Lymphocytes, especially T-cells, wander throughout the body even crossing basement membranes to wander among epithelial cells. They are classed as connective tissue cells and wherever they congregate, except in the thymus, they associate with reticular fibers forming reticular connective tissue. Lymphoid tissues, sites with large numbers of lymphocytes, vary in their degree of organization from diffuse concentrations of lymphocytes to highly structured organs.
A. Mucosa-associated lymphoid tissue (MALT) consists of large numbers of lymphocytes, plasma cells and macrophages in the lamina propria of G.I., respiratory and genitourinary tracts, especially near glands. These are sites of potential invasion. Look for areas of diffuse lymphoid tissue in esophagus and oviduct isthmus.
B. Epithelial lymphocytes - penetrate epithelial basement membrane and migrate among epithelial cells of wet epithelium.
C. After antigen exposure activated lymphocytes and antigen-presenting cells migrate to regional lymph nodes where immunologically active cells are produced. These effector T and B cells, plasma cell precursors and memory cells are returned via the circulation to the mucosa that is threatened.
II. NODULES AND NODULE AGGREGATES
A. Nodule - organizational unit of lymphoid tissue; primary nodules do not have a reaction center.
1. Organization - a compact spherical arrangement of lymphoid cells, largely B-lymphocytes, enmeshed in reticular connective tissue, including reticular fibers, reticular cells, and macrophages.
2. Secondary (Reactive) nodule - response to antigenic stimulation. It consists of a light-staining reaction (germinal) center containing large cells, where B memory and plasma cell precursors are formed. It is surrounded by a corona or mantle layer of small lymphocytes that is thicker on the side facing the source of antigens.
3. Reaction center zones - 1) a dark region containing many proliferating B-cells (centroblasts) that do not have surface immunoglobulins (SIGs) with basophilic cytoplasm as well as reticular cells and macrophages and 2) a light region consisting of large reticular cells with light pink cytoplasm and differentiating lymphocytes (centrocytes) that express SIGs and upon contact with antigen-presenting follicular dendritic cells are selected for further differentiation to memory or plasma cells or for apoptosis if they express the wrong SIGs. Macrophages remove bad cells.
4. Distribution - Nodules appear as a component of MALT and of lymph nodes and spleen. As you study these organs, locate nodules and try to identify the above features. Aggregates of nodules occur in the tonsils, appendix, cecum and Peyer's patches. In the gut-associated lymphoid tissue (GALT) and perhaps in the bronchus-associated lymphoid tissue (BALT) some of the columnar epithelial cells over lymph nodules are replaced by cells that are specialized for antigen processing. Their surface has short irregular microvillous folds and their basal cytoplasmic folds surround many lymphocytes. These "M" cells ("M" stands for microfolds) present unprocessed antigens to the underlying lymphoid tissue. These cells are especially abundant over nodules of Peyer's patch.
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Palatine tonsil 1. Stratified squamous epithelium on surface 2. Branched tonsillar crypts lined by epithelium 3. Lymph nodules (Reticular C.T.) |
1. General description - aggregates of nodules associated with epithelially lined crypts of varying size and complexity. Lymphocytes migrate through the epithelium to become salivary corpuscles. Numerous epithelial lymphocytes make epithelium almost unrecognizable.
2. Palatine - large complex crypts lined by stratified squamous epithelium on the oral surface and having a well defined connective tissue capsule basally. Some authors do not consider this a true capsule, since it is only on the basal side. Pure mucous glands are deep to the capsule but do not empty into the crypts.
3. Pharyngeal - medium sized, non-branched crypts (clefts) lined by pseudostratified columnar epithelium.
4. Lingual - many small, simple, tubular crypts in the dorsal surface of the posterior third of the tongue lined by stratified squamous epithelium, surrounded by lymph nodules. Note tongue muscle and mucous glands that empty into crypts.
C. Peyer's patches - large aggregates of lymph nodules in lamina propria and extending into the submucosa of the terminal ileum. Some of the epithelial cells overlying them have instead of a striated border numerous microfolds. These cells are called M-cells and they are thought to transport intact antigens to underlying macrophages (antigen presenting cells, APCs).
D. Appendix - many confluent nodules in lamina propria extending into the submucosa. The extent of nodules decreases with age.
III. LYMPHOID ORGANS
A. Lymph nodes. Study and look for the following features, and learn how each contributes to the functions of lymph nodes (filter lymph, produce lymphocytes, respond to foreign substances).
