The human body operates under strict homeostatic rules that must be maintained in order to support the physiological activity of the multiple organ systems working together. Therefore, it is necessary that a system be implemented to prevent foreign organisms from invading the body and disrupting this highly regulated environment.
The immune system can be considered as the host’s resident army. It is responsible for preventing a foreign invasion mounted by any of the myriad of microorganisms that exist. In addition to that, the immune system also protects the body against elements of itself that deviate from the norm.
While production of these immune cells primarily occurs in the bone marrow, education of a special lineage of immune cells takes place in the thymus. The focus of this article will be to discuss the histological architecture of the structure and evaluate the clinically significant points associated with it. Further discussion will cover the embryological development and briefly review the anatomy of the organ.
- Histological architecture
- Thymic education program
- Clinical significance
Development of the head and neck not only involves the development of the externally visible structures, but also those encased within that region as well. This portion of the human body originates from lateral and paraxial plate mesoderm (somites), ectodermal placodes, and the neural crest. Between the fourth and fifth weeks of gestation, mesenchymal tissues arranged in bulging bars are formed. These pharyngeal arches are partitioned by indentations known as pharyngeal clefts. As both these structures arise, outgrowths known as pharyngeal pouches also appear in the lateral pharyngeal walls; cranial to the foregut.
Moreover, there are:
- five pharyngeal arches (numbered on to six; five is omitted)
- four pharyngeal pouches (numbered one to four)
- four pharyngeal clefts
The arches give rise to bones, muscles and corresponding neurovasculature; and only one pharyngeal cleft differentiates into a recognizable anatomical structure (first pharyngeal cleft differentiates into the external auditory meatus). The pharyngeal pouches, however, give rise to organs within the neck, components of the middle ear and tonsils.
The ventral endoderm of the third pharyngeal pouch differentiates into the thymus. It should be noted that the thymus first appears indistinguishable from the nearby inferior parathyroid buds that arise from the dorsal endoderm of the third pharyngeal pouch. The diverticula representing the thymus progressively grow into cellular structures that are connected only by connective tissue. The developing thymus descends from the neck into the anterior thoracic cavity, pulling the inferior parathyroid with it towards its caudal location in the anterior neck. Modulation of thymic development is also dependent on the cardiac neural crest mesenchyme that is encompassed by thymic tissue. Deficit in these cell lines can result in syndromic abnormalities with significant complications for affected patients.
Histologically, there are two general cell lines of interest in the thymus. There are thymic epithelial cells as well as lymphoid cells. The thymic epithelium is important in the maturation and development of lymphoid cells that migrate into the thymus during intrauterine angiogenesis. These lymphoid progenitor cells are able to access the thymus by the 10th week of gestation. Blood vessels and nerves project through the mesenchymal septae to access the medulla of the thymus in week twelve of gestation. A well differentiated thymus is observed in its final destination by the 12th gestational week.
The thymus is an encapsulated primary lymphoid organ. Histologically, it is divided into subcapsular cortical, cortical and medullary regions within each lobule, created by the intervening connective tissue septae extending from the capsule.
Gross cross sectional dissection of the thymus reveals a darker cortical region that is more peripheral to the lighter medullary compartment. The variation in colour intensity is attributed to the density of the thymocytes in each respective area. Therefore, the darker cortex has more T – lymphocytes when compared to the lighter medulla.
There are two major categories of cells within the thymus. These are the thymic epithelial cells and thymocytes. The thymic epithelial cells are endodermal derivatives of the third pharyngeal pouch that further differentiates into specialized epithelium within the cortex and medulla. Overall, these cells are characterized by an eosinophilic cytoplasm containing intermediate filament bundles with pale, ovoid nuclei.
Cortex and cell types
The superficial subcapsular cells are arranged as a continuous squamous sheath that follows the visceral contours of the capsule; even extending within the septae into the lobules and surrounding the vascular beds within it. The cell membranes are tightly held together by desmosomes and occluding junctions. The squamous thymic epithelial cells, along with pericytes and vascular epithelium, form the blood thymus barrier. With this barrier in place, the likelihood of exposing thymocytes to improper antigens is greatly reduced.
