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Gilbert C FAURE's insight:
endothelial cells are heterogeneous!
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Lymphatic vessels return fluid and immune cells from peripheral tissues back to the circulation. The growth of new lymphatic vessels and their remodeling are critical for clearing infection and for metastasis of many cancer subtypes. Williams et al . compared the results of their functional siRNA screens with previously published mRNA data sets to identify genes that regulated lymphatic endothelial cell migration, a process critical for lymphatic vessel growth and remodeling, and genes that functioned in both lymphatic and blood endothelial cell migration. One of the top candidates to emerge from these analyses, the glycan-binding protein Galectin-1 not only promoted lymphatic vessel growth but also was important for maintaining lymphatic endothelial cell identity. Further analyses of the authors’ results may reveal lymphatic vessel–associated proteins that could be targeted to prevent edema, improve infection outcomes, or limit metastasis.
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Blood and lymphatic vessels pervade almost all body tissues and have numerous essential roles in physiology and disease. The inner lining of these networks is formed by a single layer of endothelial cells, which is specialized according to the needs of the tissue that it supplies. Whereas the general mechanisms of blood and lymphatic vessel development are being defined with increasing molecular precision, studies of the processes of endothelial specialization remain mostly descriptive. Recent insights from genetic animal models illuminate how endothelial cells interact with each other and with their tissue environment, providing paradigms for vessel type- and organ-specific endothelial differentiation. Delineating these governing principles will be crucial for understanding how tissues develop and maintain, and how their function becomes abnormal in disease.
Gilbert C FAURE's insight:
Nature reviews
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Lymphatics and lymphatic endothelial cells (LECs) possess multiple immunological functions besides affecting immune cell migration such as inhibiting T cell proliferation and antigen presentation by dendritic cells. Moreover, they control the trans-endothelial transport of multiple molecules and antigens. Emerging evidence suggests their active involvements in immunoregulation, tumor and metastases formation. In the liver, increased lymphangiogenesis, specifically at the portal area has been associated with multiple liver diseases in particular primary biliary cirrhosis, idiopathic portal hypertension, and liver malignancies. Nevertheless, the exact role and contribution of LECs to liver diseases are poorly understood. The review summarizes the current understanding of LECs in liver diseases.
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Dermal dendritic cells and epidermal Langerhans cells are APCs that migrate from skin to draining lymph nodes (LN) to drive peripheral tolerance and adaptive immunity. Their migration requires the chemokine receptor CCR7, which directs egress from the skin via dermal lymphatic vessels and extravasation into the LN parenchyma from lymph in the subcapsular sinus. CCR7 is activated by two chemokines: CCL19 and CCL21. CCL21 alone is sufficient for the migration of APCs from skin to LN. CCL19 and CCL21 also bind atypical chemokine receptor (ACKR) 4. ACKR4-mediated CCL21 scavenging by lymphatic endothelial cells lining the subcapsular sinus ceiling stabilizes interfollicular CCL21 gradients that direct lymph-borne CCR7+ APCs into the parenchyma of mouse LN. In this study, we show that ACKR4 also aids APC egress from mouse skin under steady-state and inflammatory conditions. ACKR4 plays a particularly prominent role during cutaneous inflammation when it facilitates Langerhans cell egress from skin and enables the accumulation of dermal dendritic cells in skin-draining LN. Stromal cells in mouse skin, predominantly keratinocytes and a subset of dermal lymphatic endothelial cells, express ACKR4 and are capable of ACKR4-dependent chemokine scavenging in situ. ACKR4-mediated scavenging of dermal-derived CCL19, rather than CCL21, is critical during inflammation, because the aberrant trafficking of skin-derived APCs in Ackr4-deficient mice is completely rescued by genetic deletion of Ccl19. Thus, ACKR4 on stromal cells aids the egress of APCs from mouse skin, and, during inflammation, facilitates CCR7-dependent cell trafficking by scavenging CCL19.
Gilbert C FAURE's insight:
early step of migration of langerhans cells going to lymph node is helped by stromal cells
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The lymphatic system provides a slow flow of fluid from our organs and tissues into the bloodstream.
Gilbert C FAURE's insight:
Mice With No Lymph Flow The project was prompted in part by recent studies of cultured lymphatic vessel endothelial cells that suggested that fluid forces could be an important factor in the maturation of lymphatic vessels. But there was no straightforward way to test this hypothesis in live animals.
