View source for Lymphatic system

{{Short description|Organ system in vertebrates complementary to the circulatory system}}
{{redirect|Lymphatic drainage|the massage technique|Manual lymphatic drainage}}
{{distinguish|Limbic system}}
{{Infobox anatomy
| Name        = Lymphatic system
| Latin       = systema lymphoideum
| Image       = Blausen 0623 LymphaticSystem Female.png
| Caption     = Human lymphatic system
| Width       =
| Image2      =
| Caption2    =
| Precursor   =
| System      =
| Artery      =
| Vein        =
| Nerve       =
| Lymph       =
}}

The '''lymphatic system''', or '''lymphoid system''', is an [[organ system]] in [[vertebrate]]s that is part of the [[immune system]] and complementary to the [[circulatory system]]. It consists of a large network of [[lymphatic vessel]]s, [[lymph node]]s, lymphoid organs, lymphatic tissue and [[lymph]].<ref name="Gray's2016">{{cite book |last1=Standring |first1=Susan | name-list-style = vanc |title=Gray's anatomy: the anatomical basis of clinical practice |isbn=9780702052309 |pages=68–73 |edition=Forty-first|year=2016 |publisher=Elsevier Limited }}</ref><ref name="Moore">{{cite book | vauthors = Moore K  |title=Clinically oriented anatomy |date=2018 |isbn=9781496347213 |pages=43–45 |publisher=Wolters Kluwer |edition=Eighth }}</ref> Lymph is a clear fluid carried by the lymphatic vessels back to the heart for re-circulation. The Latin word for lymph, {{Lang|la|lympha}}, refers to the deity of fresh water, "[[Lympha]]".<ref>{{cite journal | vauthors = Natale G, Bocci G, Ribatti D | title = Scholars and scientists in the history of the lymphatic system | journal = Journal of Anatomy | volume = 231 | issue = 3 | pages = 417–429 | date = September 2017 | pmid = 28614587 | pmc = 5554832 | doi = 10.1111/joa.12644 }}</ref>

Unlike the circulatory system that is a [[closed system]], the lymphatic system is open.<ref>{{Cite journal |last1=Zhang |first1=Yufan |last2=Zhang |first2=Juxiang |last3=Li |first3=Xiaowei |last4=Li |first4=Jingru |last5=Lu |first5=Shuting |last6=Li |first6=Yuqiao |last7=Ren |first7=Panting |last8=Zhang |first8=Chunfu |last9=Xiong |first9=Liqin |date=2022-06-01 |title=Imaging of fluorescent polymer dots in relation to channels and immune cells in the lymphatic system |journal=Materials Today Bio |language=en |volume=15 |pages=100317 |doi=10.1016/j.mtbio.2022.100317 |issn=2590-0064 |pmc=9213818 |pmid=35757035}}</ref><ref>{{Cite journal |last1=Hu |first1=Dan |last2=Li |first2=Long |last3=Li |first3=Sufang |last4=Wu |first4=Manyan |last5=Ge |first5=Nana |last6=Cui |first6=Yuxia |last7=Lian |first7=Zheng |last8=Song |first8=Junxian |last9=Chen |first9=Hong |date=2019-08-01 |title=Lymphatic system identification, pathophysiology and therapy in the cardiovascular diseases |url=https://doi.org/10.1016/j.yjmcc.2019.06.002 |journal=Journal of Molecular and Cellular Cardiology |volume=133 |pages=99–111 |doi=10.1016/j.yjmcc.2019.06.002 |pmid=31181226 |s2cid=184485255 |issn=0022-2828|url-access=subscription }}</ref> The human circulatory system processes an average of 20 litres of [[blood]] per day through [[Starling equation|capillary filtration]], which removes [[blood plasma|plasma]] from the [[blood]]. Roughly 17 litres of the filtered blood is reabsorbed directly into the [[blood vessel]]s, while the remaining three litres are left in the [[interstitial fluid]]. One of the main functions of the lymphatic system is to provide an accessory return route to the blood for the surplus three litres.<ref>{{Cite book|url=https://books.google.com/books?id=I9qH3eZ1pP0C&pg=PT401|title=Human Physiology: From Cells to Systems|first=Lauralee|last=Sherwood | name-list-style = vanc |date=January 1, 2012|publisher=Cengage Learning|via=Google Books|isbn=9781111577438}}</ref>

The other main function is that of immune defense. Lymph is very similar to blood plasma, in that it contains waste products and [[Wikt:cellular debris|cellular debris]], together with [[bacteria]] and [[protein]]s. The cells of the lymph are mostly [[lymphocyte]]s. Associated lymphoid organs are composed of lymphoid tissue, and are the sites either of lymphocyte production or of lymphocyte activation. These include the [[lymph node]]s (where the highest lymphocyte concentration is found), the [[spleen]], the [[thymus]], and the [[tonsil]]s. Lymphocytes are initially generated in the [[bone marrow]]. The lymphoid organs also contain other types of cells such as [[stromal cell]]s for support.<ref name="Mak(Ph.D.)2008">{{cite book| first1 = Tak W. | last1 = Mak | first2 = Mary E. | last2 = Saunders | first3 = Mary E. | last3 = Saunders | name-list-style = vanc |title=Primer to the immune response|url=https://books.google.com/books?id=RX8-gd1tJRgC&pg=PA28|access-date=12 November 2010|year=2008|publisher=Academic Press|isbn=978-0-12-374163-9|pages=28–}}</ref> Lymphoid tissue is also associated with [[mucosa]]s such as [[mucosa-associated lymphoid tissue]] (MALT).<ref name=grays>{{cite book |last1= Warwick|first1= Roger| first2 = Peter L. | last2 = Williams | name-list-style = vanc |title= Gray's anatomy|edition= Thirty-fifth|publisher= Longman|location= London|pages= 588–785|chapter= Angiology (Chapter 6)}}</ref>

Fluid from circulating blood leaks into the tissues of the body by capillary action, carrying nutrients to the cells. The fluid bathes the tissues as interstitial fluid, collecting waste products, bacteria, and damaged cells, and then drains as lymph into the lymphatic capillaries and lymphatic vessels. 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 as [[lymph duct]]s. The [[right lymphatic duct]] drains the right side of the region and the much larger left lymphatic duct, known as the [[thoracic duct]], drains the left side of the body. The ducts empty into the [[subclavian vein]]s to return to the blood circulation. Lymph is moved through the system by muscle contractions.<ref name="Peyrot">{{cite journal | vauthors = Peyrot SM, Martin BL, Harland RM | title = Lymph heart musculature is under distinct developmental control from lymphatic endothelium | journal = Developmental Biology | volume = 339 | issue = 2 | pages = 429–38 | date = March 2010 | pmid = 20067786 | pmc = 2845526 | doi = 10.1016/j.ydbio.2010.01.002 }}</ref> In some vertebrates, a [[lymph heart]] is present that pumps the lymph to the veins.<ref name="Peyrot"/><ref name="Jeltsch">{{cite journal | vauthors = Jeltsch M, Tammela T, Alitalo K, Wilting J | title = Genesis and pathogenesis of lymphatic vessels | journal = Cell and Tissue Research | volume = 314 | issue = 1 | pages = 69–84 | date = October 2003 | pmid = 12942362 | doi = 10.1007/s00441-003-0777-2 | s2cid = 23318096 }}</ref>