Deep to this layer of cells, within the cortex, are stellate thymic epithelial cells that are filled with keratinized tonofilament anchored together by desmosomes. This architectural arrangement gives rise to the cytoreticulum of the cortex. The cytoreticulum is analogous the collagenous reticular network observed in other lymphoid tissue. They both facilitate attachment of maturing lymphocytes and surrounding macrophages.
Cytoreticular cells are antigen presenting cells (APC) that express both class I and class II major histocompatibility complex (MHC I and MHC II) proteins that participate in the thymic education program. They also release cytokines that help to create the microenvironment necessary for thymic education.
An inner layer of squamous cortical thymic epithelial cells that are MHC I positive extends into the lobules of the thymus and forms the corticomedullary barrier. This functional partition separates the outer cortex from the inner medulla.
Medulla and cell types
Within the medulla, there is a second layer of squamous thymic epithelial cells that reinforces the corticomedullary barrier. The medulla also has a cytoreticulum that provides a similar microenvironment for resident dendritic cells, macrophages and more mature thymocytes.
Unique to the thymic medulla is a concentric congregation of thymic epithelial cells known as Hassall corpuscles. They are responsible for the release of cytokines that regulate dendritic activity. Other theories propose that they also remove apoptotic thymocytes. This is supported by the presence of cellular debris at the centre of the whorls that are particularly eosinophilic and partially keratinized. Furthermore, they program a special subset of thymocytes – the regulatory T-cells – that facilitate peripheral tolerance. Throughout the parenchyma of the thymus, as many as 50 thymocytes may be associated with large epithelial cells known as thymic nurse cells.
Other cell types
There are other non-thymic and non-lymphocytic cell lines that are located at different parts of the thymus based on their role within the gland. The myelogenous cell line includes dendritic cells, macrophages and monocytes. Fibroblasts are found mostly around the vessels as well as in the capsule and medulla. They are responsible for the production of collagenous material and other connective tissues that provide structural support of the gland. The monocytes are predominantly seen at the corticomedullary junction. They will differentiate into mature macrophages that are seen in both the cortex and medulla. However, they are more abundant in the cortex where they remove cellular debris.
The dendritic cells are also found at the corticomedullary junction as well as in the medulla. They are the antigen presenting cells that help with the thymocytes’ maturation. Large, circular cells with a centrally located nucleus and haphazardly arranged myofilament are found mostly in the medulla. These myoid cells are rarely seen, however.
Thymocytes are also referred to as T-lymphocytes or T-cells for short. They enter the thymus during intrauterine life. Premature T-cells or small thymocytes are primarily found in the cortex and are tightly packed between the cytoreticulum. In addition to the squamous thymic epithelial cells that occupy the subcapsular zone, there are also mitotic lymphoblasts and thymic stem cells residing in this area as well. Lymphoblasts are mononuclear, large and agranular. They differentiate into prolymphoblasts, which eventually form lymphocytes.
Let’s review the general histology of the thymus:
- There are three subtypes of epithelial cells in the cortex:
- Squamous thymic epithelial cells are important in the formation of the thymus blood barrier.
- Stellate thymic epithelial cells that form the cytoreticulum.
- Other squamous thymic epithelial cells that form the corticomedullary barrier.
- There are three subtypes of epithelial cells in the medulla:
- The squamous thymic and stellate thymic cells of the medulla have similar functions to their counterparts in the cortex.
- Hassall corpuscles.
- Other non-thymic, nonlymphoid cells include:
- Myeloid cells include monocytes, macrophages, and dendritic cells,
- Fibroblasts facilitate the production of collagenous material,
- The rarely observed myoid cells are believed to facilitate migration of lymphoid tissues across the thymus.
Thymic education program
Early T-lymphoblasts that enter the thymus do not express T-cell receptor proteins (TCR) or cluster of differentiation 4 or 8 (CD4 or CD8) proteins. Within the cortex, as the cells replicate, there is activation of the T-cell receptor alpha and beta (TCR- α and TCR-β) genes that result in the phenotypic expression of the receptor proteins. They also result in the expression of both CD4 and CD8 surface proteins.
