Lymphatic system

• Immune system

  Invertebrates have a defense system based mostly on phagocytic cells.  We have developed a more complex immune system that retains the phagocytic system in the form of monocytes/macrophages and neutrophils (as well as some others) – termed the innate immune system.  This form of defense lacks immunological memory.  But vertebrates have added a form of defence, that has high specificity and memory. It is based on the presence of trillions of lymphocytes – termed the adaptive immune system.
• Immune system: Innate immunity (non-specific)

  •Barriers against invasion (skin, mucosa)

  •Chemical defenses (stomach acid, thiocyanate in saliva, lysozyme in tears)

  •Phagocytic cells (macrophages and neutrophils)

  •Complement activated system

  •Extracellular killers (Natural killer lymphocytes and eosinophils)

  The innate immune response provides a rapid reaction to infections and, characteristically, the same magnitude of response each time the same pathogen is encountered i.e. there is no learning in the innate system.
• Immune system: Adaptive (specific) Immunity

  •Humoral (antibody) immunity

  •Cellular immunity

  •Based on lymphocytes + cell surface receptors

  •Ability to distinguish ‘self’ from ‘non-self’ is absolutely critical.

  If non-specific defenses fail the immune system provides specific or adaptive defenses. Initial contact with a foreign antigen initiates a chain of reactions that leads to immune memory and induces acquired resistance against microbial aggression.

  
• Immune system: Adaptive (specific) Immunity

  Two types of specific defenses have been identified humoral response and cellular immune response. The humoral response leads to the production of proteins called antibodies which mark the invaders for destruction by other immune cells while the cellular response targets transformed and virus infected cells for specific killer cells.

  
• Immune system: Adaptive (specific) Immunity

  The adaptive immune system is slower to react, but highly flexible and very specific.  It is based on lymphocytes and a vast array of genetically determined cell surface receptors.  The major role of the adaptive immune system is destruction (e.g. of bacteria) and therefore the ability to distinguish ‘self’ from ‘non-self’ is absolutely critical.  Lymphocytes must not react to self antigens (called immune tolerance). 

  
• Lymphoid System

  •Lymphatic vessels

  •Lymphoid organs

  •Primary

  •Bone marrow

  •Thymus

  •Secondary

  •Spleen

  •Lymph nodes

  •MALT

  •Tonsils

  •Adenoids

  •Peyer’s patches

  
• Lymphoid System

  The extensive lymphoid—or immune—system protects the body against potentially harmful effects of pathogens, foreign substances, infectious agents (bacteria and viruses), and abnormal cells. Its major functions are to serve as a source of immunocompetent cells that can react with and neutralize antigens and to distinguish self from nonself.

  The system is comprised of lymphoid tissues and organs whose main constituents are aggregates of lymphocytes and other cells of the mononuclear phagocyte system.

  
• Lymphoid System

  These cells are enmeshed in a supportive framework (stroma) of reticular cells and fibers, so lymphoid tissue is classified as a specialized reticular connective tissue. Lymphatic vessels are also part of the system.

  Lymphoid organs are classified in functional terms as primary or secondary. The thymus and bone marrow, where immature lymphocytes acquire the receptors to recognise antigen, are known as primary lymphoid tissues.

  
• Lymphoid System

  The spleen, lymph nodes and organised mucosa associated lymphoid tissues or MALT are the secondary lymphoid tissues here lymphocytes are activated in response to antigen . MALT are diffuse subepithelial lymphocyte aggregates and includes the tonsils and adenoids in the oropharynx, Peyer's patches and lymphoid aggregates of the small and large intestines respectively and a diffuse population of lymphocytes and plasma cells in the mucosae of the gastrointestinal, respiratory and genitourinary tracts.

  
• Lymphoid System

  B cells mediate humoral immunity by giving rise to plasma cells, which synthesize antibodies (or immunoglobulins) that inactivate foreign antigens. T cells, in contrast, mediate cellular immunity against microorganisms.

  Immune responses occur in secondary lymphoid organs, such as lymph nodes and spleen. All lymphoid tissue derives embryonically from mesoderm, except for the thymus, which arises from mesoderm and endoderm.