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A brain drain
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PLOS ONE: an inclusive, peer-reviewed, open-access resource from the PUBLIC LIBRARY OF SCIENCE. Reports of well-performed scientific studies from all disciplines freely available to the whole world.
Gilbert C FAURE's insight:
These data highlight the existence of at least two distinctive populations of LECs within human LNs. Of the other LEC markers, we confirmed VEGFR3 was not specific for LECs, and CD144 and CD31 stained both LECs and blood vascular endothelial cells (BECs); in contrast, CD59 and CD105 stained BECs but not LECs. We also showed that antigen-presenting cells (APCs) in the sinuses could be clearly distinguished from LECs by their expression of CD169, and their lack of expression of PROX1 and STAB2, or endothelial markers such as CD144. However, both LECs and sinus APCs were stained with DCN46, an antibody commonly used to detect CD209. CD209 is DC-SIGN
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Steady-State Antigen Scavenging, Cross-Presentation, and CD8+ T Cell Priming: A New Role for ... http://t.co/qAOqzA5I0e
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Lymph nodes, to be worthy of note, as one of the peripheral lymphoid organs of the immune system, are garrisons of B, T, and other immune cells but provide “home” for metastatic cancer cells. However, it is still a pending ...
Gilbert C FAURE's insight:
pancreatic cancer/ review
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RT @luddyka: "Modelling the lymphatic system: challenges and opportunities" #immunology #mathonco #metastasis http://t.co/3lnXzsekdv
Gilbert C FAURE's insight:
a paper from royal society
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Originating in the lymphoid organs, which include the spleen, bone marrow and the thymus, leukocytes travel along the lymphatic vessels between the organs and the lymph nodes, where they are stored, as well as through ...
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Follicular dendritic cells, conduits, lymphatic vessels, and high endothelial venules in tertiary lymphoid organ...
Gilbert C FAURE's insight:
TLOs can arise in non-lymphoid organs during chronic inflammation, as a result of autoimmune responses, graft rejection, atherosclerosis, microbial infection, and cancer. The stromal components found in SLOs including follicular dendritic cells, fibroblast reticular cells, lymphatic vessels, and high endothelial venules and possibly conduits are present in TLOs; their molecular regulation mimics that of LNs. Advances in visualization techniques and the development of transgenic mice that permit in vivo real time imaging of these structures will facilitate elucidation of their precise functions in the context of chronic inflammation. A clearer understanding of the inflammatory signals that drive non-lymphoid stromal cells to reorganize into TLO should allow the design of therapeutic interventions to impede the progression of autoimmune activity, or alternatively, to enhance anti-tumor responses.
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Recent discoveries of novel functions and diverse origins of lymphatic vessels have drastically changed our view of lymphatic vasculature. Traditionally regarded as passive conduits for fluid and immune cells, lymphatic vessels now emerge as active, tissue-specific players in major physiological and pathophysiological processes. Lymphatic vessels show remarkable plasticity and heterogeneity, reflecting their functional specialization to control the tissue microenvironment. Moreover, alternative developmental origins of lymphatic endothelial cells in some organs may contribute to the diversity of their functions in adult tissues. This review aims to summarize the most recent findings of organotypic differentiation of lymphatic endothelial cells in terms of their distinct (patho)physiological functions in skin, lymph nodes, small intestine, brain, and eye. We discuss recent advances in our understanding of the heterogeneity of lymphatic vessels with respect to the organ-specific functional and molecular specialization of lymphatic endothelium, such as the hybrid blood-lymphatic identity of Schlemm’s canal, functions of intestinal lymphatics in dietary fat uptake, and discovery of meningeal lymphatic vasculature and perivascular brain lymphatic endothelial cells.
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Dendritic cell (DC) subsets with biased capacity for CD4+ and CD8+ T cell activation are asymmetrically distributed in lymph nodes (LNs), but how this affects adaptive responses has not been extensively studied. Here we used quantitative imaging to examine the relationships among antigen dispersal, DC positioning, and T cell activation after protein immunization. Antigens rapidly drained into LNs and formed gradients extending from the lymphatic sinuses, with reduced abundance in the deep LN paracortex. Differential localization of DCs specialized for major histocompatibility complex I (MHC I) and MHC II presentation resulted in preferential activation of CD8+ and CD4+ T cells within distinct LN regions. Because MHC I–specialized DCs are positioned in regions with limited antigen delivery, modest reductions in antigen dose led to a substantially greater decline in CD8+ compared with CD4+ T cell activation, expansion, and clonal diversity. Thus, the collective action of antigen dispersal and DC positioning regulates the extent and quality of T cell immunity, with important implications for vaccine design.
