Thymus

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Thymus gland
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This article is about the organ. For culinary use of animal thymus, see Sweetbread. For the plant genus Thymus, see Thymus (plant). For other uses, see Thymus (disambiguation).

Thymus
Position of the thymus
Details
PrecursorThird pharyngeal pouch
SystemLymphatic system, part of the immune system
Lymphtracheobronchial, parasternal
FunctionSupport the development of functional T cells
Identifiers
Latinthymus
MeSHD013950
TA98A13.1.02.001
TA25152
FMA9607
Anatomical terminology

The thymus (pl.: thymuses or thymi) is a specialized primary lymphoid organ of the immune system. Within the thymus, thymus cell lymphocytes or T cells 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

epithelial cells which help the thymocytes develop. T cells that successfully develop react appropriately with 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 thymus begins to decrease in size and activity and the tissue of the thymus is gradually replaced by 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

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

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.[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 as involution.[4]

The thymus is located in the

trachea, behind the sternohyoid and sternothyroid muscles.[1]

Microanatomy

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 outer cortex rich with cells and an inner less dense medulla.[4] The lobes are divided into smaller lobules 0.5-2 mm diameter, between which extrude radiating insertions from the capsule along septa.[1]

The cortex is mainly made up of

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.[1] Other cells are also present in the thymus, including macrophages, dendritic cells, and a small amount of B cells, neutrophils and eosinophils.[3]

In the medulla, the network of epithelial cells is coarser than in the cortex, and the lymphoid cells are relatively fewer in number.

epithelial cells that increase in number throughout life.[1] They are the remains of the epithelial tubes, which grow out from the third pharyngeal 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 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.
    Micrograph showing a Hassall's corpuscle, found within the medulla of the thymus.

Blood and nerve supply

The arteries supplying the thymus are branches of the internal thoracic, and inferior thyroid arteries, with branches from the superior 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]

The

inferior thyroid veins.[2] Sometimes the veins end directly in the superior vena cava.[2]

Lymphatic vessels travel only away from the thymus, accompanying the arteries and veins. These drain into the brachiocephalic, tracheobronchial and parasternal lymph nodes.[2]

The

sympathetic chain.[2] Branches from the phrenic nerves reach the capsule of the thymus, but do not enter into the thymus itself.[2]

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.[2] The thymus in children stretches variably upwards, at times to as high as the thyroid gland.[2]

Development

Scheme showing development of branchial epithelial bodies from the thoracic cavity of the foetus. 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 third pharyngeal pouch.[4] It sometimes also involves the fourth pharyngeal pouch.[3] 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 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.[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 hematopoietic thymocytes. Iodine is also necessary for thymus development and activity.[8]

Involution

Main article: Thymic involution

The thymus continues to grow after birth reaching the relative maximum size by puberty.

neonatal 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 called thymic involution.[4] After the first year of life the amount of T cells produced begins to fall.[4] Fat and connective tissue fills 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 of

human immunodeficiency virus infection may also result in involution.[3]

Function

T cell maturation

The thymus facilitates the maturation of T cells, an important part of the immune system providing cell-mediated immunity.[11] T cells begin as hematopoietic precursors from the bone-marrow, and migrate to the thymus, where they are referred to as thymocytes. In the thymus they undergo a process of maturation, which involves ensuring the cells react against antigens ("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 distinct

T cell receptor, suited to a specific substance, called an antigen.[12] 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.[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 by sphingosine-1-phosphate.[13] Further maturation occurs in the peripheral circulation.[13] Some of this is because of hormones and cytokines secreted by cells within the thymus, including thymulin, thymopoietin, and thymosins.[4]

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.[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 proteins CD4 and CD8.[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 by apoptosis. 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]

Negative selection

T cells that attack the body's own proteins are eliminated in the thymus, called "negative selection".

T regulatory cells.[12]

Clinical significance

Immunodeficiency

As the thymus is where T cells develop, congenital problems with the development of the thymus can lead to

fungi.[16] 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.[17]

The most common congenital cause of thymus-related immune deficiency results from the deletion of the

oesophagus.[16] Very low numbers of circulating T cells are seen.[16] The condition is diagnosed by fluorescent in situ hybridization and treated with thymus transplantation.[15]

hematopoietic progenitor cells, which are the precursors of both B and T cells.[16] 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.[16]

Autoimmune disease

Autoimmune polyendocrine syndrome

candida infection of body surfaces including the inner lining of the mouth and of the nails due to dysfunction of TH17 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

graft versus host disease.[19]

Myasthenia gravis

acetylcholinesterase inhibitors such as pyridostigmine.[20]

Cancer

See also: Tumors of the hematopoietic and lymphoid tissues

Thymomas

Tumours originating from the thymic epithelial cells are called

pernicious anaemia and dermatomyositis, 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 (a carcinoma).[3] This classification is based on the appearance of the cells.[3] A WHO 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]

Lymphomas

Tumours originating from T cells of the thymus form a subset of

cytoreduction with apheresis.[23]

Tumours originating from the small population of B cells present in the thymus lead to

stem cell transplant.[25]

Thymic cysts

Further information: Cervical thymic cyst

The thymus may contain cysts, usually less than 4 cm in diameter. Thymic cysts are usually detected incidentally and do not generally cause symptoms.

CT or MRI scan of the area the cyst is suspected to be in.[3][26]

Surgical removal

congenital 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]

Society and culture

When used as food for humans, the thymus of animals is known as one of the kinds of sweetbread.[30]

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;[31] 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.[32]

Galen was the first to note that the size of the organ changed over the duration of a person's life.[33]

In the nineteenth 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.[34]

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.[35][36] Until the discovery of its immunological role, the thymus had been dismissed as a "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 in immunology have allowed the function of the thymus in T-cell maturation to be more fully understood.[14]

Other animals

The thymus is present in all

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 lampreys.[37] Hagfish possess a protothymus associated with the pharyngeal velar muscles, which is responsible for a variety of immune responses.[38]

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[39] As in humans, the guinea pig's thymus naturally atrophies as the animal reaches adulthood,[40] but the athymic hairless guinea pig (which arose from a spontaneous laboratory mutation) possesses no thymic tissue whatsoever, and the organ cavity is replaced with cystic spaces.[41]

Additional images

References

Public domain This article incorporates text in the public domain from page 1273 of the 20th edition of Gray's Anatomy (1918)

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Books

External links

Wikimedia Commons has media related to Thymus (organ).
  • 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.
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