Editing Thymus

{{short description|Endocrine gland}}
{{About|the organ of the immune system|organ of the hormone system|thyroid|culinary use of animal thymus|Sweetbread|the plant genus ''Thymus''|Thymus (plant)|other uses|Thymus (disambiguation)}}
{{Good article}}
{{Infobox anatomy
| Name        = Thymus
| Latin       = thymus
| Greek       = θύμος
| Image       = Diagram showing the position of the thymus gland CRUK 362.svg
| Caption     = Position of the human thymus
| Precursor   = [[Pharyngeal pouch (embryology)#Third pouch|Third pharyngeal pouch]] 
| System      = [[Lymphatic system]], part of the [[immune system]]
| Artery      = 
| Vein        = 
| Nerve       = 
| Lymph       = [[Tracheobronchial lymph nodes|Tracheobronchial]], [[Parasternal lymph nodes|parasternal]]
| Function    = Support the development of functional [[T cell]]s
}}

The '''thymus''' ({{plural form}}: '''thymuses''' or '''thymi''') is a specialized [[primary lymphoid organ]] of the [[immune system]]. Within the thymus, [[T cell]]s mature. T cells are critical to the [[adaptive immune system]], where the body adapts to specific foreign invaders. The thymus is located in the  upper front part of the chest, in the anterior [[superior mediastinum]], behind the [[sternum]], and in front of the [[heart]]. It is made up of two lobes, each consisting of a central medulla and an outer cortex, surrounded by a capsule.

The thymus is made up of immature [[T cells]] called [[thymocytes]], as well as lining cells called [[epithelial cells]] which help the thymocytes develop. T cells that successfully develop react appropriately with [[Major histocompatibility complex|MHC]] immune receptors of the body (called ''positive selection'') and not against proteins of the body (called ''negative selection''). The thymus is the largest and most active during the neonatal and pre-adolescent periods.  By the early teens, the [[Thymic involution|thymus begins to decrease in size and activity]] and the tissue of the thymus is gradually replaced by [[adipose tissue|fatty tissue]].  Nevertheless, some T cell development continues throughout adult life.

Abnormalities of the thymus can result in a decreased number of T cells and autoimmune diseases such as [[autoimmune polyendocrine syndrome type 1]] and [[myasthenia gravis]]. These are often associated with cancer of the tissue of the thymus, called [[thymoma]], or tissues arising from immature lymphocytes such as T cells, called [[lymphoma]]. Removal of the thymus is called a [[thymectomy]]. Although the thymus has been identified as a part of the body since the time of the [[Ancient Greeks]], it is only since the 1960s that the function of the thymus in the immune system has become clearer.

== Structure ==
The thymus is an organ that sits behind the [[Human sternum|sternum]] in the upper front part of the chest, stretching upwards towards the neck. In children, the thymus is pinkish-gray, soft, and lobulated on its surfaces.<ref name="Grays2008" /> At birth, it is about 4–6&nbsp;cm long, 2.5–5&nbsp;cm wide, and about 1&nbsp;cm thick.<ref name="Grays2016" /> It increases in size until puberty, where it may have a size of about 40–50&nbsp;g,<ref name="Robbins9th" /><ref name="Wheaters2013" /> following which it decreases in size in a process known as [[Involution (medicine)|involution]].<ref name="Wheaters2013" />

The thymus is located in the [[anterior mediastinum]].<ref>{{Cite journal |last1=Nasseri |first1=Farbod |last2=Eftekhari |first2=Farzin |date=March 2010 |title=Clinical and Radiologic Review of the Normal and Abnormal Thymus: Pearls and Pitfalls |url=http://pubs.rsna.org/doi/10.1148/rg.302095131 |journal=RadioGraphics |language=en |volume=30 |issue=2 |pages=413–428 |doi=10.1148/rg.302095131 |pmid=20228326 |issn=0271-5333}}</ref> It is made up of two lobes that meet in the upper midline, and stretch from below the [[thyroid]] in the neck to as low as the cartilage of the fourth rib.<ref name=Grays2008>{{cite book| editor-first1 = Susan | editor-last1 = Standring | editor-first2 = Neil R. | editor-last2 = Borley | name-list-style = vanc |title=Gray's Anatomy: The Anatomical Basis of Clinical Practice |date=2008|publisher=Churchill Livingstone|location=London|isbn=978-0-8089-2371-8|edition=40th|display-editors=1}}</ref> The lobes are covered by a capsule.<ref name="Robbins9th" /> The thymus lies behind the sternum, rests on the [[pericardium]], and is separated from the [[aortic arch]] and [[great vessels]] by a layer of [[fascia]]. The left [[brachiocephalic vein]] may even be embedded within the thymus.<ref name=Grays2008 /> In the neck, it lies on the front and sides of the [[vertebrate trachea|trachea]], behind the [[sternohyoid muscle|sternohyoid]] and [[sternothyroid muscle]]s.<ref name=Grays2008 />

===Microanatomy===
The thymus consists of two lobes, merged in the middle, surrounded by a capsule that extends with blood vessels into the interior.<ref name=Grays2016>{{cite book |title=Gray's Anatomy: The Anatomical Basis of Clinical Practice | editor-first1 = Susan | editor-last1 = Standring | editor-first2 = Henry | editor-last2 = Gray | name-list-style = vanc  |isbn= 9780702052309 |edition=41st |location=Philadelphia |oclc=920806541 |year=2016 |pages=983–6 }}</ref> The lobes consist of an outer {{wt|en|cortex}} rich with cells and an inner less dense {{wt|en|medulla}}.<ref name="Wheaters2013" /> The lobes are divided into smaller lobules 0.5-2 mm diameter, between which extrude radiating insertions from the capsule along {{wt|en|septa}}.<ref name=Grays2008 />

