, tonsils or Peyer’s patches, tissues known as peripheral (or secondary) lymphoid organs.1 However, in chronic inflammation, exceptional lymphocyte migration occurs largely in non-lymphoid tissues that do not recruit significant numbers of lymphocytes under normal conditions. Lymphocytes continuously recirculate from lymph nodes, through the lymph stream, into the bloodstream, and back to lymph nodes as a systemic mechanism of immune surveillance. Physiological lymphocyte migration occurs when lymphocytes home to lymph nodes, that is, move from the bloodstream to lymphoid parenchyma.2 Some have compared this process to the homing of salmon, which is guided by odor: juvenile fish are imprinted with the chemical odor of their natal river, which attracts them during the spawning season. This hypothesis was supported by the work of Scholz et al. in 1976,3 who raised two groups of coho salmon (Oncorhynchus kisutch), one with morpholine and the other with phenethyl alcohol in the hatchery. After releasing the fish in Lake Michigan between two rivers, they perfumed one river with morpholine and the other with phenethyl alcohol. At spawning season, salmon exposed to morpholine ran to the morpholine-scented river, and those exposed to phenethyl alcohol migrated to the other. Lymphocyte homing is very similar: lymphocytes return to lymph nodes guided by vascular addressin, a glycoprotein expressed on specialized venules in peripheral lymphoid organs.4,5 These venules are remarkable due to the height of their endothelial cells, which differ from the flat endothelial cells seen in typical venules; thus, they are termed high endothelial venules (HEVs).6 Vascular addressins on HEVs
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Figure 1 Schematic representation of the sequential adhesive interaction between circulating lymphocytes and high endothelial venule (HEV) endothelial cells in lymphocyte migration. The process consists of four phases: (i) tethering and rolling, mediated by the interaction between vascular addressins (6-sulfo sialyl Lewis X on peripheral lymph node addressin (PNAd) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1)) and lymphocyte homing receptors (L-selectin and integrins in low-affinity form); (ii) lymphocyte activation by chemokines resulting in a conformational change of integrins to high-affinity form; (iii) arrest, marked by a firm attachment of lymphocytes to the HEV luminal surface mediated by integrins in high-affinity form and cell adhesion molecules; and (iv) lymphocyte transmigration across HEVs.
are considered a molecular landmark or ‘zip-code’ to show lymphocytes where to migrate. Only lymphocytes expressing a homing receptor that adheres to particular vascular addressin can initiate interaction with HEVs, resulting in a multistep migration process (Fig. 1). In chronic inflammation, resultant migration of circulating lymphocytes is required to eliminate pathogenic microorganisms or neoplastic cells, even if the inflamed sites are outside of lymphoid tissue. In these cases, venular endothelial cells at inflamed sites upregulates vascular addressin expression and become taller, and venules begin to resemble HEVs.7–12 Consequently, lymphocytes recognize these HEV-like vessels in inflamed tissue as a second target and thus ‘home’ to them, employing mechanisms used in physiological lymphocyte migration. In other words, inflamed tissues originating in what were once normal non-lymphoid tissues are integrated into the lymphatic system, and lymphoid tissue similar to peripheral lymphoid organs, what we call tertiary lymphoid tissue, is formed by lymphocyte ‘homing’ through HEV-like vessels.13 Here we focus on the mechanism of physiological lymphocyte homing to peripheral lymphoid organs through HEVs, especially on the tethering and rolling step. We then provide examples of induction of HEV-like vessels in chronic inflammatory diseases, and describe how these vessels function in initiation and maintenance of lymphocyte recruitment similar to lymphocytes migrating under physiological conditions to peripheral lymphoid organs. MECHANISM OF LYMPHOCYTE MIGRATION VIA HIGH ENDOTHELIAL VENULES IN PERIPHERAL LYMPHOID ORGANS Lymphocyte migration is regulated by a multistep process mediated by sequential interactions between endothelial
cells comprising HEVs and circulating lymphocytes (Fig. 1). It is generally accepted that the process consists of four phases: (i) tethering and rolling, caused by adhesion of vascular addressins on HEVs to corresponding homing receptors expressed on lymphocytes, resulting in decreased velocity of lymphocytes in the bloodstream; (ii) activation, in which lymphocytes are stimulated by chemokines resulting in expression of high-affinity forms of integrins; (iii) arrest, marked by adhesion between cell adhesion molecules on HEVs and integrins on lymphocytes and resulting in firm attachment of lymphocytes to the luminal surface of HEVs; and (iv) transmigration of lymphocytes across HEVs.14,15 Of these steps, the tethering and rolling step mediated by vascular addressins is critical, and loss of glycoproteins functioning in this process may result in substantially reduced lymphocyte homing.16,17 Because vascular addressins function similarly to an address in HEVs of lymphoid tissue, investigators once proposed that there are several kinds of site-specific vascular addressins.18,19 Now, researchers recognize that there are two major types: (i) peripheral lymph node addressin (PNAd), expressed on HEVs predominantly in peripheral lymph nodes and tonsils; and (ii) mucosal addressin cell adhesion molecule 1 (MAdCAM-1), which under normal conditions is expressed only in gut-associated lymphoid tissue (GALT) including mesenteric lymph nodes, Peyer’s patches and gut lamina propria.18,20–24
Peripheral lymph node addressin (PNAd) PNAd is expressed on the HEV luminal surface, particularly in peripheral lymph nodes and tonsils. Studies show that
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Figure 2 Schematic representation of the carbohydrate moiety of peripheral lymph node addressin (PNAd). Both extended core 1 (GlcNAcβ1→3Galβ1→3GalNAcα1→Ser/Thr) and core 2-branched O-glycans (GlcNAcβ1→6(Galβ1→3)GalNAcα1→Ser/Thr) are capped with 6-sulfo sialyl Lewis X. Epitopes for the following antibodies are shown with boxes: MECA-79 (recognizing 6-sulfo N-acetyllactosamine attached to extended core 1 O-glycans), HECA452 (recognizing sialyl Lewis X) and NCC-ST-439 (recognizing sialyl , MECA-79; Lewis X attached to core 2-branched O-glycans). , HECA-452; , NCC-ST-439. Adapted from J Pathol 2011; 224: 67–77.66 Copyright (2015) Pathological Society of Great Britain and Ireland.
PNAd consists of a set of glycoproteins including CD34, podocalyxin-like protein, endomucin and nepmucin decorated with 6-sulfo sialyl Lewis X-capped glycans: Siaα2→ 3Galβ1→4[Fucα1→3(sulfo→6)]GlcNAcβ1→R (Fig. 2).18,20–23 L-selectin is a homing receptor found on lymphocytes, particularly naïve and central memory T and B lymphocytes, which acts as a ligand for 6-sulfo sialyl Lewis X.19 This binding initiates tethering and rolling of L-selectin-expressing lymphocytes on the luminal surface of PNAd+ HEVs, leading to selective lymphocyte migration, primarily in peripheral lymph nodes.18–23 As shown in Figure 2, the PNAd carbohydrate moiety includes 6-sulfo sialyl Lewis X attached to extended core 1 O-glycans, namely, Siaα2→3Galβ1→4[Fucα1→3(sulfo→6)] GlcNAcβ1→3Galβ1→3GalNAcα1→Ser/Thr, or 6-sulfo sialyl Lewis X attached to core 2-branched O-glycans, specifically, Siaα2→3Galβ1→4[Fucα1→3(sulfo→6)]GlcNAcβ1→6(Galβ1 →3)GalNAcα1→Ser/Thr. Both of these function as L-selectin ligands and contribute to lymphocyte tethering and rolling. Fucosylation and sulfation of the carbohydrate component of glycoproteins are especially crucial. α1,3-fucosylation of N-acetylglucosamine (GlcNAc) is catalyzed by the α1,3-fucosyltransferases (FUT) 4 and 7, whereas GlcNAc6-O-sulfation is mediated by N-acetylglucosamine-6-Osulfotransferases 1 (GlcNAc6ST-1) and 2 (GlcNAc6ST-2, also known as L-selectin ligand sulfotransferase (LSST)).16,17,25,26 GlcNAc-6-O-sulfation has received considerable attention because it is thought that sulfation regulates binding activity to L-selectin.16,17,26,27
Antibodies are available to detect particular carbohydrate structures on PNAd (Fig. 2). The monoclonal antibody MECA-79, which recognizes 6-sulfo N-acetyllactosamine attached to extended core 1 O-glycans Galβ1→4[Fucα1 →3(sulfo→6)]GlcNAcβ1→3Galβ1→3GalNAcα1→Ser/Thr, is a widely used HEV marker.18,22 In addition, the monoclonal antibodies HECA-452 (which recognizes sialyl Lewis X on both extended core 1 and core 2-branched O-glycans as well as that on N-glycans, Siaα2→3Galβ1→4(Fucα1→3) GlcNAcβ1→R), and NCC-ST-439 (which recognizes sialyl Lewis X attached to core 2-branched O-glycans regardless of GlcNAc-6-O-sulfation, Siaα2→3Galβ1→4(Fucα1→3) GlcNAcβ1→6(Galβ1→3)GalNAcα1→Ser/Thr), can detect both HEVs and HEV-like vessels.28
Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) MAdCAM-1, a 60-kD glycoprotein, was originally characterized as a vascular addressin expressed on HEVs in GALT.24 It was once named ‘mucosal addressin (MAd)’ as it was considered to function in recruitment of particular lymphocyte subsets involved in mucosal immunity.19,24 Subsequent studies demonstrated a dual function for MAdCAM-1 as both a vascular addressin functioning in the tethering and rolling step and a cell adhesion molecule participating in arrest step of lymphocyte homing. A major MAdCAM-1 ligand is the α4β7 integrin.29 Integrins are usually expressed on the leukocyte surface as a lowaffinity form. When MAdCAM-1 functions as vascular addressin, weak binding between it and the low-affinity form of α4β7 integrin triggers lymphocyte tethering and rolling.30,31 In addition, when MAdCAM-1 is post-translationally decorated with 6-sulfo sialyl Lewis X-capped carbohydrates at its mucin-like domain, it becomes MECA-79-positive and functions as an L-selectin ligand. Once lymphocytes are activated by chemokines produced by HEV endothelial cells, α4β7 integrin undergoes a conformational change to a high-affinity form. Highaffinity α4β7 integrin binds to MAdCAM-1 so firmly that lymphocytes arrest on the HEV luminal surface.30 Hence, MAdCAM-1’s function as either a vascular addressin or a cell adhesion molecule depends on the affinity state of α4β7 integrin. Because α4β7 integrin binds MAdCAM-1 at two steps of lymphocyte migration, it serves as a marker of lymphocytes destined to migrate into GALT. In particular, memory T and B lymphocytes, as well as some effector lymphocytes activated in GALT express α4β7 integrin, and these lymphocytes may function in immune surveillance and elimination of pathogens in gut mucosa.30,32
© 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
Leukocyte ‘homing’ and inflammation
MECHANISM OF LYMPHOCYTE MIGRATION VIA HIGH ENDOTHELIAL VENULE-LIKE VESSELS TO INFLAMED TISSUES As noted, chronic inflammation is characterized by the conversion of non-lymphoid to lymphoid tissue (formation of tertiary lymphoid tissues), enabling lymphocyte recruitment. This activity amplifies and propagates the immune response when tissue undergoes prolonged exposure to injurious stimuli such as pathogens, autoimmune damage or mechanical injury. Its initial phase is a morphological and functional change of postcapillary venules into HEV-like vessels in order to augment lymphocyte migration. As discussed below, endothelial cells in such pathologic conditions express several distinct adhesion molecules involved in lymphocyte recruitment.7–12 Vascular addressins (PNAd and MAdCAM-1) Expression of PNAd on venular endothelial cells in nonlymphoid tissues is induced in the process of chronic inflammation. When chronic inflammation is either absent or weak, decoration of PNAd core proteins with 6-sulfo sialyl Lewis X carbohydrates is defective on venular endothelial cells, making these venules less adhesive to L-selectin. However, once active chronic inflammation is initiated, several cytokines such as tumor necrosis factor (TNF)-α and lymphotoxin-α/β act on the venular endothelial cells to transform them into HEV-like vessels. These cytokines reportedly increase expression of GlcNAc6ST-2, and possibly GlcNAc6ST-1 as well, in endothelial cells, resulting in GlcNAc-6-O-sulfation in the sialyl Lewis X moiety.33 Consequently, these venules express complete 6-sulfo sialyl Lewis X, acquiring an ability to bind L-selectin on lymphocytes. These venular transformation to HEV-like vessels impacts in the formation of tertiary lymphoid tissues. It is noteworthy that, in chronic abdominal inflammation, expression levels of MAdCAM-1 on HEV-like vessels is also upregulated by proinflammatory cytokines such as TNF-α, interleukin (IL)-1β and IL-10.34,35 In addition, these MAdCAM-1 proteins can be glycosylated with 6-sulfo sialyl Lewis X-capped carbohydrates at its mucin-like domains as abdominal inflammation develops.9,11 Thus, lymphocyte tethering and rolling in abdominal inflammation is mediated by two independent molecular interactions: one between MAdCAM-1 and low-affinity α4β7 integrin, and the other between 6-sulfo sialyl Lewis X-capped glycans and L-selectin. This set of adhesive interactions is reminiscent of that controlling GALT-selective lymphocyte homing. Other molecules expressed on endothelial cells Both E- and P-selectins function as vascular addressins for a subset of memory and effector T lymphocytes when chronic
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inflammation is triggered. When proinflammatory cytokines TNF-α and IL-1 stimulate venular endothelium at sites of inflammation, the endothelial cells express these selectins.36 Cutaneous lymphocyte antigen (CLA),37–41 or P-selectin glycoprotein ligand 1 (PSGL-1)42–44 decorated with HECA452 carbohydrates, is expressed on memory and effector T lymphocytes as well as neutrophils and monocytes, and interact with E- and P-selectins, resulting in tethering and rolling of such leukocytes along the endothelial luminal surface. Hyaluronic acid is another vascular addressin whose ligand CD44 is expressed on memory and effector T lymphocytes.45,46 Expression of hyaluronic acid on endothelial cells is upregulated during inflammation by proinflammatory cytokines TNF-α, IL-1, IL-15 and bacterial lipopolysaccharide.47,48 This adhesive interaction plays an important role in T-lymphocyte recruitment to inflamed tissues, and reportedly contributes to lymphocyte recruitment to skin in acute graftversus-host disease (GVHD).49
HIGH ENDOTHELIAL VENULE-LIKE VESSELS IN CHRONIC INFLAMMATION Lymphocyte recruitment and consequent formation of tertiary lymphoid tissues occurs in most chronic inflammatory disorders,13 and in fact, is implicated in rheumatoid arthritis,50 Helicobacter pylori gastritis,7 inflammatory bowel disease (IBD) including ulcerative colitis and Crohn disease,8,9 autoimmune pancreatitis and sclerosing sialadenitis,11 according to the morphological, immunohistochemical and molecularbiological analysis of the activity of HEV-like vessels in these inflammatory conditions as discussed below.
Helicobacter pylori gastritis Chronic gastritis is a chronic inflammatory response to prolonged injurious stimuli in gastric mucosa,51 the most common being the spiral-shaped bacillus Helicobacter pylori, which infects over half the world’s population.52,53 Virulent products of H. pylori such as flagella, urease, adhesins and toxins induce chronic inflammation by initiating, maintaining and enhancing conversion of gastric mucosa to tertiary lymphoid tissue known as mucosa-associated lymphoid tissue (MALT).51,54 It is widely recognized that long-standing chronic gastritis is a precancerous condition that increases the risk of extranodal marginal zone lymphoma of MALT type (MALT lymphoma) and gastric carcinoma.51 To initiate and maintain MALT formation in gastric mucosa requires induction of HEV-like vessels. As shown in Figure 3, MALT formation is marked by appearance of venules composed of cuboidal endothelial cells with enlarged nuclei,
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Intriguingly, the number of HEV-like vessels induced in H. pylori gastritis is positively correlated with extent of inflammation.7 MECA-79+/HECA-452+ HEV-like vessels are induced in and around significant lymphocyte infiltrates in the lamina propria at the marked stage of chronic inflammation, whereas most venules do not show such positivity at the mild stage, as assessed by the updated Sydney system, which classifies inflammation into normal, mild, moderate and marked stages based on degree of mononuclear cell infiltration including lymphocytes and plasma cells.7,55 The number of MECA-79+/HECA-452+ HEV-like vessels, as well as the number of patients showing induction of these vessels, increases as chronic inflammation progresses.7 These results suggest that HEV-like vessels regulate the size and quantity of MALT and thus the consequent intensity of chronic inflammation. Once injurious stimuli are eliminated, or when expression of proinflammatory cytokines is reduced by anti-inflammatory drugs, HEV-like vessels transform back into normal venules, and consequently, MALT decreases in size and eventually disappears.7 Retrospective histological study shows that, after H. pylori eradication by treatment with antibiotics (amoxicillin and clarithromycin) and a proton pomp inhibitor (rabeprazole), H. pylori gastritis patients who once displayed MECA-79+/HECA-452+ HEV-like vessels no longer display such vessels and show only minimal lymphocyte infiltration.7
Ulcerative colitis
Figure 3 Immunohistochemistry of high endothelial venule (HEV)like vessels induced in human Helicobacter pylori gastritis. CD31 and CD34 mark vascular endothelial cells; MECA-79+, HECA-452+ and NCC-ST-439+ carbohydrates are expressed on HEV-like vessels. Land E-selectin•IgM chimeras both bind to the endothelial cells in the absence of EDTA. Counterstained by hematoxylin. HE, hematoxylin and eosin stain. Scale bar = 10 μm. Adapted from Proc Natl Acad Sci U S A 2004; 101: 17807-12.7 Copyright (2015) National Academy of Sciences, U.S.A.
which are morphologically similar to HEVs seen in peripheral lymphoid organs,7 and these vessels are located chiefly in T-cell zones. In addition, like HEVs, these HEV-like vessels express 6-sulfo sialyl Lewis X attached to both extended core 1 and core 2-branched O-glycans that constitute PNAd, as they stain positively for MECA-79, HECA-452 and NCC-ST439.7 Moreover, in vitro binding assays suggest that these vessels recruit L-selectin-expressing lymphocytes, as both L-selectin•IgM and E-selectin•IgM chimeras bind these vessels in a calcium-dependent manner.7 These results indicate that HEV-like vessels induced in H. pylori gastritis potentially contribute to lymphocyte migration and thus formation and maintenance of MALT.
Inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn disease are chronic inflammatory conditions resulting from inappropriate mucosal immune activation.51 Although their etiopathogenesis has not been precisely defined, many investigators believe that IBDs result from multiple causes including unusual intestinal microbial flora, intestinal epithelial dysfunction and/or autoimmune mucosal responses with or without genetic factors.51 Ulcerative colitis and Crohn disease share common histological features, including chronic mononuclear inflammatory cell infiltrates composed mainly of lymphocytes and plasma cells with occasional formation of lymphoid follicles.51 Lesion distribution, however, differs between the two diseases: in ulcerative colitis distribution is diffuse, continuous and limited to the mucosa and superficial submucosa, whereas in Crohn disease lesions occur in multiple, separate transmural areas with non-caseating granulomas.51,56 HEV-like vessels expressing MAdCAM-1, which are usually displayed selectively in GALT, are induced preferentially in inflamed sites of IBDs.9 This histopathological finding indicates that lymphocyte recruitment in inflamed intestinal mucosa is governed by mechanisms similar to those seen in physiological lymphocyte homing to GALT. Moreover in the
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Figure 4 Immunohistochemistry of high endothelial venule (HEV)-like vessels induced in human ulcerative colitis. Blood vessels in colonic mucosa were immunostained with CD34 antibody. In the active phase, mucosal addressin cell adhesion molecule 1 (MAdCAM-1)+ HEV-like vessels are present, some of which express MECA-79+ carbohydrates (upper panels). In the remission phase, MAdCAM-1 expression is maintained, whereas MECA-79 expression is decreased (lower panels). Counterstained by hematoxylin. HE, hematoxylin and eosin stain. Scale bar = 50 μm. Adapted from Inflamm Bowel Dis 2009; 15: 697–706 with permission.9
case of ulcerative colitis, MAdCAM-1 proteins can be posttranslationally glycosylated with MECA-79+ 6-sulfo sialyl Lewis X-capped carbohydrates, especially in the active phase (Fig. 4).9 This observation is supported by MECA-79positive immunoblotting of lysates from Lec2 cells transiently transfected with cDNA encoding MAdCAM-1•IgG together with core 1 extending β1,3-N-acetylglucosaminyltransferase (Core1-β3GlcNAcT) and GlcNAc6ST-1 after immunoprecipitation of MAdCAM-1.9 In addition, glycosylated MAdCAM-1 can bind L-selectin-expressing lymphocytes, because L-selectin•IgM and E-selectin•IgM chimeras bind these vessels calcium-dependently.9 Hence, HEV-like vessels induced in the active phase of ulcerative colitis can potentially recruit not only α4β7 integrin-expressing lymphocytes but also L-selection-expressing lymphocytes. As noted, expression levels of the MECA-79 glycoepitope on HEV-like vessels correlate with inflammation intensity. Indeed, our statistical analysis revealed that the frequency of MECA-79+ vessels observed in the lamina propria was significantly greater in active versus remission phases in ulcerative colitis.8,9 In active phase, expressions of GlcNAc6STs, most likely GlcNAc6ST-1, is upregulated in venular endothelial cells to complete 6-sulfo sialyl Lewis X biosynthesis.8,9 On the other hand, unlike HEVs in peripheral lymphoid organs, GlcNAc6ST-2 is not robustly induced in venular endothelial cells of inflamed gut mucosa:8,9 GlcNAc6ST-1 is broadly expressed among lymphoid and non-lymphoid tissues, whereas GlcNAc6ST-2 expression is restricted to endothelial cells found in HEVs in peripheral lymphoid organs. Also, GlcNAc6ST-1 catalyzes GlcNAc-6-O-sulfation preferentially on MAdCAM-1 but not on CD34, while GlcNAc6ST-2 substrates are both core proteins i.e. CD34 and MAdCAM-1, as well as endogenous membrane proteins of Lec2 cells (Fig. 5).9,57,58 By contrast, MAdCAM-1 expression on HEV-like vessels is not associated with inflammation intensity (Fig. 4). The
number of MAdCAM-1+ HEV-like vessels in ulcerative colitis is significantly greater than that seen in normal colonic mucosa; however, that number reportedly does not differ significantly between active and remission phases.9 Some have proposed that MAdCAM-1 is upregulated on venules as ulcerative colitis develops and that this expression persists regardless of disease activity, whereas L-selectin ligand biosynthesis on MAdCAM-1 increases in the active phase but decreases when symptoms are relieved.9 Specific lymphocyte subsets recruited via HEV-like vessels have recently been identified.8,10,12 With respect to ulcerative colitis, the number of CD3+ T cells attached to the luminal surface of MECA-79+ HEV-like vessels was greater than that of CD20+ and/or CD79α+ B cells, with high statistical significance.8 Moreover, the number of CD4+ helper T cells in these tissues greatly exceeded the number of CD8+ cytotoxic T cells.8 These results are anticipated, as helper T lymphocytes must be preferentially recruited in order to stimulate B lymphocytes, cytotoxic T lymphocytes and regulatory T lymphocytes, and eventually facilitate an adaptive immune response. The selectivity of HEV-like vessels for this type of lymphocyte recruitment is regulated by activation step of lymphocyte migration by chemokines such as the C-C motif chemokine ligand 19 (CCL19) and CCL21 and the C-X-C motif chemokine ligand 13 (CXCL13).59–61
Autoimmune pancreatitis and sclerosing sialadenitis Autoimmune pancreatitis is prolonged chronic inflammation and irreversible destruction of pancreatic tissue. This condition is pathogenically distinct from chronic pancreatitis caused by alcohol abuse, long-standing obstruction of the pancreatic duct or hereditary factors, as the former is closely associated with the presence of IgG4-secreting plasma cells.62,63 Autoimmune pancreatitis is a manifestation of
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Figure 5 Groups of Lec2 cells were transiently transfected with expression vectors encoding the core proteins CD34 (middle panels) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) (bottom panels) or vector only (pcDNA1; mock) (top panels). Each group is also transfected with β1,3-N-acetylglucosaminyltransferase plus either N-acetylglucosamine 6-O-sulfotransferase 1 (GlcNAc6ST-1, middle panels) or GlcNAc6ST-2 (right panels) expression vectors or vector only (pcDNA1; mock) (left panels), and analyzed using double immunofluorescence for the presence of the core proteins CD34 or MAdCAM-1 (red signals) and the MECA-79 glycoepitope (green signals). GlcNAc6ST-2 catalyzes GlcNAc-6-O-sulfation on N-acetyllactosamine attached to extended core 1 O-glycans (detected by MECA-79 antibody) on all core proteins examined, including Lec2 cell membrane proteins (right panels). GlcNAc6ST-1 catalyzes GlcNAc-6-O-sulfation only on MAdCAM-1 but not on CD34 and Lec2 cell membrane proteins (middle panels). Scale bar = 50 μm. Adapted from Inflamm Bowel Dis 2009; 15: 697–706 with permission.9
IgG4-related disease and occasionally accompanied by other IgG4-related diseases, such as sclerosing sialadenitis. Autoimmune pancreatitis commonly affects the head of the pancreas with duct-centric lymphoplasmacytic infiltration, dense storiform fibrosis and acini loss, often resulting in stenosis and obstruction of the large pancreatic duct and obstructive jaundice. In both autoimmune and chronic pancreatitis, marked lymphocyte infiltration eventually forms tertiary lymphoid tissues resembling GALT, although plasma cell differentiation is particularly prominent in autoimmune pancreatitis, and this similarity underlies HEV-like vessel induction. Such HEV-like vessels are MECA-79-positive, and some are also MAdCAM1-positive, like HEVs in GALT.11 In agreement with the observation that the MECA-79 glycoepitope on HEV-like vessels parallels the extent of inflammation, a recent study showed that the number of MECA-79+ vessels induced in autoimmune pancreatitis exceeded that seen in chronic pancreatitis, whereas the number of MAdCAM-1+ vessels seen in both diseases was comparable.11 Hence, the etiopathogenesis of chronic inflammation may modulate expression or biosynthesis of L-selectin ligands on HEV-like vessels. Sclerosing sialadenitis also indicates IgG4-related disease and sometimes develops as an extra-pancreatic lesion of autoimmune pancreatitis. Histopathological manifestation of sclerosing sialadenitis is similar to that of autoimmune pancreatitis and includes marked lymphocyte infiltration with IgG4-secreting plasma cell differentiation, dense storiform fibrosis and acini atrophy. The appearance and distribution of
MECA-79+ HEV-like vessels in sclerosing sialadenitis also resembles that seen in autoimmune pancreatitis, namely, significant numbers of MECA-79+ HEV-like vessels are induced around medium- to large-sized salivary ducts.11
Extra-nodal marginal zone lymphoma of MALT type (MALT lymphoma) Here, we broaden the definition of chronic inflammation to include lymphocyte neoplasms, namely, lymphoma. In the case of low-grade lymphoma such as MALT lymphoma, lymphoma cell infiltration of affected tissue mimics that seen in peripheral lymphoid organs, similar to the case of chronic inflammation. Thus, lymphoma can be regarded as a ‘malignant chronic inflammation’: lymphoma progression may be analogous to the process of lymphocyte migration in chronic inflammation, in that venules transform into HEV-like vessels that express vascular addressin, which contributes to tethering and rolling of lymphocytes and/or lymphoma cells, and triggers the type of sequential adhesive interactions previously described. This activity results in marked lymphocyte and/or lymphoma cell recruitment reminiscent of that seen in peripheral lymphoid organs. Although extranodal lymphomas occur in various tissues, they arise most commonly in the gastrointestinal tract, particularly the stomach, and their most common histological type is MALT lymphoma.51 As noted, gastric MALT lymphoma arises in the context of chronic gastritis, and in most cases is caused by H. pylori infection. Because H. pylori eradication following
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Figure 6 Immunohistochemistry of high endothelial venule (HEV)-like vessels induced in (a) human Helicobacter pylori gastritis and (b) human gastric MALT lymphoma. In H. pylori gastritis, more than half of MECA-79+ HEV-like vessels are HECA-452-/NCC-ST-439-. By contrast, in gastric MALT lymphoma, MECA-79-/HECA-452+/NCC-ST-439+ vessels are frequently observed. Scale bar = 200 μm. Adapted from J Pathol 2011; 224: 67–77.66 Copyright (2015) Pathological Society of Great Britain and Ireland.
