High endothelial venules

Last updated

High endothelial venules (HEV) are specialized post-capillary venules characterized by plump endothelial cells as opposed to the usual flatter endothelial cells found in regular venules. [1] HEVs enable lymphocytes circulating in the blood to directly enter a lymph node (by crossing through the HEV). [2] [3]

Contents

In humans, HEVs are found in all secondary lymphoid organs (with the exception of spleen, where blood exits through open arterioles and enters the red pulp), including hundreds of lymph nodes dispersed in the body, tonsils and adenoids in the pharynx, Peyer's patches (PIs) in the small intestine, appendix, and small aggregates of lymphoid tissue in the stomach and large intestine. [4] In contrast to the endothelial cells from other vessels, the high endothelial cells of HEVs have a distinctive appearance, consisting of a cuboidal morphology and with various receptors to interact with leukocytes (express specialized ligands for lymphocytes and are able to support high levels of lymphocyte extravasation). [4] HEVs enable naïve lymphocytes to move in and out of the lymph nodes from the circulatory system. HEV cells express addressins, which are specific adhesion molecules that attach to the L-selectins on lymphocytes and anchor them to the HEV wall in preparation for crossing the endothelium.

The endothelial cells of HEVs have a 'plump' appearance different from the flat morphology of endothelial cells that line other vessels, and are therefore called high endothelial cells by reference to their thickness. [4] Another characteristic of HEVs, revealed by light-microscopic examination, is the presence of a large number of lymphocytes within their walls. This illustrates the function of HEVs in lymphocyte recruitment and explains why these vessels were implicated in lymphocyte traffic from the time of their initial description.

The need for HEV

In order to have an adaptive immune response occur, T cells need to be activated. T cells become activated by recognising foreign antigens bound to antigen presenting cells (APC), in particular, dendritic cells. [5] In order for naïve T cells to bind to their specific antigen, they need to experience physical contact with those cells. Since antigen levels are usually low, contact in blood circulation would be unlikely. Therefore, T cells need a region where they can go to sample foreign antigens that have entered the body. When an APC, such as a dendritic cell, binds a foreign antigen; it becomes activated and moves into the lymph nodes (sites for antigen sampling by T cells) via afferent lymphatic vessels. Naïve T cells in the circulation regularly move through the lymph nodes via HEV in order to scan the APC for foreign antigens. When they encounter such an antigen, the cell becomes activated, resulting in the immune system mounting a response against the causative agent of the infection.

Depletion of CD11c+ dendritic cells in mouse significantly altered the phenotype of HEV. The normal phenotype of HEV is possibly maintained by DC-secreted lymphotoxin (TNF-beta). [6]

Cell movement through HEV

HEV cuboidal endothelial cells express the adhesion molecules GlyCAM-1 (in mucosal HEV this is MAdCAM-1), ICAM-1 and CD34. They also secrete the chemokine CCL21. Naïve T cells express CCR7 receptor and adhesion molecules L-selectin and LFA-1. [5] As naïve T cells move through the circulation, they 'roll' over the endothelial cells in the vessel walls. The rolling mechanism helps the L-selectin molecules on the surface of naive T cells to weakly interact with GlyCAM-1 and CD34 molecules on HEV cells. The chemokine CCL21 then binds to its receptor CCR7 expressed on the T cell. This binding induces a conformational change in the LFA-1 molecule causing it to bind tightly to ICAM-1. [7] This tight binding stops further movement of the T cell which can then move between HEV cells into the lymph node by a process termed 'diapedesis' (or extravasation).

Markers

Despite intensive efforts, few HEV-specific markers have been described. The best HEV marker currently available is a carbohydrate epitope recognized by the monoclonal antibody (mAb) MECA-79, which stains all HEVs within lymphoid tissues and does not react with postcapillary venules or large vessels in spleen, thymus or nonlymphoid tissues. MECA-79 mAb inhibits lymphocyte emigration through HEVs into lymph nodes in vivo and lymphocyte adhesion to lymph node and tonsil HEVs in vitro. Although initially produced against mouse HEVs, the mAb shows a wide crossreactivity among species. The MECA-79 carbohydrate epitope decorates a family of HEV counter-receptors for L-selectin, both in mouse and human16. Another mAb, HECA-452, recognizing a carbohydrate epitope expressed on human HEVs but not on other vessels, has been described. Nevertheless, unlike MECA-79, this mAb is not HEV specific: HECA-452 recognizes a carbohydrate epitope related to the sialyl-Lewis x and sialyl-Lewis a oligosaccharides and, in addition to reacting with high endothelium, crossreacts with monocytic cells, dendritic cells and a subset of skin-homing memory lymphocytes. [4]