Following this activation, the thymocytes must undergo further testing to ensure that receptor binding is effective and selective. Within the cortex, cytoreticular cells present MHC I and MHC II proteins to the maturing thymocytes. The TCR proteins that bind to MHC I will predominantly express CD8 proteins at the end of the thymic education program (i.e. cytotoxic T-lymphocytes). Similarly, those that bind to MHC II will express CD4 proteins at the end of maturation (i.e. helper T-lymphocytes). If the binding is successful, then the maturing lymphocytes would have passed the positive selection test and migrate into the medulla of the thymus. However, if binding fails, the cells will undergo apoptosis.
T-lymphocytes that make it to the medulla are capable of binding MHC I and MHC II proteins. However, it is important that the binding is not indiscriminate and that these cells do not bind to self-antigens. Therefore, a wide variety of tissue-specific antigens are expressed by medullary thymic epithelial cells through activation of the autoimmune regulator (AIRE) gene. The antigens produced by these cells are also transferred to adjacent dendritic cells that, along with the medullary thymic endothelial cells, will present self-antigens to the developing T-lymphocytes. If the T-lymphocytes bind to the self-antigen, then they will undergo apoptosis. The 2% of T-lymphocytes that do not bind to the self-antigen will be able to leave the thymus and carry out their functions in the periphery. From start to finish, the thymic education program takes approximately 2 weeks to be completed.
Characteristics and location
The bi-lobar thymus is a primary lymphatic endocrine gland found in the anterior mediastinum. It is enclosed by a capsular membrane that also fuses with the connective tissue that joins the left and right lobes. The organ is soft, and its shape is influenced by the surrounding structures. In relation to the size of the body, it is largest at birth, measuring up to 6 cm x 5 cm by 1 cm in length, width and thickness, and weighing approximately 10 to 15 grams.
The left lobe has been noted to be thicker than the right (11 mm to 9 mm, respectively). However, with advancing age, the thickness decreases to about 5.5 mm. Elongation of the organ is also seen throughout childhood. As the patient ages, the thymic composition changes and the lymphoid parenchyma is replaced by adipocytes. This is a characteristic feature of the thymus known as thymic involution or atrophy, and usually begins at the start of puberty.
The mediastinum is an intrathoracic space that is divided into superior and inferior portions. The inferior segment is further subdivided into anterior, middle and posterior compartments. The thymus gland extends across the superior as well as the anterior part of the inferior mediastinum. There are several key structures that are in close proximity to the thymus that can prove problematic if injured during a thymectomy.
The most superior poles of the thymus project above the suprasternal notch, with the left lobe being higher than the right lobe. In cases where the left lobe extends towards the inferior pole of the thyroid gland, it becomes attached to the lower pole of the thyroid gland via the thyrothymic ligament. The most caudal part of the organ extends as far as the fourth costochondral joint. At this level, the right lobe can be located to the right of the right lung and ascending aorta, with the superior vena cava seen posteriorly.
The structures anterior to the thymus in the superior mediastinum include the:
- investing neck fascia
- manubrium sterni
- the three most superior costochondral joints
- sternohyoid muscle
- sternothyroid muscle
- the internal thoracic arteries and veins
The phrenic nerves course along the anterolateral surface of the thymus and continue caudally toward the diaphragm. The parietal pleurae of the lungs constitute the lateral borders for the thymus. The anterior cardiac surface along with its great vessels, as well as the proximal trachea, is posteriorly related to the thymus.
Arterial supply to the thymus is provided by derivatives of the inferior thyroid and internal thoracic vessels. The superior thyroid artery provides a branch to the thymus as well. The vessels will enter each lobe of the thymus through their respective interlobular septa. Subsequently, they will enter the thymic parenchyma via the corticomedullary junction. In other cases, the branches may directly pierce the thymus to enter the parenchyma.
Venous tributaries leave the medial surface of each lobe and coalesce into common trunks. These trunks will eventually drain directly into the superior vena cava. More commonly, the trunks drain to the internal thoracic, inferior thyroid and left brachiocephalic veins.
The thymus is unique in that it does not have afferent lymphatic vessels entering it. The efferent lymphatics emerge from the corticomedullary junction, as well as the medulla itself. The vessels traverse the extravascular compartment with the thymic vasculature. They then terminate in parasternal, tracheobronchial and brachiocephalic lymph nodes.