treatment results in durable remission without recurrence in approximately 75% cases, especially cases showing infiltration of FOXP3+ regulatory T cells, gastric MALT lymphoma can be classified as an intermediary condition between a neoplasm and chronic inflammation.54,64,65 HEV-like vessels are induced in gastric MALT lymphoma as with H. pylori gastritis, but interestingly, the carbohydrate structure expressed on HEV-like vessels induced in these conditions differs.66 Immunohistochemical analysis shows that MECA-79-/HECA-452+/NCC-ST-439+ HEV-like vessels are frequently observed in gastric MALT lymphoma, whereas most HEV-like vessels in H. pylori gastritis are MECA-79positive (Fig. 6).66 Thus, MALT lymphoma is characterized by expression of a unique carbohydrate moiety of PNAd. The MECA-79-/HECA-452+/NCC-ST-439+ immunohistochemical profile suggests defects in GlcNAc-6-O-sulfation catalyzed by GlcNAc6STs and/or in core 1 extension catalyzed by Core1-β3GlcNAcT,22 while the mechanism has not been fully understood. However, two experiments show that the unusual MECA-79-/HECA-452+/NCC-ST-439+ carbohydrate structure, 6-sulfo or non-sulfated sialyl Lewis X attached to only core 2-branched O-glycans, can also bind L-selectin, as well as MECA-79+ carbohydrates. One showed that the L-selectin•IgM chimera binds to CHO/CD34/F7/C2/ LSST and CHO/CD34/F7/C2 engineered cell lines on whose surface CD34 protein is decorated with MECA-79-/HECA452+/NCC-ST-439+ carbohydrates.66 The other showed that L-selectin-expressing lymphocytes adhere to the cell surface in these lines, and that binding is lost following treatment with sialidase, Dreg-56 (an anti-L-selectin monoclonal antibody) and EDTA (Fig. 7).66 In what we term a ‘malignant chronic inflammation,’ MECA-79- HEV-like vessels, although unusual, are induced and function as an L-selectin ligand, and likely contribute to lymphoma cell migration.
It is reported that MAdCAM-1 is also expressed on HEVlike vessels in gastric MALT lymphoma.67 Since MALT lymphoma cells express α4β7 integrin,67,68 integrin-MAdCAM-1 interaction may also play an important role in lymphoma cell migration in gastric MALT lymphoma. By contrast, HEV-like vessels induced in MALT lymphoma of ocular adnexa are negative for MAdCAM-1.67 Hence, expression levels of MAdCAM-1 on HEV-like vessels in MALT lymphoma may differ from organ to organ.
CONCLUSIONS Accumulated knowledge strongly suggests that HEV-like vessels are inevitably induced where marked lymphocyte infiltration is observed over the course of chronic inflammation. HEV-like vessels contribute to initiation, maintenance and enhancement of chronic inflammation via lymphocyte migration mediated by sequential adhesive interactions similar to those seen in physiological lymphocyte homing. Vascular addressins expressed on HEV-like vessels play an important role in the tethering and rolling step of lymphocyte migration, and their presence reflects the extent of chronic inflammation. In particular, expression of MECA-79+ carbohydrates is correlated with the intensity of chronic inflammation. We present a new perspective that chronic inflammation occurs with the similar approach of physiological lymphocyte homing and that inflamed tissue is converted to tertiary lymphoid tissues, which resembles peripheral lymphoid organs in many aspects. Further studies of chronic inflammation mediated by HEV-like vessels are required to clarify and further define mechanisms governing lymphocyte homing relevant to pathological states.
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Figure 7 Lymphocyte adhesion to Chinese hamster ovary (CHO) cell lines mis-expressing various carbohydrates. We established CHO cells stably transfected with CD34 and various combinations of α1,3-fucosyltransferase 7 (F7), β1,6-N-acetylglucosaminyltransferase 1 (C2) and N-acetylglucosamine 6-O-sulfotransferase 2 (LSST). Control CHO/CD34 cells (a) are negative for any MECA-79, HECA-452 and NCC-ST-439 carbohydrates, whereas CHO/CD34/F7/C2 cells (b) and CHO/CD34/F7/C2/LSST cells (c) are positive for HECA-452 and NCC-ST-439 carbohydrates but negative for MECA-79 carbohydrates. Lymphocyte adhesion was observed with Nomarski differential interference optics. Arrows indicate adhered lymphocytes. Note that treatments with sialidase, Dreg-56 or EDTA completely abolish lymphocyte adhesion. Scale bar = 100 μm. Adapted from J Pathol 2011; 224: 67–77.66 Copyright (2015) Pathological Society of Great Britain and Ireland.
ACKNOWLEDGMENTS The authors thank Drs. Masao Hotchi, Tsutomu Katsuyama, Jun Nakayama, and Minoru Fukuda for encouragement, and Dr. Elise Lamar for critical reading of the manuscript. Yasuhiro Sakai has been announced as a winner of the Japanese Society of Pathology’s Centennial Anniversary Award for Young Scientists in 2013. Motohiro Kobayashi is a winner of the Pathology Research Award in 2013 from the Japanese Society of Pathology.
DISCLOSURE None declared.
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46 DeGrendele HC, Kosfiszer M, Estess P, Siegelman MH. CD44 activation and associated primary adhesion is inducible via T cell receptor stimulation. J Immunol 1997; 159: 2549–53. 47 Mohamadzadeh M, DeGrendele H, Arizpe H, Estess P, Siegelman M. Proinflammatory stimuli regulate endothelial hyaluronan expression and CD44/HA-dependent primary adhesion. J Clin Invest 1998; 101: 97–108. 48 Estess P, Nandi A, Mohamadzadeh M, Siegelman MH. Interleukin 15 induces endothelial hyaluronan expression in vitro and promotes activated T cell extravasation through a CD44-dependent pathway in vivo. J Exp Med 1999; 190: 9–19. 49 Milinkovic M, Antin JH, Hergrueter CA, Underhill CB, Sackstein R. CD44-hyaluronic acid interactions mediate shear-resistant binding of lymphocytes to dermal endothelium in acute cutaneous GVHD. Blood 2004; 103: 740–42. 50 van Dinther-Janssen AC, Pals ST, Scheper R, Breedveld F, Meijer CJ. Dendritic cells and high endothelial venules in the rheumatoid synovial membrane. J Rheumatol 1990; 17: 11–7. 51 Turner JR. The gastrointestinal tract. In: Kumar V, Abbas AK, Aster JC, eds. Robbins and Cotran Pathologic Basis of Disease, 9th edn. Philadelphia: WB Saunders, 2014; 749–819. 52 Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet 1984; 1: 1311–5. 53 Brown LM. Helicobacter pylori: Epidemiology and rotes of transmission. Epidemiol Rev 2000; 22: 283–97. 54 Bayerdörffer E, Neubauer A, Rudolph B et al. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet 1995; 345: 1591–4. 55 Dixon MF, Genta RM, Yardley JH, Correa P. Classification and grading of gastritis. The updated Sydney system. Am J Surg Pathol 1996; 20: 1161–81. 56 Jinno Y, Ohtani H, Nakamura S et al. Infiltration of CD19+ plasma cells with frequent labeling of Ki-67 in corticosteroidresistant active ulcerative colitis. Virchows Arch 2006; 448: 412– 21. 57 Uchimura K, Muramatsu H, Kadomatsu K et al. Molecular cloning and characterization of an N-acetylglucosamine-6-Osulfotransferase. J Biol Chem 1998; 273: 22577–83.
