The thymus is a specialized primary
lymphoid organ of the
immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...
. Within the thymus,
thymus cell lymphocyte
A lymphocyte is a type of white blood cell (leukocyte) in the immune system of most vertebrates. Lymphocytes include natural killer cells (which function in cell-mediated, cytotoxic innate immunity), T cells (for cell-mediated, cytotoxic ad ...
s or ''
T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s'' mature. T cells are critical to the
adaptive immune system
The adaptive immune system, also known as the acquired immune system, is a subsystem of the immune system that is composed of specialized, systemic cells and processes that eliminate pathogens or prevent their growth. The acquired 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
The mediastinum (from ) is the central compartment of the thoracic cavity. Surrounded by loose connective tissue, it is an undelineated region that contains a group of structures within the thorax, namely the heart and its vessels, the esophag ...
, behind the
sternum
The sternum or breastbone is a long flat bone located in the central part of the chest. It connects to the ribs via cartilage and forms the front of the rib cage, thus helping to protect the heart, lungs, and major blood vessels from injury. Sha ...
, and in front of the
heart
The heart is a muscular organ in most animals. This organ pumps blood through the blood vessels of the circulatory system. The pumped blood carries oxygen and nutrients to the body, while carrying metabolic waste such as carbon dioxide to t ...
. 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
T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
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
Adipose tissue, body fat, or simply fat is a loose connective tissue composed mostly of adipocytes. In addition to adipocytes, adipose tissue contains the stromal vascular fraction (SVF) of cells including preadipocytes, fibroblasts, vascular e ...
. 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
Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome (autoimmune polyglandular syndrome). It causes the dysfunction of multiple endocrine glands due to autoimmunity. It is a genetic disorder, inherite ...
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
Lymphoma is a group of blood and lymph tumors that develop from lymphocytes (a type of white blood cell). In current usage the name usually refers to just the cancerous versions rather than all such tumours. Signs and symptoms may include enla ...
. 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
Ancient Greece ( el, Ἑλλάς, Hellás) was a northeastern Mediterranean civilization, existing from the Greek Dark Ages of the 12th–9th centuries BC to the end of classical antiquity ( AD 600), that comprised a loose collection of cult ...
, 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 beneath the
sternum
The sternum or breastbone is a long flat bone located in the central part of the chest. It connects to the ribs via cartilage and forms the front of the rib cage, thus helping to protect the heart, lungs, and major blood vessels from injury. Sha ...
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.
At birth it is about 4–6 cm long, 2.5–5 cm wide, and about 1 cm thick.
It increases in size until puberty, where it may have a size of about 40–50 g,
following which it decreases in size in a process known as
involution
Involution may refer to:
* Involute, a construction in the differential geometry of curves
* '' Agricultural Involution: The Processes of Ecological Change in Indonesia'', a 1963 study of intensification of production through increased labour inpu ...
.
The thymus is located in the
anterior mediastinum. It is made up of two lobes that meet in the upper midline, and stretch from below the
thyroid
The thyroid, or thyroid gland, is an endocrine gland in vertebrates. In humans it is in the neck and consists of two connected lobes. The lower two thirds of the lobes are connected by a thin band of tissue called the thyroid isthmus. The thy ...
in the neck to as low as the cartilage of the fourth rib.
The lobes are covered by a capsule.
The thymus lies beneath the sternum, rests on the
pericardium
The pericardium, also called pericardial sac, is a double-walled sac containing the heart and the roots of the great vessels. It has two layers, an outer layer made of strong connective tissue (fibrous pericardium), and an inner layer made o ...
, and is separated from the
aortic arch
The aortic arch, arch of the aorta, or transverse aortic arch () is the part of the aorta between the ascending and descending aorta. The arch travels backward, so that it ultimately runs to the left of the trachea.
Structure
The aorta begins ...
and
great vessels
Great vessels are the large vessels that bring blood to and from the heart. These are:
*Superior vena cava
*Inferior vena cava
*Pulmonary arteries
* Pulmonary veins
*Aorta
Transposition of the great vessels is a group of congenital heart defec ...
by a layer of
fascia. The left
brachiocephalic vein may even be embedded within the thymus.
In the neck, it lies on the front and sides of the
trachea
The trachea, also known as the windpipe, is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air- breathing animals with lungs. The trachea extends from the ...
, behind the
sternohyoid
The sternohyoid muscle is a thin, narrow muscle attaching the hyoid bone to the sternum. It is one of the paired strap muscles of the infrahyoid muscles. It is supplied by the ansa cervicalis. It depresses the hyoid bone.