The lymphatic system was first described in the 17th century independently by [[Olaus Rudbeck]] and [[Thomas Bartholin]].<ref name="Eriksson">{{cite journal | vauthors = Eriksson G | title = [Olaus Rudbeck as scientist and professor of medicine] | journal = Svensk Medicinhistorisk Tidskrift | volume = 8 | issue = 1 | pages = 39–44 | date = 2004 | pmid = 16025602 }}</ref>

== Structure ==
[[File:Anatomy of the lymphatic system.jpg|thumb|upright=1.4|Anatomy of the lymphatic system showing primary and secondary lymphoid organs]]
The lymphatic system consists of a conducting network of lymphatic vessels, lymphoid organs, lymphoid tissues, and the circulating [[lymph]].<ref name="Gray's2016"/>

===Primary lymphoid organs===
The primary (or central) lymphoid organs, including the thymus, bone marrow, [[fetal liver]] and [[yolk sac]], are responsible for generating [[lymphocyte]]s from immature [[progenitor cell]]s in the absence of antigens.<ref>{{Cite book |title=Paul's fundamental immunology |date=2023 |publisher=Wolters Kluwer/Lippincott Williams & Wilkins |isbn=978-1-9751-4253-7 |editor-last=Flajnik |editor-first=Martin F. |edition=8th |location=Philadelphia Baltimore New York London Buenos Aires Hong Kong Sydney Tokyo |page=228 |language=en |chapter=CHAPTER 8 Lymphoid tissues and organs |editor-last2=Singh |editor-first2=Nevil J. |editor-last3=Holland |editor-first3=Steven M.}}</ref> The [[thymus]] and the [[bone marrow]] constitute the primary lymphoid organs involved in the production and early [[clonal selection]] of lymphocyte tissues.

[[Bird]] species' primary lymphoid organs include the bone marrow, thymus, [[bursa of Fabricius]], and yolk sac.<ref>{{Citation |last1=Pendl • |first1=Helene |title=Immunology |date=2016 |work=Current Therapy in Avian Medicine and Surgery |pages=400–432 |url=https://linkinghub.elsevier.com/retrieve/pii/B9781455746712000203 |access-date=2024-08-28 |publisher=Elsevier |language=en |doi=10.1016/b978-1-4557-4671-2.00020-3 |isbn=978-1-4557-4671-2 |last2=Tizard |first2=Ian|url-access=subscription }}</ref>

====Bone marrow====
{{Main|Bone marrow}}
Bone marrow is responsible for both the creation of [[T cell]] precursors and the production and maturation of [[B cell]]s, which are important cell types of the immune system. From the 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 develop further and mature. Mature T cells then join B cells in search of pathogens. The other 95% of T cells begin a process of [[apoptosis]], a form of [[programmed cell death]]: T cells that cannot interact strongly enough with self-antigens are eliminated during {{section link|T_cell#Positive_selection}}, and T cells that attack the body's own proteins are eliminated during {{section link|T_cell#Negative_selection}}.

====Thymus====
{{Main|Thymus}}
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 on [[bony fish]] showed a buildup of T cells in the thymus and spleen of lymphoid tissues in [[salmon]] and showed that there are not many T cells in non-lymphoid tissues.<ref name="Koppang">{{cite journal |vauthors=Koppang EO, Fischer U, Moore L, Tranulis MA, Dijkstra JM, Köllner B, Aune L, Jirillo E, Hordvik I |title=Salmonid T cells assemble in the thymus, spleen and in novel interbranchial lymphoid tissue |journal=J Anat |volume=217 |issue=6 |pages=728–39 |date=December 2010 |pmid=20880086 |pmc=3039185 |doi=10.1111/j.1469-7580.2010.01305.x |url=}}</ref>

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.

===Secondary lymphoid organs===
{{Further|Clonal selection}}
The secondary (or peripheral) lymphoid organs, which include [[lymph node]]s and the [[spleen]], maintain mature naive lymphocytes and initiate an [[adaptive immune system|adaptive immune response]].<ref>{{cite journal | vauthors = Ruddle NH, Akirav EM | title = Secondary lymphoid organs: responding to genetic and environmental cues in ontogeny and the immune response | journal = Journal of Immunology | volume = 183 | issue = 4 | pages = 2205–12 | date = August 2009 | pmid = 19661265 | pmc = 2766168 | doi = 10.4049/jimmunol.0804324 }}</ref> The secondary lymphoid organs are the sites of lymphocyte activation by [[antigen]]s.<ref>{{cite journal |title=Secondary Lymphoid Organs: Responding to Genetic and Environmental Cues in Ontogeny and the Immune Response1 |year=2009 |pmc=2766168 |last1=Ruddle |first1=N. H. |last2=Akirav |first2=E. M. |journal=Journal of Immunology |volume=183 |issue=4 |pages=2205–2212 |doi=10.4049/jimmunol.0804324 |pmid=19661265 }}</ref> Activation leads to [[clonal selection]] and [[affinity maturation]]. Mature lymphocytes recirculate between the blood and the secondary lymphoid organs until they encounter their specific antigen.

====Spleen====
{{Main|Spleen}}
The main functions of the spleen are:
# to produce [[immune cell]]s to fight [[antigen]]s,
# to remove [[particulate matter]] and aged blood cells, mainly [[red blood cell]]s, and
# to produce blood cells during fetal life.

The spleen synthesizes [[antibodies]] in its [[white pulp]] and removes antibody-coated bacteria and antibody-coated blood cells by way of blood and [[lymph 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's [[monocyte]]s within the [[red pulp]].<ref name="Swirski">{{cite journal | vauthors = Swirski FK, Nahrendorf M, Etzrodt M, Wildgruber M, Cortez-Retamozo V, Panizzi P, Figueiredo JL, Kohler RH, Chudnovskiy A, Waterman P, Aikawa E, Mempel TR, Libby P, Weissleder R, Pittet MJ | display-authors = 6 | title = Identification of splenic reservoir monocytes and their deployment to inflammatory sites | journal = Science | volume = 325 | issue = 5940 | pages = 612–6 | date = July 2009 | pmid = 19644120 | pmc = 2803111 | doi = 10.1126/science.1175202 | bibcode = 2009Sci...325..612S }}</ref> These monocytes, upon moving to injured tissue (e.g., the heart), turn into [[dendritic cell]]s and [[macrophage]]s while promoting tissue healing.<ref name="Swirski" /><ref name="Jia">{{cite journal | vauthors = Jia T, Pamer EG | title = Immunology. Dispensable but not irrelevant | journal = Science | volume = 325 | issue = 5940 | pages = 549–50 | date = July 2009 | pmid = 19644100 | pmc = 2917045 | doi = 10.1126/science.1178329 | bibcode = 2009Sci...325..549J }}</ref><ref>{{cite web |url=https://www.nytimes.com/2009/08/04/science/04angier.html |title=Finally, the Spleen Gets Some Respect |first=Natalie |last=Angier | name-list-style = vanc |work=The New York Times |date=August 3, 2009 |url-status=live |archive-url=https://web.archive.org/web/20180127113051/https://www.nytimes.com/2009/08/04/science/04angier.html |archive-date=2018-01-27}}</ref> The spleen is a center of activity of the [[mononuclear phagocyte system]] and can be considered analogous to a large lymph node, as its absence causes a predisposition to certain [[infection]]s. 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 on [[bony fish]] has shown that a high concentration of T cells is found in the spleen's white pulp.<ref name="Koppang"/>

