thymi

Thymus

[thahy-muhs]

In human anatomy, the thymus is an organ located in the upper anterior portion of the chest cavity just behind the sternum. Hormones produced by this organ stimulate the production of certain infection-fighting cells. It is of central importance in the maturation of T cells.

History

The thymus was known to the Ancient Greeks. 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 fine dissection of the function of the thymus in T cell maturation.

Function

In the two thymic lobes, lymphocyte precursors from the bone-marrow become thymocytes, and subsequently 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) or surgical removal 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, therefore, largely degenerated in elderly adults and is barely identifiable, consisting mostly of fatty tissue.

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.
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. Growth factors include thymopoietin and thymosin.
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. 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.

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.

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 in size and may be united or separated.

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.

During the late stages of the development of the thymic epithelium, hematopoietic lymphoid cells from bone-marrow precursors immigrate into the thymus and are aggregated to form lymphoid follicles.

The thymus continues to grow between birth and puberty and then begins to atrophy, a process directed by the high levels of circulating sex 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 cirumstances 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	less than ½ grams

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 in the medulla, 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 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.

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. Symptoms are sometimes confused with bronchitis or a strong cough because the tumor 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.

Other animals and 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 hairless "Skinny pig" breed (which arose from a spontaneous laboratory mutation) it often possesses no thymic tissue whatsoever, and the organ cavity is replaced with cystic spaces.

When animal thymic tissue is sold in a butcher shop or at a meat counter, thymus is known as sweetbread.