Structure
The sternoh ...
and
sternothyroid muscle
The sternothyroid muscle, or sternothyroideus, is an infrahyoid muscle in the neck. It acts to depress the hyoid bone. It is below the sternohyoid muscle. It is shorter and wider than the sternohyoid.
Structure
The sternothyroid arises from the ...
s.
Microanatomy
The thymus consists of two lobes, merged in the middle, surrounded by a capsule that extends with blood vessels into the interior.
The lobes consist of an outer rich with cells and an inner less dense .
The lobes are divided into smaller lobules 0.5-2mm diameter, between which extrude radiating insertions from the capsule along .
The cortex is mainly made up of
thymocyte
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 thymo ...
s and epithelial cells.
The thymocytes, immature
T cells
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell re ...
, 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
The adventitia () is the outer layer of fibrous connective tissue surrounding an organ.
The outer layer of connective tissue that surrounds an artery, or vein – the tunica externa, is also called the ''tunica adventitia''.
To some degree, its ...
to the blood vessels, which enter the cortex via septa near the junction with the medulla.
[ Other cells are also present in the thymus, including macrophages, dendritic cells, and a small amount of B cells, ]neutrophil
Neutrophils (also known as neutrocytes or heterophils) are the most abundant type of granulocytes and make up 40% to 70% of all white blood cells in humans. They form an essential part of the innate immune system, with their functions varying ...
s and eosinophil
Eosinophils, sometimes called eosinophiles or, less commonly, acidophils, are a variety of white blood cells (WBCs) and one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. A ...
s.
In the medulla, the network of epithelial cells is coarser than in the cortex, and the lymphoid cells are relatively fewer in number. Concentric, nest-like bodies called Hassall's corpuscles
Hassall's corpuscles (or thymic corpuscles (bodies)) 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 ...
(also called ''thymic corpuscles'') are formed by aggregations of the medullary epithelial cells. These are concentric, layered whorls of epithelial cells that increase in number throughout life. They are the remains of the epithelial tubes, which grow out from the third pharyngeal pouches of the embryo to form the thymus.
File:Thymus.JPG, Micrograph
A micrograph or photomicrograph is a photograph or digital image taken through a microscope or similar device to show a magnified image of an object. This is opposed to a macrograph or photomacrograph, an image which is also taken on a m ...
showing a lobule of the thymus. The cortex (deeper purple area) surrounds a less dense and lighter medulla.
File:Thymic corpuscle.jpg, Micrograph showing a Hassall's corpuscle, found within the medulla of the thymus.
Blood and nerve supply
The arteries
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
supplying the thymus are branches of the internal thoracic, and inferior thyroid arteries, with branches from the superior thyroid artery sometimes seen. 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.
The vein
Veins are blood vessels in humans and most other animals that carry blood towards the heart. Most veins carry deoxygenated blood from the tissues back to the heart; exceptions are the pulmonary and umbilical veins, both of which carry oxygenat ...
s of the thymus end in the left brachiocephalic vein, internal thoracic vein, and in the inferior thyroid veins. Sometimes the veins end directly in the superior vena cava.
Lymphatic vessel
The lymphatic vessels (or lymph vessels or lymphatics) are thin-walled vessels (tubes), structured like blood vessels, that carry lymph. As part of the lymphatic system, lymph vessels are complementary to the cardiovascular system. Lymph ve ...
s travel only away from the thymus, accompanying the arteries and veins. These drain into the brachiocephalic, tracheobronchial and parasternal lymph nodes.
The nerves supplying the thymus arise from the vagus nerve
The vagus nerve, also known as the tenth cranial nerve, cranial nerve X, or simply CN X, is a cranial nerve that interfaces with the parasympathetic control of the heart, lungs, and digestive tract. It comprises two nerves—the left and righ ...
and the cervical sympathetic chain. Branches from the phrenic nerves reach the capsule of the thymus, but do not enter into the thymus itself.
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. The thymus in children stretches variably upwards, at times to as high as the thyroid gland.
Development
The thymocytes and the epithelium of the thymus have different developmental origins. The epithelium of the thymus develops first, appearing as two outgrowths, one on either side, of the third pharyngeal pouch. It sometimes also involves the fourth pharyngeal pouch. These extend outward and backward into the surrounding mesoderm and neural crest
Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, per ...
-derived mesenchyme in front of the ventral aorta
The aorta ( ) is the main and largest artery in the human body, originating from the left ventricle of the heart and extending down to the abdomen, where it splits into two smaller arteries (the common iliac arteries). The aorta distributes o ...
. 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.
