This article is about the organ of the immune system. For the organ of the hormone system, seethyroid. For the culinary use of animal thymus, seeSweetbread. For the plant genusThymus, seeThymus (plant). For other uses, seeThymus (disambiguation).
The thymus is made up of immatureT cells calledthymocytes, as well as lining cells calledepithelial cells which help the thymocytes develop. T cells that successfully develop react appropriately withMHC immune receptors of the body (calledpositive selection) and not against proteins of the body (callednegative selection). The thymus is the largest and most active during the neonatal and pre-adolescent periods. By the early teens, thethymus begins to decrease in size and activity and the tissue of the thymus is gradually replaced byfatty 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 asautoimmune polyendocrine syndrome type 1 andmyasthenia gravis. These are often associated with cancer of the tissue of the thymus, calledthymoma, or tissues arising from immature lymphocytes such as T cells, calledlymphoma. Removal of the thymus is called athymectomy. Although the thymus has been identified as a part of the body since the time of theAncient Greeks, it is only since the 1960s that the function of the thymus in the immune system has become clearer.
The thymus is an organ that sits behind thesternum 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.[1] At birth, it is about 4–6 cm long, 2.5–5 cm wide, and about 1 cm thick.[2] It increases in size until puberty, where it may have a size of about 40–50 g,[3][4] following which it decreases in size in a process known asinvolution.[4]
The thymus consists of two lobes, merged in the middle, surrounded by a capsule that extends with blood vessels into the interior.[2] The lobes consist of an outercortex rich with cells and an inner less densemedulla.[4] The lobes are divided into smaller lobules 0.5-2 mm diameter, between which extrude radiating insertions from the capsule alongsepta.[1]
The cortex is mainly made up ofthymocytes and epithelial cells.[3] The thymocytes, immatureT cells, are supported by a network of the finely-branchedepithelial reticular cells, which is continuous with a similar network in the medulla. This network forms anadventitia to the blood vessels, which enter the cortex via septa near the junction with the medulla.[1] Other cells are also present in the thymus, includingmacrophages,dendritic cells, and a small amount ofB cells,neutrophils andeosinophils.[3]
In the medulla, the network of epithelial cells is coarser than in the cortex, and the lymphoid cells are relatively fewer in number.[1] Concentric, nest-like bodies calledHassall's corpuscles (also calledthymic corpuscles) are formed by aggregations of the medullary epithelial cells.[3] These are concentric, layered whorls ofepithelial cells that increase in number throughout life.[1] They are the remains of the epithelial tubes, which grow out from the thirdpharyngeal pouches of the embryo to form the thymus.[6]
Micrograph showing a lobule of the thymus. The cortex (deeper purple area) surrounds a less dense and lighter medulla.
Micrograph showing a Hassall's corpuscle, found within the medulla of the thymus.
Thearteries supplying the thymus are branches of theinternal thoracic, andinferior thyroid arteries, with branches from thesuperior thyroid artery sometimes seen.[2] 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.[2]
Lymphatic vessels travel only away from the thymus, accompanying the arteries and veins. These drain into the brachiocephalic, tracheobronchial and parasternallymph nodes.[2]
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.[2] The thymus in children stretches variably upwards, at times to as high as the thyroid gland.[2]
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.[4] The epithelium of the thymus develops first, appearing as two outgrowths, one on either side, of the thirdpharyngeal pouch.[4] It sometimes also involves the fourth pharyngeal pouch.[3] These extend outward and backward into the surroundingmesoderm andneural crest-derivedmesenchyme in front of the ventralaorta. Here the thymocytes and epithelium meet and join with connective tissue. Thepharyngeal 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.[7]
The epithelium forms fine lobules, and develops into a sponge-like structure. During this stage,hematopoietic bone-marrow precursors migrate into the thymus.[4] Normal development is dependent on the interaction between the epithelium and the hematopoieticthymocytes.Iodine is also necessary for thymus development and activity.[8]
The thymus continues to grow after birth reaching the relative maximum size by puberty.[2] It is most active infetal andneonatal life.[9] It increases to a mass of 20 to 50 grams by puberty.[3] It then begins to decrease in size and activity in a process calledthymic involution.[4] After the first year of life the amount of T cells produced begins to fall.[4] Fat and connective tissue fill a part of the thymic volume.[2] During involution, the thymus decreases in size and activity.[4] 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.[4] This process continues into old age, where whether with a microscope or with the human eye, the thymus may be difficult to detect,[4] although typically weighs 5–15 grams.[3] 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.[40]
