Unlike the circulatory system, which is aclosed system, the lymphatic system is open.[4][5] Lymph originates in theinterstitial fluid that leaks from blood in the circulatory system into the tissues of the body. This fluid carries nutrients to the cells and collects waste products, bacteria, and damaged cells, before draining into the lymphatic vessels as lymph. The circulatory system processes an average of 20 litres (5.3 US gal) of blood per day throughcapillary filtration, which removes plasma from the blood. Roughly 17 litres (4.5 US gal) of the filtered blood is reabsorbed directly into theblood vessels, while the remaining 3 litres (0.79 US gal) are left in the interstitial fluid. The lymphatic system provides an accessory return route to the blood for this remainder.[6]
The other main function is that of immune defense. Lymph is very similar to blood plasma, in that it contains waste products andcellular debris, together withbacteria andproteins. The cells of the lymph are mostlylymphocytes. Associated lymphoid organs are composed of lymphoid tissue, and are the sites either of lymphocyte production or of lymphocyte activation. These include thelymph nodes (where the highest lymphocyte concentration is found), thespleen, thethymus, and thetonsils. Lymphocytes are initially generated in thebone marrow. The lymphoid organs also contain other types of cells such asstromal cells for support.[7] Lymphoid tissue is also associated withmucosas such asmucosa-associated lymphoid tissue (MALT).[8]
These vessels carry the lymph throughout the body, passing through numerous lymph nodes which filter out unwanted materials such as bacteria and damaged cells. Lymph then passes into much larger lymph vessels known aslymph ducts. Theright lymphatic duct drains the right side of the region and the much larger left lymphatic duct, known as thethoracic duct, drains the left side of the body. The ducts empty into thesubclavian veins to return to the blood circulation. Lymph is moved through the system by muscle contractions.[9] In some vertebrates, alymph heart is present that pumps the lymph to the veins.[9][10]
The primary (or central) lymphoid organs, including the thymus, bone marrow,fetal liver andyolk sac, are responsible for generatinglymphocytes from immatureprogenitor cells in the absence of antigens.[12] Thethymus and thebone marrow constitute the primary lymphoid organs involved in the production and earlyclonal selection of lymphocyte tissues.
Bird species' primary lymphoid organs include the bone marrow, thymus,bursa of Fabricius, and yolk sac.[13]
Bone marrow- specificallyred bone marrow-[14] is responsible for both the creation ofT cell precursors and the production and maturation ofB cells, which are known as lymphocytes, important cell types of the immune system. From the red bone marrow, B cells immediately join the circulatory system and travel to secondary lymphoid organs in search of pathogens. T cells, on the other hand, travel from the bone marrow to the thymus, where they where undergo a multistage process to develop immunocompetency. Within thethymic cortex, developing T cells rearrange their T-cell receptor (TCR) genes and are subjected topositive selection, which ensures that only T cells capable of recognizing self-major histocompatibility complex (MHC) molecules survive. Those that bind too weakly die off. Surviving T cells then move to thethymic medulla, wherenegative selection removes T cells that bind self-antigens with high affinity, preventing autoimmune disorders. Less than 5% of T cells pass both selection tests and reach maturity; these mature T cells then join B cells in search of pathogens.
The thymus increases in size from birth in response to postnatal antigen stimulation. It is most active during the neonatal and pre-adolescent periods. The thymus is located between the inferior neck and the superior thorax. At puberty, by the early teens, the thymus begins to atrophy and regress, with adipose tissue mostly replacing the thymic stroma. However, residual T cell lymphopoiesis continues throughout adulthood, providing some immune response. The thymus is where the T lymphocytes mature and become immunocompetent. The loss or lack of the thymus results in severe immunodeficiency and subsequent high susceptibility to infection. In most species, the thymus consists of lobules divided by septa, which are made up of epithelium, which is often considered an epithelial organ. T cells mature from thymocytes, proliferate, and undergo a selection process in the thymic cortex before entering the medulla to interact with epithelial cells.
