The Lymphatic System

Learning Objectives of the Lymphatic System

• Enumerate all components of the lymphatic system.

• Classify lymphoid organs into primary and secondary categories.

• Discuss the functional significance of Mucosa-Associated Lymphoid Tissue (MALT).

• Explain the histological and functional differences between primary and secondary lymphoid nodules.

• Compare and contrast the structure and function of various lymphoid organs and tissues.

Overview of the Lymphatic System

• Composition: Consists of groups of cells, tissues, and organs that anatomically support the immune system.

• Connectivity: Lymphoid organs are interconnected via both blood and lymphatic circulation.

• Primary Functions:

  • Monitoring body surfaces and internal fluid compartments.

  • Reacting to the presence of potentially harmful substances (antigens).

Lymphoid Tissue Structure

• Stroma (Supporting Framework):

  • In most cases, it is a network of reticular fibers.

  • Consists of fibroblastic reticular cells.

• Parenchyma (Functional Components):

  • Lymphocytes.

  • Various Antigen-Presenting Cells (APCs).

  • Plasma cells.

• Classification by Organization:

  • Diffuse Lymphoid Tissue: Found within areas of loose connective tissue (CT). It is characterized by having no capsule.

  • Lymphoid Organs: These are surrounded by a capsule of connective tissue. They exhibit strong basophilia due to the abundance of lymphocytes.

Lymphoid Nodules (Follicles)

• Definition: Aggregates of B cells found within various tissues and organs.

• Follicular Dendritic Cells (FDCs):

  • Origin: Mesenchymal origin.

  • MHC Status: These cells do not express MHC class II molecules.

  • Mechanism: They help activate B cells through antigen-antibody complexes that cover their surface and bind to receptors for complement proteins and Ig Fc regions.

• Primary Lymphoid Nodule:

  • Consists of small aggregates of activated B cells organized by follicular dendritic cells.

  • Characterized by uniform cell density and uniform staining characteristics.

  • Activation Note: Not all B cells will be activated; only those that recognize the specific antigen presented by FDCs.

• Secondary Lymphoid Nodules:

  • Germinal Center (GC):

    • Slightly stained central region.

    • Contains large lymphoblasts, specifically centroblasts.

    • Site of Immunoglobulin (Ig) gene recombination, rapid proliferation, and quality control.

  • Peripheral Mantle (M):

    • Basophilic outer ring.

    • Contains naive, non-proliferating B cells.

• Progression and Dispersion:

  • Activated proliferating B cells differentiate into Plasma cells and Memory B cells.

  • After approximately a couple of weeks, the mantle and germinal center cells disperse, and the structure of the secondary nodule is lost.

The Thymus

• Anatomy: A bilobed organ located in the mediastinum.

• Primary Functions:

  • Maturation of T cells.

  • Induction of central tolerance to prevent autoimmunity.

• Development:

  • Derived from the endoderm of the third pair of pharyngeal arches.

  • Invaded by lymphoblasts originating from the bone marrow.

• Life Cycle:

  • Full function is reached at birth and continues through puberty.

  • Puberty marks its involution, where cellularity and T cell output reduce considerably.

Histology of the Thymus

• General Structure:

  • Vascularized capsule of connective tissue.

  • Septa divide the parenchyma into incomplete lobules.

• Lobule Regions:

  • Cortex: Shows stronger basophilia due to greater cellular density.

  • Medulla: Shows slighter basophilia compared to the cortex.

• Major Cells of the Thymic Cortex:

  1. T lymphoblasts (thymocytes): Extremely abundant.

  2. Macrophages.

  3. Thymic Epithelial Cells (TECs): Possess both epithelial and reticular features with large euchromatic nuclei.

Cortical Thymic Epithelial Cells (TECs)

• Type I (Squamous TECs):

  • Form a layer of cells joined by desmosomes and occluding junctions.

  • Line the connective tissue of the capsule and septa and surround vasculature.

  • Function: Form the blood-thymus barrier with pericytes and vascular endothelial cells to prevent exposure of thymocytes to circulating antigens.

• Type II (Stellate TECs):

  • Feature processes containing keratin tonofilaments joined by desmosomes.

  • Possess large euchromatic nuclei.

  • Function as a cytoreticulum supporting macrophages and lymphocytes (since the thymus lacks reticular fibers).

  • Act as APCs expressing MHC class I and MHC class II; secrete cytokines for T cell development.

• Type III TECs:

  • Located between the cortex and medulla.

  • Form a functional corticomedullary barrier through sheet-like cytoplasmic extensions and occluding junctions.

  • Express MHC class I and MHC class II.

Medullary Thymic Epithelial Cells (TECs)

• Type IV TECs:

  • Form a second layer between the medulla and cortex, close to Type III cells.

  • Cooperate with Type III cells to maintain the corticomedullary barrier using sheet-like processes and occluding junctions.

• Type V TECs:

  • Distributed throughout the medulla.

  • Processes are joined by desmosomes to form a cytoreticulum.

  • Support T lymphocytes, dendritic cells, and macrophages.

  • Express specialized proteins affecting other organs and compartmentalize groups of lymphocytes.

• Type VI TECs (Hassall’s Corpuscles):

  • Form isolated masses of concentrically arranged cells unique to the thymic medulla.

  • Characteristic features: Densely packed, flattened nuclei, keratohyaline granules, bundles of intermediate filaments, and lipid droplets.

  • Functional Role: Thought to produce interleukins for thymic differentiation, education of T lymphocytes, control of local dendritic cells, and stimulation of regulatory T cells for peripheral tolerance.

Questions & Discussion: The Blood-Thymus Barrier

• Question: Why do you need to prevent exposure of thymocytes to circulating antigens?