Like the [[thymus]], the spleen has only [[efferent lymphatic vessels]]. Both the [[short gastric arteries]] and the [[splenic artery]] supply it with blood.<ref>{{Cite book | publisher = Lippincott Williams & Wilkins | isbn = 978-0-7817-7076-7 | last = Blackbourne | first = Lorne H | name-list-style = vanc | title = Surgical recall | date = 2008-04-01 | page = [https://archive.org/details/surgicalrecall00blac/page/259 259] | url = https://archive.org/details/surgicalrecall00blac/page/259 }}</ref> The [[germinal centers]] are supplied by [[arteriole]]s called ''penicilliary radicles''.<ref>{{cite web |url=http://medical-dictionary.thefreedictionary.com/penicilliary+radicles |title=Penicilliary radicles |work=Saunders Comprehensive Veterinary Dictionary |edition=3rd |year=2007 |publisher=Elsevier, Inc. |via=The Free Dictionary by Farlex |access-date=2011-04-03 |archive-url=https://web.archive.org/web/20160304110148/http://medical-dictionary.thefreedictionary.com/penicilliary+radicles |archive-date=2016-03-04 |url-status=dead }}</ref>

In humans, until the fifth month of [[prenatal development]], the spleen creates [[red blood cells]]; after birth, the [[bone marrow]] is solely responsible for [[hematopoiesis]]. As a major lymphoid organ and a central player in the reticuloendothelial system, the spleen retains the ability to produce lymphocytes. The spleen stores [[red blood cells]] and lymphocytes. It can store enough blood cells to help in an emergency. Up to 25% of lymphocytes can be stored at any one time.<ref name="Spleen: Information, Surgery and Functions">{{cite web |url=https://chp.edu/CHP/organs+spleen+functions |archive-url=https://web.archive.org/web/20110926085253/http://www.chp.edu/CHP/organs+spleen+functions |url-status=dead |archive-date=2011-09-26 |title=Spleen: Information, Surgery and Functions |publisher=Children's Hospital of Pittsburgh - Chp.edu |date=2010-11-17 |access-date=2011-04-03 }}</ref>

====Lymph nodes====
{{Main|Lymph node}}{{Further|List of lymph nodes of the human body}}
[[File:Illu lymph node structure.png|thumb|350px|right|A lymph node showing [[Afferent lymph vessel|afferent]] and [[Efferent lymph vessel|efferent]] [[lymphatic vessel]]s]]
[[Image:Lymph node regions.svg|thumb|240px|Regional lymph nodes]]
A [[lymph 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. Several [[afferent lymph vessel]]s bring in lymph, which percolates through the substance of the lymph node and is then drained out by an [[efferent lymph vessel]]. Of the nearly 800 lymph nodes in the human body, about 300 are located in the head and neck.<ref name="SinghV">{{cite book |last1=Singh |first1=Vishram | name-list-style = vanc |title=Textbook of Anatomy Head, Neck, and Brain; Volume III |date=2017 |isbn=9788131237274 |pages=247–249 |publisher=Elsevier India |edition=2nd}}</ref> 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 the [[mediastinum]] in the chest, neck, pelvis, [[axilla]], [[groin]] (or inguinal region), and in association with the blood vessels of the intestines.<ref name=grays/>

The substance of a lymph node consists of lymphoid follicles in an outer portion called the [[Cortex (anatomy)|cortex]]. The inner portion of the node is called the [[medulla of lymph node|medulla]], which is surrounded by the cortex on all sides except for a portion known as the [[Hilum of lymph node|hilum]]. 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 (or [[thymocytes]]), the paracortex has a mixture of immature and mature T cells. Lymphocytes enter the lymph nodes through specialised [[high endothelial venule]]s 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 of [[B cell]]s (also known as B lymphocytes) occurs in the [[germinal centre]] of the lymph nodes.

Secondary lymphoid tissue provides the environment for the foreign or altered native molecules (antigens) to interact with the lymphocytes. It is exemplified by the [[lymph node]]s, and the lymphoid follicles in [[tonsil]]s, [[Peyer's patch]]es, [[spleen]], [[adenoid]]s, [[skin]], etc. that are associated with the [[mucosa-associated lymphoid tissue]] (MALT).

In the [[gastrointestinal wall]], the [[vermiform appendix|appendix]] has mucosa resembling that of the colon, but it is heavily infiltrated with lymphocytes here.

===Tertiary lymphoid organs===
Tertiary lymphoid organs (TLOs) are abnormal lymph node-like structures that form in peripheral tissues at sites of [[chronic inflammation]], such as chronic infection, [[transplanted organs]] undergoing [[graft rejection]], some [[cancer]]s, and [[autoimmune]] and autoimmune-related diseases.<ref name="TLOpowerhouses">{{cite journal | vauthors = Yin C, Mohanta S, Maffia P, Habenicht AJ | title = Editorial: Tertiary Lymphoid Organs (TLOs): Powerhouses of Disease Immunity | journal = Frontiers in Immunology | volume = 8 | pages = 228 | date = 6 March 2017 | pmid = 28321222 | pmc = 5337484 | doi = 10.3389/fimmu.2017.00228 | doi-access = free }}</ref> TLOs are often characterized by CD20<sup>+</sup> B cell zone, which is surrounded by CD3<sup>+</sup> 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 during [[ontogeny]], being dependent on [[cytokines]] and [[hematopoietic]] cells, but still drain [[interstitial fluid]] and transport lymphocytes in response to the same chemical messengers and gradients.<ref name=":2">{{Cite journal |last1=Schumacher |first1=Ton N. |last2=Thommen |first2=Daniela S. |date=2022-01-07 |title=Tertiary lymphoid structures in cancer |url=https://www.science.org/doi/10.1126/science.abf9419 |journal=Science |language=en |volume=375 |issue=6576 |pages=eabf9419 |doi=10.1126/science.abf9419 |pmid=34990248 |issn=0036-8075|url-access=subscription }}</ref><ref name="Ruddle2013">{{cite journal | vauthors = Ruddle NH | title = Lymphatic vessels and tertiary lymphoid organs | journal = The Journal of Clinical Investigation | volume = 124 | issue = 3 | pages = 953–9 | date = March 2014 | pmid = 24590281 | pmc = 3934190 | doi = 10.1172/JCI71611 }}</ref> Mature TLOs often have an active [[germinal center]], surrounded by a network of [[follicular dendritic cells]] (FDCs).<ref>{{cite journal |vauthors=Hiraoka N, Ino Y, Yamazaki-Itoh R |date=2016-06-22 |title=Tertiary Lymphoid Organs in Cancer Tissues |journal=Frontiers in Immunology |volume=7 |pages=244 |doi=10.3389/fimmu.2016.00244 |pmc=4916185 |pmid=27446075 |doi-access=free}}</ref> Although the specific composition of TLSs may vary, within the T cell compartment, the dominant subset of T cells is CD4<sup>+</sup> T follicular helper (TFH) cells, but certain number of [[Cytotoxic T cell|CD8<sup>+</sup> cytotoxic T cells]], CD4<sup>+</sup> T helper 1 (TH1) cells, and [[Regulatory T cell|regulatory T cells]] (Tregs) can also be found within the T cell zone.<ref name=":2" /> The B cell zone contains two main areas. The mantle is located at the periphery and composed of naive [[immunoglobulin D]] (IgD)<sup>+</sup> B cells surrounding the germinal centre. The latter is defined by the presence of proliferating Ki67<sup>+</sup>CD23<sup>+</sup> B cells and a CD21<sup>+</sup> FDC network, as observed in SLOs.<ref name=":3">{{Cite journal |last1=Teillaud |first1=Jean-Luc |last2=Houel |first2=Ana |last3=Panouillot |first3=Marylou |last4=Riffard |first4=Clémence |last5=Dieu-Nosjean |first5=Marie-Caroline |date=September 2024 |title=Tertiary lymphoid structures in anticancer immunity |url=https://www.nature.com/articles/s41568-024-00728-0 |journal=Nature Reviews Cancer |language=en |volume=24 |issue=9 |pages=629–646 |doi=10.1038/s41568-024-00728-0 |pmid=39117919 |issn=1474-1768|url-access=subscription }}</ref> TLOs typically contain far fewer lymphocytes, and assume an immune role only when challenged with [[antigen]]s that result in [[inflammation]]. They achieve this by importing the lymphocytes from blood and lymph.<ref name=goldsby>{{cite book | last1 = Goldsby | first1 = Richard | last2 = Kindt | first2 = TJ | last3 = Osborne | first3 = BA | last4 = Janis | first4 = Kuby | name-list-style = vanc | title = Immunology | edition = Fifth | chapter = Cells and Organs of the Immune System (Chapter 2) | orig-date = 1992 | publisher = W. H. Freeman and Company | year = 2003 | location = New York | pages = [https://archive.org/details/immunology00gold_0/page/24 24–56] | isbn = 0-7167-4947-5 | chapter-url = https://archive.org/details/immunology00gold_0/page/24 }}</ref>