The cortex is mainly made up of [[thymocyte]]s and epithelial cells.<ref name="Robbins9th" /> The thymocytes, immature [[T cells]], are supported by a network of the finely-branched [[epithelial reticular cells]], which is continuous with a similar network in the medulla. This network forms an [[adventitia]] to the blood vessels, which enter the cortex via septa near the junction with the medulla.<ref name=Grays2008/> Other cells are also present in the thymus, including [[macrophage]]s, [[dendritic cell]]s, and a small amount of [[B cell]]s, [[neutrophil]]s and [[eosinophil]]s.<ref name="Robbins9th" />

In the medulla, the network of epithelial cells is coarser than in the cortex, and the lymphoid cells are relatively fewer in number.<ref name=Grays2008 /> Concentric, nest-like bodies called [[Hassall's corpuscles]] (also called ''thymic corpuscles'') are formed by aggregations of the medullary epithelial cells.<ref name="Robbins9th" /> These are concentric, layered whorls of [[epithelial cell]]s that increase in number throughout life.<ref name=Grays2008 /> They are the remains of the epithelial tubes, which grow out from the third [[pharyngeal pouch (embryology)|pharyngeal pouches]] of the embryo to form the thymus.<ref>{{cite book |vauthors = Larsen W |title=Human Embryology |date=2001 |publisher=Elsevier |isbn=978-0-443-06583-5 |pages=366–367 |edition=3rd}}</ref>

<gallery>
File:Thymus.JPG|[[Micrograph]] showing a lobule of the thymus. The cortex (deeper purple area) surrounds a less dense and lighter medulla.
File:Thymic corpuscle.jpg|Micrograph showing a Hassall's corpuscle, found within the medulla of the thymus.
</gallery>

===Blood and nerve supply===
The [[Artery|arteries]] supplying the thymus are branches of the [[internal thoracic artery|internal thoracic]], and [[inferior thyroid artery|inferior thyroid arteries]], with branches from the [[superior thyroid artery]] sometimes seen.<ref name="Grays2016" /> The branches reach the thymus and travel with the septa of the capsule into the area between the cortex and medulla, where they enter the thymus itself; or alternatively directly enter the capsule.<ref name="Grays2016" />

The [[vein]]s of the thymus, the [[thymic veins]], end in the [[left brachiocephalic vein]], [[internal thoracic vein]], and in the [[inferior thyroid vein]]s.<ref name="Grays2016" /> Sometimes the veins end directly in the superior vena cava.<ref name="Grays2016" />

[[Lymphatic vessel]]s travel only away from the thymus, accompanying the arteries and veins. These drain into the brachiocephalic, tracheobronchial and parasternal [[lymph node]]s.<ref name="Grays2016" />

The [[nerve]]s supplying the thymus arise from the [[vagus nerve]] and the cervical [[sympathetic chain]].<ref name="Grays2016" /> Branches from the [[phrenic nerve]]s reach the capsule of the thymus, but do not enter into the thymus itself.<ref name="Grays2016" />

===Variation===
The two lobes differ slightly in size, with the left lobe usually higher than the right. Thymic tissue may be found scattered on or around the gland, and occasionally within the thyroid.<ref name="Grays2016" /> The thymus in children stretches variably upwards, at times to as high as the thyroid gland.<ref name="Grays2016" />

==Development==
[[File:Gray1175.png|thumb|Scheme showing development of branchial epithelial bodies from the thoracic cavity of the fetus. I, II, III, IV. Branchial pouches.]]
The thymocytes and the epithelium of the thymus have different developmental origins.<ref name="Wheaters2013" /> The epithelium of the thymus develops first, appearing as two outgrowths, one on either side, of the third [[pharyngeal pouch (embryology)|pharyngeal pouch]].<ref name="Wheaters2013" /> It sometimes also involves the fourth pharyngeal pouch.<ref name="Robbins9th">{{cite book |title=Robbins and Cotran Pathologic Basis of Disease |isbn=9780323296397 |edition=9th (online)|section=Chapter 13. Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus: Thymus.|last1=Kumar |first1=Vinay |last2=Abbas |first2=Abul K. |last3=Fausto |first3=Nelson |last4=Aster |first4=Jon C. | name-list-style = vanc |date=2014-08-27 |publisher=Elsevier Health Sciences }}</ref> These extend outward and backward into the surrounding [[mesoderm]] and [[neural crest]]-derived [[mesenchyme]] in front of the ventral [[aorta]]. Here the thymocytes and epithelium meet and join with connective tissue.  The [[pharynx|pharyngeal]] opening of each diverticulum is soon obliterated, but the neck of the flask persists for some time as a cellular cord.  By further proliferation of the cells lining the flask, buds of cells are formed, which become surrounded and isolated by the invading mesoderm.<ref>{{EmbryologySwiss|qblood/lymphat03}}</ref>

The epithelium forms fine lobules, and develops into a sponge-like structure. During this stage, [[hematopoietic]] bone-marrow precursors migrate into the thymus.<ref name="Wheaters2013" /> Normal development is dependent on the interaction between the epithelium and the hematopoietic [[thymocyte]]s. [[Iodine]] is also necessary for thymus development and activity.<ref>{{cite journal | vauthors = Venturi S, Venturi M | title = Iodine, thymus, and immunity | journal = Nutrition | volume = 25 | issue = 9 | pages = 977–9 | date = September 2009 | pmid = 19647627 | doi = 10.1016/j.nut.2009.06.002 }}</ref>