The epithelium forms fine lobules, and develops into a sponge-like structure. During this stage, hematopoietic bone-marrow precursors migrate into the thymus. Normal development is dependent on the interaction between the epithelium and the hematopoietic thymocyte
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 thymo ...
s. Iodine is also necessary for thymus development and activity.
Involution
The thymus continues to grow after birth reaching the relative maximum size by puberty. It is most active in fetal
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal develo ...
and neonatal life. It increases to a mass of 20 to 50 grams by puberty. It then begins to decrease in size and activity in a process called thymic involution
Thymic involution is the shrinking (involution) of the thymus with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass.
Thymus involution is one of the major characteristics of vertebrate immunology, and occ ...
. After the first year of life the amount of T cells produced begins to fall. Fat and connective tissue fills a part of the thymic volume. During involution, the thymus decreases in size and activity. 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. This process continues into old age, where whether with a microscope or with the human eye, the thymus may be difficult to detect, although typically weighs 5–15 grams. 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. ">0/sup>
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. Severe illness or human immunodeficiency virus
The human immunodeficiency viruses (HIV) are two species of ''Lentivirus'' (a subgroup of retrovirus) that infect humans. Over time, they cause acquired immunodeficiency syndrome (AIDS), a condition in which progressive failure of the immun ...
infection may also result in involution.
Function
T cell maturation
The thymus facilitates the maturation of T cell
A T cell is a type of lymphocyte. T cells are one of the important white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell r ...
s, an important part of the immune system
The immune system is a network of biological processes that protects an organism from diseases. It detects and responds to a wide variety of pathogens, from viruses to parasitic worms, as well as cancer cells and objects such as wood splint ...
providing cell-mediated immunity
Cell-mediated immunity or cellular immunity is an immune response that does not involve antibodies. Rather, cell-mediated immunity is the activation of phagocytes, antigen-specific cytotoxic T-lymphocytes, and the release of various cytokines in ...
. T cells begin as hematopoietic precursors from the bone-marrow, and migrate to the thymus, where they are referred to as thymocyte
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 thymo ...
s. In the thymus they undergo a process of maturation, which involves ensuring the cells react against antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
s ("positive selection"), but that they do not react against antigens found on body tissue ("negative selection"). Once mature, T cells emigrate from the thymus to provide vital functions in the immune system.
Each T cell has a distinct T cell receptor, suited to a specific substance, called an antigen
In immunology, an antigen (Ag) is a molecule or molecular structure or any foreign particulate matter or a pollen grain that can bind to a specific antibody or T-cell receptor. The presence of antigens in the body may trigger an immune respons ...
. 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. 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"). Positive selection occurs in the cortex and negative selection occurs in the medulla of the thymus. After this process T cells that have survived leave the thymus, regulated by sphingosine-1-phosphate
Sphingosine-1-phosphate (S1P) is a signaling sphingolipid, also known as lysosphingolipid. It is also referred to as a bioactive lipid mediator. Sphingolipids at large form a class of lipids characterized by a particular aliphatic aminoalcoho ...
. Further maturation occurs in the peripheral circulation. Some of this is because of hormones and cytokine
Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...
s secreted by cells within the thymus, including thymulin, thymopoietin
Lamina-associated polypeptide 2 (LAP2), isoforms beta/gamma is a protein that in humans is encoded by the ''TMPO'' gene. LAP2 is an inner nuclear membrane (INM) protein.
Thymopoietin is a protein involved in the induction of CD90 in the thymus. ...
, and thymosins.
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
Recombination activating gene 2 protein (also known as RAG-2) is a lymphocyte-specific protein encoded by RAG2 gene on human chromosome 11. Together with RAG1 protein, RAG2 forms a V(D)J recombinase, a protein complex required for the process of V( ...
genes. 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. If a functional T cell receptor is formed, the thymocyte will begin to express simultaneously the cell surface proteins CD4 and CD8
CD8 (cluster of differentiation 8) is a transmembrane glycoprotein that serves as a co-receptor for the T-cell receptor (TCR). Along with the TCR, the CD8 co-receptor plays a role in T cell signaling and aiding with cytotoxic T cell-antigen int ...
.
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. 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. A mature T cell expresses only CD4 or CD8, but not both. This depends on the strength of binding between the TCR and MHC class 1 or class 2. 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.
Negative selection
T cells that attack the body's own proteins are eliminated in the thymus, called "negative selection". Epithelial cells in the medulla and dendritic cells in the thymus express major proteins from elsewhere in the body. The gene that stimulates this is AIRE
Aire may refer to:
Music
* ''Aire'' (Yuri album), 1987
* ''Aire'' (Pablo Ruiz album), 1997
*''Aire (Versión Día)'', an album by Jesse & Joy
Places
*Aire-sur-la-Lys, a town in the Pas-de-Calais département in France
*Aire-la-Ville, a municip ...
