Thymus

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Thymus
Illu thymus.jpg
Thymus
Details
Precursor Third pharyngeal pouch
System Lymphatic system, part of the immune system
Lymph tracheobronchial, parasternal
FunctionSupport the development of functional T cells
Identifiers
Latin Thymus
MeSH D013950
TA98 A13.1.02.001
TA2 5152
FMA 9607
Anatomical terminology

The thymus 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 specifically to 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.

Contents

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 MHC immune receptors of the body (called positive selection,) and not against proteins of the body, (called negative selection). The thymus is 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 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 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 more clear.

Structure

The thymus is an organ that sits beneath 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 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. [1] The lobes are covered by a capsule. [3] The thymus lies beneath 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. [1] In the neck, it lies on the front and sides of 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 0.5-2mm diameter, between which extrude radiating insertions from the capsule along septa. [1]

The cortex is mainly made up of thymocytes and epithelial cells. [3] 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. [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. [1] Concentric, nest-like bodies called Hassall's corpuscles (also called thymic corpuscles) are formed by aggregations of the medullary epithelial cells. [3] These are concentric, layered whorls of 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. [5]

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 veins of the thymus end in the left brachiocephalic vein, internal thoracic vein, and in 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 nerves supplying the thymus arise from the vagus nerve and the cervical 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. Gray1175.png
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. [6]

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. [7]

Involution

The thymus continues to grow after the birth reaching the relative maximum size by puberty. [2] It is most active in fetal and neonatal life. [8] It increases to 20 - 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 weights 5 - 15 grams. [3]

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. [9] Severe illness or human immunodeficiency virus infection may also result in involution. [3]

Function

Intrathymic T Cell Differentiation.JPG

T cell maturation

The thymus facilitates the maturation of T cells, an important part of the immune system providing cell-mediated immunity. [10] 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"). [10] Once mature, T cells emigrate from the thymus to provide vital functions in the immune system. [10] [11]

Each T cell has a distinct T cell receptor, suited to a specific substance, called an antigen. [11] 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. [11] 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"). [11] Positive selection occurs in the cortex and negative selection occurs in the medulla of the thymus. [12] After this process T cells that have survived leave the thymus, regulated by sphingosine-1-phosphate. [12] Further maturation occurs in the peripheral circulation. [12] 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. [12] 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. [13] If a functional T cell receptor is formed, the thymocyte will begin to express simultaneously the cell surface proteins CD4 and CD8. [12]

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. [12] 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. [12] A mature T cell expresses only CD4 or CD8, but not both. [11] This depends on the strength of binding between the TCR and MHC class 1 or class 2. [12] 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 produces a CD4 positive T cell. [13]

Negative selection

T cells that attack the body's own proteins are eliminated in the thymus, called "negative selection". [11] Epithelial cells in the medulla and dendritic cells in the thymus express major proteins from elsewhere in the body. [12] The gene that stimulates this is AIRE. [11] [12] Thymocytes that react strongly to self antigens do not survive, and die by apoptosis. [11] [12] Some CD4 positive T cells exposed to self antigens persist as T regulatory cells. [11]

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. [8] Loss of the thymus at an early age through genetic mutation (as in DiGeorge syndrome, CHARGE syndrome, or a vary rare "nude" thymus causing absence of hair and the thymus [14] ) results in severe immunodeficiency and subsequent high susceptibility to infection by viruses, protozoa, and fungi. [15] 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. [16]

The most common congenital cause of thymus-related immune deficiency results from the deletion of the 22nd chromosome, called DiGeorge syndrome. [14] [15] 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. [15] Very low numbers of circulating T cells are seen. [15] The condition is diagnosed by fluorescent in situ hybridization and treated with thymus transplantation. [14]

Severe combined immunodeficiency (SCID) are group of rare congenital genetic diseases that can result in combined T, B, and NK cell deficiencies. [15] These syndromes are caused by mutations that affect the maturation of the hematopoietic progenitor cells, which are the precursors of both B and T cells. [15] 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. [15]

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. [17] 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. [17] 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 glands, and 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. [17] Treatment is directed at the affected organs. [17]

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. [18]

Myasthenia gravis

Myasthenia gravis is an autoimmune disease most often due to antibodies that block acetylcholine receptors, involved in signalling between nerves and muscles. [19] It is often associated with thymic hyperplasia or thymoma, [19] with antibodies produced probably because of T cells that develop abnormally. [20] Myasthenia gravis most often develops between young and middle age, causing easy fatiguing of muscle movements. [19] Investigations include demonstrating antibodies (such as against acetylcholine receptors or muscle-specific kinase), and CT scan to detect thymoma or thymectomy. [19] With regard to the thymus, removal of the thymus, called thymectomy may be considered as a treatment, particularly if a thymoma is found. [19] 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. [19]

