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High Endothelial Venules (Hevs? Are Specialized Postcapillary Venules Found in Lymphoid Tissues That Support High Levels of Lymphocyte Extra- Vasation from the Blood

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High Endothelial Venules (Hevs? Are Specialized Postcapillary Venules Found in Lymphoid Tissues That Support High Levels of Lymphocyte Extra- Vasation from the Blood High endothelialvenules (HEVs): specialized endotheliumfor lymphocytemigration Jean-Philippe Girard and Timothy A. Springer High endothelial venules (HEVs? are specialized postcapillary venules found in lymphoid tissues that support high levels of lymphocyte extra- vasation from the blood. Here, Jean-Philippe Girard and Timothy Springer highlight the unique properties of HEV endotbelium, discuss the mol- ecular mechanisms controlling HE V specialization and review evidence suggesting that HEVs could play an important role in the patbogenesis of chronic inflammatory diseases. While patrolling the body in search of foreign antigen, The specialized endothelium of HEVs lymphocytes continuously circulate from blood, through Structurd feutures of HEVs lymphoid and other tissues, and back through the lym- The endothelial cells of HEVs have a ‘plump’, al- phatics to the blood. This process, called lymphocyte most cuboidal, appearance very different from the flat recirculation, allows the dissemination of the immune morphology of endothelial cells that line other vessels, response throughout the body, and thereby provides an and are therefore called high endothelial cells by ref- effective immune surveillance for foreign Invaders and erence to their thickness (Fig. 1). Another characteris- alterations in the body’s own cells’J. tic of HIS’s, revealed by light-microscopic examina- The first critical step in lymphocyte migration tion, is the presence of a large number of lymphocytes from circulation into tissue is the adhesion of within their walls. This illustrates the function of HEVs lymphocytes to vascular endothelium. In lymphoid in lymphocyte recruitment, and explains why these ves- organs, lymphocyte adherence and transendothelial sels were implicated in lymphocyte traffic from the time migration occur at specialized postcapillary vascular of their initial description”. sites called high endothelial venules (HEVs). Although At the ultrastructural level, high endothelial cells are HEVs are particularly abundant in the T-cell areas characterized by a prominent Golgi complex, abundant surrounding the B-cell follicles, they serve as the sites polyribosomes and rough endoplasmic reticulum. This of entry both for T and B lymphocytes’. In humans, reveals an intense biosynthetic activity not observed in HEVs are found in all secondary lymphoid organs flat endothelial cells6,‘2. They also contain many mem- (with the exception of spleen, where lymphocyte brane-bound vesicular structures, multivesicular bodies, emigration occurs via the blood sinusoids in the mar- Weibel-Palade bodies and a variety of dense bodies, in- ginal zone), including hundreds of lymph nodes dis- dicating that they are involved in secretion’?. Another persed in the body, tonsils and adenoids in the phar- important feature of HEVs, revealed by ultrastructural ynx, Peyer’s patches (PI%) in the small intestine, studies, is the existence of discontinuous ‘spot-welded’ appendix, and small aggregates of lymphoid tissue in junctions between high endothelial cells’. These dis- the stomach and large intestine. Moreover, HEV-like continuous junctions differ from the tight junctions vessels are observed in chronically inflamed nonlym- that characterize capillary and arterial endothelium but phoid tissues and are believed to support lymphocyte are similar to the ‘non-occluding’ junctions found in recruitment into these sites4. In contrast to the other postcapillary venules’. This property of HEVs endothelial cells from other vessels, the high endo- probably facilitates the passage of lymphocytes between thelial cells of HEVs have a distinctive appearance, adjacent high endothelial cells and is likely to be one of express specialized ligands for lymphocytes and are the factors allowing massive lymphocyte emigration in able to support high levels of lymphocyte extra- HEVs. vasation5y6. While many reviews have discussed the molecular mechanisms of lymphocyte homing and HE V-specific markers lymphocyte-HEV interactions2,‘-9, most have focused Despite intensive efforts, very few HEV-specific on lymphocytes and the lymphocyte homing receptor markers have been described. The best HEV marker L-selectin, and considerably less attention has been currently available is a carbohydrate epitope recog- given to the HEV side of the interaction. The purpose nized by the monoclonal antibody (mAb) MECA-79 of this review is to highlight the specialized features of (Ref. 13), which stains all HEVs within lymphoid tis- the HEV endothelium that allow lymphocyte emi- sues and does not react with