. Thymocytes that react strongly to self antigens do not survive, and die by apoptosis. Some CD4 positive T cells exposed to self antigens persist as T regulatory cells.
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. Loss of the thymus at an early age through genetic mutation (as in DiGeorge syndrome
DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...
, CHARGE syndrome, or a very rare "nude" thymus causing absence of hair and the thymus) results in severe immunodeficiency and subsequent high susceptibility to infection by viruses, protozoa, and fungi
A fungus ( : fungi or funguses) is any member of the group of eukaryotic organisms that includes microorganisms such as yeasts and molds, as well as the more familiar mushrooms. These organisms are classified as a kingdom, separately from ...
. Nude mice
A nude mouse is a laboratory mouse from a strain with a genetic mutation that causes a deteriorated or absent thymus, resulting in an inhibited immune system due to a greatly reduced number of T cells. The phenotype (main outward appearance) of ...
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.
The most common congenital cause of thymus-related immune deficiency results from the deletion of the 22nd chromosome, called DiGeorge syndrome
DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...
. 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
A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
, and abnormalities of mouth (such as cleft palate
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The ...
and cleft lip
A cleft lip contains an opening in the upper lip that may extend into the nose. The opening may be on one side, both sides, or in the middle. A cleft palate occurs when the palate (the roof of the mouth) contains an opening into the nose. The te ...
), failure of development of the parathyroid glands, and the presence of a fistula between the trachea
The trachea, also known as the windpipe, is a cartilaginous tube that connects the larynx to the bronchi of the lungs, allowing the passage of air, and so is present in almost all air- breathing animals with lungs. The trachea extends from the ...
and the oesophagus
The esophagus (American English) or oesophagus (British English; both ), non-technically known also as the food pipe or gullet, is an organ in vertebrates through which food passes, aided by peristaltic contractions, from the pharynx to th ...
. Very low numbers of circulating T cells are seen. The condition is diagnosed by fluorescent in situ hybridization and treated with thymus transplantation.
Severe combined immunodeficiency
Severe combined immunodeficiency (SCID), also known as Swiss-type agammaglobulinemia, is a rare genetic disorder characterized by the disturbed development of functional T cells and B cells caused by numerous genetic mutations that result in diffe ...
(SCID) are group of rare congenital genetic diseases that can result in combined T, B, and NK cell
Natural killer cells, also known as NK cells or large granular lymphocytes (LGL), are a type of cytotoxic lymphocyte critical to the innate immune system that belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represen ...
deficiencies. These syndromes are caused by mutations that affect the maturation of the hematopoietic progenitor cell
Hematopoietic stem cells (HSCs) are the stem cells that give rise to other blood cells. This process is called haematopoiesis. In vertebrates, the very first definitive HSCs arise from the ventral endothelial wall of the embryonic aorta within t ...
s, which are the precursors of both B and T cells. A number of genetic defects can cause SCID, including IL-2 receptor
The interleukin-2 receptor (IL-2R) is a heterotrimeric protein expressed on the surface of certain immune cells, such as lymphocytes, that binds and responds to a cytokine called IL-2.
Composition
IL-2 binds to the IL-2 receptor, which ha ...
gene loss of function, and mutation resulting in deficiency of the enzyme
Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products ...
adenine deaminase.
Autoimmune disease
Autoimmune polyendocrine syndrome
Autoimmune polyendocrine syndrome type 1
Autoimmune polyendocrine syndrome type 1 (APS-1), is a subtype of autoimmune polyendocrine syndrome (autoimmune polyglandular syndrome). It causes the dysfunction of multiple endocrine glands due to autoimmunity. It is a genetic disorder, inherite ...
, is a rare genetic autoimmune syndrome that results from a genetic defect of the thymus tissues. 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. 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 gland
The adrenal glands (also known as suprarenal glands) are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex whic ...
s, and candida infection of body surfaces including the inner lining of the mouth and of the nail
Nail or Nails may refer to:
In biology
* Nail (anatomy), toughened protective protein-keratin (known as alpha-keratin, also found in hair) at the end of an animal digit, such as fingernail
* Nail (beak), a plate of hard horny tissue at the tip ...
s due to dysfunction of TH17 cells, and symptoms often beginning in childhood. Many other autoimmune diseases may also occur. Treatment is directed at the affected organs.
