Thymus

The thymus is a specialized organ of the immune system. The only known function of the thymus is the production and "education" of T-lymphocytes (T cells), which are critical cells of the adaptive immune system. The thymus is composed of two identical lobes and is located anatomically in the anterior superior mediastinum, in front of the heart and behind the sternum.

Histologically, the thymus can be divided into a central medulla and a peripheral cortex which is surrounded by an outer capsule. The cortex and medulla play different roles in the development of T-cells. Cells in the thymus can be divided into thymic stromal cells and cells of hematopoietic origin (derived from bone marrow resident hematopoietic stem cells). Developing T-cells are referred to as thymocytes and are of hematopoietic origin. Stromal cells include thymic cortical epithelial cells, thymic medullary epithelial cells, and dendritic cells.

The thymus provides an inductive environment for development of T-lymphocytes from hematopoietic progenitor cells. In addition, thymic stromal cells allow for the selection of a functional and self-tolerant T-cell repertoire. Therefore, one of the most important roles of the thymus is the induction of central tolerance.

The thymus is largest and most active during the neonatal and pre-adolescent periods. By the early teens, the thymus begins to atrophy and thymic stroma is replaced by adipose (fat) tissue. Nevertheless, residual T lymphopoiesis continues throughout adult life.

History
The thymus was known to the Ancient Greeks, and its name comes from the Greek word θυμός (thumos), meaning heart, soul, desire, life — possibly because of its location in the chest, near where emotions are subjectively felt; or else the name comes from the herb thyme (also in Greek θυμός), which became the name for a "warty excrescence", possibly due to its resemblance to a bunch of thyme.

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

Due to the large numbers of apoptotic lymphocytes, the thymus was originally dismissed as a "lymphocyte graveyard", without functional importance. The importance of the thymus in the immune system was discovered in 1961 by Jacques Miller, by surgically removing the thymus from three day old mice, and observing the subsequent deficiency in a lymphocyte population, subsequently named T-cells after the organ of their origin. Recently, advances in immunology have allowed the function of the thymus in T-cell maturation to be more fully understood.

Embryology
The two main components of the thymus, the lymphoid thymocytes and the thymic epithelial cells, have distinct developmental origins. The thymic epithelium is the first to develop, and appears in the form of two flask-shape endodermal diverticula, which arise, one on either side, from the third branchial pouch (pharyngeal pouch), and extend lateralward and backward into the surrounding mesoderm and neural crest-derived mesenchyme in front of the ventral aorta.

Here they meet and become joined to one another by connective tissue, but there is never any fusion of the thymus tissue proper. 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. Additional portions of thymus tissue are sometimes developed from the fourth branchial pouches.

During the late stages of the development of the thymic epithelium, hematopoietic bone-marrow precursors migrate into the thymus. Normal thymic development thereafter is dependent on the interaction between the thymic epithelium and the hematopoietic thymocytes.

Involution
The thymus continues to grow between birth and puberty and then begins to atrophy, this thymic involution is directed by the high levels of circulating hormones. Proportional to thymic size, thymic activity (T-cell output) is most active before puberty. Upon atrophy, the size and activity are dramatically reduced, and the organ is primarily replaced with fat (a phenomenon known as "organ involution"). 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. Patients with the autoimmune disease Myasthenia gravis commonly (70%) are found to have thymic hyperplasia or malignancy. The reason or order of these circumstances has yet to be determined by medical scientists.

Anatomy
The thymus is of a pinkish-gray color, soft, and lobulated on its surfaces. At birth it is about 5 cm in length, 4 cm in breadth, and about 6 mm in thickness. The organ enlarges during childhood, and atrophies at puberty. Unlike the liver, kidney and heart, for instance, the thymus is at its largest in children. The thymus reaches maximum weight (20 to 37 grams) by the time of puberty. The thymus of older people is scarcely distinguishable from surrounding fatty tissue. As one ages the thymus slowly shrinks, eventually degenerating into tiny islands of fatty tissue. By the age of 75 years, the thymus weighs only 6 grams. In children the thymus is grayish-pink in colour and in adults it is yellow.

The thymus will, if examined when its growth is most active, be found to consist of two lateral lobes placed in close contact along the middle line, situated partly in the thorax, partly in the neck, and extending from the fourth costal cartilage upward, as high as the lower border of the thyroid gland. It is covered by the sternum, and by the origins of the sternohyoidei and sternothyreoidei. Below, it rests upon the pericardium, being separated from the aortic arch and great vessels by a layer of fascia. In the neck, it lies on the front and sides of the trachea, behind the sternohyoidei and sternothyreoidei. The two lobes differ slightly in size and may be united or separated.

Structure
Each lateral lobe is composed of numerous lobules held together by delicate areolar tissue; the entire organ being enclosed in an investing capsule of a similar but denser structure. The primary lobules vary in size from that of a pin's head to that of a small pea, and are made up of a number of small nodules or follicles.