postcapillary venules gration in HEVs to be so efficient, and to discuss the or large vessels in spleen, thymus or nonlymphoid role of the tissue environment in the control of HEV tissues’ ‘+14. MECA-79 mAb inhibits lymphocyte emi- specialization. gration through HEVs into lymph nddes in uivo and endothelial cells17 are not recognized by L-selectin. Simi- larly, CD34 is widely expressed in endothelial cells in most organs, but functions as an L-selectin counter- receptor only when appropriately decorated by specific oligosaccharides zsJ6. Sialic acids are critical for recog- nition since sialidase treatment abolishes both L-selectin binding and lymphocyte adhesion to lymph node HEVs in vitro and in vivo16,29. The sLeX molecule has been proposed to function as an HEV ligand for L-selectin30. However, sLeX is expressed in endothelial cells that do not mediate lymphocyte recruitment in uivo31, thereby implying that the biological HEV ligands for L-selectin must be more complex than this simple tetrasaccharide. A 6’-sulfo-sLe” isoform has re- cently been identified as a major capping group of GlyCAM-1 (Ref. 32) and sulfation of both GlyCAMl Fig,. I. Ht$ endothelia~ venule (HEVj in a human tonsr% The (Ref. 331 and CD34 {,Ref. 271 has been shown to be re- ‘plump’ high endothelial cells are stained by in situ hybridrzation quired for L-selectin recognition. Sulfated ligands for with a digoxigenin-labeled cDNA probe encoding hevin, a se- L-selectin have also been detected in rat lymph nodes34. creted protein specifically expressed in HE Vs from human Sulfation may be key to the uniqueness of the HEV tonsils’O. Magnificatzon = x400. ligands. Interestingly, both in humans and rats, the HEV endothelium has been shown to be unique amongst lymphocyte adhesion to lymph node and tonsil HEVs vascular endothelium by virtue of its capacity to incor- in vit~o’~J~. Although initially produced against mouse porate large amounts of 35S04 (Refs 4,35). The re- HEVs, the mAb shows a wide crossreactivity among quirement for sulfate in high-affinity L-selectin ligands species I5. The MECA-79 carbohydrate epitope decorates provides a functional basis for this metabolic special- a family of HEV. counter-receptors for L-selectin, both ization of the HEV endothelium. The critical role of in mouse and human16J7. Another mAb, HECA-452, sulfation in HEV is further reinforced by the fact recognizing a carbohydrate epitope expressed on human that the only HEV-specific mAb currently available, HEVs but not on other vessels, has been described. MECA-79, is also sulfation dependent. Similar to However, unlike MECA-79, this mAb is not HEV spe- L-selectin, MECA-79 recognizes sulfated oligosacchar- cific: HECA-452 recognizes a carbohydrate epitope ides decorating GlyCAM-1 and CD34, and inhibition related to the sialyl-Lewis x and sialyl-Lewis a (sLe” of sulfation of these glycoproteins abrogates recogni- and sLe”) oligosaccharides and, in addition to reacting tion2’. The total absence of crossreactivity of MECA-79 with high endothelium, crossreacts with monocytic cells, with non-HEV cells of the human bodyI suggests that dendritic cells and a subset of skin-homing memory the HEV-specific sulfated oligosaccharides recognized lymphocytes9J8. by MECA-79 and L-selectin are unique structures that Two other HEV markers have been described in the are probably even more complex than 6’-sulfo-sLe”. mouse: (1) the mAb MECA-325 defines an antigen that Clustering of oligosaccharides containing 6’-sulfo-sLe” can be induced in nonlymphoid endothelial cells by on mucin-like domains may be required for recognition interferon y (IFN-y)i9; and (2) the mAb MECA-367 since free oligosaccharides released from GlyCAM-1 recognizes mucosal addressin cell adhesion molecule 1 do not bind with recognizable affinity to L-selectin36, (MAdCAM- )20, a counter-receptor for L-selectin” and and all HEV counter-receptors for L-selectin identified CY$~ integrin 21 that is expressed in mucosal HEVs and to date contain highly O-glycosylated mucin-like do- in venules of intestinal lamina propria but can be in- mains. Recently, MECA-79- ligands for L-selectin were duced in nonmucosal endothelial cells by tumor necrosis identified on KGla hematopoietic cells and neutro- factor cx (TNF-a) and IL-l (Ref. 22). phils25~37~38.CD34 from KGla cells binds less well to L-selectin than CD34 isolated from tonsil stroma, per- HEV-specific O-linked glycosylation of L-selectin haps reflecting an absence of sulfation25. counter-receptors Lymphocyte L-selectin plays a key role in the initial Lymphocyte emigration in HEVs interaction of lymphocytes with HEVs in viva by Molecular mechanisms involved in lymphocyte migration recognizing carbohydrate ligands on the following through HEVs in vivo HEV glycoproteins: glycosylation-dependent cell ad- Lymphocyte migration through HEVs in viuo is a hesion molecule 1 (G~YCAM-~)~~, CD34 (Refs 24,25) very specific and efficient process. Lymphocytes circu- and MAdCAM-
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