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Project-team INRIA-UPMC-CNRS REO Laboratoire Jacques-Louis Lions, CNRS UMR 7598, Université Pierre et Marie Curie, Place Jussieu 4, 75252 Paris Cedex 05, France
Abstract
The circulatory system has a specialized compartment that transports thelymph,Lymph originates from the interstitial fluid that enters the lumen in lymphatic vessels, or lymph vessels (capillary filtration). Interstitial fluid is the part of plasma leaking into tissues through thin walls of blood capillaries. Plasma escaping blood capillaries contains oxygen, glucose, amino acids, and other nutrients.
The circulatory system has a specialized compartment that transports thelymph,1 Lymph originates from the interstitial fluid that enters the lumen in lymphatic vessels, or lymph vessels (capillary filtration). Interstitial fluid is the part of plasma leaking into tissues through thin walls of blood capillaries. Plasma escaping blood capillaries contains oxygen, glucose, amino acids, and other nutrients.
Lymph is convected unidirectionally from tiny lymphatic capillaries that infuse almost every body’s tissue toward large thoracic veins close to the heart, i.e., subclavian veins on left and right sides of the neck base via left and right thoracic ducts (length 38–45 cm; caliber ∼ 5mm) of the lymphatic system. Lymph return a fraction of carried particulate matter to the blood stream. Therefore, lymph enables to recycle plasma.
The lymph is carried along the lymph vascular network by intrinsic contractions of mural cells of mid-size and large lymphatic vessels and by extrinsic compression of lymphatic vessels by skeletal muscle activity, among other sources of increase in external pressure such as breathing. Valves prevent lymph from flowing backward. Lymph flow can cease during long periods of complete physical inactivity.
Lymphatic vessels convey lymph from nearly all the body’s tissue, except the central nervous system, tiny vessel walls, and avascular tissues, such as the transparent structures of the eye (central cornea, lens, vitreous humor)2 and articular cartilage,3 in addition to epithelia and endothelia. Lymphatic vessels are not detected in cortical bone, but in connective tissue overlying the periosteum [318]. On the other hand, the lung, gut, genitourinary tract, and dermis of the skin contain a dense network of lymphatic vessels.
The lymphatic network not only maintains the fluid balance, but also carries fat-soluble vitamins, fatty acids, and other lipids from the digestive tract and delivers these materials to the body’s cells.Chyle 4 is an emulsion5 of lymph (continuous phase) and immiscible free fatty acids (dispersed phase). In villi of the small intestine during digestion, fatty foods processed by enzymes of digestive juices are taken up by enterocytes. In enterocytes, absorbed lipids are again processed and incorporated in chylomicrons. These lipoproteins enterlacteals (lymphatic capillaries) and form chyle. The relative low pressure of the lacteals enables entry of large molecules, whereas the higher pressure in veins allows only smaller digestion products (e.g., amino acids and sugars) to enter directly blood.
Lymph drainage is involved in immunity. The lymphatic network comprises the lymphoid tissue, particularly lymph nodes. The lymphoid system also includes all structures devoted to the production and circulation of lymphocytes (bone marrow, thymus, spleen, lymphoid follicles such as tonsils, and mucosa-associated lymphoid tissue, especially in the digestive and respiratory tracts). The lymphatic system transports leukocytes to and from the lymph nodes. Antigen-presenting cells such as dendritic cells are transferred by lymph drainage to lymph nodes where an immune response is launched.
Fluid carried out of the blood stream during normal blood circulation is filtered not only from blood capillaries, but also lymph nodes. In lymph nodes, filtered fluid permits to remove microorganisms, abnormal cells, and other materials. This fluid is then transported back into the blood stream via lymphatic vessels.
Therefore, the lymphatic system assists the immune system in removing waste, debris, dead blood cells, pathogens, and toxins. However, it also conveys cancer cells.
Lymph vessels collect and drain excess tissue fluid and transport lymph into veins, thereby returning it to blood. Lymphatic capillaries are slightly larger than blood capillaries. Their wall structure enables interstitial fluid to flow into them, but not out. Ends of mural endothelial cells overlap. When the interstitial pressure is greater than the lymphatic capillary pressure, the cells separate slightly and interstitial fluid enters the lymphatic capillary. When the lymphatic luminal pressure is greater than the interstitial pressure, endothelial cells strongly, thereby preventing lymph exit into the interstitial medium.
Unlike the blood circulation, the collecting lymphatic system is an open circuit with closed upstream ends, as the smallest, thin-walled, lymphatic capillaries located between cells are closed at one end.
4.1 Lymphatics
Lymphatic vessels are associated with lymph nodes, oval-shaped filters enclosed by a fibrous capsule, generally organized into clusters.Lymphatic capillaries are thin walled, composed of endothelium with intercellular gaps.6 The surrounding basementmembrane is small and permeable or absent. The endothelium of terminal lymphatics lacks a continuous basement membrane and tight junctions.
Lymph sacs are the earliest elements of the lymphatic vasculature out of which lymphatic vessels grow. Lymph sacs are formed by budding and differentiation toward lymphatic lineage of endothelial cells under the control ofProspero homeobox gene product Prox1 [319].
Lymphatic capillaries are similar in size to venules, without a sheath of pericytes or smooth myocytes. Larger collecting lymphatic vessels have smooth myocytes and are similar to veins with thinner walls. The wall is surrounded by a basement membrane. Lymphatic vessels have numerous semilunar valves every few millimeters that prevent back and forth lymph motion.
