Thymus

Introduction

The thymus is a primary lymphoid organ located in the anterior mediastinum. It plays a crucial role in the development and maturation of T-lymphocytes, which are essential for adaptive immunity. Its structure and function change significantly from infancy to adulthood.

Anatomy of the Thymus

Location and Gross Anatomy

The thymus is situated in the superior and anterior part of the mediastinum, posterior to the sternum and anterior to the heart and great vessels. In infants and children, it occupies a larger proportion of the thoracic cavity compared to adults.

Size and Shape

The thymus is bilobed and typically triangular or pyramidal in shape. In newborns, it weighs approximately 10-15 grams and gradually increases to about 20-50 grams during puberty. With age, the thymus undergoes involution, decreasing in size and being largely replaced by adipose tissue in adults.

Lobes and Internal Structure

Each lobe of the thymus is divided into multiple lobules by connective tissue septa. Each lobule contains an outer cortex and an inner medulla. The cortex is densely packed with immature T-lymphocytes, while the medulla contains fewer lymphocytes and specialized epithelial structures.

Capsule and Septa

The thymus is surrounded by a thin fibrous capsule that extends septa into the gland, dividing it into lobules. These septa provide structural support and contain blood vessels, lymphatics, and nerves that supply the thymus.

Histology of the Thymus

Thymic Cortex

The thymic cortex forms the outer portion of each lobule and is densely populated with immature T-lymphocytes called thymocytes. It provides a microenvironment that supports T-cell proliferation and early stages of differentiation. The cortex also contains a network of thymic epithelial cells that facilitate positive selection of T-cells.

Thymic Medulla

The medulla occupies the central portion of each lobule and contains fewer thymocytes compared to the cortex. It is rich in epithelial cells, dendritic cells, and macrophages. The medulla is the site for negative selection, where T-cells with high affinity for self-antigens are eliminated to prevent autoimmunity.

Hassall’s Corpuscles

Hassall’s corpuscles are unique structures found within the medulla, composed of concentric layers of epithelial cells. They are thought to play a role in the regulation of T-cell maturation and the induction of regulatory T-cells, contributing to immune tolerance.

Thymic Epithelial Cells

Thymic epithelial cells form a structural framework throughout the thymus and provide essential signals for thymocyte development. Cortical epithelial cells assist in positive selection, while medullary epithelial cells contribute to negative selection and the formation of Hassall’s corpuscles.

Lymphocytes in the Thymus

The thymus contains a large population of lymphocytes at various stages of maturation. Immature T-cells enter the thymus from the bone marrow, proliferate in the cortex, and undergo selection processes in both cortex and medulla before being released as functional, naive T-cells into the peripheral circulation.

Development and Embryology

Origin from the Third Pharyngeal Pouch

The thymus originates from the endoderm of the third pharyngeal pouch during the sixth week of embryonic development. The pouch gives rise to the epithelial component of the thymus, while lymphoid precursors migrate from the fetal liver and bone marrow to populate the gland.

Migration and Differentiation

During embryogenesis, the thymic primordia descend from the neck into the anterior mediastinum. Proper migration is crucial, as ectopic thymic tissue can result from incomplete descent. Once in place, thymic epithelial cells differentiate and organize into cortical and medullary regions to support T-cell development.

Postnatal Growth and Involution

The thymus reaches its maximum relative size during puberty. After this period, it gradually involutes, with lymphoid tissue being replaced by adipose tissue. Despite involution, the thymus continues to produce T-cells, although at a reduced rate, throughout adulthood.

Physiology of the Thymus

T-cell Maturation

The thymus is the primary site for T-lymphocyte development. Immature thymocytes undergo proliferation, differentiation, and selection within the cortical and medullary regions. This process ensures the production of functional T-cells capable of recognizing foreign antigens while maintaining self-tolerance.

Positive and Negative Selection

Positive selection occurs in the cortex, where thymocytes with receptors capable of recognizing self-major histocompatibility complex molecules are allowed to survive. Negative selection occurs in the medulla, eliminating thymocytes that strongly bind to self-antigens, preventing the emergence of autoreactive T-cells.

Thymic Hormones

The thymus secretes several hormones, including thymosin, thymopoietin, and thymulin, which regulate T-cell differentiation and maturation. These hormones also influence peripheral immune responses and contribute to the overall development of the adaptive immune system.