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1. Afferent lymph vessel 2. Efferent lymph vessel 3. Artery and vein 4. Lymph nodules in cortex 5. Medullary cords 6. Lymph sinuses Subcapsular Trabecular or intermediate Medullary |
1. External features - kidney shaped organs 1-25 mm in diameter. Afferent lymph vessels enter around the convex surface. Efferent vessels leave through the concave surface (hilus) along with veins and arteries.
2. Regions
a. Cortex - primary and secondary lymph nodules; secondary nodules where lymphocytes, especially B-cells, proliferate expanding B-cell clones, are not found in germ-free animals. Nodules are frequently separated from each other by connective tissue septa. Sinuses pass around the nodules.
b. Subcortical - this region is also called the paracortical and diffuse cortical area. It is a "T" dependent zone and is the site of lymphoblast formation in immune responses involving both T & B cells. Blasts of the B-cell variety migrate into nodules to form germinal centers. High endothelial (post-capillary) venules express selectin on their luminal surface that binds T-cells and facilitate their migration out of the vessel.
c. Medulla - medullary cords of lymphoid tissue containing mostly B cells and plasma cells are separated from connective tissue trabeculae by medullary sinuses.
3. Framework, vasculature and lymphoid tissue
a. Framework - dense c.t. capsule and irregular septa and trabeculae surrounded by sinuses. Sinuses are lined by loosely arranged endothelial cells between which lymphocytes freely migrate. Sinuses contain a network of stellate reticular cells and attached macrophages that phagocytose foreign particles.
b. Vasculature - arteries and larger veins follow c.t. trabeculae that radiate from the hilus. They enter medullary cords and continue into the cortex forming capillary beds in each. Cortical capillaries turn toward the hilus and open into specialized post-capillary venules (high endothelial venules, HEVs) in the subcortical region. The height of the endothelium is related to the intensity of T-cell involvement in an immune response. Selectins on the surface of circulating T cells attach lymphocytes to the HEVs and initiate diapedesis causing T cells to migrate out of the blood stream into the paracortical zone. The venules continue into the medullary cords, joining to form veins as they approach the hilar trabeculae.
c. Lymphoid tissue - a reticulum of reticular fibers and associated reticular cells with lymphoid cells filling the spaces. In lymph nodes, lymph sinuses surround both cortical and medullary lymphoid tissue. Molecular and cellular communication between the sinuses and lymphoid tissue is rapid.
d. Sinuses - narrow intermediate (cortical) sinuses convey lymph from the subcapsular sinuses to the broad, tortuous medullary sinuses. Collagen and reticular fibers covered by stellate endothelial cells, crisscross the sinuses. Macrophages cling to these, and participate in trapping foreign particles carried by the lymph. These become dendritic antigen-presenting cells priming T cells to initiate an immune response by presenting antigen fragments complexed with major histocompatibility (MHC) class II molecules. Macrophages may also come from peripheral tissues, for example Langerhans cells from the epidermis, enter lymph nodes via the afferent lymph to become dendritic cells. Lymphocytes enter the lymph as it flows through the lymph node to ultimately return to the blood stream.
B. Spleen - large, flattened oval organ covered by peritoneum (mesothelium), with blood vessels entering and leaving at the hilus. Learn to recognize the following features and the distribution of macrophages and reticular fibers.
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1. Capsule (CT and muscle) 2. Trabeculae (CT and Muscle) 3. Trabecula containing blood vessel 4. White pulp (lymphoid tissue) 5. "Central" artery in white pulp 6. Red pulp (surrounds trabeculae and white pulp) |
1. Microscopic features
a. Capsule and trabeculae - prominent c.t. capsule contains some smooth muscle and elastic fibers. Trabeculae extend into the organ.
b. White pulp - accumulations of lymphoid tissue usually surrounding a "central" artery. It participates in the immune responses of the body. The marginal zone is a complex region that provides for immunological interaction between the red and white pulp. It contains both T- and B-cells, interdigitating dendritic cells (APCs), plasma cells and marginal sinuses.
c. Red pulp - consists of venous sinuses and pulp cords. The latter consists of a reticular network containing macrophages, reticular cells and blood cells. Aged erythrocytes lose their sialic acid coat allowing macrophages to detect the underlying galactose moieties. This triggers phagocytosis and the liberated iron is transported back to the bone marrow by transferrin and heme is metabolized to bilirubin. Old and damaged platelets and neutrophils are also removed here.