Research onbony fish showed a buildup of T cells in the thymus and spleen of lymphoid tissues insalmon and showed that there are not many T cells in non-lymphoid tissues.[15]
The thymus provides an inductive environment for developing T cells from hematopoietic progenitor cells. In addition, thymic stromal cells allow for the selection of a functional and self-tolerant T cell repertoire. Therefore, one of the most important roles of the thymus is the induction of central tolerance. However, the thymus is not where the infection is fought, as the T cells have yet to become immunocompetent.
The secondary (or peripheral) lymphoid organs, which includelymph nodes and thespleen, maintain mature naive lymphocytes and initiate anadaptive immune response.[16] The secondary lymphoid organs are the sites of lymphocyte activation byantigens.[17] Activation leads toclonal selection andaffinity maturation. Mature lymphocytes recirculate between the blood and the secondary lymphoid organs until they encounter their specific antigen.
The spleen synthesizesantibodies in itswhite pulp and removes antibody-coated bacteria and antibody-coated blood cells by way of blood andlymph node circulation. The white pulp of the spleen provides immune function due to the lymphocytes housed there. The spleen also consists of red pulp, which is responsible for getting rid of aged red blood cells and pathogens. This is carried out by macrophages present in the red pulp. A study published in 2009 using mice found that the spleen contains, in its reserve, half of the body'smonocytes within thered pulp.[18] These monocytes, upon moving to injured tissue (e.g., the heart), turn intodendritic cells andmacrophages while promoting tissue healing.[18][19][20] The spleen is a center of activity of themononuclear phagocyte system and can be considered analogous to a large lymph node, as its absence causes a predisposition to certaininfections. Notably, the spleen is essential for a multitude of functions. The spleen removes pathogens and old erythrocytes from the blood (red pulp) and produces lymphocytes for immune response (white pulp). The spleen also is responsible for recycling some erythrocyte components and discarding others. For example, hemoglobin is broken down into amino acids that are reused.
Research onbony fish has shown that a high concentration of T cells is found in the spleen's white pulp.[15]
In humans, until the fifth month ofprenatal development, the spleen createsred blood cells; after birth, thebone marrow is solely responsible forhematopoiesis. As a major lymphoid organ and a central player in the reticuloendothelial system, the spleen retains the ability to produce lymphocytes. The spleen storesred blood cells and lymphocytes. It can store enough blood cells to help in an emergency. During acute blood loss the spleen contracts to release stored erythrocytes, helping to temporarily maintain blood volume and oxygen delivery.[23] Up to 25% of lymphocytes can be stored at any one time.[24]
Alymph node is an organized collection of lymphoid tissue through which the lymph passes on its way back to the blood. Lymph nodes are located at intervals along the lymphatic system. Severalafferent lymph vessels bring in lymph, which percolates through the substance of the lymph node and is then drained out by anefferent lymph vessel. Of the nearly 800 lymph nodes in the human body, about 300 are located in the head and neck.[25] Many are grouped in clusters in different regions, as in the underarm and abdominal areas. Lymph node clusters are commonly found at the proximal ends of limbs (e.g., groin or armpits) and in the neck, where lymph is collected from body regions likely to sustain pathogen contamination from injuries. Lymph nodes are particularly numerous in themediastinum in the chest, neck, pelvis,axilla,groin (or inguinal region), and in association with the blood vessels of the intestines.[8]
The substance of a lymph node consists of lymphoid follicles in an outer portion called thecortex. The inner portion of the node is called themedulla, which is surrounded by the cortex on all sides except for a portion known as thehilum. The hilum presents as a depression on the surface of the lymph node, causing the otherwise spherical lymph node to be bean-shaped or ovoid. The efferent lymph vessel directly emerges from the lymph node at the hilum. The arteries and veins supplying the lymph node with blood enter and exit through the hilum. The region of the lymph node called the paracortex immediately surrounds the medulla. Unlike the cortex, which has primarily immature T cells (orthymocytes), the paracortex has a mixture of immature and mature T cells. Lymphocytes enter the lymph nodes through specialisedhigh endothelial venules found in the paracortex.
A lymph follicle is a dense collection of lymphocytes, the number, size, and configuration of which change in accordance with the functional state of the lymph node. For example, the follicles expand significantly when encountering a foreign antigen. The selection ofB cells (also known as B lymphocytes) occurs in thegerminal centre of the lymph nodes.