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 and [[high 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.<ref name=":3" /><ref>{{Cite journal |last1=Sato |first1=Yuki |last2=Silina |first2=Karina |last3=van den Broek |first3=Maries |last4=Hirahara |first4=Kiyoshi |last5=Yanagita |first5=Motoko |date=August 2023 |title=The roles of tertiary lymphoid structures in chronic diseases |journal=Nature Reviews Nephrology |language=en |volume=19 |issue=8 |pages=525–537 |doi=10.1038/s41581-023-00706-z |pmid=37046081 |issn=1759-507X|pmc=10092939 }}</ref>

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 as [[melanoma]], [[non-small-cell lung cancer]] and [[colorectal cancer]] (reviewed by Sautès-Fridman and colleagues<ref>{{cite journal |last1=Sautès-Fridman |first1=C |last2=Petitprez |first2=F |last3=Calderaro |first3=J |last4=Fridman |first4=WH |title=Tertiary lymphoid structures in the era of cancer immunotherapy. |journal=Nature Reviews. Cancer |date=June 2019 |volume=19 |issue=6 |pages=307–325 |doi=10.1038/s41568-019-0144-6 |pmid=31092904|s2cid=155104003 |url=https://hal.sorbonne-universite.fr/hal-02274060/file/s41568-019-0144-6_sans%20marque.pdf }}</ref> in 2019), as well as [[glioma]].<ref>{{cite journal |last1=van Hooren |first1=L |last2=Vaccaro |first2=A |last3=Ramachandran |first3=M |last4=Vazaios |first4=K |last5=Libard |first5=S |last6=van de Walle |first6=T |last7=Georganaki |first7=M |last8=Huang |first8=H |last9=Pietilä |first9=I |last10=Lau |first10=J |last11=Ulvmar |first11=MH |last12=Karlsson |first12=MCI |last13=Zetterling |first13=M |last14=Mangsbo |first14=SM |last15=Jakola |first15=AS |last16=Olsson Bontell |first16=T |last17=Smits |first17=A |last18=Essand |first18=M |last19=Dimberg |first19=A |title=Agonistic CD40 therapy induces tertiary lymphoid structures but impairs responses to checkpoint blockade in glioma. |journal=Nature Communications |date=5 July 2021 |volume=12 |issue=1 |pages=4127 |doi=10.1038/s41467-021-24347-7 |pmid=34226552|pmc=8257767 |bibcode=2021NatCo..12.4127V }}</ref> 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.<ref name=":3" /> Patients with the presence of TLOs tend to have a better prognosis,<ref name=":0">{{cite journal | vauthors = Maoz A, Dennis M, Greenson JK | title = The Crohn's-Like Lymphoid Reaction to Colorectal Cancer-Tertiary Lymphoid Structures With Immunologic and Potentially Therapeutic Relevance in Colorectal Cancer | journal = Frontiers in Immunology | volume = 10 | pages = 1884 | date = 2019 | pmid = 31507584 | pmc = 6714555 | doi = 10.3389/fimmu.2019.01884 | doi-access = free }}</ref><ref name=":1">{{cite journal | vauthors = Sautès-Fridman C, Petitprez F, Calderaro J, Fridman WH | title = Tertiary lymphoid structures in the era of cancer immunotherapy | journal = Nature Reviews. Cancer | volume = 19 | issue = 6 | pages = 307–325 | date = June 2019 | pmid = 31092904 | doi = 10.1038/s41568-019-0144-6 | url = https://hal.sorbonne-universite.fr/hal-02274060/file/s41568-019-0144-6_sans%20marque.pdf | s2cid = 155104003 }}</ref> even though some certain cancer types showed an opposite effect.<ref>{{cite journal | vauthors = Finkin S, Yuan D, Stein I, Taniguchi K, Weber A, Unger K, Browning JL, Goossens N, Nakagawa S, Gunasekaran G, Schwartz ME, Kobayashi M, Kumada H, Berger M, Pappo O, Rajewsky K, Hoshida Y, Karin M, Heikenwalder M, Ben-Neriah Y, Pikarsky E | display-authors = 6 | title = Ectopic lymphoid structures function as microniches for tumor progenitor cells in hepatocellular carcinoma | journal = Nature Immunology | volume = 16 | issue = 12 | pages = 1235–44 | date = December 2015 | pmid = 26502405 | pmc = 4653079 | doi = 10.1038/ni.3290 }}</ref> Besides, TLOs with an active [[germinal center]] seem to show a better prognosis than those with TLOs without a germinal center.<ref name=":0" /><ref name=":1" /> 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 as [[immune checkpoint blockade]] treatment.<ref>{{cite journal | vauthors = Helmink BA, Reddy SM, Gao J, Zhang S, Basar R, Thakur R, Yizhak K, Sade-Feldman M, Blando J, Han G, Gopalakrishnan V, Xi Y, Zhao H, Amaria RN, Tawbi HA, Cogdill AP, Liu W, LeBleu VS, Kugeratski FG, Patel S, Davies MA, Hwu P, Lee JE, Gershenwald JE, Lucci A, Arora R, Woodman S, Keung EZ, Gaudreau PO, Reuben A, Spencer CN, Burton EM, Haydu LE, Lazar AJ, Zapassodi R, Hudgens CW, Ledesma DA, Ong S, Bailey M, Warren S, Rao D, Krijgsman O, Rozeman EA, Peeper D, Blank CU, Schumacher TN, Butterfield LH, Zelazowska MA, McBride KM, Kalluri R, Allison J, Petitprez F, Fridman WH, Sautès-Fridman C, Hacohen N, Rezvani K, Sharma P, Tetzlaff MT, Wang L, Wargo JA | display-authors = 6 | title = B cells and tertiary lymphoid structures promote immunotherapy response | journal = Nature | volume = 577 | issue = 7791 | pages = 549–555 | date = January 2020 | pmid = 31942075 | doi = 10.1038/s41586-019-1922-8 | pmc = 8762581 | bibcode = 2020Natur.577..549H | url = https://hal.sorbonne-universite.fr/hal-02456277/file/B%20cells%2008012019%20jw%20bh%20final2.pdf | s2cid = 210221106 }}</ref>

===Other lymphoid tissue===
Lymphoid tissue associated with the lymphatic system is concerned with immune functions in defending the body against [[infection]]s and the spread of [[tumour]]s. It consists of [[connective tissue]] formed of [[reticular fiber]]s, with various types of [[leukocyte]]s (white blood cells), mostly [[lymphocyte]]s enmeshed in it, through which the lymph passes.<ref>{{DorlandsDict|eight/000109096|lymphoid tissue}}</ref> Regions of the lymphoid tissue that are densely packed with lymphocytes are known as ''lymphoid follicles''. Lymphoid tissue can either be structurally well organized as lymph nodes or may consist of loosely organized lymphoid follicles known as the [[mucosa-associated lymphoid tissue]] (MALT).

