Overview
Immune system
- The immune system provides defense (immunity) against invading pathogens ranging from viruses to parasites. The components of the immune system are interconnected by blood and the lymphatic circulation.
- 2 overlapping lines of defense:
- Innate immunity (nonspecific), involving the following cells:
- Natural killer cells
- Monocytes/macrophages
- Dendritic cells
- Neutrophils, basophils, eosinophils
- Tissue mast cells
- Adaptive immunity (based on specific antigen recognition) involves the following cells:
- T and B lymphocytes (derived from lymphoid organs)
- Antigen-presenting cells
- Innate immunity (nonspecific), involving the following cells:
Lymphatic system
The lymphatic system (lymph vessels, lymph fluid, and lymphoid organs) is part of the body’s immune system.
- Lymphoid organs:
- Primary:
- Locations where lymphocytes develop from progenitor cells (initial formation)
- Include the bone marrow and thymus
- Secondary:
- Sites where lymphocytes undergo activation, proliferation, and additional maturation
- Include the spleen, lymph nodes, and MALT (i.e., tonsils)
- Primary:
- Lymphatic vessels and ducts:
- A network, similar to the blood vessels, that extend throughout the human body.
- Connect lymphoid organs and transport interstitial fluid (lymph)
- Play crucial roles in immune response and fluid balance
Anatomy of the lymphatic system:
Includes the primary (bone marrow, thymus) and secondary (spleen, lymph nodes, and MALT) lymphoid organs
Lymphatic vessels convey lymph to the larger lymphatic vessels in the torso, transporting fluid back to the venous circulation.
Lymph Nodes
Anatomy
- Lymph nodes are kidney-shaped, encapsulated lymphoid organs:
- Afferent lymphatics enter on the convex surface.
- Through the concave depression (hilum):
- The efferent lymphatic leaves.
- An artery, vein, and nerve penetrate the lymph node.
- 2–20 mm in diameter
- 500–600 lymph nodes in the body
- Seen along lymphatic vessels, occur as chains or groups (neck, groin, axillae, mesenteries, abdomen)
Lymph nodes and the lymphatic system
Image: “Blausen 0623 LymphaticSystem Female” by Blausen. License: CC BY 3.0Main functions
The main function of lymph nodes is defense against the spread of microorganisms and tumor cells:
- Filtration of lymph
- Production and recirculation of lymphocytes
- Development of plasma cells secreting antibodies
- Provide closed environments for antigen presentation
General structure
- Outer capsule (dense connective tissue):
- Afferent lymphatic vessels penetrate the capsule.
- Trabeculae extend from the outer capsule toward the center of nodules.
- Blood vessels penetrate through trabeculae.
- Within the capsule:
- Cells:
- Lymphocytes
- Plasma cells
- Dendritic cells
- Macrophages
- Other antigen-presenting cells
- Follicular dendritic cells
- Regions are formed by the cellular arrangements in the stroma of reticulin fibers and reticular cells: cortex, paracortex, and medulla.
- Cells:
Histologic section of a lymph node, identifying the capsule and the trabeculae
Image by Geoffrey Meyer, edited by Lecturio.Functional regions
- Cortex:
- Subcapsular sinus:
- Structure immediately inside the capsule
- Cortical sinuses (or trabecular sinuses) penetrate and branch internally along trabeculae.
- Through these sinuses, lymph (with antigens, antigen-presenting cells, and lymphocytes) passes and seeps into the lymphoid tissue.
- Lymphoid nodules (follicles):
- Primary follicles (inactive): highly packed B cells in reticular fibers
- Secondary follicles (active): have pale germinal centers (site of B-cell proliferation; contains lymphocytes, lymphoblasts, and follicular dendritic cells)
- Subcapsular sinus:
- Paracortex:
- T-cell zone
- Region inside the cortex
- No obvious boundaries but lacks follicles
- High endothelial venules (HEVs):
- The point of entry into lymph nodes for most circulating lymphocytes
- Found primarily in the paracortex
- Medulla:
- Medullary cords:
- Closely packed masses of lymphocytes and plasma cells
- Extend from the paracortex
- Medullary sinuses:
- Dilated spaces that are continuous with the cortical sinuses
- Contain macrophages and a meshwork of reticular cells (final filter)
- Converge at the hilum, turning into the efferent lymphatic vessel
- Medullary cords:
Illustration of a lymph node cross section:
Image: “Illustration of a node cross section” by Royal Society. License: CC BY 4.0, cropped by Lecturio.