  
• Cells of Lymphatic System

  Lymphocytes come in 3 principal forms:

  Natural Killer cells (NK cells) : kill virus infected cells and some tumour cells.

  B Lymphocytes (B cells): produce antibodies (active in humoral immunity).

  T Lymphocytes (T cells): participate in cellular immunity and are divided into several functional subsets known as T helper (CD4+) cells, cytotoxic T (CD8+) cells and suppressor T cells. These subsets can be identified in often using the immunohistochemistry for cell surface markers and the Cluster Designation (CD) molecules
• Cells of Lymphatic System

  T helper cells (Th cells): 'help' other cells to perform their effector functions by secreting a variety of mediators known as interleukins. Th cells thus provide 'help' to B cells, cytotoxic T cells and macrophages.

  •Cytotoxic T cells (Tc cells): have the ability to kill virus-infected and some cancer cells. They require interaction with Th cells to become activated and proliferate to form clones of effector cells.
• Cells of Lymphatic System

  •Suppressor T cells (Ts cells). may suppress immune responsiveness to self-antigens and possibly switch off the response when antigen is removed. The existence of this functional subset is still controversial.

  •Memory T cells develop from activated T cells to provide a 'rapid reaction force' for a subsequent encounter with the same antigen.
• Identifying cells of the immune system (not just lymphocytes) is often done using immunohistochemistry for cell surface markers termed Cluster Designation (CD) molecules. These are now systematically catalogued.

  
• Lymphocytes: Development and Fate

  B lymphocytes and natural killer (NK) lymphocytes are formed and become mature in the bone marrow and leave that compartment to seed the secondary lymphoid organs and transit through the blood to epithelia and connective tissues. Immature CD4– and CD8– T lymphocyte precursors are transported by the circulation from the bone marrow to the thymus, where they complete their maturation and leave as either CD4+or CD8+ cells.

  
• Primary Lymphoid Organ: Bone Marrow

  Bone marrow is the area where all the lymphocytes originate. In this micrograph we can see the structure of the bone marrow.

  You can see the compact bone of the peripheral part lined by the endosteum on the inner side. As we move towards the marrow cavities we can see the charachteristic cords or islands of hematopoietic cells embedded in a mesh of reticular C.T with the interspersed venous sinuosids containing blood cells

  
• Primary Lymphoid Organ: Thymus

  The thymus is located in the mediastinum and increases in size from birth to puberty.  Thereafter it regresses and becomes more and more fatty.  It has two lobes subdivided by septa (septa are unusual – connective tissue and epithelioreticular cells which have epithelial properties).  The lobules have an outer cortex that is highly cellular (and stains more intensely with H&E) and a less cellular inner medulla.
• Primary Lymphoid Organ: Thymus

  The infant thymus (a) is a lobulated organ invested by a loose collagenous capsule from which short interlobular septa containing blood vessels radiate into the substance of the organ. The thymic tissue is divided into two distinct zones, a deeply basophilic outer cortex and an inner eosinophilic medulla; distinction between the two is most marked in early childhood, as in this specimen. Notice that in each lobule a cortex and a medulla are apparent (unlike many organs where the whole organ is organized into a cortex and a medulla.

  
• Primary Lymphoid Organ: Thymus

  In the middle-aged adult, the thymus (b) is already well into the process of involution, which involves two distinct processes, fatty infiltration and lymphocyte depletion. Fat cells (adipocytes) first begin to appear at birth, their numbers slowly rising until puberty when the rate of fatty infiltration increases markedly. Fatty infiltration of the interlobular septa occurs first, spreading out into the cortex and later the medulla. Thus in the mature thymus islands of lymphoid tissue L are separated by areas of adipose tissue A.

  
• Primary Lymphoid Organ: Thymus

  Lymphocyte numbers begin to fall from about 1 year of age, the process continuing thereafter at a constant rate. Despite this, the thymus continues to provide a supply of mature T lymphocytes to the circulating pool and peripheral tissues. Lymphocyte depletion results in collapse of the epithelial framework. However, cords of epithelial cells persist and continue to secrete thymic hormones throughout life.