The atrophy is due to the increased circulating level ofsex hormones, and chemical or physical castration of an adult results in the thymus increasing in size and activity.[10] Severe illness orhuman immunodeficiency virus infection may also result in involution.[3]
The thymus facilitates the maturation ofT cells, an important part of theimmune system providingcell-mediated immunity.[11] T cells begin as hematopoietic precursors from the bone-marrow, and migrate to the thymus, where they are referred to asthymocytes. In the thymus, they undergo a process of maturation, which involves ensuring the cells react againstantigens ("positive selection"), but that they do not react against antigens found on body tissue ("negative selection").[11] Once mature, T cells emigrate from the thymus to provide vital functions in the immune system.[11][12]
Each T cell has a distinctT cell receptor, suited to a specific substance, called anantigen.[12] Most T cell receptors bind to themajor 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.[12] 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").[12] Positive selection occurs in the cortex and negative selection occurs in the medulla of the thymus.[13] After this process T cells that have survived leave the thymus, regulated bysphingosine-1-phosphate.[13] Further maturation occurs in the peripheral circulation.[13] Some of this is because of hormones andcytokines secreted by cells within the thymus, includingthymulin,thymopoietin, andthymosins.[4]
T cells have distinct T cell receptors. These distinct receptors are formed by process ofV(D)J recombination gene rearrangement stimulated byRAG1 andRAG2 genes.[13] 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.[14] If a functional T cell receptor is formed, the thymocyte will begin to express simultaneously the cell surface proteinsCD4 andCD8.[13]
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.[13] A T cell with a receptor that doesn't react, or reacts weakly, will die byapoptosis. A T cell that does react will survive and proliferate.[13] A mature T cell expresses only CD4 or CD8, but not both.[12] This depends on the strength of binding between the TCR and MHC class 1 or class 2.[13] 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.[14]
T cells that attack the body's own proteins are eliminated in the thymus, called "negative selection".[12] Epithelial cells in the medulla and dendritic cells in the thymus express major proteins from elsewhere in the body.[13] The gene that stimulates this isAIRE.[12][13] Thymocytes that react strongly to self antigens do not survive, and die by apoptosis.[12][13] Some CD4 positive T cells exposed to self antigens persist asT regulatory cells.[12]
As the thymus is where T cells develop, congenital problems with the development of the thymus can lead toimmunodeficiency, whether because of a problem with the development of the thymus gland, or a problem specific to thymocyte development. Immunodeficiency can be profound.[9] Loss of the thymus at an early age through genetic mutation (as inDiGeorge syndrome,CHARGE syndrome, or a very rare "nude" thymus causing absence of hair and the thymus[15]) results in severe immunodeficiency and subsequent high susceptibility to infection by viruses,protozoa, andfungi.[16]Nude mice with the very rare "nude" deficiency as a result ofFOXN1 mutation are a strain of research mice as a model of T cell deficiency.[17]
Autoimmune polyendocrine syndrome type 1 is a rare genetic autoimmune syndrome that results from a genetic defect of the thymus tissues.[18] Specifically, the disease results from defects in theautoimmune 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.[18] People with APECED develop an autoimmune disease that affects multipleendocrine tissues, with the commonly affected organs beinghypothyroidism of thethyroid gland,Addison's disease of theadrenal glands, andcandida infection of body surfaces including theinner lining of the mouth and of thenails due to dysfunction ofTH17 cells, and symptoms often beginning in childhood. Many other autoimmune diseases may also occur.[18] Treatment is directed at the affected organs.[18]
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 fromgraft versus host disease.[19]