Tertiary lymphoid organs (TLOs) are abnormal lymph node-like structures that form in peripheral tissues at sites ofchronic inflammation, such as chronic infection,transplanted organs undergoinggraft rejection, somecancers, andautoimmune and autoimmune-related diseases.[26] TLOs are often characterized by CD20+ B cell zone, which is surrounded by CD3+ T cell zone, similar to the lymph follicles in secondary lymphoid organs (SLOs) and are regulated differently from the normal process whereby lymphoid tissues are formed duringontogeny, being dependent oncytokines andhematopoietic cells, but still draininterstitial fluid and transport lymphocytes in response to the same chemical messengers and gradients.[27][28] Mature TLOs often have an activegerminal center, surrounded by a network offollicular dendritic cells (FDCs).[29] Although the specific composition of TLOs may vary, within the T cell compartment, the dominant subset of T cells is CD4+ T follicular helper (TFH) cells, but certain number ofCD8+ cytotoxic T cells, CD4+ T helper 1 (TH1) cells, andregulatory T cells (Tregs) can also be found within the T cell zone.[27] The B cell zone contains two main areas. The mantle is located at the periphery and composed of naiveimmunoglobulin D (IgD)+ B cells surrounding the germinal centre. The latter is defined by the presence of proliferating Ki67+CD23+ B cells and a CD21+ FDC network, as observed in SLOs.[30] TLOs typically contain far fewer lymphocytes, and assume an immune role only when challenged withantigens that result ininflammation. They achieve this by importing the lymphocytes from blood and lymph.[31]
According to the composition and activation status of the cells within the lymphoid structures, at least three organizational levels of TLOs have been described. The formation of TLOs starts with the aggregating of lymphoid cells and occasional DCs, but FDCs are lacking at this stage. The next stage is immature TLOs, also known as primary follicle-like TLS, which have an increased number of T cells and B cells with distinct T cell and B cell zones and the formation of FDCs network, but without germinal centres. Finally, fully mature (also known as secondary follicle-like) TLOs often have active germinal centres andhigh endothelial venules (HEVs), demonstrating a functional capacity by promoting T cell and B cell activation and then leading to expansion of TLS through cell proliferation and recruitment. During TLS formation, T and B cells are separated into two different but adjacent zones, with some cells having the ability to migrate from one to the other, which is a crucial step in developing an effective and coordinated immune response.[30][32]
TLOs may play a key role in the immune response to cancer and serve as a prognostic marker for immunotherapy. TLOs have been reported to present in different cancer types such asmelanoma,non-small-cell lung cancer andcolorectal cancer (reviewed by Sautès-Fridman and colleagues[33] in 2019), as well asglioma.[34] TLOs are also been seen as a read-out of treatment efficacy. For example, in patients with pancreatic ductal adenocarcinoma (PDAC), vaccination led to the formation of TLOs in responders. Within these patients, lymphocytes in TLOs displayed an activated phenotype, and in vitro experiments showed their capacity to perform effector functions.[30] Patients with the presence of TLOs tend to have a better prognosis,[35][36] even though some certain cancer types showed an opposite effect.[37] Besides, TLOs with an activegerminal center seem to show a better prognosis than those with TLOs without a germinal center.[35][36] The reason that these patients tend to live longer is that TLOs can promote an immune response against the tumors. TLOs may also enhance anti-tumor response when patients are treated with immunotherapy such asimmune checkpoint blockade treatment.[38]
Lymphoid tissue associated with the lymphatic system is concerned with immune functions in defending the body againstinfections and the spread oftumours. It consists ofconnective tissue formed ofreticular fibers, with various types ofleukocytes (white blood cells), mostlylymphocytes enmeshed in it, through which the lymph passes.[39] Regions of the lymphoid tissue that are densely packed with lymphocytes are known aslymphoid follicles. Lymphoid tissue can either be structurally well organized as lymph nodes or may consist of loosely organized lymphoid follicles known as themucosa-associated lymphoid tissue (MALT).
Thelymphatic vessels, also called lymph vessels, are thin-walled vessels that conduct lymph between different parts of the body.[41] They include the tubular vessels of thelymph capillaries, and the larger collecting vessels – theright lymphatic duct and thethoracic duct (the left lymphatic duct). The lymph capillaries are mainly responsible for the absorption of interstitial fluid from the tissues, while lymph vessels propel the absorbed fluid forward into the larger collecting ducts, where it ultimately returns to the bloodstream via one of thesubclavian veins.