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
Graft-versus-host disease (GvHD) is a syndrome, characterized by inflammation in different organs. GvHD is commonly associated with bone marrow transplants and stem cell transplants.
White blood cells of the donor's immune system which remain wit ...
.
Myasthenia gravis
Myasthenia gravis is an autoimmune disease most often due to antibodies that block acetylcholine receptors
An acetylcholine receptor (abbreviated AChR) is an integral membrane protein that responds to the binding of acetylcholine, a neurotransmitter.
Classification
Like other transmembrane receptors, acetylcholine receptors are classified according ...
, involved in signalling between nerves and muscles. It is often associated with thymic hyperplasia or thymoma, with antibodies produced probably because of T cells that develop abnormally. Myasthenia gravis most often develops between young and middle age, causing easy fatiguing of muscle movements. Investigations include demonstrating antibodies (such as against acetylcholine receptors or muscle-specific kinase), and CT scan to detect thymoma or thymectomy. With regard to the thymus, removal of the thymus, called thymectomy may be considered as a treatment, particularly if a thymoma is found. Other treatments include increasing the duration of acetylcholine action at nerve synapses by decreasing the rate of breakdown. This is done by acetylcholinesterase inhibitors
Acetylcholinesterase inhibitors (AChEIs) also often called cholinesterase inhibitors, inhibit the enzyme acetylcholinesterase from breaking down the neurotransmitter acetylcholine into choline and acetate, thereby increasing both the level and ...
such as pyridostigmine
Pyridostigmine is a medication used to treat myasthenia gravis and underactive bladder. It is also used together with atropine to end the effects of neuromuscular blocking medication of the non-depolarizing type. It is typically given by mouth ...
.
Cancer
Thymomas
Tumours originating from the thymic epithelial cells are called thymomas. They most often occur in adults older than 40. Tumours are generally detected when they cause symptoms, such as a neck mass
A neck mass or neck lump is an ambiguous mass found in the neck area. There are many different possible causes, including congenital conditions like branchial anomalies and thyroglossal duct cysts.
Workup
Workup of a neck mass includes a medical ...
or affecting nearby structures such as the superior vena cava
The superior vena cava (SVC) is the superior of the two venae cavae, the great venous trunks that return deoxygenated blood from the systemic circulation to the right atrium of the heart. It is a large-diameter (24 mm) short length vein th ...
; detected because of screening in patients with myasthenia gravis, which has a strong association with thymomas and hyperplasia; and detected as an incidental finding on imaging such as chest x-ray
A chest radiograph, called a chest X-ray (CXR), or chest film, is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common film taken in med ...
s. Hyperplasia and tumours originating form the thymus are associated with other autoimmune diseases – such as hypogammaglobulinemia
Hypogammaglobulinemia is a problem with the immune system in which not enough gamma globulins are produced in the blood (thus '' hypo-'' + ''gamma'' + ''globulin'' + '' -emia''). This results in a lower antibody count, which impairs the immune sys ...
, Graves disease
Graves' disease (german: Morbus Basedow), also known as toxic diffuse goiter, is an autoimmune disease that affects the thyroid. It frequently results in and is the most common cause of hyperthyroidism. It also often results in an enlarged thyro ...
, pure red cell aplasia
Pure red cell aplasia (PRCA) or erythroblastopenia refers to a type of aplastic anemia affecting the precursors to red blood cells but usually not to white blood cells. In PRCA, the bone marrow ceases to produce red blood cells. There are multiple ...
, pernicious anaemia
Pernicious anemia is a type of vitamin B12 deficiency anemia, a disease in which not enough red blood cells are produced due to the malabsorption of vitamin B12. Malabsorption in pernicious anemia results from the lack or loss of intrinsic ...
and dermatomyositis
Dermatomyositis (DM) is a long-term inflammatory disorder which affects skin and the muscles. Its symptoms are generally a skin rash and worsening muscle weakness over time. These may occur suddenly or develop over months. Other symptoms may inc ...
, likely because of defects in negative selection in proliferating T cells.
Thymomas can be benign; benign but by virtue of expansion, invading beyond the capsule of the thymus ("invasive thyoma"), or malignant (a carcinoma). This classification is based on the appearance of the cells. A WHO
Who or WHO may refer to:
* Who (pronoun), an interrogative or relative pronoun
* Who?, one of the Five Ws in journalism
* World Health Organization
Arts and entertainment Fictional characters
* Who, a creature in the Dr. Seuss book '' Horton He ...
classification also exists but is not used as part of standard clinical practice. Benign tumours confined to the thymus are most common; followed by locally invasive tumours, and then by carcinomas. There is variation in reporting, with some sources reporting malignant tumours as more common. Invasive tumours, although not technically malignant, can still spread () to other areas of the body. Even though thymomas occur of epithelial cells, they can also contain thymocytes. Treatment of thymomas often requires surgery to remove the entire thymus. This may also result in temporary remission of any associated autoimmune conditions.