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doi:10.1111/pin.12294
Review Article
Lymphocyte ‘homing’ and chronic inflammation
Yasuhiro Sakai and Motohiro Kobayashi Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, Eiheiji, Japan
Chronic inflammation is a response to prolonged exposure to injurious stimuli that harm and destroy tissues and promote lymphocyte infiltration into inflamed sites. Following progressive accumulation of lymphocytes, the histology of inflamed tissue begins to resemble that of peripheral lymphoid organs, which can be referred to as lymphoid neogenesis or formation of tertiary lymphoid tissues. Lymphocyte recruitment to inflamed tissues is also reminiscent of lymphocyte homing to peripheral lymphoid organs. In the latter, under physiological conditions, homing receptors expressed on lymphocytes adhere to vascular addressin expressed on high endothelial venules (HEVs), initiating a lymphocyte migration process composed of sequential adhesive interactions. Intriguingly, in chronic inflammation, HEV-like vessels are induced de novo, despite the fact that the inflamed site is not originally lymphoid tissue, and these vessels contribute to lymphocyte recruitment in a manner similar to physiological lymphocyte homing. In this review, we first describe physiological lymphocyte homing mechanisms focusing on vascular addressins. We then describe HEV-like vessel-mediated pathogenesis seen in various chronic inflammatory disorders such as Helicobacter pylori gastritis, inflammatory bowel disease (IBD), autoimmune pancreatitis and sclerosing sialadenitis, as well as chronic inflammatory cell neoplasm MALT lymphoma, with reference to our work and that of others. Key words: autoimmune pancreatitis, chronic inflammation, Helicobacter pylori gastritis, high endothelial venule (HEV), inflammatory bowel disease (IBD), lymphocyte homing, MALT lymphoma, mucosal addressin cell adhesion molecule 1 (MAdCAM-1), peripheral lymph node addressin (PNAd), tertiary lymphoid tissue.
Correspondence: Motohiro Kobayashi, MD, PhD, Division of Tumor Pathology, Department of Pathological Sciences, Faculty of Medical Sciences, University of Fukui, 23-3 Matsuoka-Shimoaizuki, Eiheiji, Fukui 910-1193, Japan. Email: [email protected] Received 28 October 2014. Accepted for publication 4 March 2015. © 2015 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd
It is well-established that inflammatory disorders have their roots in infiltration of tissue by inflammatory cells, and lymphocyte infiltration is a critical step in tissue damage resulting from chronic inflammation. Thus, it is important to clarify how lymphocytes emigrate from the bloodstream to inflamed tissues in order to understand any chronic inflammatory disorder. Extravascular lymphocyte migration is not an unusual event: even in non-inflammatory states, lymphocytes are mobilized to lymph nodes, tonsils or Peyer’s patches, tissues known as peripheral (or secondary) lymphoid organs.1 However, in chronic inflammation, exceptional lymphocyte migration occurs largely in non-lymphoid tissues that do not recruit significant numbers of lymphocytes under normal conditions. Lymphocytes continuously recirculate from lymph nodes, through the lymph stream, into the bloodstream, and back to lymph nodes as a systemic mechanism of immune surveillance. Physiological lymphocyte migration occurs when lymphocytes home to lymph nodes, that is, move from the bloodstream to lymphoid parenchyma.2 Some have compared this process to the homing of salmon, which is guided by odor: juvenile fish are imprinted with the chemical odor of their natal river, which attracts them during the spawning season. This hypothesis was supported by the work of Scholz et al. in 1976,3 who raised two groups of coho salmon (Oncorhynchus kisutch), one with morpholine and the other with phenethyl alcohol in the hatchery. After releasing the fish in Lake Michigan between two rivers, they perfumed one river with morpholine and the other with phenethyl alcohol. At spawning season, salmon exposed to morpholine ran to the morpholine-scented river, and those exposed to phenethyl alcohol migrated to the other. Lymphocyte homing is very similar: lymphocytes return to lymph nodes guided by vascular addressin, a glycoprotein expressed on specialized venules in peripheral lymphoid organs.4,5 These venules are remarkable due to the height of their endothelial cells, which differ from the flat endothelial cells seen in typical venules; thus, they are termed high endothelial venules (HEVs).6 Vascular addressins on HEVs
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Figure 1 Schematic representation of the sequential adhesive interaction between circulating lymphocytes and high endothelial venule (HEV) endothelial cells in lymphocyte migration. The process consists of four phases: (i) tethering and rolling, mediated by the interaction between vascular addressins (6-sulfo sialyl Lewis X on peripheral lymph node addressin (PNAd) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1)) and lymphocyte homing receptors (L-selectin and integrins in low-affinity form); (ii) lymphocyte activation by chemokines resulting in a conformational change of integrins to high-affinity form; (iii) arrest, marked by a firm attachment of lymphocytes to the HEV luminal surface mediated by integrins in high-affinity form and cell adhesion molecules; and (iv) lymphocyte transmigration across HEVs.
are considered a molecular landmark or ‘zip-code’ to show lymphocytes where to migrate. Only lymphocytes expressing a homing receptor that adheres to particular vascular addressin can initiate interaction with HEVs, resulting in a multistep migration process (Fig. 1). In chronic inflammation, resultant migration of circulating lymphocytes is required to eliminate pathogenic microorganisms or neoplastic cells, even if the inflamed sites are outside of lymphoid tissue. In these cases, venular endothelial cells at inflamed sites upregulates vascular addressin expression and become taller, and venules begin to resemble HEVs.7–12 Consequently, lymphocytes recognize these HEV-like vessels in inflamed tissue as a second target and thus ‘home’ to them, employing mechanisms used in physiological lymphocyte migration. In other words, inflamed tissues originating in what were once normal non-lymphoid tissues are integrated into the lymphatic system, and lymphoid tissue similar to peripheral lymphoid organs, what we call tertiary lymphoid tissue, is formed by lymphocyte ‘homing’ through HEV-like vessels.13 Here we focus on the mechanism of physiological lymphocyte homing to peripheral lymphoid organs through HEVs, especially on the tethering and rolling step. We then provide examples of induction of HEV-like vessels in chronic inflammatory diseases, and describe how these vessels function in initiation and maintenance of lymphocyte recruitment similar to lymphocytes migrating under physiological conditions to peripheral lymphoid organs. MECHANISM OF LYMPHOCYTE MIGRATION VIA HIGH ENDOTHELIAL VENULES IN PERIPHERAL LYMPHOID ORGANS Lymphocyte migration is regulated by a multistep process mediated by sequential interactions between endothelial
cells comprising HEVs and circulating lymphocytes (Fig. 1). It is generally accepted that the process consists of four phases: (i) tethering and rolling, caused by adhesion of vascular addressins on HEVs to corresponding homing receptors expressed on lymphocytes, resulting in decreased velocity of lymphocytes in the bloodstream; (ii) activation, in which lymphocytes are stimulated by chemokines resulting in expression of high-affinity forms of integrins; (iii) arrest, marked by adhesion between cell adhesion molecules on HEVs and integrins on lymphocytes and resulting in firm attachment of lymphocytes to the luminal surface of HEVs; and (iv) transmigration of lymphocytes across HEVs.14,15 Of these steps, the tethering and rolling step mediated by vascular addressins is critical, and loss of glycoproteins functioning in this process may result in substantially reduced lymphocyte homing.16,17 Because vascular addressins function similarly to an address in HEVs of lymphoid tissue, investigators once proposed that there are several kinds of site-specific vascular addressins.18,19 Now, researchers recognize that there are two major types: (i) peripheral lymph node addressin (PNAd), expressed on HEVs predominantly in peripheral lymph nodes and tonsils; and (ii) mucosal addressin cell adhesion molecule 1 (MAdCAM-1), which under normal conditions is expressed only in gut-associated lymphoid tissue (GALT) including mesenteric lymph nodes, Peyer’s patches and gut lamina propria.18,20–24
Peripheral lymph node addressin (PNAd) PNAd is expressed on the HEV luminal surface, particularly in peripheral lymph nodes and tonsils. Studies show that
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Figure 2 Schematic representation of the carbohydrate moiety of peripheral lymph node addressin (PNAd). Both extended core 1 (GlcNAcβ1→3Galβ1→3GalNAcα1→Ser/Thr) and core 2-branched O-glycans (GlcNAcβ1→6(Galβ1→3)GalNAcα1→Ser/Thr) are capped with 6-sulfo sialyl Lewis X. Epitopes for the following antibodies are shown with boxes: MECA-79 (recognizing 6-sulfo N-acetyllactosamine attached to extended core 1 O-glycans), HECA452 (recognizing sialyl Lewis X) and NCC-ST-439 (recognizing sialyl , MECA-79; Lewis X attached to core 2-branched O-glycans). , HECA-452; , NCC-ST-439. Adapted from J Pathol 2011; 224: 67–77.66 Copyright (2015) Pathological Society of Great Britain and Ireland.