The tissues of the lymphatic system are responsible for maintaining the balance of thebody fluids. Its network of capillaries and collecting lymphatic vessels efficiently drain and transport extravasated fluid, along with proteins and antigens, back to the circulatory system. Numerous intraluminal valves in the vessels ensure a unidirectional flow of lymph without reflux.[42] Two valve systems, a primary and a secondary valve system, are used to achieve this unidirectional flow.[43] The capillaries are blind-ended, and the valves at the ends of capillaries use specialised junctions together with anchoring filaments to allow a unidirectional flow to the primary vessels. When interstitial fluid increases, it causes swelling that stretches collagen fibers anchored to adjacent connective tissue, opening the unidirectional valves at the ends of these capillaries and facilitating the entry and subsequent drainage of excess lymph fluid. The collecting lymphatics, however, propel the lymph by the combined actions of the intraluminal valves and lymphatic muscle cells.[44]
Lymphatic tissues begin to develop by the end of the fifth week of embryonic development. Lymphatic vessels develop fromlymph sacs that arise from developing veins, which are derived frommesoderm. The first lymph sacs to appear are the paired jugular lymph sacs at the junction of the internal jugular andsubclavian veins. From the jugular lymph sacs, lymphatic capillary plexuses spread to the thorax, upper limbs, neck, and head. Some of the plexuses enlarge and form lymphatic vessels in their respective regions. Each jugular lymph sac retains at least one connection with its jugular vein, the left one developing into the superior portion of the thoracic duct. Thespleen develops from mesenchymal cells between layers of the dorsal mesentery of the stomach. Thethymus arises as an outgrowth of the third pharyngeal pouch.[45]
Nutrients in food are absorbed viaintestinal vili (greatly enlarged in the picture) to blood and lymph. Long-chainfatty acids (and otherlipids with similar fat solubility like some medicines) are absorbed to the lymph and move in it enveloped insidechylomicrons. They move via the thoracic duct of the lymphatic system and finally enter the blood via the left subclavian vein, thus bypassing the liver'sfirst-pass metabolism completely.
Lymph vessels calledlacteals are at the beginning of thegastrointestinal tract, predominantly in the small intestine. While most other nutrients absorbed by thesmall intestine are passed on to theportal venous system to drain via theportal vein into theliver for processing, fats (lipids) are passed on to the lymphatic system to be transported to the blood circulation via thethoracic duct. (There are exceptions, for examplemedium-chain triglycerides are fatty acid esters of glycerol that passively diffuse from the GI tract to the portal system.) The enriched lymph originating in the lymphatics of thesmall intestine is calledchyle. The nutrients that are released into the circulatory system are processed by theliver, having passed through the systemic circulation.
The lymphatic system plays a major role in the body's immune system, as the primary site for cells relating toadaptive immune system includingT-cells andB-cells.
In addition to carrying waste products, cellular debris, nutrients, and proteins, the lymph may also contain antigens that can interact with naive lymphocytes in the lymph nodes.[53] These cells in the lymphatic system react toantigens presented or found by the cells directly or by otherdendritic cells.
When an antigen is recognized, an immunological cascade begins involving the activation and recruitment of more and more cells, the production ofantibodies andcytokines and the recruitment of other immunological cells such asmacrophages.
The study of lymphatic drainage of various organs is important in the diagnosis, prognosis, and treatment of cancer. The lymphatic system, because of its closeness to many tissues of the body, is responsible for carrying cancerous cells between the various parts of the body in a process calledmetastasis. The intervening lymph nodes can trap the cancer cells. If they are not successful in destroying the cancer cells the nodes may become sites of secondary tumours.