Lymphomas
Tumours originating from T cells of the thymus form a subset of acute lymphoblastic leukaemia
Acute lymphoblastic leukemia (ALL) is a cancer of the lymphoid line of blood cells characterized by the development of large numbers of immature lymphocytes. Symptoms may include feeling tired, pale skin color, fever, easy bleeding or bruisin ...
(ALL). These are similar in symptoms, investigation approach and management to other forms of ALL. Symptoms that develop, like other forms of ALL, relate to deficiency of platelet
Platelets, also called thrombocytes (from Greek θρόμβος, "clot" and κύτος, "cell"), are a component of blood whose function (along with the coagulation factors) is to react to bleeding from blood vessel injury by clumping, thereby i ...
s, resulting in bruising or bleeding; immunosuppression resulting in infections; or infiltration by cells into parts of the body, resulting in an enlarged liver
Hepatomegaly is the condition of having an enlarged liver. It is a non-specific medical sign having many causes, which can broadly be broken down into infection, hepatic tumours, or metabolic disorder. Often, hepatomegaly will present as an abdomi ...
, spleen
The spleen is an organ found in almost all vertebrates. Similar in structure to a large lymph node, it acts primarily as a blood filter. The word spleen comes . , lymph nodes
A lymph node, or lymph gland, is a kidney-shaped organ of the lymphatic system and the adaptive immune system. A large number of lymph nodes are linked throughout the body by the lymphatic vessels. They are major sites of lymphocytes that inclu ...
or other sites. Blood test might reveal a large amount of white blood cells or lymphoblast
__NOTOC__
A lymphoblast is a modified naive lymphocyte with altered cell morphology. It occurs when the lymphocyte is activated by an antigen (from antigen-presenting cells) and increased in volume by nucleus and cytoplasm growth as well as new mRN ...
s, and deficiency in other cell lines – such as low platelets or anaemia
Anemia or anaemia (British English) is a blood disorder in which the blood has a reduced ability to carry oxygen due to a lower than normal number of red blood cells, or a reduction in the amount of hemoglobin. When anemia comes on slowly, t ...
. 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
A karyotype is the general appearance of the complete set of metaphase chromosomes in the cells of a species or in an individual organism, mainly including their sizes, numbers, and shapes. Karyotyping is the process by which a karyotype is disce ...
may reveal specific abnormalities that may influence prognosis or treatment, such as the Philadelphia translocation. Management can include multiple courses of chemotherapy
Chemotherapy (often abbreviated to chemo and sometimes CTX or CTx) is a type of cancer treatment that uses one or more anti-cancer drugs (chemotherapeutic agents or alkylating agents) as part of a standardized chemotherapy regimen. Chemotherap ...
, stem cell transplant
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produc ...
, and management of associated problems, such as treatment of infections with antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
, and blood transfusions
Blood transfusion is the process of transferring blood products into a person's circulation intravenously. Transfusions are used for various medical conditions to replace lost components of the blood. Early transfusions used whole blood, but mod ...
. Very high white cell counts may also require cytoreduction
Debulking is the reduction of as much of the bulk (volume) of a tumour without the intention of a complete eradication. It is usually achieved by surgical removal. When performed for curative intent, it is a different procedure, which is called sur ...
with apheresis
Apheresis ( ἀφαίρεσις (''aphairesis'', "a taking away")) is a medical technology in which the blood of a person is passed through an apparatus that separates out one particular constituent and returns the remainder to the circulation ...
.
Tumours originating from the small population of B cells present in the thymus lead to primary mediastinal (thymic) large B cell lymphoma
Primary mediastinal (thymic) large B-cell lymphoma is a distinct type of diffuse large B-cell lymphoma involving the mediastinum, recognized in the WHO 2008 classification.
Signs and symptoms
Superior vena cava syndrome occurs in 30–50%, and ...
s. These are a rare subtype of Non-Hodgkins lymphoma
Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tiredness. ...
