Editing Lymphatic system (section)

== 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|lymphocytes]] from immature [[Progenitor cell|progenitor cells]] 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|Avian]] species's 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}}</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 which cannot interact strongly enough with self-antigens are eliminated during {{section link|T_cell#Positive_selection}} while 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 adult life, 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 the development of 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|clonal expansion]], 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
# 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 that are housed there. The spleen also consists of red pulp which is responsible for getting rid of aged red blood cells, as well as 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 (such as 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 important 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 erythrocytes 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 are found in the white pulp of the spleen.<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 the human 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 (groin, armpits) and in the neck, where lymph is collected from regions of the body likely to sustain pathogen contamination from injuries. Lymph nodes are particularly numerous in the [[mediastinum]] in the chest, neck, pelvis, [[axilla]], [[groin|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 mostly 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, or ''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 here it is heavily infiltrated with lymphocytes.

===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}}</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}}</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 increased number of T cells and B cells with distinct T cell and B cell zones as well as 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 then leading to expansion of TLS through cell proliferation and recruitment. During TLS formation, T cells 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 the development of 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 are now being identified to have an important role in the immune response to cancer and to be 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 in <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>) 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 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 that 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 immune response against tumor can be promoted by TLOs. 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 work to 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, in turn opening the unidirectional valves at the ends of these capillaries, facilitating the entry and subsequent drainage of excess lymph fluid. The collecting lymphatics, however, act to 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>

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