===Involution===
{{main|Thymic involution}}

The thymus continues to grow after birth reaching the relative maximum size by puberty.<ref name="Grays2016" /> It is most active in [[fetal]] and [[neonatal]] life.{{sfn|Davidson's|2018|p=67}} It increases to a mass of 20 to 50 grams by puberty.<ref name="Robbins9th" /> It then begins to decrease in size and activity in a process called [[thymic involution]].<ref name="Wheaters2013" /> After the first year of life the amount of T cells produced begins to fall.<ref name="Wheaters2013" /> Fat and connective tissue fills a part of the thymic volume.<ref name="Grays2016" />  During involution, the thymus decreases in size and activity.<ref name="Wheaters2013" /> Fat cells are present at birth, but increase in size and number markedly after puberty, invading the gland from the walls between the lobules first, then into the cortex and medulla.<ref name="Wheaters2013" /> This process continues into old age, where whether with a microscope or with the human eye, the thymus may be difficult to detect,<ref name=Wheaters2013>{{cite book |last1=Young |first1=Barbara |last2=O'Dowd |first2=Geraldine |last3=Woodford |first3=Phillip | name-list-style = vanc |title=Wheater's functional histology: a text and colour atlas.|publisher=Elsevier |location=Philadelphia |date=2013|isbn=9780702047473 |edition=6th|pages=204–6}}</ref> although typically weighs 5–15 grams.<ref name="Robbins9th" /> Additionally, there is an increasing body of evidence showing that age-related thymic involution is found in most, if not all, vertebrate species with a thymus, suggesting that this is an evolutionary process that has been conserved.<sup>[[doi:10.1016/j.it.2009.05.001|[40]]]</sup>

The atrophy is due to the increased circulating level of [[sex hormones]], and chemical or physical castration of an adult results in the thymus increasing in size and activity.<ref>{{cite journal | vauthors = Sutherland JS, Goldberg GL, Hammett MV, Uldrich AP, Berzins SP, Heng TS, Blazar BR, Millar JL, Malin MA, Chidgey AP, Boyd RL | display-authors = 6 | title = Activation of thymic regeneration in mice and humans following androgen blockade | journal = Journal of Immunology | volume = 175 | issue = 4 | pages = 2741–53 | date = August 2005 | pmid = 16081852 | doi = 10.4049/jimmunol.175.4.2741 | doi-access = free }}</ref> Severe illness or [[human immunodeficiency virus]] infection may also result in involution.<ref name="Robbins9th" />

== Function ==
[[File:Intrathymic T Cell Differentiation.JPG|right|frameless]]

===T cell maturation===
The thymus facilitates the maturation of [[T cell]]s, an important part of the [[immune system]] providing [[cell-mediated immunity]].<ref name=GH2016>{{cite book |last1=Hall |first1=John E. | name-list-style = vanc |title=Guyton and Hall textbook of medical physiology |year=2016 |publisher=Elsevier |location=Philadelphia |isbn=978-1-4557-7016-8 |edition=13th|pages=466–7}}</ref> T cells begin as hematopoietic precursors from the bone-marrow, and migrate to the thymus, where they are referred to as [[thymocyte]]s. In the thymus, they undergo a process of maturation, which involves ensuring the cells react against [[antigen]]s ("positive selection"), but that they do not react against antigens found on body tissue ("negative selection").<ref name=GH2016 /> Once mature, T cells emigrate from the thymus to provide vital functions in the immune system.<ref name=GH2016 /><ref name="Robbins9thC6" />

Each T cell has a distinct [[T cell receptor]], suited to a specific substance, called an [[antigen]].<ref name="Robbins9thC6">{{cite book |title=Robbins and Cotran Pathologic Basis of Disease |isbn=9780323296397 |edition=9th (online)|section=Chapter 6. Diseases of the immune system. The normal immune system.|last1=Kumar |first1=Vinay |last2=Abbas |first2=Abul K. |last3=Fausto |first3=Nelson |last4=Aster |first4=Jon C. | name-list-style = vanc |date=2014-08-27 |publisher=Elsevier Health Sciences }}</ref> Most T cell receptors bind to the [[major histocompatibility complex]] on cells of the body. The MHC presents an antigen to the T cell receptor, which becomes active if this matches the specific T cell receptor.<ref name="Robbins9thC6" /> In order to be properly functional, a mature T cell needs to be able to bind to the MHC molecule ("positive selection"), and not to react against antigens that are actually from the tissues of body ("negative selection").<ref name="Robbins9thC6" /> Positive selection occurs in the cortex and negative selection occurs in the medulla of the thymus.<ref name="MDB2019" /> After this process T cells that have survived leave the thymus, regulated by [[sphingosine-1-phosphate]].<ref name="MDB2019" /> Further maturation occurs in the peripheral circulation.<ref name="MDB2019" /> Some of this is because of hormones and [[cytokine]]s secreted by cells within the thymus, including [[thymulin]], [[thymopoietin]], and [[thymosin]]s.<ref name="Wheaters2013" />

===Positive selection===
T cells have distinct T cell receptors. These distinct receptors are formed by process of [[V(D)J recombination]] gene rearrangement stimulated by [[RAG1]] and [[RAG2]] genes.<ref name="MDB2019">{{cite book|last1=Hohl|first1=Tobias M.| veditors = Bennett JE, Dolin R, Blaser MJ |title=Mandell, Douglas, and Bennett's principles and practice of infectious diseases|date=2019|publisher=Elsevier|isbn=9780323482554|edition=9th (online)|chapter=6. Cell mediated defence against infection: Thymic selection of CD4+ and CD8+ T Cells}}</ref> This process is error-prone, and some thymocytes fail to make functional T-cell receptors, whereas other thymocytes make T-cell receptors that are autoreactive.<ref name=":0" /> If a functional T cell receptor is formed, the thymocyte will begin to express simultaneously the cell surface proteins [[CD4]] and [[CD8]].<ref name="MDB2019" />