The prenatal thymus is innervated by the vagus nerve prior to its decent into the mediastinum. Subsequently, after descending into the mediastinum, sympathetic branches of the stellate (cervicothoracic) ganglion enter the gland by way of the interlobular septa, alongside the vascular structures. Each lobe of the thymus is therefore pierced medially, laterally and dorsally. The derivatives of the sympathetic and vagus nerves ramify in the corticomedullary junction.
A dysfunctional thymus is often associated with autoimmune disorders and an immunocompromised state. There is quite an array of disorders associated with the thymus. These include, but are not limited to, hypoplastic and hyperplastic thymus, neoplasms of the thymus and syndromic anomalies associated with thymic dysfunction.
Thymic neoplasia includes carcinoid masses, lymphomas as well as germ cell tumors. However, they are not all referred to as thymomas. The term thymoma is reserved for thymic masses that are made up of thymic epithelial cells and their associated small thymocytes. This disorder is rarely seen in children, and most often present in patients older than 40 years old. There is no gender or racial redisposition noted to date.
The tumors are usually found in the anterosuperior mediastinum. However, it can also be included as a differential for an anterior neck mass as it has been observed in the neck, adjacent to the thyroid gland.
The majority of patients present with symptoms relating to a mass effect (i.e. compression of neighbouring structures resulting in complications); others are discovered incidentally during routine workup for myasthenia gravis. The association between thymomas and myasthenia gravis, as well as other autoimmune disorders (i.e. Graves’ disease, pernicious anaemia, pure red cell aplasia, dermatomyositis and polymyositis) is based on the concept that the thymomas contain a lot of immature thymocytes and the changes in the architecture interrupts normal education. It is also possible that there is disturbance of the thymus-blood barrier and self-antigen binding thymocytes can still escape into the medulla and eventually , the general circulation.
They can be classified into non-invasive thymoma, invasive thymoma, and thymic carcinoma. Half of the cases of thymomas are non-invasive and are composed of medullary type thymic epithelial cells, or mixed with both medullary and cortical thymic epithelial cells. The medullary type resembles the normal thymic medulla and therefore contains fewer thymocytes. As a result, they are less likely to become infiltrative (i.e. breaching the capsule). The invasive subtypes are locally invasive and are defined as thymomas that penetrate the capsule into surrounding structures. There can be a mixture of thymocytes, with atypical cells; suggesting an aggressive tumour. The most aggressive form is fortunately the least common. The thymic carcinomas often metastasize to the lungs and are composed of lymphoepithelioma-like carcinoma. Histologically, they resemble nasopharyngeal carcinomas; that is, they have indistinct boundaries and are arranged in sheets of cells.
Another cause of an enlarged thymus is thymic hyperplasia. It is characterized by thymic follicular hyperplasia, i.e. the presence of B-lymphocytes in the thymus. Not only is this occasionally a feature of myasthenia gravis, but it can also be seen in chronic inflammatory conditions as well (including, but not limited to systemic lupus erythematosus, scleroderma and rheumatoid arthritis).
Hypoplasticity and DiGeorge syndrome
In addition to the causes of an increase in the size of the thymus, a prominent cause of a hypoplastic thymus can be observed in DiGeorge Syndrome. A microdeletion of sub-band 2, band 1, region 1 of the long arm of chromosome 22 (i.e. Chr 22q11.2) results in a constellation of symptoms including velocardiofacial defects, parathyroid dysfunction and underdevelopment of the thymus. Consequently, the patient experiences a spectrum of immunodeficiencies, as well as possible autoimmune complications.
The immunodeficiency arises because of defective T-lymphocyte maturation. This also results in poor B-cell maturation as T-helper cells also participate in B-cell growth. A series of autoimmune complications have been observed among patients with DiGeorge syndrome that were not seen in patients of similar ages without the chromosomal deletion. These disorders include autoimmune, haemolytic anaemia, idiopathic thrombocytopenic purpura and juvenile rheumatoid arthritis.
These patients often have an associated suppression of the AIRE gene. Consequently, negative selection in the medulla will be inadequate and the resulting T-cells will bind indiscriminately to self-antigens. While the majority of patients with DiGeorge syndrome developed from a spontaneous mutation, a small fraction of patients inherited the disease.