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Lymphatic anatomy: microanatomy and physiology
Published in Charles F. Levenback, Ate G.J. van der Zee, Robert L. Coleman, Clinical Lymphatic Mapping in Gynecologic Cancers, 2022
Erin K. Crane, Charles F. Levenback
The lymphatic system begins with small lymphatic capillaries (terminal lymphatics), which function as sites of fluid exchange. Terminal lymphatics have blind ends and are lined by a single layer of overlapping endothelial cells, with fenestrations ranging in size from 10 to 25 μm12 (Figure 2.1). These cells are anchored by collagen filaments to the surrounding connective tissue. A combination of diapedesis, hydrostatic forces, and colloidal gradients guides particles and fluid into the gaps between overlapping endothelial cells. It has been hypothesized that the contraction and relaxation of the filaments facilitate permeation through the endothelial cells, forming microvalves between the lymphatics and interstitium.13
Adhesion Pathways Controlling Recruitment Responses of Lymphocytes During Allergic Inflammatory Reactions In Vivo
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Donald Y. M. Leung, Louis J. Picker
Four successive steps have been identified in the recruitment of lymphocytes into sites of inflammation (Fig. 1). The first step involves so-called primary adhesion, in which free-flowing lymphocytes interact with endothelial cells via constitutively expressed homing receptors and endothelial cell ligands. This primary adhesion is transient and reversible under shear stress. In the case of lymphocytes, it is manifested by either a slow rolling, or a transient, immediate arrest (12,13). The second step involves the rapid activation of lymphocytes adhering to endothelial cell ligands. These transiently interacting cells are released back into the circulation unless secondary adhesion (step 3) occurs. This latter event is “triggered,” during step 2, by specific activating stimuli, which are thought to be chemoattractant substances operating through G protein-linked receptors (12). Secondary adhesion is thus activation-dependent and mediates a firm attachment that is stable under shear stress. In some instances an intermediate step, mediated by distinct adhesion molecules, may “bridge” primary and secondary adhesion by reducing the initially “too high” rolling velocity of the primary interaction to levels more commensurate with effective secondary adhesion (6). Once activation-dependent secondary adhesion mechanisms are brought fully into play, the cell arrests stably on the endothelial surface, and these secondary adhesion events serve as a prelude to the final step of extravasation—diapedesis into the tissue.
Immunopathogenesis of Vanishing Bile Duct Syndromes
Published in Gianfranco Alpini, Domenico Alvaro, Marco Marzioni, Gene LeSage, Nicholas LaRusso, The Pathophysiology of Biliary Epithelia, 2020
John M. Vierling, Marius Braun, Haimei Wang
Activated leukocytes interact with adhesion molecules on cytokine-activated endothelial cells, leading to transendothelial diapedesis into tissues.21,22 Τ cell CD40L induces endothelial expression of adhesion molecules E-selectin, ICAM-1 and VCAM-1. Th1 cells selectively express glycosyl transferases required for synthesis of specific ligands for endothelial E- and P-selectins, which facilitate preferential transendothelial migration of Th1 cells into sites of inflammation.23 Cytokines and chemokines, such as IL-6, IL-8 and leukemia inhibitory factor, as well as growth factors, such as granulocyte-macrophage colony stimulating factor, also facilitate trafficking of leukocytes into tissues. Endothelial cells expressing low levels of CD40L also stimulate B7 expression by B cells and provide a proinflammatory stimulus to monocytes. Whether activated endothelial cells also function as “professional” APCs remains controversial.
SOD3 boosts T cell infiltration by normalizing the tumor endothelium and inducing laminin-α4
Published in OncoImmunology, 2020
Lorena Carmona-Rodríguez, Diego Martínez-Rey, Emilia Mira, Santos Mañes
Leukocyte extravasation from the bloodstream into a tissue entails sequential adhesion steps regulated by adhesion receptors and chemokines that culminates in crossing of the endothelial cell (EC) layer. Adhesion receptors, common to all endothelia, are necessary for diapedesis of all leukocyte types. Downmodulation of the main EC adhesion molecules (ICAM-1 or VCAM-1) is a feature of tumors with “immune desertification”. Inflamed tumors can also fine-tune infiltration of effector and suppressor immune cells by modulating chemokine expression.2 To reach the tumor parenchyma, leukocytes must also cross the EC-BM, the main extracellular matrix structure that lies beneath EC.3 EC-BM constituents include type IV collagen, fibronectin, perlecan, nidogen, and laminins. Laminins are particularly interesting, since the laminin-α4 (LAMA4) subunit enhances, whereas laminin-α5 (LAMA5) inhibits T cell diapedesis.3 How the TME influences EC-BM is not known precisely, although it can be predicted that tumor blood vessel abnormalities affect EC-BM composition and integrity.
Eosinophil accumulation predicts response to melanoma treatment with immune checkpoint inhibitors
Published in OncoImmunology, 2020
Sonja C. S. Simon, Xiaoying Hu, Jasper Panten, Mareike Grees, Simon Renders, Daniel Thomas, Rebekka Weber, Torsten J. Schulze, Jochen Utikal, Viktor Umansky
Eosinophils from melanoma patients before treatment showed patterns of platelet activation and vascular interaction as compared to the post-treatment group and to HD. It has been reported that eosinophils were able to activate platelets, leading to degranulation or increased adhesion,33 and could create complexes with platelets in the peripheral blood of asthma patients.34 Correspondingly, platelets are known to be activated in cancer patients due to education by tumor cells.35 Moreover, one of the top DEG upregulated in the pre-treatment group was RAP1B, coding for a small GTPase, which has been described to activate α4 integrins on eosinophils.36 These α4 integrins were shown to be responsible for the initial step of eosinophil diapedesis,37 supporting the observed expression of genes involved in vascular interaction. Diapedesis is crucial for eosinophil migration into tumor tissue, which has been described as an inflammatory host response to tumor initiation in a melanoma mouse model.38 Taken together, the gene expression profile of the pre-treatment group indicates the possibility of eosinophil migration to the tumor tissue of melanoma patients as an immune defense reaction.8
Endothelial alterations in a canine model of immune thrombocytopenia
Published in Platelets, 2019
Dana N. LeVine, Rachel E. Cianciolo, Keith E. Linder, Petra Bizikova, Adam J. Birkenheuer, Marjory B. Brooks, Abdelghaffar K. Salous, Shila K. Nordone, Dwight A. Bellinger, Henry Marr, Sam L. Jones, Thomas H. Fischer, Yu Deng, Marshall Mazepa, Nigel S. Key
Recent work by Goerge and colleagues suggests one possible explanation for the relatively mild bleeding and the overall minor changes in endothelial ultrastructure observed in the model dogs [52]. This group demonstrated that thrombocytopenic hemorrhage only occurs in the face of inflammation [52]. In order for bleeding to occur, leukocyte diapedesis may be necessary in combination with the vascular destabilizing effects of thrombocytopenia [53,54]. Ultrastructural studies have not been performed to look at the combined effects of inflammation and hemorrhage. As our dogs had minimal to no cutaneous inflammation (Supplementary Table 1), they may have lacked a second “hit” necessary to create sufficient vascular damage for significant bleeding to occur. We suspect mild bleeding is also the reason we did not identify a correlation between bleed score and endothelial structural changes.