The follicles are irregular in shape and are more or less fused together, especially toward the interior of the organ. Each follicle is from 1 to 2 mm in diameter and consists of a medullary and a cortical portion, and these differ in many essential particulars from each other.

Cortex
The cortical portion is mainly composed of lymphoid cells, supported by a network of finely-branched epithelial reticular cells, which is continuous with a similar network in the medullary portion. This network forms an adventitia to the blood vessels.

The cortex is the location of the earliest events in thymocyte development, where T cell receptor gene rearrangement and positive selection takes place.

Medulla
In the medullary portion, the reticulum is coarser than in the cortex, the lymphoid cells are relatively fewer in number, and there are found peculiar nest-like bodies, the concentric corpuscles of Hassall. 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 are the remains of the epithelial tubes, which grow out from the third branchial pouches of the embryo to form the thymus. Each follicle is surrounded by a vascular plexus, from which vessels pass into the interior, and radiate from the periphery toward the center, forming a second zone just within the margin of the medullary portion. In the center of the medullary portion there are very few vessels, and they are of minute size.

The medulla is the location of the latter events in thymocyte development. Thymocytes that reach the medulla have already successfully undergone T cell receptor gene rearrangement and positive selection, and have been exposed to a limited degree of negative selection. The medulla is specialised to allow thymocytes to undergo additional rounds of negative selection to remove auto-reactive T-cells from the mature repertoire. The gene AIRE is expressed by the thymic medullary epithelium, and drives the transcription of organ-specific genes such as insulin to allow maturing thymocytes to be exposed to a more complex set of self-antigens than is present in the cortex.

Vasculature
The arteries supplying the thymus are derived from the internal mammary, and from the superior thyroid and inferior thyroids.

The veins end in the left brachiocephalic vein (innominate vein), and in the thyroid veins.

The nerves are exceedingly minute; they are derived from the vagi and sympathetic nervous system. Branches from the descendens hypoglossi and phrenic reach the investing capsule, but do not penetrate into the substance of the organ.

Function
In the two thymic lobes, hematopoietic precursors from the bone-marrow, referred to as thymocytes, mature into T-cells. Once mature, T-cells emigrate from the thymus and constitute the peripheral T-cell repertoire responsible for directing many facets of the adaptive immune system. Loss of the thymus at an early age through genetic mutation (as in DiGeorge Syndrome ) results in severe immunodeficiency and a high susceptibility to infection.

The stock of T-lymphocytes is built up in early life, so the function of the thymus is diminished in adults. It is largely degenerated in elderly adults and is barely identifiable, consisting mostly of fatty tissue, but it continues its endocrine function. Involution of the thymus has been linked to loss of immune function in the elderly, susceptibility to infection and to cancer.

The ability of T-cells to recognize foreign antigens is mediated by the T cell receptor. The T cell receptor undergoes genetic rearrangement during thymocyte maturation, resulting in each T-cell bearing a unique T-cell receptor, specific to a limited set of peptide:MHC combinations. The random nature of the genetic rearrangement results in a requirement of central tolerance mechanisms to remove or inactivate those T cells which bear a T cell receptor with the ability to recognise self-peptides.

Phases of thymocyte maturation
The generation of T-cells expressing distinct T-cell receptors occurs within the thymus, and can be conceptually divided into three phases:


 * 1) A rare population of hematopoietic progenitor cells enter the thymus from the blood, and expands by cell division to generate a large population of immature thymocytes.
 * 2) Immature thymocytes each make distinct T-cell receptors by a process of gene rearrangement.  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.
 * 3) Immature thymocytes undergo a process of selection, based on the specificity of their T-cell receptors.  This involves selection of T-cells that are functional (positive selection), and elimination of T-cells that are autoreactive (negative selection).

Cells that pass both levels of selection are released into the bloodstream to perform vital immune functions.

Disease Associations
The immune system is a multicomponent interactive system. It effectively protects the host from various infections. An improperly functioning immune system can cause discomfort, disease or even death. The type of malfunction falls into one or more of the following major groups: hypersensitivity or allergy, auto-immune disease, or immunodeficiency.

Hypersensitivity
Allergy result from an inappropriate and excessive immune response to common antigens. Substances that trigger an allergic response are called allergens. Allergies involve mainly IgE, antibodies, and histamine. Mast cells release the histamine. Sometimes an allergen may cause a sudden and severe, possibly fatal reaction in a sensitive individual; this is called anaphylaxis.

Immunodeficiency
As the thymus is the organ of T-cell development, any congenital defect in thymic genesis or a defect in thymocyte development can lead to a profound T cell primary immunodeficiency. Defects that affect both the T cell and B cell lymphocyte lineages result in Severe Combined Immunodeficiency Syndrome (SCIDs). Acquired T cell deficiencies can also affect thymocyte development in the thymus.

