From Wikipedia, the free encyclopedia
The
thymus is a specialized organ in the
immune system. The functions of the thymus are the "schooling" of T-
lymphocytes (
T cells), which are critical cells of the adaptive immune system, and the production and secretion of
thymosins, hormones which control T-lymphocyte activities and various other aspects of the 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.
[1][2]
Galen was the first to note that the size of the organ changed over the duration of a person's life.
[3]
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.
[4][5] Recently, advances in
immunology have allowed the function of the thymus in T-cell maturation to be more fully understood.
Development
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.
[6]
During the late stages of the development of the thymic epithelium,
hematopoietic bone-marrow precursors migrate into the thymus. Normal thymic development thereafter is dependant 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, a process 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.
[7] Patients with the
autoimmune disease Myasthenia gravis commonly (70%) are found to have thymic
hyperplasia or malignancy.
[8] The reason or order of these circumstances has yet to be determined by medical scientists.
| Age | Mass |
| birth | about 15 grams; |
| puberty | about 35 grams |
| twenty-five years | 25 grams |
| sixty years | less than 15 grams |
| seventy years | as low as 5 grams |
Anatomy
anterior view of chest showing location and size of adult thymus
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.
[9] 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.
[9] 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.
[9]
Structure
Minute structure of thymus.
Each lateral lobe is composed of numerous
lobules held together by delicate
areolar tissue; the entire organ being enclosed in an investing
capsule[10] 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
[11], 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[12]) results in severe
immunodeficiency and a high susceptibility to infection.
[13]
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.
[14] 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:
- 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.[15]
- 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.[16]
- 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).
| type: | functional (positive selection) | autoreactive (negative selection) |
| location: | cortex | medulla |
 | In order to be positively-selected, thymocytes will have to interact with several cell surface molecules, MHC/HLA, to ensure reactivity and specificity[17].
Positive selection eliminates (apoptosis) weak binding cells and only takes high medium binding cells. (Binding refers to the ability of the T-cell receptors to bind to either MHC class I/II or peptide molecules.)
| Negative selection is not 100% complete. Some autoreactive T-cells escape thymic censorship, and are released into the circulation.
Additional mechanisms of tolerance active in the periphery exist to silence these cells such as anergy, deletion, and regulatory T cells.
If these peripheral tolerance mechanisms also fail, autoimmunity may arise.
|
Cells that pass both levels of selection are released into the
bloodstream to perform vital immune functions.
Disease Associations
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 (SCID). Acquired
T cell deficiencies can also affect
thymocyte development in the thymus.
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.
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
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.
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 mechansism of
central tolerance. Patients with APECED develop an autoimmune disease that affects multiple
endocrine tissues.
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.
Tumours originating from the thymic epithelial cells are called
thymomas, and are found in about 10-15% of patients with
myasthenia gravis.
[18] 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.
Tumours originating from the thymocytes are called thymic
lymphomas.
[18] 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.
[19]
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
[20].
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 [21] and also occurs in 5 out of 6 human fetuses.
[22] 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.
Animal thymic tissue sold in a butcher shop or at a meat counter is known as
sweetbread.
In animals
Thymus is present in
mammals, where it plays the same immunological function as in human beings.
References
- ^ Online Etymology Dictionary
- ^ Liddell Scott Greek-English Lexicon
- ^ 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. PMID 16549602. http://radiographics.rsnajnls.org/cgi/content/full/26/2/335.
- ^ Miller JF (2002). "The discovery of thymus function and of thymus-derived lymphocytes". Immunol. Rev. 185: 7–14. doi:10.1034/j.1600-065X.2002.18502.x. PMID 12190917.
- ^ Miller JF (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. PMID 15140026.
- ^ Swiss embryology (from UL, UB, and UF) qblood/lymphat03
- ^ Sutherland JS. Activation of thymic regeneration in mice and humans following androgen blockade. J Immunol 2005 15;175(4):2741-53
- ^ Kumar, Parveen, Michael Clark (2002). Clinical Medicine 5th edn.. Saunders. pp. 1222. ISBN 0-702-02606-9.
- ^ a b c Gray, H. (1918). (bartleby.com) "4c. The Thymus". Anatomy of the Human Body. Philadelphia: Lea & Febiger. http://www.bartleby.com/107/274.html (bartleby.com).
- ^ Histology at BU 07403loa
- ^ Histology at BU 07401loa
- ^ Hussain, I., P.H. Win and S. Guduri (February 2, 2006). "DiGeorge Syndrome". eMedicine. http://www.emedicine.com/med/topic567.htm. Retrieved 2008-09-29.
- ^ Miller JF. The discovery of thymus function and of thymus-derived lymphocytes. Immunol Rev 185:7-14, 2002. full text
- ^ "Thymus". http://www.tiscali.co.uk/reference/encyclopaedia/hutchinson/m0008212.html. Retrieved 2007-12-03.
- ^ Schwarz BA, Bhandoola A. Trafficking from the bone marrow to the thymus: a prerequisite for thymopoiesis. Immunol Rev 209:47, 2006. full text
- ^ Sleckman BP, Lymphocyte antigen receptor gene assembly: multiple layers of regulation. Immunol Res 32:153-8, 2005. full text
- ^ Baldwin TA, Hogquist KA, Jameson SC, The fourth way? Harnessing aggressive tendencies in the thymus. “J Immunol.” 173:6515-20, 2004. [1]
- ^ a b Huete-Garin, A.; S.S. Sagel (2005). "Chapter 6: "Mediastinum", Thymic Neoplasm". In J.K.T. Lee, S.S. Sagel, R.J. Stanley and J.P. Heiken. Computed Body Tomography with MRI Correlation. Philadelphia: Lippincott Williams & Wilkins. pp. 311–324. ISBN 0781745268.
- ^ Shore RE, Woodward E, Hildreth N, et al., Thyroid tumors following thymus irradiation. J Natl Cancer Inst 74:1177-1184, 1985.
- ^ [2]
- ^ Terszowski G et al. (2006) Evidence for a Functional Second Thymus in Mice. Science. 2 March 2006. PMID 16513945
- ^ Surprise organ discovered in mice, Nature News, 2 March 2006
- This article was originally based on an entry from a public domain edition of Gray's Anatomy. As such, some of the information contained within it may be outdated.
Additional images
Endocrine system (thymus is #4)
| | Scheme showing development of branchial epithelial bodies. I, II, III, IV. Branchial pouches.
|