Role in Immune System Development

The thymus is essential for establishing a functional and self-tolerant T-cell repertoire. It supports the development of helper T-cells, cytotoxic T-cells, and regulatory T-cells, all of which are critical for immune defense, immunological memory, and prevention of autoimmunity.

Clinical Significance

Thymic Disorders

• Thymic Hyperplasia: Enlargement of the thymus, often associated with autoimmune diseases or stress, usually asymptomatic but can be detected on imaging.
• Thymoma: Tumor arising from thymic epithelial cells, may be benign or malignant, frequently associated with myasthenia gravis.
• Thymic Cysts: Benign fluid-filled structures that may be congenital or acquired, often incidental findings on imaging.
• Thymic Carcinoma: Rare malignant tumor with aggressive behavior and potential for metastasis, requiring surgical and oncologic management.

Thymus and Autoimmune Diseases

• Myasthenia Gravis: Autoimmune disorder often associated with thymic abnormalities, characterized by weakness of skeletal muscles due to antibodies against acetylcholine receptors.
• DiGeorge Syndrome: Congenital absence or hypoplasia of the thymus, leading to T-cell immunodeficiency and associated cardiac and facial anomalies.

Thymus in Immunodeficiency

• Severe Combined Immunodeficiency (SCID): Genetic disorder resulting in defective T-cell development, often linked to thymic hypoplasia or dysfunction.
• Other T-cell Deficiencies: Conditions that impair thymic function or T-cell maturation, leading to increased susceptibility to infections.

Diagnostic Evaluation

Imaging Studies

• CT Scan: Provides detailed anatomical visualization of the thymus and is useful for detecting masses, hyperplasia, or cysts.
• MRI: Offers high-resolution images without radiation exposure, helpful for distinguishing thymic tissue from surrounding structures.
• Ultrasound: Primarily used in pediatric patients to assess thymic size and structure, as it is non-invasive and radiation-free.

Laboratory Tests

Laboratory evaluation may include immunophenotyping of peripheral blood T-cells to assess thymic output. Specific antibody tests may be performed to detect autoimmune conditions associated with thymic abnormalities, such as myasthenia gravis.

Biopsy and Histopathology

In cases of suspected thymic tumors or unclear imaging findings, tissue biopsy may be performed. Histopathological examination distinguishes between thymoma, thymic carcinoma, cysts, or hyperplasia and guides therapeutic decisions.

Treatment and Management

Medical Management

Medical treatment is primarily directed at associated autoimmune or immunodeficiency conditions. Immunosuppressive therapy, corticosteroids, or symptomatic treatment may be used depending on the specific disorder.

Surgical Approaches

Surgical resection, typically via thymectomy, is indicated for thymomas, thymic carcinomas, and select cases of myasthenia gravis. Minimally invasive techniques, including video-assisted thoracoscopic surgery, are increasingly used for appropriate cases.

Postoperative Considerations

Following thymectomy, patients require monitoring for complications, including infection and respiratory issues. Long-term follow-up includes assessment of immune function, recurrence of thymic pathology, and management of associated autoimmune conditions.

References

1. Moore KL, Dalley AF, Agur AMR. Clinically Oriented Anatomy. 9th ed. Philadelphia: Wolters Kluwer; 2020.
2. Williams PL, Warwick R, Dyson M, Bannister LH. Gray’s Anatomy. 39th ed. London: Elsevier; 2005.
3. Abbas AK, Lichtman AH, Pillai S. Basic Immunology: Functions and Disorders of the Immune System. 6th ed. Philadelphia: Elsevier; 2021.
4. Adams RD, Victor M. Principles of Neurology. 11th ed. New York: McGraw-Hill; 2019.
5. Steinman RM, et al. The Thymus in Health and Disease. Annu Rev Immunol. 2019;37:333-58.
6. Gordon J, Manley NR. Mechanisms of thymus organogenesis and morphogenesis. Development. 2011;138(18):3865-78.
7. Haynes BF, Hale LP, et al. The human thymus during aging. Immunol Rev. 2000;175:57-69.
8. Martins VC, et al. Thymic epithelial cells and T-cell development. Nat Rev Immunol. 2014;14:823-34.