Lymphatic system

The lymphatic system is part of the adaptive immune system as well as the circulatory system and comprises the thymus and bone marrow (primary lymph organs); mucosa-associated lymphatic tissue (MALT), the spleen, and the lymph nodes (secondary lymphatic organs); the lymphatic vessels and capillaries; and the lymph fluid. The primary function of the lymphatic system is to return excess interstitial fluid and waste products, such as proteins and cellular debris, to the bloodstream. The interstitial fluid is absorbed by lymphatic capillaries throughout the body via diffusion. The lymph fluid is then transported through the network of lymphatic vessels and lymph nodes to the right lymphatic duct, which drains into the right subclavian vein, and the thoracic duct, which drains into the left subclavian vein. Its secondary function is immune defense, which mainly involves the transport of leukocytes (esp. lymphocytes) between the bone marrow and the lymph nodes and the stimulation of immune response through the transport of antigen-presenting cells to the lymph nodes. Another function is the transport of fats as chyle from the digestive system to the bloodstream. Accordingly, lymph fluid is transparent when initially formed from the interstitial fluid but adopts a milky appearance as it accumulates proteins, fats, cellular debris, and leukocytes.
The lymph nodes are the main sites for lymph filtration and the storage of lymphocytes, including B cells, which mature and differentiate in the bone marrow, and T cells, which likewise form in the bone marrow but migrate to the thymus for maturation. Antigen presentation induces the differentiation and proliferation of B lymphocytes and the activation of T lymphocytes. Following antigen presentation, mature lymphocytes differentiate into effector cells in the secondary lymph organs. Lymph node clusters exist throughout the body, some of which are palpable (e.g., cervical lymph nodes) while others are not (e.g., mediastinal lymph nodes). They may become enlarged in response to inflammatory processes due to local infection, malignancy, or granulomatous disease.

Lymphocytes form and mature in the primary lymphatic organs (the bone marrow and thymus). Both B lymphocytes and T lymphocytes arise from hematopoietic stem cells in the bone marrow. While B lymphocytes remain within the bone marrow during the process of maturation, T lymphocytes migrate to the thymus to mature and differentiate.

Bone marrow

• B lymphocytes and T lymphocytes originate from pluripotent stem cells in the bone marrow.
  • T lymphocytes migrate to the thymus to mature and differentiate.
  • B lymphocytes mature in the marrow and migrate to secondary lymphatic organs to form follicles and proliferate.

Bone marrow: B cell maturation; Thymus: T cell maturation

Thymus

• Function: maturation and differentiation of T lymphocytes
• Location
  • Superior anterior mediastinum
  • Retrosternal, precordial
• Structure: bilobar organ surrounded by a fibrous capsule
  • Neonates and infants
    • The largest and most active thymus
    • A prominent thymic shadow can be seen on chest x-ray (thymic sail sign).
    • Involution begins at 1 year of age. ^[1]
  • Adults
    • Atrophic, mostly replaced by fatty tissue
    • Thymus undergoes age-related thymic involution.
• Histology
  • Thymic epithelial cells, dendritic cells, and macrophages
  • Thymic cortex
    • Peripheral region
    • Dark
    • Densely packed, immature T lymphocytes (thymocytes)
  • Thymic medulla
    • Central region
    • Light
    • Fewer cells: mature T lymphocytes and Hassall corpuscles that consist of concentrically arranged eosinophilic reticular cells (onion-like appearance)
• Embryology
  • Thymus epithelium arises from the 3^rd pharyngeal pouch (endoderm).
  • Thymic lymphocytes originate from the mesoderm.
• Clinical significance
  • Thymic hypoplasia or aplasia: DiGeorge syndrome, SCID
  • True thymic hyperplasia : secondary to steroid therapy, chemotherapy
  • Thymic lymphoid hyperplasia : certain autoimmune diseases (e.g., myasthenia gravis, SLE, and rheumatoid arthritis)
  • Thymoma: tumor of thymic epithelial cells
    • Seen in the context of myasthenia gravis, pure red cell aplasia, immunodeficiency with thymoma
    • An asymptomatic thymoma is usually detected as an incidental finding on a chest x-ray, where it appears as an anterior mediastinal mass.
    • Symptomatic thymomas typically manifest in individuals 40–60 years of age with thoracic symptoms (e.g., chest pain, cough, dyspnea, SVC syndrome) or paraneoplastic syndromes.
    • Treatment: options include surgery, chemotherapy, and/or radiotherapy.
  • Thymic carcinoma: more aggressive than thymoma (mediastinal invasion and extrathoracic metastasis)

The Thymus arises from the Third pharyngeal pouch.

DiGeorge syndrome is caused by abnormal development of the 3^rd and 4^th pharyngeal pouches, which prevents the formation of thymus and parathyroid glands. As a result, patients with DiGeorge syndrome have an increased susceptibility to hypocalcemia and viral and fungal infections.

The secondary lymphatic organs are the spleen, lymph nodes, and mucosa-associated lymphatic tissue (e.g., the Peyer patches and tonsils). It is in the secondary lymphatic organs that antigen presentation occurs. They are also the site of differentiation of mature, naive lymphocytes into effector cells.