Myasthenia gravis is an autoimmune disease most often due to antibodies that blockacetylcholine receptors, involved in signallingbetween nerves and muscles.[20] It is often associated with thymic hyperplasia or thymoma,[20] with antibodies produced probably because of T cells that develop abnormally.[21] Myasthenia gravis most often develops between young and middle age, causing easy fatiguing of muscle movements.[20] Investigations include demonstrating antibodies (such as against acetylcholine receptors ormuscle-specific kinase), andCT scan to detect thymoma or thymectomy.[20] With regard to the thymus, removal of the thymus, calledthymectomy may be considered as a treatment, particularly if a thymoma is found.[20] Other treatments include increasing the duration of acetylcholine action at nerve synapses by decreasing the rate of breakdown. This is done byacetylcholinesterase inhibitors such aspyridostigmine.[20]
Tumours originating from the thymic epithelial cells are calledthymomas.[3] They most often occur in adults older than 40.[3] Tumours are generally detected when they cause symptoms, such as aneck mass or affecting nearby structures such as thesuperior vena cava;[21] detected because of screening in patients with myasthenia gravis, which has a strong association with thymomas and hyperplasia;[3] and detected as anincidental finding on imaging such aschest X-rays.[21]Hyperplasia and tumours originating from the thymus are associated with other autoimmune diseases – such ashypogammaglobulinemia,Graves disease,pure red cell aplasia,pernicious anaemia anddermatomyositis, likely because of defects in negative selection in proliferating T cells.[3][22]
Thymomas can be benign; benign but by virtue of expansion, invading beyond the capsule of the thymus ("invasive thymoma"), or malignant (acarcinoma).[3] This classification is based on the appearance of the cells.[3] AWHO classification also exists but is not used as part of standard clinical practice.[3] Benign tumours confined to the thymus are most common; followed by locally invasive tumours, and then by carcinomas.[3] There is variation in reporting, with some sources reporting malignant tumours as more common.[22] Invasive tumours, although not technically malignant, can still spread (metastasise) to other areas of the body.[3] Even though thymomas occur of epithelial cells, they can also contain thymocytes.[3] Treatment of thymomas often requires surgery to remove the entire thymus.[22] This may also result in temporary remission of any associated autoimmune conditions.[22]
Tumours originating from T cells of the thymus form a subset ofacute lymphoblastic leukaemia (ALL).[23] These are similar in symptoms, investigation approach and management to other forms of ALL.[23] Symptoms that develop, like other forms of ALL, relate to deficiency ofplatelets, resulting in bruising or bleeding; immunosuppression resulting in infections; or infiltration by cells into parts of the body, resulting in anenlarged liver,spleen,lymph nodes or other sites.[23] Blood test might reveal a large amount of white blood cells orlymphoblasts, and deficiency in other cell lines – such as low platelets oranaemia.[23]Immunophenotyping will reveal cells that areCD3, a protein found on T cells, and help further distinguish the maturity of the T cells. Genetic analysis includingkaryotyping may reveal specific abnormalities that may influence prognosis or treatment, such as thePhiladelphia translocation.[23] Management can include multiple courses ofchemotherapy,stem cell transplant, and management of associated problems, such as treatment of infections withantibiotics, andblood transfusions. Very high white cell counts may also requirecytoreduction withapheresis.[23]
Tumours originating from the small population of B cells present in the thymus lead toprimary mediastinal large B cell lymphomas.[24] These are a rare subtype ofNon-Hodgkin lymphoma, although by the activity of genes and occasionally microscopic shape, unusually they also have the characteristics ofHodgkin lymphomas.[25] that occur most commonly in young and middle-aged, more prominent in females.[25] Most often, when symptoms occur it is because of compression of structures near the thymus, such as thesuperior vena cava or theupper respiratory tract; when lymph nodes are affected it is often in the mediastinum andneck groups.[25] Such tumours are often detected with abiopsy that is subject toimmunohistochemistry. This will show the presence ofclusters of differentiation, cell surface proteins – namelyCD30, withCD19,CD20 andCD22, and with the absence ofCD15. Other markers may also be used to confirm the diagnosis.[25] Treatment usually includes the typical regimens ofCHOP orEPOCH or other regimens; regimens generally includingcyclophosphamide, ananthracycline,prednisone, and other chemotherapeutics; and potentially also astem cell transplant.[25]
The thymus may contain cysts, usually less than 4 cm in diameter. Thymic cysts are usually detected incidentally and do not generally cause symptoms.[3] Thymic cysts can occur along the neck or in the chest (mediastinum).[26] Cysts usually just contain fluid and are lined by eithermany layers of flat cells orcolumn-shaped cells.[26] Despite this, the presence of a cyst can cause problems similar to those of thymomas, by compressing nearby structures,[3] and some may contact internal walls (septa) and be difficult to distinguish from tumours.[26] When cysts are found, investigation may include a workup for tumours, which may includeCT orMRI scan of the area the cyst is suspected to be in.[3][26]