Cancer

Thymomas

Tumours originating from the thymic epithelial cells are called thymomas. [3] They most often occur in adults older than 40. [3] Tumours are generally detected when they cause symptoms, such as a neck mass or affecting nearby structures such as the superior vena cava; [20] detected because of screening in patients with myasthenia gravis, which has a strong association with thymomas and hyperplasia; [3] and detected as an incidental finding on imaging such as chest x-rays. [20] Hyperplasia and tumours originating form 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. [3] [21]

Thymomas can be benign; benign but by virtue of expansion, invading beyond the capsule of the thymus ("invasive thyoma"), 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. [21] 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. [21] This may also result in temporary remission of any associated autoimmune conditions. [21]

Lymphomas

Tumours originating from T cells of the thymus form a subset of acute lymphoblastic leukaemia (ALL). [22] These are similar in symptoms, investigation approach and management to other forms of ALL. [22] Symptoms that develop, like other forms of ALL, relate to deficiency of platelets, resulting in bruising or bleeding; immunosuppression resulting in infections; or infiltration by cells into parts of the body, resulting in an enlarged liver, spleen, lymph nodes or other sites. [22] Blood test might reveal a large amount of white blood cells or lymphoblasts, and deficiency in other cell lines - such as low platelets or anaemia. [22] Immunophenotyping will reveal cells that are 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. [22] 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. [22]

Tumours originating from the small population of B cells present in the thymus lead to primary mediastinal (thymic) large B cell lymphomas. [23] These are a rare subtype of Non-Hodgkins lymphoma, although by the activity of genes and occasionally microscopic shape, unusually they also have the characteristics of Hodgkins lymphomas. [24] that occur most commonly in young and middle-aged, more prominent in females. [24] Most often, when symptoms occur it is because of compression of structures near the thymus, such as the superior vena cava or the upper respiratory tract; when lymph nodes are affected it is often in the mediastinum and neck groups. [24] 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. [24] Treatment usually includes the typical regimens of CHOP or EPOCH or other regimens; regimens generally including cyclophosphamide, an anthracycline, prednisone, and other chemotherapeutics; and potentially also a stem cell transplant. [24]

Thymic cysts

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). [25] Cysts usually just contain fluid and are lined by either many layers of flat cells or column-shaped cells. [25] 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. [25] When cysts are found, investigation may include a workup for tumours, which may include CT or MRI scan of the area the cyst is suspected to be in. [3] [25]

Surgical removal

Thymectomy is the surgical removal of the thymus. [2] The usual reason for removal is to gain access to the heart for surgery to correct congenital heart defects in the neonatal period. [26] 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. [26] Removal of the thymus in infancy results in often fatal immunodeficiency, because functional T cells have not developed. [2] In older children and adults, which have a functioning lymphatic system with mature T cells also situated in other lymphoid organs, the effect is lesser, and limited to failure to mount immune responses against new antigens. [2]

Society and culture

When used as food for humans, the thymus of animals is known as one of the kinds of sweetbread. [27]

History

The thymus was known to the ancient Greeks, and its name comes from the Greek word θυμός (thumos), meaning "anger", or "heart, soul, desire, life", possibly because of its location in the chest, near where emotions are subjectively felt; [28] 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. [29]

Galen was the first to note that the size of the organ changed over the duration of a person's life. [30]

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. [31]

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. [32] [33] Until the discovery of its immunological role, the thymus had been dismissed as a "evolutionary accident", without functional importance. [13] 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. [13] 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. [13] The subtypes of T cells (CD8 and CD4) were identified by 1975. [13] The way that these subclasses of T cells matured - positive selection of cells that functionally bound to MHC receptors - was known by the 1990s. [13] The important role of the AIRE gene, and the role of negative selection in preventing autoreactive T cells from maturing, was understood by 1994. [13]

Recently, advances in immunology have allowed the function of the thymus in T-cell maturation to be more fully understood. [13]

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, a discrete thymus-like lympho-epithelial structure, termed the thymoid, was discovered in the gills of larval lampreys. [34] Hagfish possess a protothymus associated with the pharyngeal velar muscles, which is responsible for a variety of immune responses. [35]

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 [36] As in humans, the guinea pig's thymus naturally atrophies as the animal reaches adulthood, [37] 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. [38]

Additional images

Related Research Articles

Lymphatic system Organ system in vertebrates

The lymphatic system, or lymphoid system, is an organ system in vertebrates that is part of the circulatory system and the immune system. It is made up of a large network of lymphatic vessels, lymphatic or lymphoid organs, and lymphoid tissues. The vessels carry a clear fluid called lymph towards the heart.

T cell Type of lymphocyte

A T cell is a type of lymphocyte, which develops in the thymus gland and plays a central role in the immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor on the cell surface. These immune cells originate as precursor cells, derived from bone marrow, and develop into several distinct types of T cells once they have migrated to the thymus gland. T cell differentiation continues even after they have left the thymus.