Furthermore, two other HEV markers have been described in the mouse:

  1. the mAb MECA-325 defines an antigen that can be induced in nonlymphoid endothelial cells by interferon γ ( IFN- γ); and
  2. the mAb MECA-367 recognizes mucosal addressin cell adhesion molecule 1 (MAdCAM-1), a counter-receptor for L-selectin and α4β7 integrin that is expressed in mucosal HEVs and in venules of intestinal lamina propria but can be induced in nonmucosal endothelial cells by tumor necrosis factor cx (TNF- α) and IL-l. [4]

In chronic human inflammatory disease

The vessels with HEV characteristics appear in human tissue in association with long-standing chronic inflammation. [4] In rheumatoid arthritis, it has been observed that the level of sulfate incorporation as well as the 'plumpness' (or 'tallness') of the endothelium in areas of lymphocytic infiltration in the synovial membrane are closely related to the concentration of the lymphocytes in the perivascular infiltrates. [4] Similarly, expression of MECA-79 and HECA-452 on these vessels is most pronounced in association with extensive lymphoid infiltrates. Therefore, the development of bona fide HEVs in the synovial membrane of patients with rheumatoid arthritis is likely to facilitate large-scale influx of lymphocytes, leading to amplification and maintenance of chronic inflammation. The development of HEVs after prolonged inflammatory stimulus is not restricted to diseased synovium, but can also occur in other tissues, particularly the gut and thyroid. During chronic inflammation of the gut in inflammatory bowel diseases (Crohn's disease and ulcerative colitis) or the thyroid in autoimmune thyroiditis (Graves' disease and Hashimoto's thyroiditis), areas of dense lymphocytic infiltration contain vessels with plump endothelium expressing MECA-79 and HECA-452. These observations suggest that HEVs could play an important role in the pathogenesis of these diseases by mediating abnormal lymphocyte recruitment to the gut or the thyroid. MECA-79+ venules with plump endothelium have also been detected in other sites of chronic inflammation, including many cutaneous inflammatory lesions. The presence of MECA-79+ HEV-like vessels in many different human chronic inflammatory diseases indicates that L-selectin is likely to play a major role in lymphocyte emigration at chronic inflammatory sites. [4]

Related Research Articles

<span class="mw-page-title-main">Lymphatic system</span> Organ system in vertebrates complementary to the circulatory system

The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the immune system, and complementary to the circulatory system. It consists of a large network of lymphatic vessels, lymph nodes, lymphoid organs, lymphatic tissue and lymph. Lymph is a clear fluid carried by the lymphatic vessels back to the heart for re-circulation. The Latin word for lymph, lympha, refers to the deity of fresh water, "Lympha".

<span class="mw-page-title-main">Lymph node</span> Organ of the lymphatic system

A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that include B and T cells. Lymph nodes are important for the proper functioning of the immune system, acting as filters for foreign particles including cancer cells, but have no detoxification function.

<span class="mw-page-title-main">Selectin</span> Family of cell adhesion molecules

The selectins are a family of cell adhesion molecules. All selectins are single-chain transmembrane glycoproteins that share similar properties to C-type lectins due to a related amino terminus and calcium-dependent binding. Selectins bind to sugar moieties and so are considered to be a type of lectin, cell adhesion proteins that bind sugar polymers.

Gut-associated lymphoid tissue (GALT) is a component of the mucosa-associated lymphoid tissue (MALT) which works in the immune system to protect the body from invasion in the gut.

<span class="mw-page-title-main">ICAM-1</span> Mammalian protein found in Homo sapiens

ICAM-1 also known as CD54 is a protein that in humans is encoded by the ICAM1 gene. This gene encodes a cell surface glycoprotein which is typically expressed on endothelial cells and cells of the immune system. It binds to integrins of type CD11a / CD18, or CD11b / CD18 and is also exploited by rhinovirus as a receptor for entry into respiratory epithelium.