2. Organization and function -
Vascular c.t. trabeculae radiating from the hilus, carry both veins and arteries, but arteries soon leave the trabeculae and become surrounded by white pulp. The white pulp, consisting of a periarterial lymphatic sheath, PALS (mostly T-cells with B-cells at the periphery), is enlarged at intervals to form lymph nodules (splenic nodules) on one side of the central artery. Small branches of the central artery supply the white pulp, the venous drainage being by way of the red pulp. As the central artery leaves the white pulp, it forms several branches, the penicillar arteries. Sheathed arteries arise from the penicillar arteries and are surrounded by a special sheath (ellipsoid) of reticular fibers and macrophages. The blood from these arteries spills into the reticular connective tissue of the red pulp where macrophages remove old cells and foreign debris. The blood then enters rather large venous sinuses lined by very elongated endothelial cells separated by narrow slits through which the blood leaves the red pulp to enter the venous system. If the blood goes directly from the sheathed arteries into the sinuses it must percolate out and back into those sinuses if the macrophages in the red pulp are to do their work. The venous sinuses empty into veins that lead to trabecular veins.
C. Thymus - Two lobed organ divided into incomplete lobules by primary and secondary c.t. septa from the capsule. Study the following description.
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1. Thin CT capsule and interlobular septa 2. Cortex (small lymphocytes, macrophages and epithelial reticular cells) 3. Medulla (Thymic corpuscles, epithelial reticular cells, large lymphocytes) |
1. Microscopic organization
a. Regions - the cortex consists of a peripheral zone of closely packed lymphocytes, that do not form nodules, capping over numerous protrusions of the less cellular medulla.
b. Framework and stroma - the thin c.t. Capsule and septa provide external support. Internally, the reticular network characteristic of lymphoid tissue elsewhere is replaced by cytoplasmic processes of epithelial reticular cells joined by desmosomes. Six types have been identified, 3 in the cortex and 3 in the medulla. Some of these cells form a thin layer with occluding junctions just under the capsule and around blood vessels contributing to a blood-thymus barrier. Another set with occluding junctions forms a cortico-medullary barrier. Others form a meshwork of cytoplasmic processes in the cortex to support the lymphocytes and still others form the thymic corpuscles. They are the source of several hormones that promote the development of T-cells. Thymosin is one of them. Epithelial reticular cells do not arise from mesoderm as do the reticular cells of other lymphoid organs, but instead come from endoderm (pharyngeal pouch epithelium) although some may come from ectoderm (thymic corpuscles, Hassall's bodies).
c. Vasculature - arteries follow the c.t. Septa to the cortico-medullary junction between lobules where arterioles enter the lobules. From arterioles in the C-M junction, capillaries enter the cortex, then turn back on themselves to empty into venules in the medulla. Many lymphocytes enter the blood stream through these venules. The medullary veins ultimately leave through c.t. septa accompanying the arteries. A sheath of epithelial reticular cells, macrophages surrounding capillaries, and capillary endothelial cells with tight junctions, make an effective blood-thymus barrier.
Immunologically incompetent T-cells from the bone marrow populate the outer cortex where they proliferate and begin to express several surface molecules. T-cell receptors (TCR) specifically bind antigens.
T-helper cells express Cluster of Differentiation 4 marker (CD4) that works with TCR to detect major histocompatibility II (MHC II) complexes with epitope (derived from endocytosed foreign agents) on the surface of APCs.
Cytotoxic and suppressor T-cells express CD8 that works with TCR to detect MHC I-antigen complexes. The antigen in this case is derived from the cytosol (viruses, etc.) and processed by proteasomes.Most T-cells that develop have TCRs that are directed against self or have CD4 or CD8 that fails to detect self specific MHC I or II. These undergo apoptosis and are removed by macrophages. This is negative selection. Cells that can distinguish between self and nonself are retained. This is positive selection. Macrophages can be demonstrated with the PAS stain because of their high content of lysosomes. Lymph drainage is limited to the capsule and septa. The thymus reaches its maximum development at puberty. Subsequently, it undergoes involution, being replaced by fat, so that eventually little more than the Hassall's bodies remain. Involution has begun in a young adult.
IV. MONONUCLEAR PHAGOCYTIC (RETICULO-ENDOTHELIAL) SYSTEM
The older term, reticulo-endothelial (R-E) is a misnomer since it refers to the reticular and endothelial cells of the spleen, lymph node, and liver, that were formerly thought to have a great potential for becoming phagocytic, but do not have that capacity. Actually the phagocytic activity previously ascribed to reticular and endothelial cells, is now known to be only associated with macrophages. The present term "mononuclear phagocytic system" refers to macrophages wherever they are found. It includes the monocytes, tissue macrophages, microglia of the central nervous system, osteoclasts in bone, foreign-body giant cells, Kupffer cells in liver, and Langerhan's cells in stratified squamous epithelium. Antigen-presenting cells are special forms of macrophages that serve to process antigens and present them on their surface complexed with MHC so that lymphocytes are activated to mount an immune response.
