Editing Lymphatic system (section)

===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>