• Reasoning: Thymocytes must undergo positive and negative selection; they need to be trained (educated) first. We must show them our own antigens (self-antigens) to see whether they react.

• Outcome of Selection:

  • If they react to self-antigens during negative selection: They are eliminated via apoptosis.

  • If they do not react: They survive because they do not attack the body's own tissues.

• Conclusion: Preventing exposure to external circulating antigens ensures the thymus only tests for reactions against internal self-antigens, avoiding premature activation.

T Cell Selection Processes

• Positive Selection (Cortex): Allows the survival of only those T cells with functional T-cell receptors (TCRs) that successfully recognize MHC class I and MHC class II molecules.

• Negative Selection (Medulla): Allows the survival of only those T cells that do not bind tightly to self-antigens presented on dendritic cells.

Mucosa-Associated Lymphoid Tissue (MALT)

• Definition: Large collections of lymphoid tissue in the connective tissue of mucosae.

• Components:

  • Lymphocytes (including intraepithelial lymphocytes).

  • Plasma cells (site of IgA secretion).

  • Antigen Presenting Cells (APCs).

• Statistics: Contains $70\%$ of the immune cells in the body. Most are B lymphocytes, though $CD4+$ Th cells are the most abundant T cells.

• Nodular MALT Locations: Tonsils, Peyer patches, and the Appendix.

Specific MALT Structures

• Tonsils: Irregular masses associated with the epithelium of the oral cavity and nasopharynx.

  • Palatine Tonsils: Covered by stratified squamous epithelium; feature $10$ to $20$ deep invaginations called tonsillar crypts. Abundant secondary nodules are present.

  • Lingual Tonsils: Similar to palatine but lack distinct capsules.

  • Pharyngeal Tonsil: Single tonsil covered with respiratory epithelium; has invaginations but lacks true crypts.

• Peyer Patches:

  • Located in the mucosa and submucosa of the ileum (small intestine).

  • Consist of a dozen nodules without a CT capsule.

  • Covered by simple columnar epithelium and specialized epithelial M cells.

  • M cell Function: M cells have apical microfolds (not a brush border) to sample luminal antigens. They possess basal intracellular pockets that host transient populations of lymphocytes and dendritic cells.

  • Mechanism: Antigens pass through M cells to underlying lymphoid tissue; dendritic cells and lymphocytes initiate an adaptive immune response; B cells differentiate into IgA-producing plasma cells; enterocytes transport IgA to neutralize antigens in the lumen.

• Appendix: Contains abundant nodular lymphoid tissue within the submucosa.

Lymph Nodes

• Physical Characteristics: Bean-shaped, encapsulated organs ranging from $10\,mm \times 2.5\,cm$.

• Distribution: Total of $400$ to $450$ nodes, mainly in axillary, inguinal, and major blood vessel regions of the neck, thorax, and abdomen.

• Functions:

  • Filter lymph.

  • Prevent the spread of microorganisms (MO) and tumor cells.

  • Sites for antigen presentation and activation of non-IgA secreting plasma cells.

• Structure:

  • Convex surface with afferent lymphatics (containing valves).

  • Concave depression (hilum) for efferent lymphatics, arteries, and veins.

  • Stroma: Capsule of dense irregular CT, trabeculae, and a reticular supporting network.

Regions of the Lymph Node

• Cortex:

  • Contains lymphoid nodules filled with B cells, FDCs, and macrophages.

  • Subcapsular sinus is located immediately under the capsule.

  • Cortical (trabecular) sinuses are lined by discontinuous endothelium and penetrated by reticulin fibers.

• Paracortex:

  • Deeper extension of the cortex with no nodules.

  • Rich in T lymphocytes.

  • High Endothelial Venules (HEVs): Entrance point for $90\%$ of lymphocytes into the node. Characterized by enlarged or cuboidal endothelial cells with apical surface glycoproteins that facilitate tethering and diapedesis.

• Medulla:

  • Medullary Cords: Branched masses of tissue containing B and T lymphocytes and many plasma cells.

  • Medullary Sinuses: Dilated spaces between cords lined with discontinuous endothelium. They contain a meshwork of reticular cell processes (final filter), many macrophages, and neutrophils (if a bacterial infection is present).

The Spleen

• General Facts: Largest lymphoid organ; located in the left upper abdominal quadrant; size is approximately $12 \times 7 \times 3\,cm$.

• Functions:

  • Exclusively filters blood (no lymph filtration).

  • Main site of erythrocyte (RBC) destruction.

  • Site of antibody production; activated lymphocytes are delivered directly into the blood.

• Stroma: Fine CT capsule, trabeculae (carrying blood vessels and nerves), and reticular tissue.

• Splenic Pulp:

  • White Pulp ($20\%$): Consists of lymphoid nodules and the Periarteriolar Lymphoid Sheath (PALS), which surrounds the central arteriole.

  • Red Pulp ($80\%$): Site of RBC removal. Consists of blood-filled sinusoids and Splenic Cords (of Billroth). Billroth cords contain reticular cells, fibers, B and T cells, macrophages, other leukocytes, and erythrocytes.

Red Pulp Sinusoids and Circulation

• Stave Cells: Unusual endothelial cells lining the sinusoids, oriented parallel to blood flow. They allow for the separation of healthy RBCs from effete (old/damaged) RBCs.

• Sinusoid Structure: Sparsely wrapped by reticular fibers with a highly discontinuous basal lamina.

• Splenic Circulation:

  • Closed Circulation: Blood flows from penicillar arterioles directly into sinusoids.

  • Open Circulation: Blood is dumped from penicillar arterioles into the splenic cords, requiring RBCs to squeeze through stave cells to re-enter the sinusoids.

Histological Comparison Table