The [[central nervous system]] also has lymphatic vessels. The search for T cell gateways into and out of the [[meninges]] uncovered functional [[meningeal lymphatic vessels]] lining the [[dural venous sinuses|dural sinuses]], anatomically integrated into the membrane surrounding the brain.<ref name=Neural_immune_system>{{cite journal | vauthors = Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J | display-authors = 6 | title = Structural and functional features of central nervous system lymphatic vessels | journal = Nature | volume = 523 | issue = 7560 | pages = 337–41 | date = July 2015 | pmid = 26030524 | pmc = 4506234 | doi = 10.1038/nature14432 | quote = 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. | bibcode = 2015Natur.523..337L }}
* {{cite web |date=October 3, 2017 |title=NIH researchers uncover drain pipes in our brains |website=National Institutes of Health |url=https://www.nih.gov/news-events/news-releases/nih-researchers-uncover-drain-pipes-our-brains}}</ref>

===Lymphatic vessels===
{{main|Lymphatic vessel}}
[[File:2202 Lymphatic Capillaries big.png|thumb|280px|Lymph capillaries in the tissue spaces]]
The [[lymphatic vessel]]s, also called lymph vessels, are thin-walled vessels that conduct lymph between different parts of the body.<ref name="Robbins18">{{cite book | vauthors = Kumar V |title=Robbins basic pathology |date=2018 |isbn=9780323353175 |page=363 |publisher=Elsevier |edition=Tenth}}</ref> They include the tubular vessels of the [[lymph capillaries]], and the larger collecting vessels – the [[right lymphatic duct]] and the [[thoracic 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 the [[subclavian veins]].

The tissues of the lymphatic system are responsible for maintaining the balance of the [[body fluid]]s. 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.<ref>{{cite journal | vauthors = Vittet D | title = Lymphatic collecting vessel maturation and valve morphogenesis | journal = Microvascular Research | volume = 96 | pages = 31–7 | date = November 2014 | pmid = 25020266 | doi = 10.1016/j.mvr.2014.07.001 }}</ref> Two valve systems, a primary and a secondary valve system, are used to achieve this unidirectional flow.<ref>{{cite journal | vauthors = Heppell C, Richardson G, Roose T | title = A model for fluid drainage by the lymphatic system | journal = Bulletin of Mathematical Biology | volume = 75 | issue = 1 | pages = 49–81 | date = January 2013 | pmid = 23161129 | doi = 10.1007/s11538-012-9793-2 | s2cid = 20438669 }}</ref> 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.<ref>{{cite journal | vauthors = Bazigou E, Wilson JT, Moore JE | title = Primary and secondary lymphatic valve development: molecular, functional and mechanical insights | journal = Microvascular Research | volume = 96 | pages = 38–45 | date = November 2014 | pmid = 25086182 | pmc = 4490164 | doi = 10.1016/j.mvr.2014.07.008 }}</ref>

{{Clear}}

==Development==
{{unsourced|section|date=December 2024}}
The development of the lymphatic vascular system is a highly coordinated process essential for maintaining fluid [[homeostasis]], [[immune surveillance]], and lipid absorption. [[Lymphangiogenesis]], the formation of lymphatic vessels from pre-existing ones, is primarily driven by the migration and differentiation of lymphatic [[endothelial cells]] (LECs) under the influence of molecular signals such as vascular endothelial growth factor C ([[VEGF-C]]).The maturation and specialization of lymphatic vessels involve complex interactions with surrounding tissues, ensuring the proper function of lymphatic drainage and [[Immune cell trafficking]]. Recent advances in vitro and in vivo studies have provided deeper insights into the mechanisms regulating lymphatic vascular development, as well as the processes governing its maintenance and aging. Understanding these pathways is critical, as disruptions in lymphatic development are implicated in [[congenital disorders]], inflammatory diseases,<ref>{{Cite journal |last1=Hokari |first1=Ryota |last2=Tomioka |first2=Akira |date=2021-08-17 |title=The role of lymphatics in intestinal inflammation |journal=Inflammation and Regeneration |volume=41 |issue=1 |pages=25 |doi=10.1186/s41232-021-00175-6 |doi-access=free |issn=1880-8190 |pmc=8371859 |pmid=34404493}}</ref> and [[cancer metastasis]].

Lymphatic tissues begin to develop by the end of the fifth week of embryonic development. Lymphatic vessels develop from [[lymph sacs]] that arise from developing veins, which are derived from [[mesoderm]]. The first lymph sacs to appear are the paired jugular lymph sacs at the junction of the internal jugular and [[Subclavian vein|subclavian 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.The [[spleen]] develops from mesenchymal cells between layers of the dorsal mesentery of the stomach. The [[thymus]] arises as an outgrowth of the third pharyngeal pouch.<ref>{{Cite journal |last1=González-Loyola |first1=Alejandra |last2=Petrova |first2=Tatiana V. |date=February 2021 |title=Development and aging of the lymphatic vascular system |journal=Advanced Drug Delivery Reviews |language=en |volume=169 |pages=63–78 |doi=10.1016/j.addr.2020.12.005|doi-access=free |pmid=33316347 }}</ref>