Thymectomy is the surgical removal of the thymus.[2] The usual reason for removal is to gain access to the heart for surgery to correctcongenital heart defects in the neonatal period.[27] Other indications for thymectomy include the removal of thymomas and the treatment of myasthenia gravis.[2] In neonates the relative size of the thymus obstructs surgical access to the heart and its surrounding vessels.[27]
Removal of the thymus in infancy results in often fatal immunodeficiency, because functional T cells have not developed.[2][28] 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,[2] an increase in cancers, and an increase in all-cause mortality.[29]
The thymus was known to theancient Greeks, and its name comes from the herbthyme (in Greek: θύμος), which became the name for a "warty excrescence", possibly due to its resemblance to a bunch of thyme.[31]
Galen was the first to note that the size of the organ changed over the duration of a person's life.[32]
In the 19th century, a condition was identified asstatus thymicolymphaticus defined by an increase in lymphoid tissue and an enlarged thymus. It was thought to be a cause ofsudden infant death syndrome but is now an obsolete term.[33]
The importance of the thymus in the immune system was discovered in 1961 byJacques 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.[34][35] Until the discovery of its immunological role, the thymus had been dismissed as an "evolutionary accident", without functional importance.[14] 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.[14] 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.[14] The subtypes of T cells (CD8 and CD4) were identified by 1975.[14] The way that these subclasses of T cells matured – positive selection of cells that functionally bound to MHC receptors – was known by the 1990s.[14] The important role of the AIRE gene, and the role of negative selection in preventing autoreactive T cells from maturing, was understood by 1994.[14]
Recently, advances inimmunology have allowed the function of the thymus in T-cell maturation to be more fully understood.[14]
The thymus is present in alljawed 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 thethymoid, was discovered in the gills of larvallampreys.[36]Hagfish possess a protothymus associated with the pharyngeal velar muscles, which is responsible for a variety ofimmune responses.[37]
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 themouse.[38] As in humans, theguinea pig's thymus naturally atrophies as the animal reaches adulthood,[39] but the athymichairless guinea pig (which arose from a spontaneous laboratory mutation) possesses no thymic tissue whatsoever, and the organ cavity is replaced withcystic spaces.[40]
^abcdefghStandring S, et al., eds. (2008).Gray's Anatomy: The Anatomical Basis of Clinical Practice (40th ed.). London: Churchill Livingstone.ISBN978-0-8089-2371-8.
^abcdefghijklmnopqrstuvKumar V, Abbas AK, Fausto N, Aster JC (2014-08-27). "Chapter 13. Diseases of White Blood Cells, Lymph Nodes, Spleen, and Thymus: Thymus.".Robbins and Cotran Pathologic Basis of Disease (9th (online) ed.). Elsevier Health Sciences.ISBN9780323296397.
^abcdefghijklYoung B, O'Dowd G, Woodford P (2013).Wheater's functional histology: a text and colour atlas (6th ed.). Philadelphia: Elsevier. pp. 204–6.ISBN9780702047473.
^abcHall JE (2016).Guyton and Hall textbook of medical physiology (13th ed.). Philadelphia: Elsevier. pp. 466–7.ISBN978-1-4557-7016-8.
^abcdefghiKumar V, Abbas AK, Fausto N, Aster JC (2014-08-27). "Chapter 6. Diseases of the immune system. The normal immune system.".Robbins and Cotran Pathologic Basis of Disease (9th (online) ed.). Elsevier Health Sciences.ISBN9780323296397.
^abcdefghijkHohl TM (2019). "6. Cell mediated defence against infection: Thymic selection of CD4+ and CD8+ T Cells". In Bennett JE, Dolin R, Blaser MJ (eds.).Mandell, Douglas, and Bennett's principles and practice of infectious diseases (9th (online) ed.). Elsevier.ISBN9780323482554.
^Wadhera A, Maverakis E, Mitsiades N, Lara PN, Fung MA, Lynch PJ (October 2007). "Thymoma-associated multiorgan autoimmunity: a graft-versus-host-like disease".Journal of the American Academy of Dermatology.57 (4):683–9.doi:10.1016/j.jaad.2007.02.027.PMID17433850.
^Nishino M, Ashiku SK, Kocher ON, Thurer RL, Boiselle PM, Hatabu H (2006). "The thymus: a comprehensive review".Radiographics.26 (2):335–48.doi:10.1148/rg.262045213.PMID16549602.
^Sapolsky RM (2004).Why zebras don't get ulcers (3rd ed.). New York: Henry Hold and Co./Owl Books. pp. 182–185.ISBN978-0805073690.
^Miller JF (June 2004). "Events that led to the discovery of T-cell development and function--a personal recollection".Tissue Antigens.63 (6):509–17.doi:10.1111/j.0001-2815.2004.00255.x.PMID15140026.
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.