[54] The lymphatic system (LS) comprises lymphoid organs and a network of vessels responsible for transporting interstitial fluid, antigens, lipids, cholesterol, immune cells, and other materials throughout the body. Dysfunction or abnormal development of the LS has been linked to numerous diseases, making it critical for fluid balance, immune cell trafficking, and inflammation control. Recent advancements, including single-cell technologies, clinical imaging, and biomarker discovery, have improved the ability to study and understand the LS, providing potential pathways for disease prevention and treatment. Studies have shown that the lymphatic system also plays a role in modulating immune responses, with dysfunction linked to chronic inflammatory and autoimmune conditions, as well as cancer progression.
Lymphadenopathy refers to one or more enlarged lymph nodes. Small groups or individually enlarged lymph nodes are generallyreactive in response toinfection orinflammation. This is calledlocal lymphadenopathy. When many lymph nodes in different areas of the body are involved, this is calledgeneralised lymphadenopathy. Generalised lymphadenopathy may be caused byinfections such asinfectious mononucleosis,tuberculosis andHIV,connective tissue diseases such asSLE andrheumatoid arthritis, andcancers, including both cancers of tissue within lymph nodes, discussed below, andmetastasis of cancerous cells from other parts of the body, that have arrived via the lymphatic system.[55][56]
Lymphedema is theswelling caused by the accumulation of lymph, which may occur if the lymphatic system is damaged or has malformations. It usually affects limbs, though the face, neck and abdomen may also be affected. In an extreme state, calledelephantiasis, the edema progresses to the extent that the skin becomes thick with an appearance similar to the skin onelephant limbs.[57]
Causes are unknown in most cases, but sometimes there is a previous history of severe infection, usually caused by aparasitic disease, such aslymphatic filariasis.
Lymphedema can also occur aftersurgical removal of lymph nodes in the armpit (causing the arm to swell due to poor lymphatic drainage) or groin (causing swelling of the leg). Conventional treatment is bymanual lymphatic drainage andcompression garments. Two drugs for the treatment of lymphedema are in clinical trials: Lymfactin[58] andUbenimex/Bestatin. There is no evidence to suggest that the effects of manual lymphatic drainage are permanent.[59]
Cancer of the lymphatic system can be primary or secondary.Lymphoma refers to cancer that arises fromlymphatic tissue. Lymphoid leukaemias and lymphomas are now considered to be tumours of the same type of cell lineage. They are called "leukaemia" when in the blood or marrow and "lymphoma" when in lymphatic tissue. They are grouped together under the name "lymphoid malignancy".[60]
Lymphoma is generally considered as eitherHodgkin lymphoma ornon-Hodgkin lymphoma. Hodgkin lymphoma is characterised by a particular type of cell, called aReed–Sternberg cell, visible under microscope. It is associated with past infection with theEpstein–Barr virus, and generally causes a painless "rubbery" lymphadenopathy. It isstaged, usingAnn Arbor staging.Chemotherapy generally involves theABVD and may also involveradiotherapy.[55] Non-Hodgkin lymphoma is a cancer characterised by increased proliferation ofB-cells orT-cells, generally occurs in an older age group than Hodgkin lymphoma. It is treated according to whether it ishigh-grade orlow-grade, and carries a poorer prognosis than Hodgkin lymphoma.[55]
Hippocrates, in the 5th century BC, was one of the first people to mention the lymphatic system. In his workOn Joints, he briefly mentioned the lymph nodes in one sentence. Rufus ofEphesus, a Roman physician, identified the axillary, inguinal and mesenteric lymph nodes as well as the thymus during the 1st to 2nd century AD.[61] The first mention of lymphatic vessels was in the 3rd century BC byHerophilos, a Greek anatomist living inAlexandria, who incorrectly concluded that the "absorptive veins of the lymphatics," by which he meant thelacteals (lymph vessels of the intestines), drained into thehepatic portal veins, and thus into the liver.[61] The findings of Ruphus and Herophilos were further propagated by the Greek physicianGalen, who described the lacteals and mesenteric lymph nodes which he observed in his dissection of apes and pigs in the 2nd century AD.[61]