The major histocompatibility complex (MHC) is a large locus on vertebrate DNA containing a set of closely linked polymorphic genes that code for cell surface proteins essential for the adaptive immune system. This locus got its name because it was discovered in the study of tissue compatibility upon transplantation. Later studies revealed that tissue rejection due to incompatibility is an experimental artifact masking the real function of MHC molecules - binding an antigen derived from self-proteins or from pathogen and the antigen presentation on the cell surface for recognition by the appropriate T-cells. MHC molecules mediate interactions of leukocytes, also called white blood cells (WBCs), which are immune cells, with other leukocytes or with body cells. The MHC determines compatibility of donors for organ transplant, as well as one's susceptibility to an autoimmune disease via cross-reacting immunization.

Thymoma A thymus cancer that derives from epithelial cells located in the thymus. The tumor cells in a thymoma look similar to the normal cells of the thymus, grow slowly, and rarely spread beyond the thymus.

A thymoma is a tumor originating from the epithelial cells of the thymus that may be benign or malignant. Thymomas are frequently associated with the neuromuscular disorder myasthenia gravis; thymoma is found in 20% of patients with myasthenia gravis. Once diagnosed, thymomas may be removed surgically. In the rare case of a malignant tumor, chemotherapy may be used.

The regulatory T cells, formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Tregs are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Tregs express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4 cells. Because effector T cells also express CD4 and CD25, Tregs are very difficult to effectively discern from effector CD4+, making them difficult to study. Recent research has found that the cytokine TGFβ is essential for Tregs to differentiate from naïve CD4+ cells and is important in maintaining Treg homeostasis.

Central tolerance, also known as negative selection, is the process of eliminating any developing T or B lymphocytes that are reactive to self. Through elimination of autoreactive lymphocytes, tolerance ensures that the immune system does not attack self peptides. Lymphocyte maturation occurs in primary lymphoid organs such as the bone marrow and the thymus. In mammals, B cells mature in the bone marrow and T cells mature in the thymus.

Immune tolerance, or immunological tolerance, or immunotolerance, is a state of unresponsiveness of the immune system to substances or tissue that have the capacity to elicit an immune response in a given organism. It is induced by prior exposure to that specific antigen and contrasts with conventional immune-mediated elimination of foreign antigens. Tolerance is classified into central tolerance or peripheral tolerance depending on where the state is originally induced—in the thymus and bone marrow (central) or in other tissues and lymph nodes (peripheral). The mechanisms by which these forms of tolerance are established are distinct, but the resulting effect is similar.

A Thymocyte is an immune cell present in the thymus, before it undergoes transformation into a T cell. Thymocytes are produced as stem cells in the bone marrow and reach the thymus via the blood. Thymopoiesis describes the process which turns thymocytes into mature T cells according to either negative or positive selection. This selection process is vitally important in shaping the population of thymocytes into a peripheral pool of T cells that are able to respond to foreign pathogens but remain tolerant towards the body's own antigens. Positive selection selects cells which are able to bind MHC class I or II molecules with at least a weak affinity. This eliminates those T cells which would be non-functional due to an inability to bind MHC. Negative selection destroys thymocytes with a high affinity for self peptides or MHC. This eliminates cells which would direct immune responses towards self-proteins in the periphery. Negative selection is not 100% effective, and some autoreactive T cells escape and are released into the circulation. Additional mechanisms of peripheral tolerance exist to silence these cells, but if these fail, autoimmunity may arise.

MHC-restricted antigen recognition, or MHC restriction, refers to the fact that a T cell can interact with a self-major histocompatibility complex molecule and a foreign peptide bound to it, but will only respond to the antigen when it is bound to a particular MHC molecule.

Hassalls corpuscles

Hassall's corpuscles are structures found in the medulla of the human thymus, formed from eosinophilic type VI epithelial reticular cells arranged concentrically. These concentric corpuscles are composed of a central mass, consisting of one or more granular cells, and of a capsule formed of epithelioid cells. They vary in size with diameters from 20 to more than 100μm, and tend to grow larger with age. They can be spherical or ovoid and their epithelial cells contain keratohyalin and bundles of cytoplasmic fibres. Later studies indicate that Hassall's corpuscles differentiate from medullary thymic epithelial cells after they lose autoimmune regulator (AIRE) expression. They are named for Arthur Hill Hassall, who discovered them in 1846.

Autoimmune regulator A transcription factor expressed in the medulla (inner part) of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease.

The autoimmune regulator (AIRE) is a protein that in humans is encoded by the AIRE gene. It is a 13kb gene on chromosome 21q22.3 that has 545 amino acids. AIRE is a transcription factor expressed in the medulla of the thymus. It is part of the mechanism which eliminates self-reactive T cells that would cause autoimmune disease. It exposes T cells to normal, healthy proteins from all parts of the body, and T cells that react to those proteins are destroyed.