  
• Primary Lymphoid Organ: Thymus

  The normal process of slow thymic involution associated with aging should be distinguished from acute thymic involution, which may occur in response to severe disease and metabolic stress associated with pregnancy, lactation, infection, surgery, malnutrition, malignancy and other systemic insults. Stress involution is characterised by greatly increased lymphocyte death and is probably mediated by high levels of corticosteroids; thus the size and activity of the adult thymus are often underestimated if examined after prolonged illness.

  
• Thymus: Cortex

  The thymic cortex is packed with immature and maturing T cells, often called thymocytes. In the outer cortex large lymphocytes (lymphoblasts) divide by mitosis to produce clones of smaller mature T cells. These undergo further maturation as they move deeper into the cortex towards the medulla. It is during this process that (the TCR genes are rearranged) the cells acquire the surface markers or phenotype of mature helper and cytotoxic T cells. Several mitotic figures Mt can be seen in the outer cortex in this micrograph.

  
• Thymus: Cortex

  Cells failing to make these adjustments successfully die by apoptosis and are taken up by pale-stained macrophages Ma at the corticomedullary junction. Note also in this micrograph, a small capillary lined by flattened endothelial cells E entering the cortex from the capsule C. Around the capillary the basement membrane BM of epithelial cells can be discerned at the interface between the thymic framework and supporting tissue elements.

  
• Thymus: Cortex

  The epithelial framework of the cortex is more delicate and finely branched than that of the medulla and the cells cannot be distinguished in this micrograph, being obscured by the mass of lymphocytes.

  
• Thymus: Medulla

  The dominant feature of the thymic medulla is the robust epithelial component Ep. The epithelial cells have large pale-stained nuclei, eosinophilic cytoplasm and prominent basement membranes. A particular feature in the medulla are the lamellated Hassall's corpuscles H that first appear in fetal life and increase in number and size thereafter. These are formed from groups of keratinised epithelial cells and may represent a degenerative phenomenon.

  
• Thymus: Medulla

  Also found in the medulla is a type of antigen presenting cell, known as a thymic interdigitating cell, which expresses high levels of both class I and II MHC proteins. It appears that these cells present normal self-components, self-antigens, to maturing T cells that are coming from the cortex. Any self-reactive T cells that identify themselves by becoming activated are destroyed by apoptosis. This is known as clonal deletion or negative selection. So thymus is the organ where self-reactive T cells are removed, preventing the development of autoimmunity in the body

  
• Thymus: Medulla

  At the end of their journey through the thymus, the mature T cells enter the blood vessels and lymphatics to join the pool of circulating T lymphocytes and finally populate other lymphoid organs.

  
• In the cortex the developing T cells must express the correct surface antigens and recognize self and foreign antigens to survive (this is positive selection).

  In the medulla maturing T cells that recognize self antigens are eliminated (this is negative selection). 

  Only those T lymphocytes which do not show reactivity to self antigens are passed on from medulla to the bloodstream.

  
• Blood Thymus Barrier

  In the thymus, ERCs perform many functions. These reticular cells, called thymic nurse cells, are invested by a basal lamina and form part of the blood-thymus barrier in the cortex. Their cytoplasmic processes, which are linked by desmosomes, support clusters of maturing lymphocytes in the subjacent, intervening spaces of the cortex. The thin processes partially invest the endothelium of continuous (nonfenestrated) capillaries in the cortex. The basal lamina of these reticular cells is often fused with the thick basal lamina of the capillary endothelium.

  
• Blood Thymus Barrier

  Together, these cellular and extracellular structures create a physical barrier that protects immature lymphocytes from foreign blood-borne antigens. This barrier prevents premature exposure of lymphocytes to foreign and self-antigens so that an immune reaction does not occur. By electron microscopy, ERCs contain lysosomes, electron-dense granules, and abundant intermediate filaments, or tonofilaments.

  
• Lymphatic Vessels and Lymph Nodes

  -Drainage of lymph into the vascular system.

  Surveillance of tissue for signs of antigens from foreign invaders such as bacteria.

  -Delivery of absorbed fats from the small intestine into the vascular system via lymphatic vessels (lacteals) in the villi of the small intestine.