PNAd consists of a set of glycoproteins including CD34, podocalyxin-like protein, endomucin and nepmucin decorated with 6-sulfo sialyl Lewis X-capped glycans: Siaα2→ 3Galβ1→4[Fucα1→3(sulfo→6)]GlcNAcβ1→R (Fig. 2).18,20–23 L-selectin is a homing receptor found on lymphocytes, particularly naïve and central memory T and B lymphocytes, which acts as a ligand for 6-sulfo sialyl Lewis X.19 This binding initiates tethering and rolling of L-selectin-expressing lymphocytes on the luminal surface of PNAd+ HEVs, leading to selective lymphocyte migration, primarily in peripheral lymph nodes.18–23 As shown in Figure 2, the PNAd carbohydrate moiety includes 6-sulfo sialyl Lewis X attached to extended core 1 O-glycans, namely, Siaα2→3Galβ1→4[Fucα1→3(sulfo→6)] GlcNAcβ1→3Galβ1→3GalNAcα1→Ser/Thr, or 6-sulfo sialyl Lewis X attached to core 2-branched O-glycans, specifically, Siaα2→3Galβ1→4[Fucα1→3(sulfo→6)]GlcNAcβ1→6(Galβ1 →3)GalNAcα1→Ser/Thr. Both of these function as L-selectin ligands and contribute to lymphocyte tethering and rolling. Fucosylation and sulfation of the carbohydrate component of glycoproteins are especially crucial. α1,3-fucosylation of N-acetylglucosamine (GlcNAc) is catalyzed by the α1,3-fucosyltransferases (FUT) 4 and 7, whereas GlcNAc6-O-sulfation is mediated by N-acetylglucosamine-6-Osulfotransferases 1 (GlcNAc6ST-1) and 2 (GlcNAc6ST-2, also known as L-selectin ligand sulfotransferase (LSST)).16,17,25,26 GlcNAc-6-O-sulfation has received considerable attention because it is thought that sulfation regulates binding activity to L-selectin.16,17,26,27
Antibodies are available to detect particular carbohydrate structures on PNAd (Fig. 2). The monoclonal antibody MECA-79, which recognizes 6-sulfo N-acetyllactosamine attached to extended core 1 O-glycans Galβ1→4[Fucα1 →3(sulfo→6)]GlcNAcβ1→3Galβ1→3GalNAcα1→Ser/Thr, is a widely used HEV marker.18,22 In addition, the monoclonal antibodies HECA-452 (which recognizes sialyl Lewis X on both extended core 1 and core 2-branched O-glycans as well as that on N-glycans, Siaα2→3Galβ1→4(Fucα1→3) GlcNAcβ1→R), and NCC-ST-439 (which recognizes sialyl Lewis X attached to core 2-branched O-glycans regardless of GlcNAc-6-O-sulfation, Siaα2→3Galβ1→4(Fucα1→3) GlcNAcβ1→6(Galβ1→3)GalNAcα1→Ser/Thr), can detect both HEVs and HEV-like vessels.28
Mucosal addressin cell adhesion molecule 1 (MAdCAM-1) MAdCAM-1, a 60-kD glycoprotein, was originally characterized as a vascular addressin expressed on HEVs in GALT.24 It was once named ‘mucosal addressin (MAd)’ as it was considered to function in recruitment of particular lymphocyte subsets involved in mucosal immunity.19,24 Subsequent studies demonstrated a dual function for MAdCAM-1 as both a vascular addressin functioning in the tethering and rolling step and a cell adhesion molecule participating in arrest step of lymphocyte homing. A major MAdCAM-1 ligand is the α4β7 integrin.29 Integrins are usually expressed on the leukocyte surface as a lowaffinity form. When MAdCAM-1 functions as vascular addressin, weak binding between it and the low-affinity form of α4β7 integrin triggers lymphocyte tethering and rolling.30,31 In addition, when MAdCAM-1 is post-translationally decorated with 6-sulfo sialyl Lewis X-capped carbohydrates at its mucin-like domain, it becomes MECA-79-positive and functions as an L-selectin ligand. Once lymphocytes are activated by chemokines produced by HEV endothelial cells, α4β7 integrin undergoes a conformational change to a high-affinity form. Highaffinity α4β7 integrin binds to MAdCAM-1 so firmly that lymphocytes arrest on the HEV luminal surface.30 Hence, MAdCAM-1’s function as either a vascular addressin or a cell adhesion molecule depends on the affinity state of α4β7 integrin. Because α4β7 integrin binds MAdCAM-1 at two steps of lymphocyte migration, it serves as a marker of lymphocytes destined to migrate into GALT. In particular, memory T and B lymphocytes, as well as some effector lymphocytes activated in GALT express α4β7 integrin, and these lymphocytes may function in immune surveillance and elimination of pathogens in gut mucosa.30,32
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MECHANISM OF LYMPHOCYTE MIGRATION VIA HIGH ENDOTHELIAL VENULE-LIKE VESSELS TO INFLAMED TISSUES As noted, chronic inflammation is characterized by the conversion of non-lymphoid to lymphoid tissue (formation of tertiary lymphoid tissues), enabling lymphocyte recruitment. This activity amplifies and propagates the immune response when tissue undergoes prolonged exposure to injurious stimuli such as pathogens, autoimmune damage or mechanical injury. Its initial phase is a morphological and functional change of postcapillary venules into HEV-like vessels in order to augment lymphocyte migration. As discussed below, endothelial cells in such pathologic conditions express several distinct adhesion molecules involved in lymphocyte recruitment.7–12 Vascular addressins (PNAd and MAdCAM-1) Expression of PNAd on venular endothelial cells in nonlymphoid tissues is induced in the process of chronic inflammation. When chronic inflammation is either absent or weak, decoration of PNAd core proteins with 6-sulfo sialyl Lewis X carbohydrates is defective on venular endothelial cells, making these venules less adhesive to L-selectin. However, once active chronic inflammation is initiated, several cytokines such as tumor necrosis factor (TNF)-α and lymphotoxin-α/β act on the venular endothelial cells to transform them into HEV-like vessels. These cytokines reportedly increase expression of GlcNAc6ST-2, and possibly GlcNAc6ST-1 as well, in endothelial cells, resulting in GlcNAc-6-O-sulfation in the sialyl Lewis X moiety.33 Consequently, these venules express complete 6-sulfo sialyl Lewis X, acquiring an ability to bind L-selectin on lymphocytes. These venular transformation to HEV-like vessels impacts in the formation of tertiary lymphoid tissues. It is noteworthy that, in chronic abdominal inflammation, expression levels of MAdCAM-1 on HEV-like vessels is also upregulated by proinflammatory cytokines such as TNF-α, interleukin (IL)-1β and IL-10.34,35 In addition, these MAdCAM-1 proteins can be glycosylated with 6-sulfo sialyl Lewis X-capped carbohydrates at its mucin-like domains as abdominal inflammation develops.9,11 Thus, lymphocyte tethering and rolling in abdominal inflammation is mediated by two independent molecular interactions: one between MAdCAM-1 and low-affinity α4β7 integrin, and the other between 6-sulfo sialyl Lewis X-capped glycans and L-selectin. This set of adhesive interactions is reminiscent of that controlling GALT-selective lymphocyte homing. Other molecules expressed on endothelial cells Both E- and P-selectins function as vascular addressins for a subset of memory and effector T lymphocytes when chronic
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inflammation is triggered. When proinflammatory cytokines TNF-α and IL-1 stimulate venular endothelium at sites of inflammation, the endothelial cells express these selectins.36 Cutaneous lymphocyte antigen (CLA),37–41 or P-selectin glycoprotein ligand 1 (PSGL-1)42–44 decorated with HECA452 carbohydrates, is expressed on memory and effector T lymphocytes as well as neutrophils and monocytes, and interact with E- and P-selectins, resulting in tethering and rolling of such leukocytes along the endothelial luminal surface. Hyaluronic acid is another vascular addressin whose ligand CD44 is expressed on memory and effector T lymphocytes.45,46 Expression of hyaluronic acid on endothelial cells is upregulated during inflammation by proinflammatory cytokines TNF-α, IL-1, IL-15 and bacterial lipopolysaccharide.47,48 This adhesive interaction plays an important role in T-lymphocyte recruitment to inflamed tissues, and reportedly contributes to lymphocyte recruitment to skin in acute graftversus-host disease (GVHD).49
HIGH ENDOTHELIAL VENULE-LIKE VESSELS IN CHRONIC INFLAMMATION Lymphocyte recruitment and consequent formation of tertiary lymphoid tissues occurs in most chronic inflammatory disorders,13 and in fact, is implicated in rheumatoid arthritis,50 Helicobacter pylori gastritis,7 inflammatory bowel disease (IBD) including ulcerative colitis and Crohn disease,8,9 autoimmune pancreatitis and sclerosing sialadenitis,11 according to the morphological, immunohistochemical and molecularbiological analysis of the activity of HEV-like vessels in these inflammatory conditions as discussed below.