Red and blue denote arteries and veins, respectively. Yellow arrows indicate lymph flow.
Af: afferent vessels
Ef: efferent vessels
F: follicle
IS: intermediate sinuses
LL: lymphatic labyrinth
MS: medullary sinuses
SS: subcapsular sinuses
Histologic section of the lymph node showing the cortex, paracortex, and medulla
Image by Geoffrey Meyer, edited by Lecturio.
Structure and functional regions of a lymph node comprising a collagen-rich fibrous capsule and an underlying subcapsular sinus (SCS).
Image: “The structure of the lymph node” by Colbeck, Ager, Gallimore and Jones. License: CC BY 4.0
Cells are segregated into (1) the cortex (consisting of B cells, T follicular helper cells, and follicular dendritic cells arranged in primary follicles, in which B cells survey antigens presented on the follicular dendritic cell stromal network); and (2) the paracortex (accommodates T cells, dendritic cells, and fibroblastic reticular cells, which form stromal cell networks and reticular fibers).
The inner medulla is composed of lymphatic tissues (medullary cords) separated by medullary sinuses consisting of lymph.
Vasculature
- Lymph travels from afferent lymphatics → subcapsular sinus → trabecular sinuses → medullary sinuses → efferent lymphatics
- High endothelial venules (HEVs):
- Endothelium in HEVs has cell adhesion molecules that help in the diapedesis of T cells.
- These venules orchestrate extravasation of lymphocytes into the lymph node.
- After entering the lymphoid tissue, T cells stay in the paracortex and B cells migrate into nodules.
Lymph node vascular structure:
Image: “The lymph node vascular structure” by Jeucken, Koning, Mebius and Tas. License: CC BY 4.0
Consists of blood vessels (BVs), high endothelial venules (HEVs), and lymphatic vessels (LVs).
Blood vessels can be found throughout the whole lymph node, with specialized HEVs located within the T-cell areas. High endothelial venules are specialized BVs that orchestrate extravasation of lymphocytes into the lymph node. Afferent LVs enter the lymph node, where they transit into sinuses that ultimately exit via the efferent LV.
Histologic section of a lymph node showing an afferent vessel
Image by Geoffrey Meyer, edited by Lecturio.
Histologic section of a lymph node showing an efferent vessel
Image by Geoffrey Meyer, edited by Lecturio.
MALT
Anatomy
- Collections of lymphoid follicles beneath mucosal linings that stand guard against antigens
- Lymphoid follicles, similar to lymph nodes, have germinal centers.
- Located in the digestive, respiratory, or urogenital mucosa:
- GI-, or gut-, associated lymphoid tissue (GALT): tonsils, Peyer’s patches, appendix, and lymphocyte infiltrations along the GI tract
- Respiratory: bronchial/tracheal-associated lymphoid tissue (BALT), nose-associated lymphoid tissue (NALT)
- Genitourinary: vulvovaginal-associated lymphoid tissue (VALT)
- Areas commonly invaded by pathogens due to easy entry through lumens open to the external environment
- Contains 70% of the body’s immune cells; B lymphocytes are the predominant cellular population.
Main Function
Mount an immune response against pathogens encountered in the mucosa of the GI, respiratory, and genitourinary tracts.
Structure of the tonsils
- Large and irregular collections of lymphoid tissue within the oropharyngeal cavity
- With a pseudocapsule (made of condensed connective tissue)
- Variable epithelial surfaces, with deep depressions (crypts)
- Waldeyer ring:
- Group of lymphoid tissues in the oropharynx that provide initial protection to pathogens entering via the mouth
- Pharyngeal tonsils:
- Located on the posterior wall of the nasopharynx
- Lined by pseudostratified ciliated columnar epithelium (respiratory epithelium)
- Do not have crypts
- Chronic inflammation can lead to hypertrophied tonsils (and adenoids).
- Palatine tonsils (faucial tonsils):
- Paired tonsils in the lateral oropharynx, posteriorly on the soft palate
- Covered by nonkeratinized stratified squamous epithelium infiltrated with lymphocytes
- With smooth surface and invaginations (crypts) into tonsil parenchyma
- Follicles/nodules are found around the crypts.