In the mid 16th century,Gabriele Falloppio (discoverer of thefallopian tubes), described what is now known as the lacteals as "coursing over the intestines full of yellow matter."[61] In about 1563Bartolomeo Eustachi, a professor of anatomy, described the thoracic duct in horses asvena alba thoracis.[61] The next breakthrough came when in 1622 a physician,Gaspare Aselli, identified lymphatic vessels of the intestines in dogs and termed themvenae albae et lacteae, which are now known as simply the lacteals. The lacteals were termed the fourth kind of vessels (the other three being the artery, vein and nerve, which was then believed to be a type of vessel), and disproved Galen's assertion that chyle was carried by the veins. But, he still believed that the lacteals carried the chyle to the liver (as taught by Galen).[62] He also identified the thoracic duct but failed to notice its connection with the lacteals.[61] This connection was established byJean Pecquet in 1651, who found a white fluid mixing with blood in a dog's heart. He suspected that fluid to bechyle as its flow increased when abdominal pressure was applied. He traced this fluid to the thoracic duct, which he then followed to a chyle-filled sac he called thechyli receptaculum, which is now known as thecisternae chyli; further investigations led him to find that lacteals' contents enter the venous system via the thoracic duct.[61][62] Thus, it was proven convincingly that the lacteals did not terminate in theliver, thus disproving Galen's second idea: that the chyle flowed to the liver.[62]Johann Veslingius drew the earliest sketches of the lacteals in humans in 1641.[63]
The idea that blood recirculates through the body rather than being produced anew by the liver and the heart was first accepted as a result of works ofWilliam Harvey—a work he published in 1628. In 1652,Olaus Rudbeck (1630–1702) discovered certain transparent vessels in the liver that contained clear fluid (and not white), and thus named themhepatico-aqueous vessels. He also learned that they emptied into the thoracic duct and that they had valves.[62] He announced his findings in the court ofQueen Christina of Sweden, but did not publish his findings for a year,[64] and in the interim similar findings were published byThomas Bartholin, who additionally published that such vessels are present everywhere in the body, not just in the liver. He is also the one to have named them "lymphatic vessels."[62] This had resulted in a bitter dispute between one of Bartholin's pupils, Martin Bogdan,[65] and Rudbeck, whom he accused ofplagiarism.[64]
Galen's ideas prevailed in medicine until the 17th century. It was thought that blood was produced by the liver from chyle contaminated with ailments by the intestine and stomach, to which various spirits were added by other organs, and that this blood was consumed by all the organs of the body. This theory required that the blood be consumed and produced many times over. Even in the 17th century, his ideas were defended by some physicians.[66][67][68]
UVA School of Medicine researchers Jonathan Kipnis and Antoine Louveau discovered previously unknown vessels connecting thehuman brain directly to the lymphatic system. The discovery "redrew the map" of the lymphatic system, rewrote medicaltextbooks, and struck down long-held beliefs about how theimmune system functions in the brain. The discovery may help greatly in combating neurological diseases frommultiple sclerosis toAlzheimer's disease.[70]
"Claude Galien". Lithograph by Pierre Roche Vigneron. (Paris: Lith de Gregoire et Deneux,c. 1865)
Lymph originates in theClassical Latin wordlympha "water",[71] which is also the source of the English wordlimpid. The spelling withy andph was influenced byfolk etymology withGreekνύμϕη (nýmphē) "nymph".[72]
The adjective used for the lymph-transporting system islymphatic. The adjective used for the tissues where lymphocytes are formed islymphoid. Lymphatic comes from the Latin wordlymphaticus, meaning "connected to water."
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^Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, et al. (July 2015)."Structural and functional features of central nervous system lymphatic vessels".Nature.523 (7560):337–41.Bibcode:2015Natur.523..337L.doi:10.1038/nature14432.PMC4506234.PMID26030524.we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes. The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system. The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction.
^Hu, Dan; Li, Long; Li, Sufang; Wu, Manyan; Ge, Nana; Cui, Yuxia; Lian, Zheng; Song, Junxian; Chen, Hong (2019-08-01). "Lymphatic system identification, pathophysiology and therapy in the cardiovascular diseases".Journal of Molecular and Cellular Cardiology.133:99–111.doi:10.1016/j.yjmcc.2019.06.002.ISSN0022-2828.PMID31181226.S2CID184485255.
^Khan, A. R., Headland, S. E., Norling, L. V., & Lombardi, G. (2024). The emerging importance of lymphatics in health and disease: an update. *Journal of Clinical Investigation, 134*(1), e171582.https://doi.org/10.1172/JCI171582
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