Corpus: Thymus

The thymus is a primary lymphoid organ located in the upper mediastinum. It is responsible for the proliferation and maturation of T lymphocytes.

2.1. Macroscopy

The thymus consists of two asymmetrical lobes connected to each other. It is located in the upper anterior mediastinum, extending from the upper edge of the sternum to the cartilage of the 4th rib. The thymus is situated in front of the aorta, superior vena cava, brachiocephalic veins, and pericardium.

The thymus' volume and weight vary in literature. Generally, it weighs about 10 to 15 g in newborns, reaching 35 to 50 g during puberty. Some sources report:

• End of 1st year of life: maximum volume of 27 cm³ and 27 g
• Adolescence: 21 cm³ and 21 g
• Old age: 20 cm³ and 18 g

With age, the thymus undergoes fatty degeneration (thymus involution) and regresses, often becoming macroscopically indistinct in adults, forming the "thymus fat body." The cortex proportion decreases linearly up to age 40, after which the decrease is minimal. Remnants of the cortex and medulla can still be identified in old age.

Three stages of thymus development are distinguished histologically:

• Thymus epithelialis (embryonic stage)
• Thymus lymphaticus (from birth to puberty)
• Thymus adiposus or corpus adiposum retrosternale (after puberty or adulthood)

Hormones influence thymus growth: androgens and estrogens inhibit growth, while somatotropin promotes it. Glucocorticoids reduce thymus cell numbers and volume.

2.2. Vascular supply

The thymus receives arterial blood from the thymic rami of the internal thoracic artery and the inferior thyroid artery. Venous blood drains via thymic veins into the brachiocephalic veins.

Arterial branches penetrate the thymus through connective tissue septa at the medullary-cortical junction, supplying both medulla and cortex. High-endothelial venules in this area facilitate lymphocyte diapedesis. Capillaries in the medulla are permeable to foreign antigens, while the cortex is protected by the blood-thymus barrier, which consists of endothelial cells, perivascular connective tissue, and thymic epithelial cells. The precise function of this barrier is not fully understood.

2.3. Lymphatic vessels

The thymus has no afferent lymphatic vessels. Efferent lymphatics drain from the medulla via connective tissue septa to the mediastinal lymph nodes, allowing mature lymphocytes to exit via blood vessels and lymphatic pathways.

2.4. Innervation

The thymus is innervated by sympathetic fibers from the cervical ganglia of the sympathetic trunk and parasympathetically via the recurrent laryngeal nerve of the vagus nerve. These autonomic fibers penetrate through connective tissue septa to reach blood vessels, lymphatic cells, and thymic epithelial cells, likely mediating neuroimmunological interactions.

The thymus is encapsulated by collagenous connective tissue. In the fetal thymus, a clear division into cortex and medulla is evident. The darker cortex is characterized by special epithelial cells and densely packed immature lymphocytes, which differentiate there. The cortex is divided into pseudolobules by invaginations of the organ capsule.

The lighter medulla contains mature T lymphocytes, macrophages, mast cells, interdigitating dendritic cells, fibroblasts, and epithelial cells. These epithelial cells form Hassall bodies, onion-skin-like structures that likely play a role in regulatory T cell differentiation.

Thymic epithelial cells are classified into cortical (cTECs) and medullary thymic epithelial cells (mTECs), also called reticular epithelial cells (RECs). They have diverse functions critical for T cell maturation, with six types of thymic epithelial cells identified, reflecting different stages of differentiation. The thymus is thus referred to as a lymphoepithelial organ.

Myoid cells, found in the corticomedullary junction, are striated muscle cells whose function remains currently (2022) unclear.

The thymus develops from the endoderm of the 3rd and 4th pharyngeal pouches, with contributions from the ectoderm of the 3rd pharyngeal furrow. The organ capsule and blood vessels originate from mesoderm.

In the 4th embryonic week, the paired tube-like structures of the primordial thymus migrate caudally, losing connection to the pharyngeal pouch by the 6th week. These parts lie adjacent without fusing, and scattered tissue may persist between cervical viscera.

Initially, the thymus is epithelial. By the 8th week, lymphocytic precursors migrate in, derived from the yolk sac, fetal liver, and postnatal bone marrow. Ectomesenchymal cells from the neural crest surround the thymus, promoting epithelial differentiation. Cortex and medulla differentiation begins by the 12th week and is completed by the 17th week. Cortical epithelial cells arise from endoderm, while medullary epithelial cells and subcapsular layers derive from ectoderm.

The thymus is essential for T lymphocyte maturation, differentiation, and elimination of ineffective T cells. During fetal development, lymphocytes from the bone marrow migrate to the thymus for immunological "training," interacting with thymic epithelial cells in a process called thymopoiesis.

Two selection processes occur:

1. Positive selection: Cortical thymic epithelial cells present peptides with MHC molecules to immature T cells. Cells with medium affinity binding receive survival signals, ensuring their maturation into CD8+ or CD4+ T cells. Thymocytes that do not bind or bind weakly undergo apoptosis.
2. Negative selection: Positively selected thymocytes that bind self-antigens are destroyed via apoptosis, mediated by macrophages, dendritic cells, and medullary thymic epithelial cells.

More than 90 % of T cells perish during selection. The surviving naive T lymphocytes leave the thymus via the bloodstream and travel to secondary lymphatic organs (e.g., spleen, lymph nodes) where they participate in immune defense. The blood-thymus barrier prevents exposure to foreign antigens during maturation.

Key factors for T cell maturation include direct cell contact with epithelial cells and T cells, mediated by interleukins and chemokines, and thymic tissue hormones such as thymomodulin, thymostimulin (TP-1), thymopentin (TP-5), thymic serum factor (THF), and thymosins (e.g., thymosin α1, thymosin β4).

Pre-T cells initially lack CD4 and CD8 markers. As they pass through thymic layers, they differentiate and eventually express both markers at the corticomedullary border. After selection, the T cells express only one marker and exit the thymus.

6.1. Diseases

Thymic diseases include:

• Aplasia (as seen in DiGeorge syndrome)
• Thymic dysplasia
• Thymic hyperplasia or hypoplasia
• Thymitis
• Thymoma and thymic carcinoma
• Myasthenia gravis

6.2. Pharmacology

The therapeutic potential of thymic peptide hormones is currently (2022) under clinical investigation.