Wall Of High Endothelial Venules Research Articles

Distinctive Subpopulations of Stromal Cells Are Present in Human Lymph Nodes Infiltrated with Melanoma.

Metastasis of human tumors to lymph nodes (LN) is a universally negative prognostic factor. LN stromal cells (SC) play a crucial role in enabling T-cell responses, and because tumor metastases modulate their structure and function, this interaction may suppress immune responses to tumor antigens. The SC subpopulations that respond to infiltration of malignant cells into human LNs have not been defined. Here, we identify distinctive subpopulations of CD90+ SCs present in melanoma-infiltrated LNs and compare them with their counterparts in normal LNs. The first population (CD90+ podoplanin+ CD105+ CD146+ CD271+ VCAM-1+ ICAM-1+ α-SMA+) corresponds to fibroblastic reticular cells that express various T-cell modulating cytokines, chemokines, and adhesion molecules. The second (CD90+ CD34+ CD105+ CD271+) represents a novel population of CD34+ SCs embedded in collagenous structures, such as the capsule and trabeculae, that predominantly produce extracellular matrix. We also demonstrated that these two SC subpopulations are distinct from two subsets of human LN pericytes, CD90+ CD146+ CD36+ NG2- pericytes in the walls of high endothelial venules and other small vessels, and CD90+ CD146+ NG2+ CD36- pericytes in the walls of larger vessels. Distinguishing between these CD90+ SC subpopulations in human LNs allows for further study of their respective impact on T-cell responses to tumor antigens and clinical outcomes.

Differences in lymphocyte subsets in the wall of high endothelial venules and the lymphatics of human palatine tonsils.

Lymphocyte trafficking plays a critical role in disseminating specifically primed lymphocytes all over the body. Most concepts on the interaction of adhesion molecules on lymphocyte subsets and specialized endothelia such as those in high endothelial venules (HEV) are based on animal experiments as kinetic studies cannot be performed in humans. We therefore characterized lymphocyte subsets in the wall of HEV and in the lumen of lymphatics of 18 human palatine tonsils by immunohistology. All subsets studied were found in the wall of HEV (% of lymphocytes): 32% CD20+, 50% CD3+, 14% CD4+, 32% CD8+ and also 21% CD45RA+ and 39% CD45RO+. In the lymphatics, used to indicate lymphocytes emigrating from the tonsils, a different composition was found; e.g. many more T cells and three times more CD45RA+ than RO+ lymphocytes. Thus, HEV are not a selective entry site nor lymphatics an exit for specific lymphocyte subsets only, at least in these tonsils with chronic stimulation.

Association of Neutrophils with High Endothelial Venules in the Neonatal Rat Lymph Nodes: A Probable Relation to Immunoincompetence

The endothelium of the high endothelial venules (HEVs) of lymph nodes is normally considered to inhibit an association with neutrophils. The present paper shows that for a few weeks after birth, however, neutrophils are commonly associated with the walls of HEVs, the extent depending on the site of the lymph node. Overall, neutrophils increase in numbers in rat nodes from birth until about day 11, and vanish progressively thereafter. Moreover, neutrophils are more abundant in the nodes of standard neonates than in the nodes of pathogen-free neonates raised in an aseptic milieu. It is concluded that the postnatal recruitment of neutrophils by nodal HEVs relates to the then prevailing state of immaturity of the immune system. An explanation is proposed as to why neonatal HEVs of nodes recruit neutrophils and not only lymphocytes, as is the case later in ontogeny.

The unique ultrastructure of high-endothelial venules in inguinal lymph nodes of the pig.