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Recently developed cancer immunotherapy approaches including immune checkpoint inhibitors and chimeric antigen receptor (CAR) T cell transfer are showing promising results both in trials and in clinical practice. These approaches reflect increasing recognition of the crucial role of the tumor microenvironment in cancer development and progression. Cancer cells do not act alone, but develop a complex relationship with the environment in which they reside. The host immune response to tumors is critical to the success of immunotherapy; however the determinants of this response are incompletely understood. The immune cell infiltrate in tumors varies widely in density, composition, and clinical significance. The tumor vasculature is a key component of the microenvironment that can influence tumor behavior and treatment response, and can be targeted through the use of anti-angiogenic drugs. Blood vascular and lymphatic endothelial cells have important roles in the trafficking of immune cells and controlling the microenvironment, and modulate the immune response. Improving access to the tumor through vascular alteration with anti-angiogenic drugs may prove an effective combinatorial strategy with immunotherapy approaches, and might be applicable to many tumor types. In this review we briefly discuss the host’s immune response to cancer and the treatment strategies utilizing this response, before focusing on the pathological features of tumor blood and lymphatic vessels and the contribution these might make to tumor immune evasion.
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J Clin Invest. 2016 Aug 15. pii: 79434. doi: 10.1172/JCI79434. [Epub ahead of print]
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J Physiol Sci. 2015 Jan;65(1):51-66. doi: 10.1007/s12576-014-0343-6. Epub 2014 Nov 7. Research Support, Non-U.S. Gov't; Review
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Approximately 28 million Americans live with Type 2 diabetes, a condition characterized by high blood sugar levels. The immune system plays a part in type 2 diabetes. Researchers have linked insul...
Gilbert C FAURE's insight:
The results showed that when an individual has Type 2 diabetes, cells in the lymphatic vessels aren’t producing enough nitric oxide, which is essential to maintaining the integrity of their endothelial layer so that they function properly. The researchers found that by giving the lymphatic vessels L-arginine, an amino acid commonly found in red meat, poultry, dairy products and nutritional supplements, they were able to boost their nitric oxide production and restore their ability to act as a barrier.
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Lymphatic Cells Shill for Breast Cancer Genetic Engineering & Biotechnology News “Moreover, tumor-conditioned LECs promote angiogenesis in these organs, allowing tumor extravasation and colonization.” The authors, led by Aleksander Popel, Ph.D.,...
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Antigen-bearing dendritic cells transit through the lymphatics via chemokine receptor CCR7-dependent chemotactic cues. Rot and colleagues show that the atypical chemokine receptor CCRL1 establishes chemokine polarity in the subscapsular sinus that enables entry into the lymph node.
Gilbert C FAURE's insight:
Afferent lymph–borne dendritic cells essentially rely on the chemokine receptor CCR7 for their transition from the subcapsular lymph node sinus into the parenchyma, a migratory step driven by putative gradients of CCR7 ligands. We found that lymph node fringes indeed contained physiological gradients of the chemokine CCL21, which depended on the expression of CCRL1, the atypical receptor for the CCR7 ligands CCL19 and CCL21. Lymphatic endothelial cells lining the ceiling of the subcapsular sinus, but not those lining the floor, expressed CCRL1, which scavenged chemokines from the sinus lumen. This created chemokine gradients across the sinus floor and enabled the emigration of dendritic cells. In vitro live imaging revealed that spatially confined expression of CCRL1 was necessary and sufficient for the creation of functional chemokine gradients.
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CD44 Binds to Macrophage Mannose Receptor on Lymphatic Endothelium and Supports Lymphocyte Migration via Afferent... http://t.co/TjPX97XTPm
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... of Lymph Node-fat Pad Chimeras for the Study of Lymph Node Stromal Cell Origin. Lymph nodes (LNs) are key organs of the immune system situated at strategic sites in the body, along the lymphatic vasculature network.
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This page describes secondary (peripheral) lymphatic organs, and is part of Art Anderson's immunology 522 lecture for the Foundation for Advanced Education in the Sciences (FAES) at NIH.
Gilbert C FAURE's insight:
art, your page appeared on scoop.it don't resist to post
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(2010) Measles virus infection of alveolar marcrophages and dendritic cells precedes spread to lymphatic organs in transgenic mice expression human signaling lymphocytic activation molecules (SLAM, CD150).
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