The survival and nature of the T cell then depends on its interaction with surrounding thymic epithelial cells. Here, the T cell receptor interacts with the MHC molecules on the surface of epithelial cells.<ref name="MDB2019" /> A T cell with a receptor that doesn't react, or reacts weakly, will die by [[apoptosis]]. A T cell that does react will survive and proliferate.<ref name="MDB2019" /> A mature T cell expresses only CD4 or CD8, but not both.<ref name="Robbins9thC6" /> This depends on the strength of binding between the TCR and MHC class 1 or class 2.<ref name="MDB2019" /> A T cell receptor that binds mostly to MHC class I tends to produce a mature "cytotoxic" CD8 positive T cell; a T cell receptor that binds mostly to MHC class II tends to produce a CD4 positive T cell.<ref name=":0" />

===Negative selection===
T cells that attack the body's own proteins are eliminated in the thymus, called "negative selection".<ref name="Robbins9thC6" /> Epithelial cells in the medulla and dendritic cells in the thymus express major proteins from elsewhere in the body.<ref name="MDB2019" /> The gene that stimulates this is [[AIRE]].<ref name="Robbins9thC6" /><ref name="MDB2019" />  Thymocytes that react strongly to self antigens do not survive, and die by apoptosis.<ref name="Robbins9thC6" /><ref name="MDB2019" /> Some CD4 positive T cells exposed to self antigens persist as [[T regulatory cell]]s.<ref name="Robbins9thC6" />

==Clinical significance==
===Immunodeficiency===
As the thymus is where T cells develop, congenital problems with the development of the thymus can lead to [[immunodeficiency]], whether because of a problem with the development of the thymus gland, or a problem specific to thymocyte development. Immunodeficiency can be profound.{{sfn|Davidson's|2018|p=67}} Loss of the thymus at an early age through genetic mutation (as in [[DiGeorge syndrome]], [[CHARGE syndrome]], or a very rare "nude" thymus causing absence of hair and the thymus{{sfn|Harrison's|2015|pp=2493}}) results in severe immunodeficiency and subsequent high susceptibility to infection by viruses, [[protozoa]], and [[fungi]].{{sfn|Davidson's|2018|pp=79-80}} [[Nude mouse|Nude mice]] with the very rare "nude" deficiency as a result of [[FOXN1]] mutation are a strain of research mice as a model of T cell deficiency.<ref>{{cite book |last1=Fox |first1=James G. | name-list-style = vanc |title=The Mouse in Biomedical Research: Immunology |date=2006 |publisher=Elsevier |isbn=978-0-08-046908-9 |pages=277 |url=https://books.google.com/books?id=63K0IifQIrgC&pg=PA277 |language=en}}</ref>

The most common congenital cause of thymus-related immune deficiency results from the deletion of the [[Chromosome 22 (human)|22nd chromosome]], called [[DiGeorge syndrome]].{{sfn|Harrison's|2015|pp=2493}}{{sfn|Davidson's|2018|pp=79-80}} This results in a failure of development of the third and fourth pharyngeal pouches, resulting in failure of development of the thymus, and variable other associated problems, such as [[congenital heart disease]], and abnormalities of mouth (such as [[cleft palate]] and [[cleft lip]]), failure of development of the [[parathyroid glands]], and the presence of a fistula between the [[trachea]] and the [[oesophagus]].{{sfn|Davidson's|2018|pp=79-80}} Very low numbers of circulating T cells are seen.{{sfn|Davidson's|2018|pp=79-80}} The condition is diagnosed by [[fluorescence in situ hybridization|fluorescent in situ hybridization]] and treated with [[thymus transplantation]].{{sfn|Harrison's|2015|pp=2493}}

[[Severe combined immunodeficiency]] (SCID) are group of rare congenital genetic diseases that can result in combined T, B, and [[NK cell]] deficiencies.{{sfn|Davidson's|2018|pp=79-80}} These syndromes are caused by mutations that affect the maturation of the [[hematopoietic progenitor cell]]s, which are the precursors of both B and T cells.{{sfn|Davidson's|2018|pp=79-80}} A number of genetic defects can cause SCID, including [[IL-2 receptor]] gene loss of function, and mutation resulting in deficiency of the [[enzyme]] [[adenine deaminase]].{{sfn|Davidson's|2018|pp=79-80}}

===Autoimmune disease===
====Autoimmune polyendocrine syndrome====
[[Autoimmune polyendocrine syndrome type 1]] is a rare genetic autoimmune syndrome that results from a genetic defect of the thymus tissues.{{sfn|Harrison's|2015|pp=2756-7}} Specifically, the disease results from defects in the [[autoimmune regulator]] (AIRE) gene, which stimulates expression of self antigens in the epithelial cells within the medulla of the thymus. Because of defects in this condition, self antigens are not expressed, resulting in T cells that are not conditioned to tolerate tissues of the body, and may treat them as foreign, stimulating an immune response and resulting in autoimmunity.{{sfn|Harrison's|2015|pp=2756-7}}  People with APECED develop an autoimmune disease that affects multiple [[endocrine]] tissues, with the commonly affected organs being [[hypothyroidism]] of the [[thyroid gland]], [[Addison's disease]] of the [[adrenal gland]]s, and [[candida infection]] of body surfaces including the [[oral mucosa|inner lining of the mouth]] and of the [[nail (anatomy)|nail]]s due to dysfunction of [[T helper 17 cell|TH17 cells]], and symptoms often beginning in childhood. Many other autoimmune diseases may also occur.{{sfn|Harrison's|2015|pp=2756-7}} Treatment is directed at the affected organs.{{sfn|Harrison's|2015|pp=2756-7}}