== Function ==
The lymphatic system has multiple interrelated functions:<ref>{{cite web|url=http://www.lymphnotes.com/article.php/id/151/|title=The functions of the Lymphatic System. | work = lymphnotes.com  |access-date=Feb 25, 2011}}</ref><ref>{{Cite journal |last1=Hu |first1=Dan |last2=Li |first2=Long |last3=Li |first3=Sufang |last4=Wu |first4=Manyan |last5=Ge |first5=Nana |last6=Cui |first6=Yuxia |last7=Lian |first7=Zheng |last8=Song |first8=Junxian |last9=Chen |first9=Hong |date=2019-08-01 |title=Lymphatic system identification, pathophysiology and therapy in the cardiovascular diseases |url=https://doi.org/10.1016/j.yjmcc.2019.06.002 |journal=Journal of Molecular and Cellular Cardiology |volume=133 |pages=99–111 |doi=10.1016/j.yjmcc.2019.06.002 |pmid=31181226 |s2cid=184485255 |issn=0022-2828|url-access=subscription }}</ref><ref>{{Cite journal |last1=Munn |first1=Lance L. |last2=Padera |first2=Timothy P. |date=2014-11-01 |title=Imaging the lymphatic system |journal=Microvascular Research |series=SI: Lymphatics in Development and Pathology |language=en |volume=96 |pages=55–63 |doi=10.1016/j.mvr.2014.06.006 |issn=0026-2862 |pmc=4268344 |pmid=24956510}}</ref><ref>{{Cite journal |last1=Chong |first1=Chloé |last2=Scholkmann |first2=Felix |last3=Bachmann |first3=Samia B. |last4=Luciani |first4=Paola |last5=Leroux |first5=Jean-Christophe |last6=Detmar |first6=Michael |last7=Proulx |first7=Steven T. |date=2016-03-10 |title=In vivo visualization and quantification of collecting lymphatic vessel contractility using near-infrared imaging |journal=Scientific Reports |language=en |volume=6 |issue=1 |pages=22930 |doi=10.1038/srep22930 |issn=2045-2322 |pmc=4785392 |pmid=26960708|bibcode=2016NatSR...622930C }}</ref><ref>{{Cite journal |last1=Zhang |first1=Yufan |last2=Zhang |first2=Juxiang |last3=Li |first3=Xiaowei |last4=Li |first4=Jingru |last5=Lu |first5=Shuting |last6=Li |first6=Yuqiao |last7=Ren |first7=Panting |last8=Zhang |first8=Chunfu |last9=Xiong |first9=Liqin |date=2022-06-01 |title=Imaging of fluorescent polymer dots in relation to channels and immune cells in the lymphatic system |journal=Materials Today Bio |language=en |volume=15 |pages=100317 |doi=10.1016/j.mtbio.2022.100317 |issn=2590-0064 |pmc=9213818 |pmid=35757035}}</ref><ref>{{Cite journal |last1=Schineis |first1=Philipp |last2=Runge |first2=Peter |last3=Halin |first3=Cornelia |date=2019-01-01 |title=Cellular traffic through afferent lymphatic vessels |url=https://www.sciencedirect.com/science/article/pii/S1537189118300971 |journal=Vascular Pharmacology |series=Pioneering updates in vascular biology |language=en |volume=112 |pages=31–41 |doi=10.1016/j.vph.2018.08.001 |pmid=30092362 |s2cid=51955021 |issn=1537-1891|url-access=subscription }}</ref><ref>{{Cite journal |last1=Chavhan |first1=Govind B. |last2=Lam |first2=Christopher Z. |last3=Greer |first3=Mary-Louise C. |last4=Temple |first4=Michael |last5=Amaral |first5=Joao |last6=Grosse-Wortmann |first6=Lars |date=2020-07-01 |title=Magnetic Resonance Lymphangiography |url=https://doi.org/10.1016/j.rcl.2020.02.002 |journal=Radiologic Clinics of North America |volume=58 |issue=4 |pages=693–706 |doi=10.1016/j.rcl.2020.02.002 |pmid=32471538 |s2cid=218943574 |issn=0033-8389|url-access=subscription }}</ref>
* It is responsible for the removal of <!--"excess"--this gives a wrong impression that the removal of interstitial fluid is an occasional event, which it is not. KC Panchal--> [[interstitial fluid]] from tissues
* It absorbs and transports [[fatty acid]]s and [[fat]]s as [[chyle]] from the digestive system
* It transports [[white blood cells]] to and from the lymph nodes into the bones
* The lymph transports [[antigen-presenting cell]]s, such as [[dendritic cells]], to the lymph nodes where an immune response is stimulated.

===Fat absorption===
[[File:Nutrient absorbtion to blood and lymph.png|thumb|280x280px|Nutrients in food are absorbed via [[Intestinal villus|intestinal vili]] (greatly enlarged in the picture) to blood and lymph. Long-chain [[fatty acid]]s (and other [[lipid]]s with similar fat solubility like some medicines) are absorbed to the lymph and move in it enveloped inside [[chylomicron]]s. They move via the thoracic duct of the lymphatic system and finally enter the blood via the left subclavian vein, thus bypassing the liver's [[First pass effect|first-pass metabolism]] completely.]]
[[Lymph vessel]]s called [[lacteal]]s are at the beginning of the [[gastrointestinal tract]], predominantly in the small intestine. While most other nutrients absorbed by the [[small intestine]] are passed on to the [[portal venous system]] to drain via the [[portal vein]] into the [[liver]] for processing, fats ([[lipids]]) are passed on to the lymphatic system to be transported to the blood circulation via the [[thoracic duct]]. (There are exceptions, for example [[medium-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 the [[small intestine]] is called [[chyle]]. The nutrients that are released into the circulatory system are processed by the [[liver]], having passed through the systemic circulation.

===Immune function===
The lymphatic system plays a major role in the body's immune system, as the primary site for cells relating to [[adaptive immune system]] including [[T-cell]]s and [[B-cells]].

Cells in the lymphatic system react to [[antigen presentation|antigens presented]] or found by the cells directly or by other [[dendritic cells]].

When an antigen is recognized, an immunological cascade begins involving the activation and recruitment of more and more cells, the production of [[antibody|antibodies]] and [[cytokines]] and the recruitment of other immunological cells such as [[macrophages]].

==Clinical significance==
{{main|Lymphatic disease}}
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 called [[metastasis]]. 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.

<ref>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 </ref> 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.

=== Imaging Techniques ===
Recent advancements in imaging modalities have significantly enhanced the visualization and understanding of the lymphatic system. Dynamic contrast-enhanced magnetic resonance [[lymphangiogram]] (DCMRL) technology has emerged as a non-invasive technique providing [[high resolution]] images of lymphatic vessels and nodes, aiding in the diagnosis of lymphatic disorders and guiding interventional procedures.<ref>{{Cite journal |last1=Itkin |first1=Maxim |last2=Nadolski |first2=Gregory J. |date=March 2018 |title=Modern Techniques of Lymphangiography and Interventions: Current Status and Future Development |url=http://link.springer.com/10.1007/s00270-017-1863-2 |journal=CardioVascular and Interventional Radiology |language=en |volume=41 |issue=3 |pages=366–376 |doi=10.1007/s00270-017-1863-2 |pmid=29256071 |issn=0174-1551|url-access=subscription }}</ref> 

Near-infrared fluorescence (NIRF) imaging utilizes [[indocyanine green]] as a contrast agent to offer real-time visualization of superficial lymphatic flow, proving valuable in both clinical and research settings. These technologies have revolutionized the assessment of lymphatic function and [[pathology]], facilitating early detection and treatment of related diseases.<ref>{{Cite journal |last1=Namikawa |first1=Tsutomu |last2=Sato |first2=Takayuki |last3=Hanazaki |first3=Kazuhiro |date=December 2015 |title=Recent advances in near-infrared fluorescence-guided imaging surgery using indocyanine green |url=http://link.springer.com/10.1007/s00595-015-1158-7 |journal=Surgery Today |language=en |volume=45 |issue=12 |pages=1467–1474 |doi=10.1007/s00595-015-1158-7 |pmid=25820596 |issn=0941-1291|url-access=subscription }}</ref>

===Enlarged lymph nodes===
{{Main|Lymphadenopathy}}
[[Lymphadenopathy]] refers to one or more enlarged lymph nodes. Small groups or individually enlarged lymph nodes are generally ''reactive'' in response to [[infection]] or [[inflammation]]. This is called ''local'' lymphadenopathy. When many lymph nodes in different areas of the body are involved, this is called ''generalised'' lymphadenopathy. Generalised lymphadenopathy may be caused by [[infection]]s such as [[infectious mononucleosis]], [[tuberculosis]] and [[HIV]], [[connective tissue disease]]s such as [[systemic lupus erythematosis|SLE]] and [[rheumatoid arthritis]], and [[cancer]]s, including both cancers of tissue within lymph nodes, discussed below, and [[metastasis]] of cancerous cells from other parts of the body, that have arrived via the lymphatic system.<ref name=DAVIDSONS2010B>{{cite book |editor-first1=Nicki R. |editor-last1=Colledge |editor-first2=Stuart H. |editor-last2=Ralston |editor-first3=Brian R. |editor-last3=Walker |name-list-style= vanc |title=Davidson's principles and practice of medicine |date=2011 |publisher=Churchill Livingstone / Elsevier |location=Edinburgh / New York |isbn=978-0-7020-3085-7 |pages=1001, 1037–1040 |edition=21st |oclc=844959047}}</ref><ref name= Moore1961>{{cite journal | vauthors = Moore GE |title= Tumour cells and their spread |journal= Can Med Assoc J |date=May 1961 | volume = 84| issue = 19|pages=1051–1053|doi= |pmid=13772299 |pmc= 1939597}}</ref>

===Lymphedema===
{{Main|Lymphedema}}
[[Lymphedema]] is the [[edema|swelling]] 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, called [[elephantiasis]], the edema progresses to the extent that the skin becomes thick with an appearance similar to the skin on [[elephant]] limbs.<ref>{{Cite web | first =  James D. | last = Douketis | name-list-style = vanc | title = Lymphedema| url = http://www.merck.com/mmhe/sec03/ch037/ch037b.html | work = Merck Manual }}</ref>

Causes are unknown in most cases, but sometimes there is a previous history of severe infection, usually caused by a [[parasitic disease]], such as [[lymphatic filariasis]].