, although by the activity of genes and occasionally microscopic shape, unusually they also have the characteristics of Hodgkins lymphoma
Hodgkin lymphoma (HL) is a type of lymphoma, in which cancer originates from a specific type of white blood cell called lymphocytes, where multinucleated Reed–Sternberg cells (RS cells) are present in the patient's lymph nodes. The condition w ...
s. that occur most commonly in young and middle-aged, more prominent in females. Most often, when symptoms occur it is because of compression of structures near the thymus, such as the superior vena cava
The superior vena cava (SVC) is the superior of the two venae cavae, the great venous trunks that return deoxygenated blood from the systemic circulation to the right atrium of the heart. It is a large-diameter (24 mm) short length vein th ...
or the upper respiratory tract
The respiratory tract is the subdivision of the respiratory system involved with the process of respiration in mammals. The respiratory tract is lined with respiratory epithelium as respiratory mucosa.
Air is breathed in through the nose to t ...
; when lymph nodes are affected it is often in the mediastinum and neck groups. Such tumours are often detected with a biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...
that is subject to immunohistochemistry
Immunohistochemistry (IHC) is the most common application of immunostaining. It involves the process of selectively identifying antigens (proteins) in cells of a tissue section by exploiting the principle of antibodies binding specifically to an ...
. This will show the presence of clusters of differentiation
The cluster of differentiation (also known as cluster of designation or classification determinant and often abbreviated as CD) is a protocol used for the identification and investigation of cell surface molecules providing targets for immunophen ...
, cell surface proteins – namely CD30
CD30, also known as TNFRSF8 ( TNF receptor superfamily member 8), is a cell membrane protein of the tumor necrosis factor receptor family and a tumor marker.
Function
This receptor is expressed by activated, but not by resting, T and B cel ...
, with CD19, CD20
B-lymphocyte antigen CD20 or CD20 is expressed on the surface of all B-cells beginning at the pro-B phase ( CD45R+, CD117+) and progressively increasing in concentration until maturity.
In humans CD20 is encoded by the ''MS4A1'' gene.
This gene ...
and CD22, and with the absence of CD15
Sialyl LewisX (sLeX), also known as cluster of differentiation 15s (CD15s) or stage-specific embryonic antigen 1 (SSEA-1), is a tetrasaccharide carbohydrate which is usually attached to O- glycans on the surface of cells. It is known to play a vi ...
. Other markers may also be used to confirm the diagnosis. Treatment usually includes the typical regimens of CHOP or EPOCH
In chronology and periodization, an epoch or reference epoch is an instant in time chosen as the origin of a particular calendar era. The "epoch" serves as a reference point from which time is measured.
The moment of epoch is usually decided by ...
or other regimens; regimens generally including cyclophosphamide, an anthracycline
Anthracyclines are a class of drugs used in cancer chemotherapy that are extracted from ''Streptomyces'' bacterium. These compounds are used to treat many cancers, including leukemias, lymphomas, breast, stomach, uterine, ovarian, bladder canc ...
, prednisone
Prednisone is a glucocorticoid medication mostly used to suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium due to cancer and ad ...
, and other chemotherapeutics; and potentially also a stem cell transplant
Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood in order to replicate inside of a patient and to produc ...
.
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. Thymic cysts can occur along the neck or in the chest ( mediastinum). Cysts usually just contain fluid and are lined by either many layers of flat cells or column-shaped cells. Despite this, the presence of a cyst can cause problems similar to those of thymomas, by compressing nearby structures, and some may contact internal walls () and be difficult to distinguish from tumours. When cysts are found, investigation may include a workup for tumours, which may include CT or MRI scan
Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to form pictures of the anatomy and the physiological processes of the body. MRI scanners use strong magnetic fields, magnetic field gradients, and radio waves ...
of the area the cyst is suspected to be in.
Surgical removal
Thymectomy
A thymectomy is an operation to remove the thymus. It usually results in remission of myasthenia gravis with the help of medication including steroids. However, this remission may not be permanent. Thymectomy is indicated when thymoma are present ...
is the surgical removal of the thymus. The usual reason for removal is to gain access to the heart for surgery to correct congenital heart defects
A congenital heart defect (CHD), also known as a congenital heart anomaly and congenital heart disease, is a defect in the structure of the heart or great vessels that is present at birth. A congenital heart defect is classed as a cardiovascular ...
in the neonatal period. Other indications for thymectomy include the removal of thymomas and the treatment of myasthenia gravis. In neonates the relative size of the thymus obstructs surgical access to the heart and its surrounding vessels. Removal of the thymus in infancy results in often fatal immunodeficiency, because functional T cells have not developed. 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, and limited to failure to mount immune responses against new antigens.
Society and culture
When used as food for humans, the thymus of animals is known as one of the kinds of sweetbread
Sweetbread is a culinary name for the thymus (also called throat, gullet, or neck sweetbread) or pancreas (also called stomach, belly or gut sweetbread), typically from calf (french: ris de veau, es, hígado) or lamb (). Sweetbreads have a ri ...