====Thymoma-associated multiorgan autoimmunity====
[[Thymoma-associated multiorgan autoimmunity]] can occur in people with thymoma. In this condition, the T cells developed in the thymus are directed against the tissues of the body. This is because the malignant thymus is incapable of appropriately educating developing thymocytes to eliminate self-reactive T cells. The condition is virtually indistinguishable from [[graft versus host disease]].<ref>{{cite journal | vauthors = Wadhera A, Maverakis E, Mitsiades N, Lara PN, Fung MA, Lynch PJ | title = Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease | journal = Journal of the American Academy of Dermatology | volume = 57 | issue = 4 | pages = 683–9 | date = October 2007 | pmid = 17433850 | doi = 10.1016/j.jaad.2007.02.027 }}</ref>

====Myasthenia gravis====
[[Myasthenia gravis]] is an autoimmune disease most often due to antibodies that block [[acetylcholine receptors]], involved in signalling [[neuromuscular junction|between nerves and muscles]].{{sfn|Davidson's|2018|pp=1141-43}} It is often associated with thymic hyperplasia or thymoma,{{sfn|Davidson's|2018|pp=1141-43}} with antibodies produced probably because of T cells that develop abnormally.<ref name=":2">{{cite journal | vauthors = Engels EA | title = Epidemiology of thymoma and associated malignancies | journal = Journal of Thoracic Oncology | volume = 5 | issue = 10 Suppl 4 | pages = S260-5 | date = October 2010 | pmid = 20859116 | pmc = 2951303 | doi = 10.1097/JTO.0b013e3181f1f62d }}</ref> Myasthenia gravis most often develops between young and middle age, causing easy fatiguing of muscle movements.{{sfn|Davidson's|2018|pp=1141-43}} Investigations include demonstrating antibodies (such as against acetylcholine receptors or [[MuSK protein|muscle-specific kinase]]), and [[CT chest|CT scan]] to detect thymoma or thymectomy.{{sfn|Davidson's|2018|pp=1141-43}} With regard to the thymus, removal of the thymus, called [[thymectomy]] may be considered as a treatment, particularly if a thymoma is found.{{sfn|Davidson's|2018|pp=1141-43}} Other treatments include increasing the duration of acetylcholine action at nerve synapses by decreasing the rate of breakdown. This is done by [[acetylcholinesterase inhibitors]] such as [[pyridostigmine]].{{sfn|Davidson's|2018|pp=1141-43}}

===Cancer===
{{See also|Tumors of the hematopoietic and lymphoid tissues}}

====Thymomas====
Tumours originating from the thymic epithelial cells are called [[thymomas]].<ref name="Robbins9th" /> They most often occur in adults older than 40.<ref name="Robbins9th" /> Tumours are generally detected when they cause symptoms, such as a [[neck mass]] or affecting nearby structures such as the [[superior vena cava]];<ref name=":2" /> detected because of screening in patients with myasthenia gravis, which has a strong association with thymomas and hyperplasia;<ref name="Robbins9th" /> and detected as an [[Incidental medical findings|incidental finding]] on imaging such as [[chest X-ray]]s.<ref name=":2" /> [[Hyperplasia]] and tumours originating from the thymus are associated with other autoimmune diseases – such as [[hypogammaglobulinemia]], [[Graves disease]], [[pure red cell aplasia]], [[pernicious anaemia]] and [[dermatomyositis]], likely because of defects in negative selection in proliferating T cells.<ref name="Robbins9th" />{{sfn|Harrison's|2015|pp=2759}}

Thymomas can be benign; benign but by virtue of expansion, invading beyond the capsule of the thymus ("invasive thymoma"), or malignant (a [[carcinoma]]).<ref name="Robbins9th" /> This classification is based on the appearance of the cells.<ref name="Robbins9th" /> A [[World Health Organization|WHO]] classification also exists but is not used as part of standard clinical practice.<ref name="Robbins9th" /> Benign tumours confined to the thymus are most common; followed by locally invasive tumours, and then by carcinomas.<ref name="Robbins9th" /> There is variation in reporting, with some sources reporting malignant tumours as more common.{{sfn|Harrison's|2015|pp=2759}} Invasive tumours, although not technically malignant, can still spread ({{wt|en|metastasise}}) to other areas of the body.<ref name="Robbins9th" /> Even though thymomas occur of epithelial cells, they can also contain thymocytes.<ref name="Robbins9th" /> Treatment of thymomas often requires surgery to remove the entire thymus.{{sfn|Harrison's|2015|pp=2759}} This may also result in temporary remission of any associated autoimmune conditions.{{sfn|Harrison's|2015|pp=2759}}

====Lymphomas====

Tumours originating from T cells of the thymus form a subset of [[acute lymphoblastic leukaemia]] (ALL).<ref name="Williams9eChapter91">{{cite book |last1=Larson |first1=Richard A. | name-list-style = vanc |title=Williams hematology (online) |date=2015 |publisher=McGraw-Hill Education |isbn=978-0071833004 |edition=9th |chapter=Chapter 91: Acute Lymphoblastic Leukemia}}</ref> These are similar in symptoms, investigation approach and management to other forms of ALL.<ref name="Williams9eChapter91" /> Symptoms that develop, like other forms of ALL, relate to deficiency of [[platelet]]s, resulting in bruising or bleeding; immunosuppression resulting in infections; or infiltration by cells into parts of the body, resulting in an [[hepatomegaly|enlarged liver]], [[splenomegaly|spleen]], [[lymphadenopathy|lymph nodes]] or other sites.<ref name="Williams9eChapter91" /> Blood test might reveal a large amount of white blood cells or [[lymphoblast]]s, and deficiency in other cell lines – such as low platelets or [[anaemia]].<ref name="Williams9eChapter91" /> [[Immunophenotyping]] will reveal cells that are [[CD3 (immunology)|CD3]], a protein found on T cells, and help further distinguish the maturity of the T cells. Genetic analysis including [[karyotyping]] may reveal specific abnormalities that may influence prognosis or treatment, such as the [[Philadelphia translocation]].<ref name="Williams9eChapter91" /> Management can include multiple courses of [[chemotherapy]], [[stem cell transplant]], and management of associated problems, such as treatment of infections with [[antibiotics]], and [[blood transfusions]]. Very high white cell counts may also require [[cytoreduction]] with [[apheresis]].<ref name="Williams9eChapter91" />