Lymph nodes in pigs are unique in their inverted structure, with the medulla in the periphery and the cortex in central areas. Furthermore, in this species most migrating lymphocytes do not use the classical route via efferent lymphatics to leave the lymph node. High-endothelial venules (HEV) are the entry sites for lymphocytes and in pigs probably also the exit site for recirculating lymphocytes. Therefore, the blood vessels and especially the HEV of the pig superficial inguinal lymph node were investigated as to whether morphological peculiarities could be found in the vascular system, using vascular casting, transmission- and scanning electron microscopy. A thin layer of capillary network surrounded the periphery of the lymph node and HEV branched acutely. The endothelial cells of HEV possessed well developed cytoplasmic organelles, interdigitated with each other, and demonstrated local cell-cell contacts. There were unusual cells bridging the adluminal wall of HEV. These cells were called intravascular bridging cells. They were characterized by an often invaginated nucleus, few pinocytotic vesicles, many microvilli on the surface, wide, flat, cytoplasmic processes like a pseudopod, Weibel-Palade bodies and local cell-cell contacts with endothelial cells. The pseudopod-like processes ramified over the endothelial junctions and covered lymphocytes. Lymphocytes were seen in different phases of migration between endothelial cells and in the intercellular junctions. The previous functional studies on the peculiar route of lymphocyte recirculation in pig lymph nodes are extended by these morphological data, showing a unique structure of HEV in pigs.

Mechanisms of human lymphocyte migration and their role in the pathogenesis of disease.

Lymphocyte recirculation is an essential component of the functional immune system, providing a means for constant surveillance of the organism's tissues by immunocompetent cells and, moreover, facilitating interactions between different cell types engaged in the immune response. Adhesive interactions between recirculating lymphocytes and the wall of high endothelial venules (HEV) are thought to play a central role in this process. These interactions are mediated by lymphocyte homing receptors expressed on the lymphocyte cell surface which recognize tissue-specific molecules on the endothelium. Moreover, LFA-1 is also involved in the regulation of lymphocyte traffic. In addition, recent evidence indicating that these mechanisms may also play a role in the pathogenesis of chronic inflammatory diseases and non-Hodgkin's lymphomas is discussed.

MEL-14 and LFA-1, organ specific and non-specific adhesion molecules involved in homing of human lymphocytes.

In the process of recirculation lymphocytes migrate from the blood into the surrounding tissues by adhering to and crossing the wall of high endothelial venules (1–4). Recently we and others have provided evidence that in man, like in rodents, a system of organ-specific receptors mediates lymphocyte-HEV recognition and thus presumably controls lymphocyte homing to lymphoid tissues and sites of inflammation (4–7).KeywordsHuman LymphocytePeripheral Lymph NodeHigh Endothelial VenuleSignificant Additive EffectLymphocyte RecirculationThese keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

The expression of lymphocyte adhesion molecules on cultured high endothelial cells.

Lymphocytes enter lymph nodes (LN) from the blood by penetrating the walls of high endothelial venules (HEV). The initial step in this process involves the selective adhesion of lymphocytes to the luminal surface of high endothelial cells. Detailed studies of this adhesion process using the frozen section assay developed by Stamper and Woodruff (1) have identified receptors on the surfaces of rat (2) and mouse (3) lymphocytes which mediate adhesion to HEV in LN cryostat sections. These receptors also mediate lymphocyte migration into LN of intact recipients. A natural conclusion from these studies is that HEV express surface adhesion molecules (ligands or complementary receptors) for lymphocytes and the expression of adhesion molecules by HEV regulates lymphocyte migration from the blood. At least two sets of lymphocyte receptor-HEV adhesion molecules exist in rodents. One directs lymphocyte migration into peripheral LN and the second directs lymphocyte migration into Peyer’s patches (3–5). The expression of lymphocyte adhesion molecules by HEV is poorly understood. The role of endothelium in this intriguing process could be studied using isolated high endothelial cells (HEC). The recent successes achieved with the isolation and long-term culture of aortic, venous and capillary endothelium prompted an attempt at the isolation of HEC from rat lymph nodes.

Intercellular contacts of lymphocytes during migration across high-endothelial venules of lymph nodes. An electron microscopic study.

The migration of lymphocytes across the wall of high-endothelial venules was studied by electron microscopic examination of murine lymph nodes fixed with glutaraldehyde and tannic acid. Regions of close membrane apposition, referred to in the present study as "intercellular contacts," were observed between migrating lymphocytes and endothelial cells of the vessel wall. At high magnification the intercellular contacts resolve into pentalaminar structures resembling gap junctions. However, the location of these contacts suggests that they are regions of membrane adherence utilized for locomotion of the lymphocytes across the endothelium. At present, it is unclear whether these intercellular contacts are communicating junctions or sites of membrane adherence.