Helicobacter pylori gastritis Chronic gastritis is a chronic inflammatory response to prolonged injurious stimuli in gastric mucosa,51 the most common being the spiral-shaped bacillus Helicobacter pylori, which infects over half the world’s population.52,53 Virulent products of H. pylori such as flagella, urease, adhesins and toxins induce chronic inflammation by initiating, maintaining and enhancing conversion of gastric mucosa to tertiary lymphoid tissue known as mucosa-associated lymphoid tissue (MALT).51,54 It is widely recognized that long-standing chronic gastritis is a precancerous condition that increases the risk of extranodal marginal zone lymphoma of MALT type (MALT lymphoma) and gastric carcinoma.51 To initiate and maintain MALT formation in gastric mucosa requires induction of HEV-like vessels. As shown in Figure 3, MALT formation is marked by appearance of venules composed of cuboidal endothelial cells with enlarged nuclei,
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Intriguingly, the number of HEV-like vessels induced in H. pylori gastritis is positively correlated with extent of inflammation.7 MECA-79+/HECA-452+ HEV-like vessels are induced in and around significant lymphocyte infiltrates in the lamina propria at the marked stage of chronic inflammation, whereas most venules do not show such positivity at the mild stage, as assessed by the updated Sydney system, which classifies inflammation into normal, mild, moderate and marked stages based on degree of mononuclear cell infiltration including lymphocytes and plasma cells.7,55 The number of MECA-79+/HECA-452+ HEV-like vessels, as well as the number of patients showing induction of these vessels, increases as chronic inflammation progresses.7 These results suggest that HEV-like vessels regulate the size and quantity of MALT and thus the consequent intensity of chronic inflammation. Once injurious stimuli are eliminated, or when expression of proinflammatory cytokines is reduced by anti-inflammatory drugs, HEV-like vessels transform back into normal venules, and consequently, MALT decreases in size and eventually disappears.7 Retrospective histological study shows that, after H. pylori eradication by treatment with antibiotics (amoxicillin and clarithromycin) and a proton pomp inhibitor (rabeprazole), H. pylori gastritis patients who once displayed MECA-79+/HECA-452+ HEV-like vessels no longer display such vessels and show only minimal lymphocyte infiltration.7
Ulcerative colitis
Figure 3 Immunohistochemistry of high endothelial venule (HEV)like vessels induced in human Helicobacter pylori gastritis. CD31 and CD34 mark vascular endothelial cells; MECA-79+, HECA-452+ and NCC-ST-439+ carbohydrates are expressed on HEV-like vessels. Land E-selectin•IgM chimeras both bind to the endothelial cells in the absence of EDTA. Counterstained by hematoxylin. HE, hematoxylin and eosin stain. Scale bar = 10 μm. Adapted from Proc Natl Acad Sci U S A 2004; 101: 17807-12.7 Copyright (2015) National Academy of Sciences, U.S.A.
which are morphologically similar to HEVs seen in peripheral lymphoid organs,7 and these vessels are located chiefly in T-cell zones. In addition, like HEVs, these HEV-like vessels express 6-sulfo sialyl Lewis X attached to both extended core 1 and core 2-branched O-glycans that constitute PNAd, as they stain positively for MECA-79, HECA-452 and NCC-ST439.7 Moreover, in vitro binding assays suggest that these vessels recruit L-selectin-expressing lymphocytes, as both L-selectin•IgM and E-selectin•IgM chimeras bind these vessels in a calcium-dependent manner.7 These results indicate that HEV-like vessels induced in H. pylori gastritis potentially contribute to lymphocyte migration and thus formation and maintenance of MALT.
Inflammatory bowel diseases (IBDs) such as ulcerative colitis and Crohn disease are chronic inflammatory conditions resulting from inappropriate mucosal immune activation.51 Although their etiopathogenesis has not been precisely defined, many investigators believe that IBDs result from multiple causes including unusual intestinal microbial flora, intestinal epithelial dysfunction and/or autoimmune mucosal responses with or without genetic factors.51 Ulcerative colitis and Crohn disease share common histological features, including chronic mononuclear inflammatory cell infiltrates composed mainly of lymphocytes and plasma cells with occasional formation of lymphoid follicles.51 Lesion distribution, however, differs between the two diseases: in ulcerative colitis distribution is diffuse, continuous and limited to the mucosa and superficial submucosa, whereas in Crohn disease lesions occur in multiple, separate transmural areas with non-caseating granulomas.51,56 HEV-like vessels expressing MAdCAM-1, which are usually displayed selectively in GALT, are induced preferentially in inflamed sites of IBDs.9 This histopathological finding indicates that lymphocyte recruitment in inflamed intestinal mucosa is governed by mechanisms similar to those seen in physiological lymphocyte homing to GALT. Moreover in the
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Figure 4 Immunohistochemistry of high endothelial venule (HEV)-like vessels induced in human ulcerative colitis. Blood vessels in colonic mucosa were immunostained with CD34 antibody. In the active phase, mucosal addressin cell adhesion molecule 1 (MAdCAM-1)+ HEV-like vessels are present, some of which express MECA-79+ carbohydrates (upper panels). In the remission phase, MAdCAM-1 expression is maintained, whereas MECA-79 expression is decreased (lower panels). Counterstained by hematoxylin. HE, hematoxylin and eosin stain. Scale bar = 50 μm. Adapted from Inflamm Bowel Dis 2009; 15: 697–706 with permission.9
case of ulcerative colitis, MAdCAM-1 proteins can be posttranslationally glycosylated with MECA-79+ 6-sulfo sialyl Lewis X-capped carbohydrates, especially in the active phase (Fig. 4).9 This observation is supported by MECA-79positive immunoblotting of lysates from Lec2 cells transiently transfected with cDNA encoding MAdCAM-1•IgG together with core 1 extending β1,3-N-acetylglucosaminyltransferase (Core1-β3GlcNAcT) and GlcNAc6ST-1 after immunoprecipitation of MAdCAM-1.9 In addition, glycosylated MAdCAM-1 can bind L-selectin-expressing lymphocytes, because L-selectin•IgM and E-selectin•IgM chimeras bind these vessels calcium-dependently.9 Hence, HEV-like vessels induced in the active phase of ulcerative colitis can potentially recruit not only α4β7 integrin-expressing lymphocytes but also L-selection-expressing lymphocytes. As noted, expression levels of the MECA-79 glycoepitope on HEV-like vessels correlate with inflammation intensity. Indeed, our statistical analysis revealed that the frequency of MECA-79+ vessels observed in the lamina propria was significantly greater in active versus remission phases in ulcerative colitis.8,9 In active phase, expressions of GlcNAc6STs, most likely GlcNAc6ST-1, is upregulated in venular endothelial cells to complete 6-sulfo sialyl Lewis X biosynthesis.8,9 On the other hand, unlike HEVs in peripheral lymphoid organs, GlcNAc6ST-2 is not robustly induced in venular endothelial cells of inflamed gut mucosa:8,9 GlcNAc6ST-1 is broadly expressed among lymphoid and non-lymphoid tissues, whereas GlcNAc6ST-2 expression is restricted to endothelial cells found in HEVs in peripheral lymphoid organs. Also, GlcNAc6ST-1 catalyzes GlcNAc-6-O-sulfation preferentially on MAdCAM-1 but not on CD34, while GlcNAc6ST-2 substrates are both core proteins i.e. CD34 and MAdCAM-1, as well as endogenous membrane proteins of Lec2 cells (Fig. 5).9,57,58 By contrast, MAdCAM-1 expression on HEV-like vessels is not associated with inflammation intensity (Fig. 4). The
number of MAdCAM-1+ HEV-like vessels in ulcerative colitis is significantly greater than that seen in normal colonic mucosa; however, that number reportedly does not differ significantly between active and remission phases.9 Some have proposed that MAdCAM-1 is upregulated on venules as ulcerative colitis develops and that this expression persists regardless of disease activity, whereas L-selectin ligand biosynthesis on MAdCAM-1 increases in the active phase but decreases when symptoms are relieved.9 Specific lymphocyte subsets recruited via HEV-like vessels have recently been identified.8,10,12 With respect to ulcerative colitis, the number of CD3+ T cells attached to the luminal surface of MECA-79+ HEV-like vessels was greater than that of CD20+ and/or CD79α+ B cells, with high statistical significance.8 Moreover, the number of CD4+ helper T cells in these tissues greatly exceeded the number of CD8+ cytotoxic T cells.8 These results are anticipated, as helper T lymphocytes must be preferentially recruited in order to stimulate B lymphocytes, cytotoxic T lymphocytes and regulatory T lymphocytes, and eventually facilitate an adaptive immune response. The selectivity of HEV-like vessels for this type of lymphocyte recruitment is regulated by activation step of lymphocyte migration by chemokines such as the C-C motif chemokine ligand 19 (CCL19) and CCL21 and the C-X-C motif chemokine ligand 13 (CXCL13).59–61
Autoimmune pancreatitis and sclerosing sialadenitis Autoimmune pancreatitis is prolonged chronic inflammation and irreversible destruction of pancreatic tissue. This condition is pathogenically distinct from chronic pancreatitis caused by alcohol abuse, long-standing obstruction of the pancreatic duct or hereditary factors, as the former is closely associated with the presence of IgG4-secreting plasma cells.62,63 Autoimmune pancreatitis is a manifestation of