Tumours originating from the small population of B cells present in the thymus lead to [[primary mediastinal large B cell lymphoma]]s.<ref name="PMLBCL2014">{{cite journal | vauthors = Dabrowska-Iwanicka A, Walewski JA | title = Primary mediastinal large B-cell lymphoma | journal = Current Hematologic Malignancy Reports | volume = 9 | issue = 3 | pages = 273–83 | date = September 2014 | pmid = 24952250 | doi = 10.1007/s11899-014-0219-0 | pmc = 4180024 }}</ref> These are a rare subtype of [[Non-Hodgkin lymphoma]], although by the activity of genes and occasionally microscopic shape, unusually they also have the characteristics of [[Hodgkin lymphoma]]s.<ref name="Williams9eChapter98"/> that occur most commonly in young and middle-aged, more prominent in females.<ref name="Williams9eChapter98"/> Most often, when symptoms occur it is because of compression of structures near the thymus, such as the [[superior vena cava syndrome|superior vena cava]] or the [[upper respiratory tract]]; when lymph nodes are affected it is often in the mediastinum and [[cervical lymph nodes|neck]] groups.<ref name="Williams9eChapter98"/> Such tumours are often detected with a [[biopsy]] that is subject to [[immunohistochemistry]]. This will show the presence of [[clusters of differentiation]], cell surface proteins – namely [[CD30]], with [[CD19]], [[CD20]] and [[CD22]], and with the absence of [[CD15]]. Other markers may also be used to confirm the diagnosis.<ref name="Williams9eChapter98">{{cite book |last1=Smith |first1=Stephen D. |last2=Press |first2=Oliver W. | name-list-style = vanc |title=Williams hematology (online) |date=2015 |publisher=McGraw-Hill Education |isbn=978-0071833004 |edition=9th |chapter=Chapter 98. Diffuse Large B-Cell Lymphoma and Related Diseases}}</ref> Treatment usually includes the typical regimens of [[CHOP (chemotherapy)|CHOP]] or [[EPOCH (chemotherapy)|EPOCH]] or other regimens; regimens generally including [[cyclophosphamide]], an [[anthracycline]], [[prednisone]], and other chemotherapeutics; and potentially also a [[stem cell transplant]].<ref name="Williams9eChapter98"/>

===Thymic cysts===
{{Further|Cervical thymic cyst}}
The thymus may contain cysts, usually less than 4&nbsp;cm in diameter. Thymic cysts are usually detected incidentally and do not generally cause symptoms.<ref name="Robbins9th" /> Thymic cysts can occur along the neck or in the chest ([[mediastinum]]).<ref name="Goldstein2015">{{cite journal |last1=Goldstein |first1=Alan J. |last2=Oliva |first2=Isabel |last3=Honarpisheh |first3=Hedieh |last4=Rubinowitz |first4=Ami |title=A Tour of the Thymus: A Review of Thymic Lesions with Radiologic and Pathologic Correlation |journal=Canadian Association of Radiologists Journal |date=1 February 2015 |volume=66 |issue=1 |pages=5–15 |doi=10.1016/j.carj.2013.09.003|pmid=24736228 |s2cid=33986973 |doi-access=free }}</ref> Cysts usually just contain fluid and are lined by either [[Stratified squamous epithelium|many layers of flat cells]] or [[columnar epithelium|column-shaped cells]].<ref name="Goldstein2015" /> Despite this, the presence of a cyst can cause problems similar to those of thymomas, by compressing nearby structures,<ref name="Robbins9th" /> and some may contact internal walls ({{wt|en|septa}}) and be difficult to distinguish from tumours.<ref name="Goldstein2015" /> When cysts are found, investigation may include a workup for tumours, which may include [[Computed tomography|CT]] or [[Magnetic resonance imaging|MRI scan]] of the area the cyst is suspected to be in.<ref name="Robbins9th" /><ref name="Goldstein2015" />

===Surgical removal===
[[Thymectomy]] is the surgical removal of the thymus.<ref name="Grays2016" /> The usual reason for removal is to gain access to the heart for surgery to correct [[congenital heart defects]] in the neonatal period.<ref name=":1">{{cite journal | vauthors = Eysteinsdottir JH, Freysdottir J, Haraldsson A, Stefansdottir J, Skaftadottir I, Helgason H, Ogmundsdottir HM | title = The influence of partial or total thymectomy during open heart surgery in infants on the immune function later in life | journal = Clinical and Experimental Immunology | volume = 136 | issue = 2 | pages = 349–55 | date = May 2004 | pmid = 15086401 | pmc = 1809033 | doi = 10.1111/j.1365-2249.2004.02437.x }}</ref> Other indications for thymectomy include the removal of thymomas and the treatment of myasthenia gravis.<ref name="Grays2016" /> In neonates the relative size of the thymus obstructs surgical access to the heart and its surrounding vessels.<ref name=":1" /> 