DiGeorge Syndrome
DiGeorge Syndrome is a genetic disorder caused by the deletion of a small section of chromosome 22. This results in a midline congenital defect including thymic aplasia, or congenital deficiency of a thymus. Patients may present with a profound immunodeficiency disease, due to the lack of T cells. No other immune cell lineages are affected by the congenital absence of the thymus. DiGeorge Syndrome is the most common congenital cause of thymic aplasia in humans. In mice, the nude mouse strain are congenitally thymic deficent. These mice are an important model of primary T cell deficiency.

SCID
Severe combined immunodeficiency syndromes (SCID) are group of rare congenital genetic diseases that result in combined T lymphocyte and B lymphocyte deficencies. These syndromes are cause by defective hematopoietic progenitor cells which are the precursors of both B- and T-cells. This results in a severe reduction in developing thymocytes in the thymus and consequently thymic atrophy. A number of genetic defects can cause SCID, including IL-7 receptor deficiency, common gamma chain deficiency, and recombination activating gene deficiency. The gene for the disease called ADA (adenine deaminase) is located on chromosomes 20.

HIV/AID
The HIV virus causes an acquired T-cell immunodeficiency syndrome (AIDS) by specifically killing CD4+ T-cells. Whereas the major effect of the virus is on mature peripheral T-cells, the HIV virus can also infect developing thymocytes in the thymus, most of which express CD4.

Autoimmune Disease
Autoimmune diseases are caused by a hyperactive immune system that instead of attacking foreign pathogens reacts against the host organism (self) causing disease. One of the primary functions of the thymus is to prevent autoimmunity through the process of central tolerance, immunologic tolerance to self antigens.

APECED
Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED) is an extremely rare genetic autoimmune syndrome. However, this disease highlights the importance of the thymus in prevention of autoimmunity. This disease is caused by deficiency of the Autoimmune Regulator (AIRE) gene in the thymus. AIRE allows for the ectopic expression of tissue-specific proteins in the thymus medulla, such as proteins that would normally only be expressed in the eye or pancreas. This expression in the thymus, allows for the deletion of autoreactive thymocytes by exposing them to self-antigens during their development, a mechanism of central tolerance. Patients with APECED develop an autoimmune disease that affects multiple endocrine tissues.

Myasthenia gravis
Myasthenia gravis is an autoimmune disease caused by antibodies that block acetylcholine receptors. Myasthenia gravis is often associated with thymic hypertrophy. Thymectomy may be necessary to treat the disease.

Cancer
Two primary forms of tumours originate in the thymus.

Thymomas
Tumours originating from the thymic epithelial cells are called thymomas, and are found in about 10-15% of patients with myasthenia gravis. Symptoms are sometimes confused with bronchitis or a strong cough because the tumour presses on the recurrent laryngeal nerve. All thymomas are potentially cancerous, but they can vary a great deal. Some grow very slowly. Others grow rapidly and can spread to surrounding tissues. Treatment of thymomas often requires surgery to remove the entire thymus.

Lymphomas
Tumours originating from the thymocytes are called thymic lymphomas. Lymphomas or leukemias of thymocyte origin are classified as Precursor T acute lymphoblastic leukemia/lymphoma (T-ALL).

People with an enlarged thymus, particularly children, were treated with intense radiation in the years before 1950. There is an elevated incidence of thyroid cancer and leukemia in treated individuals.

Thymectomy
Thymectomy is the surgical removal of the thymus. The most common reason for thymectomy in the United States is to gain surgical access to the heart in surgeries to correct congenital heart defects that are performed in the neonatal period. In neonates, but not older children or adults, the relative size of the thymus obstructs surgical access to the heart. Surprisingly, removal of the thymus does not result in a T cell immunodeficiency. This is because sufficient T cells are generated during fetal life prior to birth. These T cells are long-lived and can proliferate by homeostatic proliferation throughout the lifetime of the patient. However, there is evidence of premature immune aging in patients thymectomized during early childhood.

Other indications for thymectomy include the removal of thymomas and the treatment of myastenia gravis. Thymectomy is not indicated for the treatment of primary thymic lymphomas. However, a thymic biopsy may be necessary to make the pathologic diagnosis.

Second thymus
The thymus is also present in most vertebrates, with similar structure and function as the human thymus. Some animals have multiple secondary (smaller) thymi in the neck; this phenomenon has been reported for mice and also occurs in 5 out of 6 human fetuses. As in humans, the Guinea pig's thymus naturally atrophies as the animal reaches adulthood, but in the athymic hairless guinea pig (which arose from a spontaneous laboratory mutation) possessed no thymic tissue whatsoever, and the organ cavity is replaced with cystic spaces.

In 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 human beings. Recently, a discrete thymus-like lympho-epithelial structure, termed the thymoid, was disovered in the gills of larval lampreys. Hagfish possess a protothymus associated with the pharyngeal velar muscles, which is responsible for a variety of immune responses. Little is known about the immune mechanisms of tunicates or of Amphioxus.

When used for consumption, animal thymic tissue is known as (one of the kinds of) sweetbread.

Additional images
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