<span class="mw-page-title-main">L-selectin</span> Mammalian protein found in Homo sapiens

L-selectin, also known as CD62L, is a cell adhesion molecule found on the cell surface of leukocytes, and the blastocyst. It is coded for in the human by the SELL gene. L-selectin belongs to the selectin family of proteins, which recognize sialylated carbohydrate groups containing a Sialyl LewisX (sLeX) determinant. L-selectin plays an important role in both the innate and adaptive immune responses by facilitating leukocyte-endothelial cell adhesion events. These tethering interactions are essential for the trafficking of monocytes and neutrophils into inflamed tissue as well as the homing of lymphocytes to secondary lymphoid organs. L-selectin is also expressed by lymphoid primed hematopoietic stem cells and may participate in the migration of these stem cells to the primary lymphoid organs. In addition to its function in the immune response, L-selectin is expressed on embryonic cells and facilitates the attachment of the blastocyst to the endometrial endothelium during human embryo implantation.

<span class="mw-page-title-main">Follicular dendritic cells</span> Immune cells found in lymph nodes

Follicular dendritic cells (FDC) are cells of the immune system found in primary and secondary lymph follicles of the B cell areas of the lymphoid tissue. Unlike dendritic cells (DC), FDCs are not derived from the bone-marrow hematopoietic stem cell, but are of mesenchymal origin. Possible functions of FDC include: organizing lymphoid tissue's cells and microarchitecture, capturing antigen to support B cell, promoting debris removal from germinal centers, and protecting against autoimmunity. Disease processes that FDC may contribute include primary FDC-tumor, chronic inflammatory conditions, HIV-1 infection development, and neuroinvasive scrapie.

<span class="mw-page-title-main">Addressin</span> Protein-coding gene in the species Homo sapiens

Mucosal vascular addressin cell adhesion molecule 1 (MAdCAM-1) is a protein that in humans is encoded by the MADCAM1 gene. The protein encoded by this gene is an endothelial cell adhesion molecule that interacts preferentially with the leukocyte beta7 integrin LPAM-1, L-selectin, and VLA-4 on myeloid cells to direct leukocytes into mucosal and inflamed tissues. It is a member of the immunoglobulin superfamily and is similar to ICAM-1 and VCAM-1.

<span class="mw-page-title-main">CCL21</span> Mammalian protein found in Homo sapiens

Chemokine ligand 21 (CCL21) is a small cytokine belonging to the CC chemokine family. This chemokine is also known as 6Ckine, exodus-2, and secondary lymphoid-tissue chemokine (SLC). CCL21 elicits its effects by binding to a cell surface chemokine receptor known as CCR7. The main function of CCL21 is to guide CCR7 expressing leukocytes to the secondary lymphoid organs, such as lymph nodes and Peyer´s patches.

Glycosylation-dependent cell adhesion molecule-1 (GLYCAM1) is a proteoglycan ligand expressed on cells of the high endothelial venules in lymphoid tissues. It is the ligand for the receptor L-selectin allowing for naive lymphocytes to exit the bloodstream into lymphoid tissues. GLYCAM1 binds to L-selectin by presenting one or more O-linked carbohydrates to the lectin domain of the leukocyte cell surface selectin. Data suggests that GLYCAM1 is a hormone-regulated milk protein that is part of the milk mucin complex.

Lymphocyte homing receptors are cell adhesion molecules expressed on lymphocyte cell membranes that recognize addressins on target tissues. Lymphocyte homing refers to adhesion of the circulating lymphocytes in blood to specialized endothelial cells within lymphoid organs. These diverse tissue-specific adhesion molecules on lymphocytes and on endothelial cells contribute to the development of specialized immune responses.

<span class="mw-page-title-main">Leukocyte extravasation</span> Movement of white blood cells out of blood vessels and towards the inflamed site

In immunology, leukocyte extravasation is the movement of leukocytes out of the circulatory system (extravasation) and towards the site of tissue damage or infection. This process forms part of the innate immune response, involving the recruitment of non-specific leukocytes. Monocytes also use this process in the absence of infection or tissue damage during their development into macrophages.

In immunology, peripheral tolerance is the second branch of immunological tolerance, after central tolerance. It takes place in the immune periphery. Its main purpose is to ensure that self-reactive T and B cells which escaped central tolerance do not cause autoimmune disease. Peripheral tolerance can also serve a purpose in preventing an immune response to harmless food antigens and allergens.