Minor histocompatibility antigen

Minor histocompatibility antigen are receptors on the cellular surface of donated organs that are known to give an immunological response in some organ transplants. They cause problems of rejection less frequently than those of the major histocompatibility complex (MHC). Minor histocompatibility antigens (MiHAs) are diverse, short segments of proteins and are referred to as peptides. These peptides are normally around 9-12 amino acids in length and are bound to both the major histocompatibility complex (MHC) class I and class II proteins. Peptide sequences can differ among individuals and these differences arise from SNPs in the coding region of genes, gene deletions, frameshift mutations, or insertions. About a third of the characterized MiHAs come from the Y chromosome. The proteins are composed of a single immunogenic HLA allele. Prior to becoming a short peptide sequence, the proteins expressed by these polymorphic or diverse genes need to be digested in the proteasome into shorter peptides. These endogenous or self peptides are then transported into the endoplasmic reticulum with a peptide transporter pump called TAP where they encounter and bind to the MHC class I molecule. This contrasts with MHC class II molecules's antigens which are peptides derived from phagocytosis/endocytosis and molecular degradation of non-self entities' proteins, usually by antigen-presenting cells. MiHA antigens are either ubiquitously expressed in most tissue like skin and intestines or restrictively expressed in the immune cells.

Clonal deletion is the removal through apoptosis of B cells and T cells that have expressed receptors for self before developing into fully immunocompetent lymphocytes. This prevents recognition and destruction of self host cells, making it a type of negative selection or central tolerance. Central tolerance prevents B and T lymphocytes from reacting to self. Thus, clonal deletion can help protect individuals against autoimmunity. Clonal deletion is thought to be the most common type of negative selection. It is one method of immune tolerance.

Thymic nurse cells (TNCs) are large epithelial cells found in the cortex of the thymus and also in cortico-medullary junction. They have their own nucleus and are known to internalize thymocytes through extensions of plasma membrane. The cell surfaces of TNCs and their cytoplasmic vacuoles express MHC Class I and MHC Class II antigens. The interaction of these antigens with the developing thymocytes determines whether the thymocytes undergo positive or negative selection.

Seong Hoe Park is a Korean immunologist and pathologist and a distinguished professor of pathology at the Seoul National University College of Medicine. He served as the chair of the Department of Pathology (2000–2004), the chair of the Graduate Program of Immunology (2002–2006), the president of Center for Animal Resource Development (2004–2006) at Seoul National University. He was the president of the Korean Association of Immunologists (2000–2001). Throughout his career as a T cell immunologist, Park established the theory of T cell-T cell interaction in human thymus, in which T cells expressing MHC class II drive previously unrecognized types of T cells and provide another significant developmental mechanism of T cells.

Medullary thymic epithelial cells (mTECs) represent a unique stromal cell population of the thymus which plays an essential role in the establishment of central tolerance. Therefore, mTECs rank among cells relevant for the development of functional mammal immune system.

Antigen transfer in the thymus is the transmission of self-antigens between thymic Antigen presenting cells (APCs) which contributes to the establishment of T cell central tolerance.

Cortical thymic epithelial cells (cTECs) form unique parenchyma cell population of the thymus which critically contribute to the development of T cells.

Thymic epithelial cells (TECs) are specialized cells with high degree of anatomic, phenotypic and functional heterogeneity that are located in the thymic epithelium within the thymic stroma. Thymus, as a primary lymphoid organ, mediates T cell development and maturation. Thymic microenvironment is established by TEC network filled with thymocytes in different developing stages. TECs and thymocytes are the most important components in the thymus, that are necessary for production functionally competent T lymphocytes and self tolerance. Dysfunction of TECs causes several immunodeficiencies and autoimmune diseases.

Promiscuous gene expression (PGE), formerly referred to as ectopic expression, is a process specific to the thymus that plays a pivotal role in the establishment of central tolerance. This phenomenon enables generation of self-antigens, so called tissue-restricted antigens (TRAs), which are in the body expressed only by one or few specific tissues. These antigens are represented for example by insulin from the pancreas or defensins from the gastrointestinal tract. Antigen-presenting cells (APCs) of the thymus, namely medullary thymic epithelial cells (mTECs), dendritic cells (DCs) and B cells are capable to present peptides derived from TRAs to developing T cells and hereby test, whether their T cell receptors (TCRs) engage self entities and therefore their occurrence in the body can potentially lead to the development of autoimmune disease. In that case, thymic APCs either induce apoptosis in these autoreactive T cells or they deviate them to become T regulatory cells, which suppress self-reactive T cells in the body that escaped negative selection in the thymus. Thus, PGE is crucial for tissues protection against autoimmunity.

References

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

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