[[Lymphangiomatosis]] is a disease involving multiple cysts or lesions formed from lymphatic vessels.{{Off topic sentence|date=June 2019}}

Lymphedema can also occur after [[Lymphadenectomy|surgical 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 by [[manual lymphatic drainage]] and [[compression garment]]s. Two drugs for the treatment of lymphedema are in clinical trials: Lymfactin<ref name=lymfactin>{{Cite web| last = Herantis Pharma| title = Lymfactin® for lymphedema| date = 2015-07-21| url = http://herantis.com/pipeline/lymfactin-for-lymphedema/| access-date = 2018-12-28| archive-url = https://web.archive.org/web/20181208163642/http://herantis.com/pipeline/lymfactin-for-lymphedema/| archive-date = 2018-12-08| url-status = dead}}</ref> and [[Ubenimex]]/[[Bestatin]]. There is no evidence to suggest that the effects of manual lymphatic drainage are permanent.<ref>{{cite journal | vauthors = Martín ML, Hernández MA, Avendaño C, Rodríguez F, Martínez H | title = Manual lymphatic drainage therapy in patients with breast cancer related lymphoedema | journal = BMC Cancer | volume = 11 | issue = 1 | pages = 94 | date = March 2011 | pmid = 21392372 | pmc = 3065438 | doi = 10.1186/1471-2407-11-94 | doi-access = free }}</ref>

===Cancer===
[[File: Reed-Sternberg lymphocyte nci-vol-7172-300.jpg|thumbnail|[[Reed–Sternberg cell]]s ]]
{{Main|Lymphoma}}
[[Cancer]] of the lymphatic system can be primary or secondary. [[Lymphoma]] refers to cancer that arises from [[lymphatic 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".<ref name="FauciBraunwald2009">{{cite book| first1 = Anthony S. | last1 = Fauci | first2 = Eugene | last2 = Braunwald | first3 = Dennis | last3 = Kasper | first4 = Stephen | last4 = Hauser | first5 = Dan L. | last5 = Longo | name-list-style = vanc |title=Harrison's Manual of Medicine |url= https://books.google.com/books?id=66XKIuh8P-AC&pg=PA352 |access-date=12 November 2010 |date=19 March 2009 |publisher=McGraw Hill Professional |isbn=978-0-07-147743-7 |pages=352–}}</ref>

Lymphoma is generally considered as either [[Hodgkin lymphoma]] or [[non-Hodgkin lymphoma]]. Hodgkin lymphoma is characterised by a particular type of cell, called a [[Reed–Sternberg cell]], visible under microscope. It is associated with past infection with the [[Epstein–Barr virus]], and generally causes a painless "rubbery" lymphadenopathy. It is [[cancer staging|staged]], using [[Ann Arbor staging]]. [[Chemotherapy]] generally involves the [[ABVD]] and may also involve [[radiotherapy]].<ref name=DAVIDSONS2010B /> Non-Hodgkin lymphoma is a cancer characterised by increased proliferation of [[B-cell]]s or [[T-cells]], generally occurs in an older age group than Hodgkin lymphoma. It is treated according to whether it is ''[[Grading (tumors)|high-grade]]'' or ''low-grade'', and carries a poorer prognosis than Hodgkin lymphoma.<ref name=DAVIDSONS2010B />

[[Lymphangiosarcoma]] is a malignant [[soft tissue sarcoma|soft tissue tumour]], whereas [[lymphangioma]] is a benign tumour occurring frequently in association with [[Turner syndrome]]. [[Lymphangioleiomyomatosis]] is a benign tumour of the smooth muscles of the lymphatics that occurs in the lungs.

[[Lymphoid leukaemia]] is another form of cancer where the host is devoid of different lymphatic cells.

===Other===
{{div col|colwidth=18em}}
* [[Castleman's disease]]
* [[Chylothorax]]
* [[Kawasaki disease]]
* [[Kikuchi disease]]
* [[Lipedema]]
* [[Lymphangitis]]
* [[Lymphatic filariasis]]
* [[Lymphocytic choriomeningitis]]
* [[Solitary lymphatic nodule]]
{{div col end}}

==History==
[[Hippocrates]], in the 5th century BC, was one of the first people to mention the lymphatic system. In his work ''On Joints'', he briefly mentioned the lymph nodes in one sentence. Rufus of [[Ephesus]], a Roman physician, identified the axillary, inguinal and mesenteric lymph nodes as well as the thymus during the 1st to 2nd century AD.<ref name=Ambrose2006>{{cite journal | vauthors = Ambrose CT | title = Immunology's first priority dispute--an account of the 17th-century Rudbeck-Bartholin feud | journal = Cellular Immunology | volume = 242 | issue = 1 | pages = 1–8 | date = July 2006 | pmid = 17083923 | doi = 10.1016/j.cellimm.2006.09.004 }}</ref> The first mention of lymphatic vessels was in the 3rd century BC by [[Herophilos]], a Greek anatomist living in [[Alexandria]], who incorrectly concluded that the "absorptive veins of the lymphatics," by which he meant the [[lacteal]]s (lymph vessels of the intestines), drained into the [[hepatic portal vein]]s, and thus into the liver.<ref name=Ambrose2006/> The findings of Ruphus and Herophilos were further propagated by the Greek physician [[Galen]], who described the lacteals and mesenteric lymph nodes which he observed in his dissection of apes and pigs in the 2nd century AD.<ref name=Ambrose2006/>