  
• Lymphatic Vessels and Lymph Nodes

  Lymph nodes are bean- or kidney-shaped lymphoid organs, 2-20 mm in diameter; 500-600 nodes are found in the body. They are seen along lymphatic vessels, and lymph percolates through them. They occur, often as chains or groups, in strategic regions such as the neck, groin, mesenteries, axillae, and abdomen. Cells of the lymphoid system are found in connective tissues throughout the body and can travel in the bloodstream or in lymphatic vessels—the lymph—draining part of the circulatory system.

  
• Lymph Vessels

  By light microscopy, they are similar to capillaries and veins. Lymphatic vessels have wide distribution in many, but not all, body regions. Originating as blind-ended channels in connective tissue spaces, they are then thin-walled lymphatic capillaries (100 μm in diameter) that anastomose and become larger. Lymphatic capillaries look similar to blood capillaries except that they lack a basal lamina. Small anchoring filaments connect endothelial cells to adjacent collagen fibers and help prevent vessel collapse.

  
• Lymph Vessels

  Lymphatic capillaries are most abundant in connective tissue of the skin (dermis); beneath mucous membranes of the respiratory, gastrointestinal, and genitourinary tracts; and in connective tissue spaces of the liver. These vessels absorb interstitial fluid, which fills the extracellular connective tissue matrix. This fluid and wandering lymphocytes are taken up and added back to the circulation. Like veins, lymphatic vessels have valves and thin walls; contraction of surrounding skeletal muscles causes lymph to move.

  
• Lymph Vessels

  The large lymphatic ducts drain into the subclavian veins, right at the angle junction where the jugular vein and subclavian vein join together.

  
• Secondary Lymphoid Organ: Lymph Node

  -Encapsulated

  -Seeded with B lymphocytes & T lymphocytes

  -Capsule

  -Trabeculae

  -Cortex

  -Paracortex

  -Medulla

  -Subcapsular sinus

  -Filtration of lymph

  -Production of lymphocytes

  -Synthesis of antibodies

  -Recirculation of lymphocytes by selective re-entry

  
• Secondary Lymphoid Organ: Lymph Node

  Lymph nodes are encapsulated, highly organized structures interposed along larger lymph vessels. They derive originally from mesenchyme. During development, specific regions of each node are seeded with B lymphocytes from the bone marrow and T lymphocytes from the thymus. An outer capsule of dense fibrous connective tissue that sends delicate, radiating partitions called trabeculae into the interior of the nodes. These beamlike structures of collagen fibers provide support and serve as conduits for blood vessels supplying the nodes.

  
• Secondary Lymphoid Organ: Lymph Node

  The most common cells of lymph nodes are lymphocytes, macrophages and other APCs, plasma cells, and reticular cells; follicular dendritic cells are present within the lymphoid nodules. The different arrangement of the cells and of the reticular fiber stroma supporting the cells creates a cortex, a medulla, and an intervening paracortex. Note the flow of lymph within these organs, entering via afferent lymphatics on the convex side of the node, passing through unlined sinuses within the lymphoid tissue, and leaving through an efferent lymphatic at the hilum

  
• Secondary Lymphoid Organ: Lymph Node

  Valves in the lymphatic vessels assure the one-way flow of lymph. A small artery and vein are entering and leaving at the hilum and form a capillary network across the node.

  Main functions of lymph nodes are filtration of lymph before its return to the thoracic duct; production of lymphocytes that are added to lymph; synthesis of antibodies (mainly IgG); and recirculation of lymphocytes by their selective re-entry from blood to lymph across walls of specialized efferent lymphatics.

  
• Lymph Node

  The green arrows indicate the circulation pathway of lymphocytes that enter the lymph node with the flow of lymph. Afferent lymphatic vessels carry lymph from the surrounding tissues and neighboring lymph nodes into this elaborate network of lymphatic sinuses. The wall of the sinuses allows lymph to percolate freely into the superficial and deep cortex, allowing lymphocytes to engage in immunosurveillance. The lymphocytes that enter the tissue à migrate back to the sinuses and leave the lymph node with the flow of the lymph.