.
History
The thymus was known to the ancient Greeks
Ancient Greece ( el, Ἑλλάς, Hellás) was a northeastern Mediterranean civilization, existing from the Greek Dark Ages of the 12th–9th centuries BC to the end of classical antiquity ( AD 600), that comprised a loose collection of cult ...
, 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; 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.
Galen
Aelius Galenus or Claudius Galenus ( el, Κλαύδιος Γαληνός; September 129 – c. AD 216), often Anglicized as Galen () or Galen of Pergamon, was a Greek physician, surgeon and philosopher in the Roman Empire. Considered to be one of ...
was the first to note that the size of the organ changed over the duration of a person's life.
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
Sudden infant death syndrome (SIDS) is the sudden unexplained death of a child of less than one year of age. Diagnosis requires that the death remain unexplained even after a thorough autopsy and detailed death scene investigation. SIDS usuall ...
but is now an obsolete term.
The importance of the thymus in the immune system was discovered in 1961 by Jacques Miller
Jacques Francis Albert Pierre Miller AC FRS FAA (born 2 April 1931) is a French-Australian research scientist. He is known for having discovered the function of the thymus and for the identification, in mammalian species of the two major subset ...
, 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. Until the discovery of its immunological role, the thymus had been dismissed as a "evolutionary accident", without functional importance. 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. 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. The subtypes of T cells (CD8 and CD4) were identified by 1975. The way that these subclasses of T cells matured – positive selection of cells that functionally bound to MHC receptors – was known by the 1990s. The important role of the AIRE gene, and the role of negative selection in preventing autoreactive T cells from maturing, was understood by 1994.
Recently, advances in immunology
Immunology is a branch of medicineImmunology for Medical Students, Roderick Nairn, Matthew Helbert, Mosby, 2007 and biology that covers the medical study of immune systems in humans, animals, plants and sapient species. In such we can see there ...
have allowed the function of the thymus in T-cell maturation to be more fully understood.
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 lamprey
Lampreys (sometimes inaccurately called lamprey eels) are an ancient extant lineage of jawless fish of the order Petromyzontiformes , placed in the superclass Cyclostomata. The adult lamprey may be characterized by a toothed, funnel-like s ...
s. Hagfish
Hagfish, of the class Myxini (also known as Hyperotreti) and order Myxiniformes , are eel-shaped, slime-producing marine fish (occasionally called slime eels). They are the only known living animals that have a skull but no vertebral column, ...
possess a protothymus associated with the pharyngeal velar muscles, which is responsible for a variety of immune
In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...
responses.
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
A mouse ( : mice) is a small rodent. Characteristically, mice are known to have a pointed snout, small rounded ears, a body-length scaly tail, and a high breeding rate. The best known mouse species is the common house mouse (''Mus musculus' ...
As in humans, the guinea pig
The guinea pig or domestic guinea pig (''Cavia porcellus''), also known as the cavy or domestic cavy (), is a species of rodent belonging to the genus '' Cavia'' in the family Caviidae. Breeders tend to use the word ''cavy'' to describe the ...
's thymus naturally atrophies as the animal reaches adulthood, 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 cyst
A cyst is a closed sac, having a distinct envelope and division compared with the nearby tissue. Hence, it is a cluster of cells that have grouped together to form a sac (like the manner in which water molecules group together to form a bubble) ...
ic spaces.
Additional images
File:Thoracic cavity of foetus 2.JPG, Thymus of a fetus
A fetus or foetus (; plural fetuses, feti, foetuses, or foeti) is the unborn offspring that develops from an animal embryo. Following embryonic development the fetal stage of development takes place. In human prenatal development, fetal deve ...
File:Radiology 1300566 Nevit.jpg, On chest X-ray
A chest radiograph, called a chest X-ray (CXR), or chest film, is a projection radiograph of the chest used to diagnose conditions affecting the chest, its contents, and nearby structures. Chest radiographs are the most common film taken in med ...
, the thymus appears as a radiodense
Radiodensity (or radiopacity) is opacity to the radio wave and X-ray portion of the electromagnetic spectrum: that is, the relative inability of those kinds of electromagnetic radiation to pass through a particular material. Radiolucency or hypod ...
(brighter in this image) mass by the upper lobe of the child's right (left in image) lung.
References
Books
*
*
External links
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.
{{Authority control
Immune system
Lymphatic system
Lymphatics of the torso
Lymphoid organ
Mammal anatomy
Organs (anatomy)