In the mid 16th century, [[Gabriele Falloppio]] (discoverer of the [[fallopian tube]]s), described what is now known as the lacteals as "coursing over the intestines full of yellow matter."<ref name=Ambrose2006/> In about 1563 [[Bartolomeo Eustachi]], a professor of anatomy, described the thoracic duct in horses as ''vena alba thoracis.''<ref name=Ambrose2006/> The next breakthrough came when in 1622 a physician, [[Gaspare Aselli]], identified lymphatic vessels of the intestines in dogs and termed them ''venae 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).<ref name=flourens>{{cite book | vauthors = Flourens P |year=1859|title=A History of the Discovery of the Circulation of the Blood|chapter= Chapter 3: Aselli, Pecquet, Rudbeck, Bartholin |pages=[https://archive.org/details/ahistorydiscove01flougoog/page/n67 67]–99|url=https://archive.org/details/ahistorydiscove01flougoog | quote = william harvey. |publisher=Rickey, Mallory & company|access-date=2008-07-11}}</ref> He also identified the thoracic duct but failed to notice its connection with the lacteals.<ref name=Ambrose2006/> This connection was established by [[Jean Pecquet]] in 1651, who found a white fluid mixing with blood in a dog's heart. He suspected that fluid to be [[chyle]] 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 the ''chyli receptaculum,'' which is now known as the [[cisterna chyli|cisternae chyli]]; further investigations led him to find that lacteals' contents enter the venous system via the thoracic duct.<ref name=Ambrose2006/><ref name=flourens/> Thus, it was proven convincingly that the lacteals did not terminate in the [[liver]], thus disproving Galen's second idea: that the chyle flowed to the liver.<ref name=flourens/> [[Johann Veslingius]] drew the earliest sketches of the lacteals in humans in 1641.<ref>{{Cite journal |last1=Natale |first1=Gianfranco |last2=Bocci |first2=Guido |last3=Ribatti |first3=Domenico |date=September 2017 |title=Scholars and scientists in the history of the lymphatic system |journal=Journal of Anatomy |volume=231 |issue=3 |pages=417–429 |doi=10.1111/joa.12644 |issn=0021-8782 |pmc=5554832 |pmid=28614587}}</ref>

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 of [[William 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 them ''hepatico-aqueous vessels''. He also learned that they emptied into the thoracic duct and that they had valves.<ref name=flourens/> He announced his findings in the court of [[Christina, Queen of Sweden|Queen Christina of Sweden]], but did not publish his findings for a year,<ref name=eriksson>{{cite journal | vauthors = Eriksson G | title = [Olaus Rudbeck as scientist and professor of medicine] | language = sv | journal = Svensk Medicinhistorisk Tidskrift | volume = 8 | issue = 1 | pages = 39–44 | year = 2004 | pmid = 16025602 }}</ref> and in the interim similar findings were published by [[Thomas 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."<ref name=flourens/> This had resulted in a bitter dispute between one of Bartholin's pupils, Martin Bogdan,<ref>{{cite web |url=http://www.ilab.org/db/detail.php?booknr=349906004 |title=Disputatio anatomica, de circulatione sanguinis |trans-title=Account of Rudbeck's work on lymphatic system and dispute with Bartholin |website=[[International League of Antiquarian Booksellers]] |access-date= 2008-07-11}} {{Dead link|date=September 2010|bot=H3llBot}}</ref> and Rudbeck, whom he accused of [[plagiarism]].<ref name=eriksson/>

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.<ref>{{Cite book |url=https://www.worldcat.org/oclc/1088603298 |title=Brill's companion to the reception of Galen |date=2019 |others=Petros Bouras-Vallianatos, Barbara Zipser |isbn=978-90-04-39435-3 |location=Leiden |chapter=Chapter 25, "Galen in an Age of Change (1650–1820)", Maria Pia Donato |oclc=1088603298}}</ref><ref>{{Cite book |last=Mitchell |first=Peter |url=https://www.worldcat.org/oclc/65207019 |title=The Purple island and anatomy in early seventeenth-century literature, philosophy, and theology |date=2007 |publisher=Fairleigh Dickinson University Press |isbn=978-0-8386-4018-0 |location=Madison [NJ] |pages=217 |oclc=65207019}}</ref><ref>{{Cite web |title=Galen {{!}} Biography, Achievements, & Facts {{!}} Britannica |url=https://www.britannica.com/biography/Galen |access-date=2022-12-07 |website=www.britannica.com |language=en}}</ref>

[[Alexander Monro (secundus)|Alexander Monro]], of the [[University of Edinburgh Medical School]], was the first to describe the function of the lymphatic system in detail.<ref>{{cite book|last1=Turner|first1=A. Logan | name-list-style = vanc |title=Story of a Great Hospital: The Royal Infirmary of Edinburgh 1729-1929|url=https://archive.org/details/b29980537|date=1937|publisher=Oliver and Boyd|page=[https://archive.org/details/b29980537/page/360 360]}}</ref>

[[University of Virginia School of Medicine|UVA School of Medicine]] researchers Jonathan Kipnis and Antoine Louveau discovered previously unknown vessels connecting the [[human brain]] directly to the lymphatic system. The discovery "redrew the map" of the lymphatic system, rewrote medical [[Textbook|textbooks]], and struck down long-held beliefs about how the [[immune system]] functions in the brain. The discovery may help greatly in combating neurological diseases from [[multiple sclerosis]] to [[Alzheimer's disease]].<ref>{{Cite web |date=2015-12-03 |title=Two UVA Findings in the Running for Year's Biggest Scientific Breakthroughs {{!}} UVA Today |url=https://news.virginia.edu/content/two-uva-findings-running-years-biggest-scientific-breakthroughs |access-date=2024-08-31 |website=news.virginia.edu |language=en}}</ref>

<gallery widths="150px" heights="150px">
Image:Galen detail.jpg|[[Galen|"Claude Galien"]]. Lithograph by Pierre Roche Vigneron. (Paris: Lith de Gregoire et Deneux, {{Circa|1865}})
Gabriele_Falloppio.jpg|[[Gabriele Falloppio]]
Image:Bartolomeus Eustachius.jpg|Portrait of [[Bartolomeo Eustachi|Eustachius]]
File:Olaus Rudbeck Sr (portrait by Martin Mijtens Sr, 1696).jpg|[[Olaus Rudbeck]] in 1696.
File:Thomas bartholin.jpg|[[Thomas Bartholin]]
</gallery>

===Etymology===
''Lymph'' originates in the [[Classical Latin]] word ''{{lang|la|lympha}}'' "water",<ref>{{L&S|lympha|ref}}</ref> which is also the source of the English word ''limpid''. The spelling with ''y'' and ''ph'' was influenced by [[folk etymology]] with [[Ancient Greek|Greek]] {{lang|grc|νύμϕη}} (''{{transliteration|grc|nýmphē}}'') "[[nymph]]".<ref>{{Cite OED|lymph}}</ref>

The adjective used for the lymph-transporting system is ''lymphatic''. The adjective used for the tissues where lymphocytes are formed is ''lymphoid''. Lymphatic comes from the Latin word ''{{lang|la|lymphaticus}}'', meaning "connected to water."

== See also ==
{{Portal|Biology|Medicine}}
* [[List of lymph nodes of the human body|List of lymphatic nodes of the human body]]
* [[American Society of Lymphology]]
* [[Glymphatic system]] and [[Meningeal lymphatic vessels]] - equivalent for the [[central nervous system]]
* [[Innate lymphoid cell]]s
* [[Lymphangiogenesis]]
* [[Lymphangion]]
* [[Mononuclear phagocyte system]]
* [[Waldemar Olszewski]] – discovered fundamental processes in human tissues connected with function of the lymphatic system
* [[Trogocytosis]]

== References ==
{{Reflist|30em}}

== External links ==
{{Commons category|Lymphatic system}}
{{Wikibooks|Anatomy and Physiology of Animals|Lymphatic System}}
{{Library resources box |by=no |onlinebooks=no |others=no |about=yes |label=Lymphatic system}}
* [https://web.archive.org/web/20060815143239/http://www.emc.maricopa.edu/faculty/farabee/BIOBK/BioBookIMMUN.html Lymphatic System]
* [https://www.innerbody.com/image/lympov.html Lymphatic System Overview] (innerbody.com)

{{Lymphoid system}}
{{Lymphatic trunks and ducts}}
{{Lymphatic system anatomy}}
{{Authority control}}

{{DEFAULTSORT:Lymphatic System}}
[[Category:Lymphatic system| ]]
[[Category:Angiology]]
[[Category:Animal anatomy]]