- Tubal tonsils:
- Lateral wall of nasopharynx (around the Eustachian tube opening)
- Forms upper lateral aspect of Waldeyer ring
- Covered by pseudostratified ciliated columnar epithelium
- No crypts
- Lingual tonsils:
- Surface of the posterior 3rd of the tongue
- Lined by nonkeratinized stratified squamous epithelium
Tonsils in the oropharyngeal area, front view:
Image: “Blausen 0859 Tonsils&Adenoids” by Blausen. License: CC BY 3.0
Pharyngeal, palatine and lingual tonsilsTonsils in the oropharyngeal area, side view:
Image: “Blausen 0861 Tonsils&Throat Anatomy2” by Blausen. License: CC BY 3.0
Pharyngeal, palatine, and lingual tonsils.
The tubal tonsils (not pictured) are in the area of the nasopharynx.
Cross section of a tonsil (left) and close up of the bottom of a tonsillar crypt (right).
Image by Geoffrey Meyer, edited by Lecturio.
On the right, a lymphatic nodule (activated lymphoid tissue) can be seen very close to the bottom of the crypt.
Structure of Peyer’s patches and MALT in the appendix
- Peyer’s patches:
- The mucosa of the small intestine has many projecting villi.
- Large aggregates of lymphoid nodules in the lamina propria of the distal part of the small intestine (ileum)
- Covered by simple columnar epithelium
- Contain specialized endothelial cells called M (or microfold) cells:
- Have an intraepithelial pocket in the basolateral surface, which is distinctively porous to the populations of lymphocytes and dendritic cells.
- Collect antigens from the intestinal epithelium
- The M cells bind the antigens, which then undergo transcytosis, which exposes the antigens to the immune cells.
- The antigens are taken up by dendritic cells and are presented to T helper (Th) cells.
- Th cells trigger the B cells to differentiate into plasma cells (producing IgA antibodies).
- IgA goes into gut lumen, where the antigen is bound and neutralized.
- Appendix:
- Close-ended, narrow, short projection of the cecum
- Filled with MALT in the mucosa
- Cases of appendicitis can occur with obstructions owing to lymphoid hyperplasia.
Histologic section of the ileum showing Peyer’s patches
Image by Geoffrey Meyer.
Cross section of an appendix:
Image by Geoffrey Meyer.
Lymphoid nodules can be seen reacting to an antigen from the lumen.
Cross section of stomach mucosa showing inactive lymphoid tissue (left) and cross section of intestine mucosa showing active lymphoid tissue (right):
Image by Geoffrey Meyer, edited by Lecturio.
Lymphoid tissues stand guard until they are activated and form nodules, with germinal centers.
Spleen
Anatomy
- The spleen is a coffee-bean–shaped organ located in the LUQ of the abdomen, beneath the diaphragm.
- Anterolateral to the left kidney
- Protected by the 9th–11th ribs
- About 12 x 7 x 3 cm in size
- Hilum (medial surface of the spleen): where the splenic artery and nerves enter and the splenic vein and lymphatics leave
Main Functions
- Site of production of antibodies and activated lymphocytes
- Storage and breakdown of platelets
- Stores mononuclear phagocytes, filtering germs that are in the bloodstream
- Site of destruction of old erythrocytes
Structure
- Capsule:
- Surrounds the spleen
- Outer dense connective tissue
- Trabeculae emerge and penetrate the splenic parenchyma or splenic pulp.
- Red pulp:
- Occupies most of the organ
- Color due to high content of blood cells of all types
- Contains mainly blood-filled splenic cords (of Billroth) and sinuses
- Splenic cords:
- Contain reticular tissue with abundant T and B lymphocytes, macrophages, other leukocytes, and RBCs
- Separated by the sinusoids
- Splenic sinuses:
- Long vascular channels
- Lined by elongated endothelial cells called stave cells (separate healthy from ineffective erythrocytes)
- Cells that cannot pass between stave cells are eliminated by macrophages.
- White pulp:
- Consists mainly of lymphoid nodules and the periarteriolar lymphoid sheaths (PALS)
- PALS:
- T cells with some macrophages, dendritic cells, and plasma cells surrounding central arterioles
- Central arterioles are small branches formed from the trabecular artery.
- Lymphoid nodules:
- Formed when B cells are activated by antigen(s) in the blood.