Removal of the thymus in infancy results in often fatal immunodeficiency, because functional T cells have not developed.<ref name="Grays2016" /><ref>{{Cite journal |last1=Prelog |first1=Martina |last2=Wilk |first2=Cordula |last3=Keller |first3=Michael |last4=Karall |first4=Thomas |last5=Orth |first5=Dorothea |last6=Geiger |first6=Ralf |last7=Walder |first7=Gernot |last8=Laufer |first8=Guenther |last9=Cottogni |first9=Marco |last10=Zimmerhackl Lothar |first10=Bernd |last11=Stein |first11=Joerg |last12=Grubeck-Loebenstein |first12=Beatrix |last13=Wuerzner |first13=Reinhard |date=2008-01-30 |title=Diminished response to tick-borne encephalitis vaccination in thymectomized children |url=https://www.sciencedirect.com/science/article/pii/S0264410X07013412 |journal=Vaccine |volume=26 |issue=5 |pages=595–600 |doi=10.1016/j.vaccine.2007.11.074 |pmid=18178293 |issn=0264-410X}}</ref> In older children and adults, which have a functioning lymphatic system with mature T cells also situated in other lymphoid organs, the effect is reduced, but includes failure to mount immune responses against new antigens,<ref name="Grays2016" /> an increase in cancers, and an increase in all-cause mortality.<ref>{{Cite journal |last1=Kooshesh |first1=Kameron A. |last2=Foy |first2=Brody H. |last3=Sykes |first3=David B. |last4=Gustafsson |first4=Karin |last5=Scadden |first5=David T. |date=2023-08-03 |title=Health Consequences of Thymus Removal in Adults |journal=New England Journal of Medicine |language=en |volume=389 |issue=5 |pages=406–417 |doi=10.1056/NEJMoa2302892 |pmid=37530823 |s2cid=260377788 |issn=0028-4793|pmc=10557034 }}</ref>

==Society and culture==
When used as food for humans, the thymus of animals is known as one of the kinds of [[sweetbread]].<ref>{{Cite web|url=https://www.bbc.co.uk/food/sweetbread|title=Sweetbread recipes – BBC Food |website=BBC Food|access-date=2019-12-12}}</ref>

==History==
The thymus was known to the [[ancient Greeks]], and its name comes from the Greek word θυμός (''thumos''), meaning "anger",  or in Ancient Greek, "heart, soul, desire, life", possibly because of its location in the chest, near where emotions are subjectively felt;<ref>{{Cite web|url=https://www.perseus.tufts.edu/hopper/text?doc=Perseus:text:1999.04.0057:entry=qumo/s|title=θυμός| first1 = Henry George | last1 = Liddell | first2 = Robert | last2 = Scott | name-list-style = vanc |website=A Greek-English Lexicon|access-date=2019-12-10}}</ref> or else the name comes from the herb ''thyme'' (also in Greek ''θύμος'' or ''θυμάρι''), which became the name for a "warty excrescence", possibly due to its resemblance to a bunch of thyme.<ref>{{Cite web|url=https://www.etymonline.com/word/thymus|title=thymus {{!}} Origin and meaning of thymus by Online Etymology Dictionary|website=www.etymonline.com|language=en|access-date=2019-12-10}}</ref>

[[Galen]] was the first to note that the size of the organ changed over the duration of a person's life.<ref>{{cite journal | vauthors = Nishino M, Ashiku SK, Kocher ON, Thurer RL, Boiselle PM, Hatabu H | title = The thymus: a comprehensive review | journal = Radiographics | volume = 26 | issue = 2 | pages = 335–48 | year = 2006 | pmid = 16549602 | doi = 10.1148/rg.262045213 }}</ref>

In the 19th century, a condition was identified as ''status thymicolymphaticus'' defined by an increase in lymphoid tissue and an enlarged thymus. It was thought to be a cause of [[sudden infant death syndrome]] but is now an obsolete term.<ref>{{cite book|last1=Sapolsky|first1=Robert M. | name-list-style = vanc |author-link=Robert Sapolsky|title=Why zebras don't get ulcers|date=2004|publisher=Henry Hold and Co./Owl Books|location=New York|isbn=978-0805073690|pages=182–185|edition=3rd}}</ref>

The importance of the thymus in the immune system was discovered in 1961 by [[Jacques Miller]], by surgically removing the thymus from one-day-old mice, and observing the subsequent deficiency in a lymphocyte population, subsequently named T cells after the organ of their origin.<ref>{{cite journal | vauthors = Miller JF | title = The discovery of thymus function and of thymus-derived lymphocytes | journal = Immunological Reviews | volume = 185 | issue = 1 | pages = 7–14 | date = July 2002 | pmid = 12190917 | doi = 10.1034/j.1600-065X.2002.18502.x | s2cid = 12108587 }}</ref><ref>{{cite journal | vauthors = Miller JF | title = Events that led to the discovery of T-cell development and function--a personal recollection | journal = Tissue Antigens | volume = 63 | issue = 6 | pages = 509–17 | date = June 2004 | pmid = 15140026 | doi = 10.1111/j.0001-2815.2004.00255.x }}</ref> Until the discovery of its immunological role, the thymus had been dismissed as an "evolutionary accident", without functional importance.<ref name=":0" /> The role the thymus played in ensuring mature T cells tolerated the tissues of the body was uncovered in 1962, with the finding that T cells of a transplanted thymus in mice demonstrated tolerance towards tissues of the donor mouse.<ref name=":0" /> B cells and T cells were identified as different types of lymphocytes in 1968, and the fact that T cells required maturation in the thymus was understood.<ref name=":0" /> The subtypes of T cells (CD8 and CD4) were identified by 1975.<ref name=":0" /> The way that these subclasses of T cells matured – positive selection of cells that functionally bound to MHC receptors – was known by the 1990s.<ref name=":0" /> The important role of the AIRE gene, and the role of negative selection in preventing autoreactive T cells from maturing, was understood by 1994.<ref name=":0" />

Recently, advances in [[immunology]] have allowed the function of the thymus in T-cell maturation to be more fully understood.<ref name=":0">{{cite journal | vauthors = Miller JF | title = The golden anniversary of the thymus | journal = Nature Reviews. Immunology | volume = 11 | issue = 7 | pages = 489–95 | date = May 2011 | pmid = 21617694 | doi = 10.1038/nri2993 | s2cid = 21191923 }}</ref>