Spleen

• Function
  • Filtration of old or misshapen RBCs and platelets
  • Vital role in forming and initiating a humoral immune response through B and T lymphocytes
  • See “Spleen” for more information.
• Location
  • Underneath the left part of the diaphragm
  • Close to the left kidney (anterolateral)
  • Behind the ninth, tenth, and eleventh ribs
• Structure
  • White pulp is responsible for antigen filtration and presentation, and contains the following structures:
    • Lymphoid follicles: house large numbers of B lymphocytes
    • Periarteriolar lymphatic sheath: contains T lymphocytes
  • Red pulp: responsible for blood filtration

Lymph nodes

Function

• Nonspecific lymph filtration: macrophages within lymph node
• Storage and circulation of B cells and T cells
• Immune system activation: Antigen presentation induces differentiation and proliferation of B lymphocytes and activation of T lymphocytes.

Location

• Throughout the body in close proximity to organs and large vessels
• See “Lymph nodes clusters” below.

Structure

• Bean-shaped organ; surrounded by fibrous capsule with trabeculae
• The trabecular sinus leads lymph from the subcapsular sinus to the medullary sinus.
• The hilus
  • Allows blood vessels and efferent lymphatic vessels to enter or leave the lymph node
  • Typically, only one or a small number of efferent lymphatic vessels leave the lymph node, compared to the larger number of afferent lymphatic vessels that enter the lymph node through the cortex.
• The entering artery and vein branch into a large capillary network, which forms the post-capillary high endothelial venules.

Histology

• Cortex (B-cell zone): contains lymphoid follicles, which is the site of B lymphocyte storage, differentiation, and proliferation
  • Secondary lymphoid follicle (active): dense mantle zone; surrounding a pale germinal center
  • Primary lymphoid follicle (inactive): dense aggregates of naive B lymphocytes
• Paracortex (T-cell zone)
  • Region between the cortex and medulla
  • Contains T lymphocytes and high endothelial venules, which allows circulating B and T lymphocytes to enter or leave the bloodstream
  • Site of T-cell activation
• Medulla
  • Medullary cords: tightly packed with plasma cells and lymphocytes
  • Medullary sinus of the lymph node
    • Composed of macrophages, reticular cells
    • Connected to the efferent lymphatic structures

Clinical significance

• Inflammatory or immune reactions (e.g., due to EBV infection) → reactive paracortical hyperplasia → clinically apparent lymphadenopathy (see “Lymphadenopathy”)
• Depletion of paracortical lymphocytes: DiGeorge syndrome

Mucosa-associated lymphoid tissues (MALT)

MALT include the tonsils, Peyer patches, and solitary lymphoid follicles of the mucosa; . The structure of MALT resembles that of other secondary lymphatic organs but it is also composed of a specialized reticular epithelium (follicle-associated epithelium) with a humoral defense mechanism . The follicle-associated epithelium of the gut-associated lymphatic tissue (GALT) contains M cells, which allow transcytosis of antigens into the lamina propria.

Peyer patches

• Function
  • Immune system activation in response to ingested pathogens
  • M cells transport antigens from the intestinal lumen to antigen-presenting cells (e.g., macrophages) → B cells within the germinal center detect antigens and differentiate to plasma cells that secrete IgA → IgA acquires a secretory component and becomes secretory IgA → secretory IgA is transported across the intestinal epithelium and secreted on the luminal surface of the gut
• Location: ileum (lamina propria and submucosa)
• Histology
  • Aggregates of lymphoid follicles: contain numerous lymphocytes and dendritic cells
  • Follicle-associated epithelium : site of specialized M cells

Tonsils

• Function: Waldeyer tonsillar ring (first line of defense against inhaled or ingested pathogens)
• Structure: similar to other secondary lymphatic organs
• Location and histology

Inducible bronchus associated lymphoid tissue (iBALT) ^[2][3][4]

• Location: walls of the upper and lower respiratory tracts (in the perivascular spaces)
• Function: immune system activation in response to antigens encountered in the upper and lower respiratory tracts following inflammation or infection
• Structure and histology
  • Central, large B-cell follicles with or without adjacent T-cell areas
  • Numerous follicular dendritic cells
  • Contains specialized stromal cells, lymphatics, and high endothelial venules
  • Lacks an M cell-containing dome epithelium

Overview

• Lymph
  • Drained by the lymph capillaries from body tissues, then circulates through lymphatic vessels and secondary lymphatic organs
  • Lymph reenters blood circulation via the thoracic duct and right lymphatic duct.
• Chyle (lymph and triglycerides) is taken up from the intestine during digestion and conveyed by the thoracic duct to empty into the venous system.
  • Thoracic duct
    • Drains lymph fluid from all body sections except for the right arm, the right side of the thorax, and the right head and neck region (including the left side of the thorax and upper limb)
    • Cisterna chyli; : a dilated lymphatic sac that lies near the left crus of the diaphragm, from which the thoracic duct arises ^[5]
    • The thoracic duct continues from the cisterna chyli, ascends the posterior mediastinum (thoracic aorta to its left), and empties into the left venous arch (junction of the left subclavian vein and left internal jugular vein).
    • Drains up to 4 liters of lymph per day
    • Injury to the thoracic duct may result in chylothorax.
  • Right lymphatic duct
    • Drains lymph fluid from the right arm, the right side of the thorax, and the right head and neck region.
    • Originates from the junction of the right subclavian trunk, the right bronchomediastinal trunk, and the right jugular trunk
    • Empties into the right venous arch (junction of the right subclavian vein and right internal jugular vein)

Lymph node clusters

Palpable lymph nodes

Head and neck

Upper extremity

Abdomen and lower extremity

The testicles, epididymis, and seminal ducts are drained by the deep, iliac, and lumbar lymph nodes.

Nonpalpable lymph nodes ^[7][8]

Thoracic

Abdominal

Pelvic