Lymph from the upper right quarter of the body drains into the right lymphatic duct, and subsequently into the right subclavian vein, otherwise into the thoracic duct, and then into the left subclavian vein. Additional lymphaticovenous anastomoses occur in renal, hepatic, and adrenal veins, as well as lymph nodes.
Collecting lymphatic vessels convey interstitial fluid at low pressure down to veins in which luminal pressure is higher. Between valved segments, lymphatic vessels are made of lymphangions that contain smooth myocytes aimed at cyclically pumping lymph against a pressure gradient. Using a mathematical model of lymphangion, optimal lymphangion length downstream from a symmetrical junction is equal to 1.26 times upstream lymphangion length [320].
Lymphatics are able to generate myogenic constriction and dilation in response to intraluminal pressure changes, especially to prevent overdistension in edema.Substance-P increases both magnitude and rate of lymphatic vessel constriction, as well as the pressure range over which constriction occurs [321].
4.2 Lymphoid Tissues
Several types oflymphoid tissues exist [322]. Genetically preprogrammed anatomically distinct lymphoid organs include lymph nodes and spleen. Prepatterned environment-dependent mucosal-associated lymphoid tissues are represented by Peyer patches and gut-associated lymphoid tissue,7 tonsils, adenoids, and nasal-associated and bronchial-associated lymphoid tissues. These 2 groups of secondary lymphoid organs trap and concentrate antigens at many loci throughout the body to initiate an adaptive immune response. The spleen detects blood-borne pathogens. T-cell maturation occurs in the thymus.
During embryonic development, circulating hematopoietic cells gather at predestined sites throughout the body and form B- and T-cell-specific regions of secondary lymphoid organs. Tertiary lymphoid structures appear with local, prolonged inflammation. Paracrine signaling regulates the organization and induction of immunocyte populations that lead to the formation of secondary and tertiary lymphoid structures.
4.2.1 Thymus
The thymus is located in the upper anterior region of the chest cavity behind the sternum and partly in the neck. In the thymus, lymphocyte precursors from the bone marrow become thymocytes to subsequently mature into T lymphocytes. The thymus becomes atrophic during puberty.
The thymus possesses 2 lobes. Each lobe is enclosed in a capsule. It is composed of numerous lobules that contain multiple small follicles. Each follicle is made of a medullary and a cortical region. Each follicle is surrounded by a vascular plexus. The cortex is mainly composed of lymphoid lineage cells supported by a network of epithelial reticular cells.
Early and late events in thymocyte development occur in the cortex and medulla, respectively. The medulla has a coarser reticulum and concentric corpuscles of Hassall filled with lymphoid lineage and granular cells and enclosed by epithelioid cells.
4.2.2 Spleen
The spleen and tonsils are large lymphoid organs that have functions similar to lymph nodes, although the spleen filters blood cells rather than lymph. The spleen is located in the left upper abdomen below the rib cage. It destroys old erythrocytes and serves as a center of the reticuloendothelial system.
Like the thymus, the spleen possesses only efferent lymphatic vessels. It is subdivided into 2 regions — the red and white pulp. The red pulp that operates as a blood filter contains blood sinuses (or sinusoids), splenic cords of reticular fibers, and a marginal zone along the white pulp. The white pulp that participates in fighting infections is composed of Malpighian corpuscles made of lymphoid follicles rich in B lymphocytes and peri-arteriolar lymphoid sheaths rich in T lymphocytes.
In the spleen, follicular dendritic and fibroblastic reticular cells represent B- and T-cell zone stromal cells, respectively. Fibroblastic reticular cells form continuous sheaths around a mesh of collagen fibers and act as a backbone for the T-cell zone.
Blood-convected pathogen antigens are trapped and processed in the marginal zone by dendritic cells, macrophages, and marginal-zone B lymphocytes. In the B-cell zone, antibody responses and germinal center reactions are initiated, whereas in the T-cell zone, mature dendritic cells activate naive T lymphocytes. The territory of B- and T-cell zones is determined by chemokines. Chemokine CXCL13 on the one hand and CCL19 and CCL21 on the other form the B- and T-cell zones, respectively. Chemokines CCL19 and CCL21 also contribute to macrophage positioning in the marginal zone.
4.2.3 Other Secondary Lymphoid Tissues
Secondary lymphoid organs during embryonic and early postnatal period develop owing to interaction of CD3 − , CD4 + , CD45 + (PTPRc + ) lymphoid-tissue inducer cells with stromal lymphoid-tissue organizer cells.8Tumor-necrosis factor receptor superfamily member TNFRSF39 of stromal lymphoid organizer cells interact with the lymphokine and TNFRSF3 heterotrimeric ligand TNFSF2–TNFSF32 10 of lymphoid-tissue inducer cells to organize the architecture of secondary lymphoid organs and preserve their integrity.
The structure of secondary lymphoid organs maximizes the efficacy of immune responses to viral infection. Later in life, structural integrity of secondary lymphoid organs can be altered by infection, as antiviral cytotoxic T cells destroy stromal cells of infected T-cell zone. Reacquisition of immune responsiveness requires rebuilding of architecture of secondary lymphoid organs owing to crosstalk between lymphoid-tissue inducer cells and stromal lymphoid-tissue organizer cells. Secondary lymphoid organs are repaired when lymphoid-tissue inducer cells proliferate and accumulate in secondary lymphoid organs during peak infection and then interact with fibroblastic reticular cells of the T-cell zone [323].
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