==Other animals==
The thymus is present in all [[Gnathostomes|jawed vertebrates]], where it undergoes the same shrinkage with age and plays the same immunological function as in other vertebrates. Recently, in 2011, a discrete thymus-like lympho-epithelial structure, termed the ''thymoid'', was discovered in the gills of larval [[lamprey]]s.<ref>{{cite journal | vauthors = Bajoghli B, Guo P, Aghaallaei N, Hirano M, Strohmeier C, McCurley N, Bockman DE, Schorpp M, Cooper MD, Boehm T | display-authors = 6 | title = A thymus candidate in lampreys | journal = Nature | volume = 470 | issue = 7332 | pages = 90–4 | date = February 2011 | pmid = 21293377 | doi = 10.1038/nature09655 | bibcode = 2011Natur.470...90B | s2cid = 4417477 }}</ref> [[Hagfish]] possess a protothymus associated with the pharyngeal velar muscles, which is responsible for a variety of [[immune system|immune]] responses.<ref>{{cite journal | vauthors = Riviere HB, Cooper EL, Reddy AL, Hildemann WH |year=1975 |title=In Search of the Hagfish Thymus |journal=American Zoologist |volume=15 |issue=1 |pages=39–49 |jstor=3882269 |doi=10.1093/icb/15.1.39  |url=https://academic.oup.com/icb/article-pdf/15/1/39/6051623/15-1-39.pdf |doi-access=free }}</ref>

The thymus is also present in most other vertebrates with similar structure and function as the human thymus. A second thymus in the neck has been reported sometimes to occur in the [[mouse]].<ref>{{cite journal | vauthors = Terszowski G, Müller SM, Bleul CC, Blum C, Schirmbeck R, Reimann J, Pasquier LD, Amagai T, Boehm T, Rodewald HR | display-authors = 6 | title = Evidence for a functional second thymus in mice | journal = Science | volume = 312 | issue = 5771 | pages = 284–7 | date = April 2006 | pmid = 16513945 | doi = 10.1126/science.1123497 | bibcode = 2006Sci...312..284T | s2cid = 24553384 | doi-access = free }}</ref> As in humans, the [[guinea pig]]'s thymus naturally atrophies as the animal reaches adulthood,<ref>{{cite book |last1=Suckow |first1=Mark A. |last2=Stevens |first2=Karla A. |last3=Wilson |first3=Ronald P. |title=The Laboratory Rabbit, Guinea Pig, Hamster, and Other Rodents |date=2012 |publisher=Academic Press |isbn=978-0-12-380920-9 |pages=583 |url=https://books.google.com/books?id=HhEs-xsYp6IC&q=guinea+pig+thymus&pg=PA583 |language=en}}</ref> but the athymic [[Guinea pig#In scientific research|hairless guinea pig]] (which arose from a spontaneous laboratory mutation) possesses no thymic tissue whatsoever, and the organ cavity is replaced with [[cyst]]ic spaces.<ref>{{cite book |last1=Gershwin |first1=M. Eric |last2=Merchant |first2=Bruce |title=Immunologic Defects in Laboratory Animals 1 |date=2012 |publisher=Springer Science & Business Media |isbn=978-1-4757-0325-2 |page=289 |url=https://books.google.com/books?id=vZS1BwAAQBAJ&q=hairless+guinea+pig+athymic&pg=PA291 |language=en}}</ref>

==Additional images==
<gallery>
File:Function of the thymus - Inside the Thymus.webm|Explanation of the thymus's function
File:Thoracic cavity of foetus 2.JPG|Thymus of a [[fetus]]
File:Radiology 1300566 Nevit.jpg|On [[chest X-ray]], the thymus appears as a [[Radiodensity|radiodense]] (brighter in this image) mass by the upper lobe of the child's right (left in image) lung.
</gallery>

== References ==
{{Gray's}}
{{Reflist}}

===Books===
{{refbegin}}
* {{cite book|title=Davidson's principles and practice of medicine|editor-last1=Ralston |editor-first1=Stuart H. |editor-last2=Penman |editor-first2=Ian D. |editor-last3=Strachan |editor-first3=Mark W. |editor-last4=Hobson |editor-first4=Richard P. | name-list-style = vanc |date=2018 |publisher=Elsevier |isbn=978-0-7020-7028-0 |edition=23rd|ref={{harvid|Davidson's|2018}}}}
* {{cite book |last1=Kasper |first1=Dennis |last2=Fauci |first2=Anthony |last3=Hauser |first3=Stephen |last4=Longo |first4=Dan |last5=Jameson |first5=J. |last6=Loscalzo |first6=Joseph | name-list-style = vanc |title=Harrison's Principles of Internal Medicine |date=2015 |publisher=McGraw-Hill Professional |isbn=9780071802154 |edition=19th |ref={{harvid|Harrison's|2015}}}}
{{refend}}

== External links ==
{{Commons|Thymus (organ)}}
* [https://www.youtube.com/watch?v=9E_UxnC_L2o T cell development in the thymus.] Video by Janice Yau, describing stromal signaling and tolerance. Department of Immunology and Biomedical Communications, University of Toronto. Master's Research Project, Master of Science in Biomedical Communications. 2011.

{{Human systems and organs}}
{{Lymphatic system}}
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[[Category:Thymus| ]]
[[Category:Endocrine system anatomy]]
[[Category:Immune system]]
[[Category:Lymphatic system]]
[[Category:Lymphatics of the torso]]
[[Category:Lymphoid organ]]
[[Category:Mammal anatomy]]
[[Category:Organs (anatomy)]]