- Can displace the central arteriole peripherally
- Marginal zone is the region between the white and red pulp where antigen-presenting cells and macrophages catch antigens.
Vasculature
- Arterial supply:
- Splenic artery (hilum) → trabecular arteries → central arterioles (white pulp)
- Branches leave the white pulp → enter the red pulp (penicillar arterioles) and lose the sheath of lymphocytes → capillaries (some have a sheath of antigen-presenting cells)
- Some capillaries from the penicillar arterioles dump blood into the stroma of the splenic cords:
- Plasma and other blood elements return to the vasculature by passing through the stave cells into the sinusoids.
- Functional platelets, leukocytes, or erythrocytes (which are flexible) have no problem reentering the blood vessel.
- Effete erythrocytes cannot enter and are removed by macrophages.
- Blood then leaves the spleen via the splenic vein.
Diagram of the spleen (from left to right):
Image: “Spleen” by OpenStax. License: CC BY 4.0, cropped by Lecturio.
The spleen is a highly vascularized organ in the LUQ of the abdomen.
The hilum is the area where the splenic artery enters and the splenic vein leaves the spleen. A cross section of the spleen would show that the majority of the splenic parenchyma contains the red pulp (filled with all types of blood cells). The white pulp contains mainly lymphoid nodules and the periarteriolar lymphoid sheaths (PALS), which surround the central arteriole.
Cross section of a spleen:
Image by Geoffrey Meyer, edited by Lecturio.
In a gross specimen, the white pulp and red pulp can be identified and differentiated owing to their difference in color and placement. White pulp agglomerates around blood vessels, while red pulp makes up the rest of the parenchyma.
Histologic section of the spleen:
Image by Geoffrey Meyer, edited by Lecturio.
The periarterial lymphoid sheath (PALS) engulfs a central arteriole. A lymphoid nodule has formed, surrounded by T cells, indicating that an antigen was detected in the splenic blood supply and an immune response was initiated.
Clinical Relevance
- Hodgkin lymphoma (HL): malignancy of B lymphocytes originating in lymph nodes. The pathognomic histologic finding of HL is a Hodgkin Reed-Sternberg (HRS) cell (giant multinucleated B cell with eosinophilic inclusions). The disease presents most commonly with lymphadenopathy, night sweats, weight loss, fever, and at times, splenomegaly and hepatomegaly. Diagnostic testing includes lymph node histologic analysis showing HRS cells. Hodgkin lymphoma is managed with chemotherapy and radiotherapy.
- Tonsillitis: inflammation of the pharynx or pharyngeal tonsils, thus also called pharyngitis. An infectious etiology in the setting of tonsillitis is referred to as infectious pharyngitis, caused by viruses (most common), bacteria, or fungi. Among the bacteria, group A hemolytic Streptococcus is the most frequent cause. Testing for group A streptococcal (GAS) infection in the setting of tonsillitis is essential, as this infection can lead to rheumatic fever and glomerulonephritis in children and adolescents. Antibiotic treatment is recommended in a confirmed GAS infection for this population.
- Splenomegaly: enlargement of the spleen. Splenomegaly is a clinical finding that may be seen in disorders like lymphoma, infectious mononucleosis, sepsis, and rheumatic diseases. Splenic congestion (which can occur in the setting of liver cirrhosis) and splenic tumors are possible causes of splenomegaly.
- Appendicitis: inflammation of the vermiform appendix. In young patients, lymphoid tissue underneath the mucosa undergoes a process of hyperplasia (increase in the number of cells) that can cause obstruction of the lumen and initiate inflammation.
References
- Grethlein, S. (2019). Mucosa-associated lymphoid tissue lymphomas (MALTomas). Medscape. Retrieved July 9, 2021, from https://emedicine.medscape.com/article/207891-overview
- Mescher, A.L. (Ed.). (2021). The immune system & lymphoid organs. In: Junqueira’s Basic Histology Text and Atlas, 16th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=3047§ionid=255121636
- Panneerselvam, D., Budh, D.P. (2021). Peyer Patches. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK557457/
- Scoville, S., Caligiuri, M.A. (2021). The organization and structure of lymphoid tissues. In: Kaushansky, K., et al. (Eds.), Williams Hematology, 10th ed. McGraw-Hill. https://accessmedicine.mhmedical.com/content.aspx?bookid=2962§ionid=252523494