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Figure 5 Groups of Lec2 cells were transiently transfected with expression vectors encoding the core proteins CD34 (middle panels) and mucosal addressin cell adhesion molecule 1 (MAdCAM-1) (bottom panels) or vector only (pcDNA1; mock) (top panels). Each group is also transfected with β1,3-N-acetylglucosaminyltransferase plus either N-acetylglucosamine 6-O-sulfotransferase 1 (GlcNAc6ST-1, middle panels) or GlcNAc6ST-2 (right panels) expression vectors or vector only (pcDNA1; mock) (left panels), and analyzed using double immunofluorescence for the presence of the core proteins CD34 or MAdCAM-1 (red signals) and the MECA-79 glycoepitope (green signals). GlcNAc6ST-2 catalyzes GlcNAc-6-O-sulfation on N-acetyllactosamine attached to extended core 1 O-glycans (detected by MECA-79 antibody) on all core proteins examined, including Lec2 cell membrane proteins (right panels). GlcNAc6ST-1 catalyzes GlcNAc-6-O-sulfation only on MAdCAM-1 but not on CD34 and Lec2 cell membrane proteins (middle panels). Scale bar = 50 μm. Adapted from Inflamm Bowel Dis 2009; 15: 697–706 with permission.9
IgG4-related disease and occasionally accompanied by other IgG4-related diseases, such as sclerosing sialadenitis. Autoimmune pancreatitis commonly affects the head of the pancreas with duct-centric lymphoplasmacytic infiltration, dense storiform fibrosis and acini loss, often resulting in stenosis and obstruction of the large pancreatic duct and obstructive jaundice. In both autoimmune and chronic pancreatitis, marked lymphocyte infiltration eventually forms tertiary lymphoid tissues resembling GALT, although plasma cell differentiation is particularly prominent in autoimmune pancreatitis, and this similarity underlies HEV-like vessel induction. Such HEV-like vessels are MECA-79-positive, and some are also MAdCAM1-positive, like HEVs in GALT.11 In agreement with the observation that the MECA-79 glycoepitope on HEV-like vessels parallels the extent of inflammation, a recent study showed that the number of MECA-79+ vessels induced in autoimmune pancreatitis exceeded that seen in chronic pancreatitis, whereas the number of MAdCAM-1+ vessels seen in both diseases was comparable.11 Hence, the etiopathogenesis of chronic inflammation may modulate expression or biosynthesis of L-selectin ligands on HEV-like vessels. Sclerosing sialadenitis also indicates IgG4-related disease and sometimes develops as an extra-pancreatic lesion of autoimmune pancreatitis. Histopathological manifestation of sclerosing sialadenitis is similar to that of autoimmune pancreatitis and includes marked lymphocyte infiltration with IgG4-secreting plasma cell differentiation, dense storiform fibrosis and acini atrophy. The appearance and distribution of
MECA-79+ HEV-like vessels in sclerosing sialadenitis also resembles that seen in autoimmune pancreatitis, namely, significant numbers of MECA-79+ HEV-like vessels are induced around medium- to large-sized salivary ducts.11
Extra-nodal marginal zone lymphoma of MALT type (MALT lymphoma) Here, we broaden the definition of chronic inflammation to include lymphocyte neoplasms, namely, lymphoma. In the case of low-grade lymphoma such as MALT lymphoma, lymphoma cell infiltration of affected tissue mimics that seen in peripheral lymphoid organs, similar to the case of chronic inflammation. Thus, lymphoma can be regarded as a ‘malignant chronic inflammation’: lymphoma progression may be analogous to the process of lymphocyte migration in chronic inflammation, in that venules transform into HEV-like vessels that express vascular addressin, which contributes to tethering and rolling of lymphocytes and/or lymphoma cells, and triggers the type of sequential adhesive interactions previously described. This activity results in marked lymphocyte and/or lymphoma cell recruitment reminiscent of that seen in peripheral lymphoid organs. Although extranodal lymphomas occur in various tissues, they arise most commonly in the gastrointestinal tract, particularly the stomach, and their most common histological type is MALT lymphoma.51 As noted, gastric MALT lymphoma arises in the context of chronic gastritis, and in most cases is caused by H. pylori infection. Because H. pylori eradication following
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Figure 6 Immunohistochemistry of high endothelial venule (HEV)-like vessels induced in (a) human Helicobacter pylori gastritis and (b) human gastric MALT lymphoma. In H. pylori gastritis, more than half of MECA-79+ HEV-like vessels are HECA-452-/NCC-ST-439-. By contrast, in gastric MALT lymphoma, MECA-79-/HECA-452+/NCC-ST-439+ vessels are frequently observed. Scale bar = 200 μm. Adapted from J Pathol 2011; 224: 67–77.66 Copyright (2015) Pathological Society of Great Britain and Ireland.
treatment results in durable remission without recurrence in approximately 75% cases, especially cases showing infiltration of FOXP3+ regulatory T cells, gastric MALT lymphoma can be classified as an intermediary condition between a neoplasm and chronic inflammation.54,64,65 HEV-like vessels are induced in gastric MALT lymphoma as with H. pylori gastritis, but interestingly, the carbohydrate structure expressed on HEV-like vessels induced in these conditions differs.66 Immunohistochemical analysis shows that MECA-79-/HECA-452+/NCC-ST-439+ HEV-like vessels are frequently observed in gastric MALT lymphoma, whereas most HEV-like vessels in H. pylori gastritis are MECA-79positive (Fig. 6).66 Thus, MALT lymphoma is characterized by expression of a unique carbohydrate moiety of PNAd. The MECA-79-/HECA-452+/NCC-ST-439+ immunohistochemical profile suggests defects in GlcNAc-6-O-sulfation catalyzed by GlcNAc6STs and/or in core 1 extension catalyzed by Core1-β3GlcNAcT,22 while the mechanism has not been fully understood. However, two experiments show that the unusual MECA-79-/HECA-452+/NCC-ST-439+ carbohydrate structure, 6-sulfo or non-sulfated sialyl Lewis X attached to only core 2-branched O-glycans, can also bind L-selectin, as well as MECA-79+ carbohydrates. One showed that the L-selectin•IgM chimera binds to CHO/CD34/F7/C2/ LSST and CHO/CD34/F7/C2 engineered cell lines on whose surface CD34 protein is decorated with MECA-79-/HECA452+/NCC-ST-439+ carbohydrates.66 The other showed that L-selectin-expressing lymphocytes adhere to the cell surface in these lines, and that binding is lost following treatment with sialidase, Dreg-56 (an anti-L-selectin monoclonal antibody) and EDTA (Fig. 7).66 In what we term a ‘malignant chronic inflammation,’ MECA-79- HEV-like vessels, although unusual, are induced and function as an L-selectin ligand, and likely contribute to lymphoma cell migration.
It is reported that MAdCAM-1 is also expressed on HEVlike vessels in gastric MALT lymphoma.67 Since MALT lymphoma cells express α4β7 integrin,67,68 integrin-MAdCAM-1 interaction may also play an important role in lymphoma cell migration in gastric MALT lymphoma. By contrast, HEV-like vessels induced in MALT lymphoma of ocular adnexa are negative for MAdCAM-1.67 Hence, expression levels of MAdCAM-1 on HEV-like vessels in MALT lymphoma may differ from organ to organ.
CONCLUSIONS Accumulated knowledge strongly suggests that HEV-like vessels are inevitably induced where marked lymphocyte infiltration is observed over the course of chronic inflammation. HEV-like vessels contribute to initiation, maintenance and enhancement of chronic inflammation via lymphocyte migration mediated by sequential adhesive interactions similar to those seen in physiological lymphocyte homing. Vascular addressins expressed on HEV-like vessels play an important role in the tethering and rolling step of lymphocyte migration, and their presence reflects the extent of chronic inflammation. In particular, expression of MECA-79+ carbohydrates is correlated with the intensity of chronic inflammation. We present a new perspective that chronic inflammation occurs with the similar approach of physiological lymphocyte homing and that inflamed tissue is converted to tertiary lymphoid tissues, which resembles peripheral lymphoid organs in many aspects. Further studies of chronic inflammation mediated by HEV-like vessels are required to clarify and further define mechanisms governing lymphocyte homing relevant to pathological states.
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Figure 7 Lymphocyte adhesion to Chinese hamster ovary (CHO) cell lines mis-expressing various carbohydrates. We established CHO cells stably transfected with CD34 and various combinations of α1,3-fucosyltransferase 7 (F7), β1,6-N-acetylglucosaminyltransferase 1 (C2) and N-acetylglucosamine 6-O-sulfotransferase 2 (LSST). Control CHO/CD34 cells (a) are negative for any MECA-79, HECA-452 and NCC-ST-439 carbohydrates, whereas CHO/CD34/F7/C2 cells (b) and CHO/CD34/F7/C2/LSST cells (c) are positive for HECA-452 and NCC-ST-439 carbohydrates but negative for MECA-79 carbohydrates. Lymphocyte adhesion was observed with Nomarski differential interference optics. Arrows indicate adhered lymphocytes. Note that treatments with sialidase, Dreg-56 or EDTA completely abolish lymphocyte adhesion. Scale bar = 100 μm. Adapted from J Pathol 2011; 224: 67–77.66 Copyright (2015) Pathological Society of Great Britain and Ireland.
ACKNOWLEDGMENTS The authors thank Drs. Masao Hotchi, Tsutomu Katsuyama, Jun Nakayama, and Minoru Fukuda for encouragement, and Dr. Elise Lamar for critical reading of the manuscript. Yasuhiro Sakai has been announced as a winner of the Japanese Society of Pathology’s Centennial Anniversary Award for Young Scientists in 2013. Motohiro Kobayashi is a winner of the Pathology Research Award in 2013 from the Japanese Society of Pathology.
DISCLOSURE None declared.
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