<span class="mw-page-title-main">C-C chemokine receptor type 7</span> Protein-coding gene in the species Homo sapiens

C-C chemokine receptor type 7 is a protein that in humans is encoded by the CCR7 gene. Two ligands have been identified for this receptor: the chemokines ligand 19 (CCL19/ELC) and ligand 21 (CCL21). The ligands have similar affinity for the receptor, though CCL19 has been shown to induce internalisation of CCR7 and desensitisation of the cell to CCL19/CCL21 signals. CCR7 is a transmembrane protein with 7 transmembrane domains, which is coupled with heterotrimeric G proteins, which transduce the signal downstream through various signalling cascades. The main function of the receptor is to guide immune cells to immune organs by detecting specific chemokines, which these tissues secrete.

The following outline is provided as an overview of and topical guide to immunology:

Lymph node stromal cells are essential to the structure and function of the lymph node whose functions include: creating an internal tissue scaffold for the support of hematopoietic cells; the release of small molecule chemical messengers that facilitate interactions between hematopoietic cells; the facilitation of the migration of hematopoietic cells; the presentation of antigens to immune cells at the initiation of the adaptive immune system; and the homeostasis of lymphocyte numbers. Stromal cells originate from multipotent mesenchymal stem cells.

Skin immunity is a property of skin that allows it to resist infections from pathogens. In addition to providing a passive physical barrier against infection, the skin also contains elements of the innate and adaptive immune systems which allows it to actively fight infections. Hence the skin provides defense in depth against infection.

Gut-specific homing is the mechanism by which activated T cells and antibody-secreting cells (ASCs) are targeted to both inflamed and non-inflamed regions of the gut in order to provide an effective immune response. This process relies on the key interaction between the integrin α4β7 and the addressin MadCAM-1 on the surfaces of the appropriate cells. Additionally, this interaction is strengthened by the presence of CCR9, a chemokine receptor, which interacts with TECK. Vitamin A-derived retinoic acid regulates the expression of these cell surface proteins.

<span class="mw-page-title-main">Bronchus-associated lymphoid tissue</span>

Bronchus-associated lymphoid tissue (BALT) is a tertiary lymphoid structure. It is a part of mucosa-associated lymphoid tissue (MALT), and it consists of lymphoid follicles in the lungs and bronchus. BALT is an effective priming site of the mucosal and systemic immune responses.

Peripheral node addressin, often referred to as PNAd, are glycoprotein ligands. More formally, the term includes "lymph" to specify the node: peripheral lymph node addressin.

References

  1. ↑ Blanchard L, Girard JP (November 2021). "High endothelial venules (HEVs) in immunity, inflammation and cancer". Angiogenesis. 24 (4): 719–753. doi:10.1007/s10456-021-09792-8. PMC   8487881 . PMID   33956259.
  2. ↑ Kuby, Janis; Kindt, Thomas J.; Goldsby, Richard A.; Osborne, Barbara A. (2007). Kuby Immunology. New York: W.H. Freeman. ISBN   978-1-4292-0211-4. Table 14-1
  3. ↑ Rapini, Ronald P.; Bolognia, Jean L.; Jorizzo, Joseph L. (2007). Dermatology: 2-Volume Set. St. Louis: Mosby. p. 73. ISBN   978-1-4160-2999-1.
  4. 1 2 3 4 5 6 7 8 Girard JP, Springer TA (1995). "High endothelial venules (HEVs): specialized endothelium for lymphocyte migration". Immunol. Today. 16 (9): 449–57. doi:10.1016/0167-5699(95)80023-9. PMID   7546210.
  5. 1 2 Janeway, Charles (2005). Immunobiology: the immune system in health and disease. New York: Garland Science. ISBN   0-8153-4101-6.
  6. ↑ Dendritic cells control lymphocyte entry to lymph nodes through high endothelial venules. Nature. 2011 Nov 13;479(7374):542-6. doi : 10.1038/nature10540
  7. ↑ Miranda Robertson; Anthony L. Defranco; Richard Locksley (2007). Immunity: The Immune Response to Infectious and Inflammatory Disease (Primers in Biology). Oxford University Press, USA. pp. 16, 50, 130. ISBN   978-0-19-920614-8.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.