The migration of lymphocytes across specialized vascular endothelium: IV. Prednisolone acts at several points on the recirculation pathways of lymphocytes

Radioactively labelled thoracic duct lymphocytes from syngeneic rat donors were injected iv into recipients which had been given a continuous iv infusion of prednisolone at 1 mg/hr for 15–18 hr previously. The tissue distribution and recirculation into lymph of the labelled lymphocytes were compared quantitatively in the prednisolone-treated and control recipients by scintillation counting and autoradiography. The most prominent effect of prednisolone was to retard recirculating lymphocytes within the tissues to which they are normally distributed by the blood, namely the bone marrow, the spleen, and the lymph nodes. Although lymphocyte traffic was almost completely frozen by prednisolone, recirculating lymphocytes were not killed. A second effect of prednisolone was to impair the influx of lymphocytes from the blood into lymph nodes. Different groups of lymph nodes varied in the extent to which prednisolone inhibited the entry of lymphocytes, and previous antigenic stimulation completely exempted lymph nodes from this inhibition. Lymphocytes took a longer time to cross the walls of high endothelial venules in the lymph nodes of prednisolone-treated rats. A third effect of prednisolone was to increase the rate at which lymphocytes entered the bone marrow from the blood by crossing sinusoidal endothelium.

The route of migration of lymphocytes from blood to spleen and mesenteric lymph nodes in the pig.

Porcine peripheral blood lymphocytes were labelled with tritiated uridine in vitro and transfused into normal young pigs. Serial biopsies were taken from the spleen and mesenteric lymph nodes, and the localization of labelled lymphocytes determined on autoradiographs. Four to five hours after cell infusion samples of Peyer's patches, tonsils and small intestine were taken and the labelled lymphocytes classified by their localization in different organ compartments. In spleens most labelled cells were found in the red pulp and about 30% in the marginal zone. Within 4 to 5 h there was a constant increase in labelled lymphocytes in the compartment of the white pulp with more cells localized in the periarteriolar lymphatic sheath than in the corona. In lymph nodes about two thirds of all labelled cells were seen in the wall of high endothelial venules 15 min after cell infusion. Labelled cells then decreased in the vessel wall, but, at the same time, increased in the neighbourhood of these vessels and other parts of the paracortex. After 5 h about 10% of labelled lymphocytes had already migrated into the corona. In tonsils and Peyer's patches a comparable distribution of labelled cells was found in the organ compartments. The kinetics and the route of migration in the spleen and lymph nodes are therefore comparable to data for other species, despite the peculiar structure of pig lymph nodes and the paucity of lymphocytes in efferent lymphatics in pigs.

Migration of B lymphocytes in lymphoid organs of lethally irradiated, thymocyte-reconstituted mice.

The migration of radiolabeled intravenously injected B lymphocytes through thymus-dependent areas was studied in lymphoid organs of mice with experimentally defined T cell domains (B cell-deprived mice or "T" mice). In the spleen, B cells were found to enter the peri-arteriolar lymphoid sheath (PALS) by two routes: (i) via the marginal zone, and (ii) via reticulum sheaths surrounding terminal arterioles. B cells migrated through the peripheral and central PALS and initiated the formation of primary follicles in the peripheral PALS 6 h after injection. Distinct primary follicles were noted at 18 h after injection of the labelled B cells. After 24 h small numbers of labelled cells were also noted in the efferent lymphatic vessels of the spleen. The reconstitution of B cell compartments in the mesenteric lymph node was delayed compared to the spleen. B cells entered the nodal stroma across the wall of high endothelial venules in the paracortex and by 6 h were found scattered throughout the paracortex. Isolated clusters of a few labeled cells were noted in the outer cortex at 18 h after cell transfer. Defined primary nodules were seen only 24 h after reconstitution. A minority of labeled cells was found at 24 h in the cortico-medullary junctions and in medullary cords. The present study shows that B lymphocytes traverse T cell domains on their way to their own specific B cell compartments. The immunological significance of this particular migration route is discussed in view of data on the cellular cooperation of B cells, T cells and macrophages during the humoral immune response.