I. GENERALIZED IMMUNE RESPONSE
A. Definitions - Innate or nonadaptive and adaptive responses
The innate or nonadaptive immune response is essentially the inflammatory response. It is the body's response to all kinds of insults and is nonspecific. It involves degranulation of mast cells that leads to the dilation and increased permeability of blood vessels. This facilitates the recruitment of complement proteins and neutrophils and macrophages that phagocytose foreign particles. Lymphocytes, known as natural killer (NK) cells (they lack T and B cell receptors and are therefore also called null cells) are also attracted to the site. They nonspecifically attack virally infected cells, cancer and microorganisms. The innate response is not enhanced by repeated exposures to the insult.
The adaptive immune response is a highly specific (differentiates between self and nonself), complex defensive reaction in which specific lymphocytes respond to specific, foreign antigens (Ag) so that ultimately antibodies (Ab) (humoral immune response) and/or cytotoxic cells (cell-mediated immune response) are produced to inactivate or destroy the foreign Ag. Complement, a system of proteins produced by the liver, and macrophages cooperate with lymphoid cells in these immune responses. The speed and degree of response is enhanced by repeated exposures
B. Basic events of adaptive immune responses to the first and second exposure to an Ag. These events occur in the B-cell (humoral) response as well as in the T-cell (cell-mediated) response.
Lymphocytes are of two classes - B-cells and T-cells. As they come from their primary sites of origin (bone marrow and thymus) each virgin cell expresses surface immunoglobulins (SIGs) or T-cell receptors (TCRs) that are relatively specific for one epitope (antigenic determinant). These receptors have low affinity but broad specificity, and there are relatively few cells that are reactive for a given antigen. Therefore the primary response is relatively slow and weak. Blastogenic transformation triggered by Ag binding to a specific lymphocyte, results in loss of the surface receptors and proliferation of that antigenically specific lymphocyte. It now appears that during this process receptor editing occurs so that the memory and effector cells that are produced have a higher affinity and specificity for the antigen.
2. Secondary
As a result of the primary response there are now many specific lymphocytes (memory cells) available, therefore the response is rapid and strong and binding affinities are greater and more precise.
Stem cells (small lymphocytes) from bone marrow enter the primary lymphoid organ (the bursa of Fabricius in birds or the mammalian equivalent, that is most likely bone marrow). In the bursa, they proliferate and differentiate into immunocompetent cells, that then populate the secondary lymphoid organs. Immunocompetent cells are capable of being programmed by Ag.
A. Distribution and circulation
1. Blood - circulating lymphocytes about 10% are B-cells
2. Nodules - B-cells are localized to the small lymphocyte cap of nodules and the dark region of reaction centers.
3. Lymph nodes and spleen - B-cells are concentrated in cortical nodules of lymph nodes and at the periphery of the periarterial lymphoid sheath in the spleen.
B. Receptors and activation
1. Surface - immunoglobulin molecules (IgD or IgM) are distributed on the outer surface of virgin B-cells. These are specific for a single antigen. In the presence of antigen, they become aggregated to one side (cap) and are then ingested by the cell. These events appear to trigger activation.
2. Activation or blastogenic transformation
a. Direct - specific Ag binds to and activates only those lymphocytes bearing the specific AB
b. Indirect - a complex interaction of Ag with macrophages, T-cells, and B-cells
C. Results of activation
1. Memory cells - many small lymphocytes bearing AB specific for the Ag. These cells "seed" lymphoid tissues throughout the body.
2. Effector cells - medium to large lymphocytes and plasma cells producing antibody. These lymphocytes are distributed to the GI lamina propria and lymphoid organs, where they become plasma cells.
III. T-LYMPHOCYTES
Stem cells from the bone marrow enter the thymus where they proliferate and differentiate into competent T-cells. Since T-cells have the capacity to destroy cells that are not marked as self, all those cells that arise in the thymus that would destroy self undergo apoptosis. This is about 90% of those formed.
A. Distribution and circulation
1. Blood - about 80% of circulating lymphocytes are T-cells.
2. Lymph nodes - concentrated in subcortical zone of lymph nodes. This region fails to be populated in congenital absence of thymus (thymus dependent region).
3. Spleen - T-cells are the predominant cell in the periarterial sheath, except in the marginal region where B-cells often form lymph nodules.
B. Receptors and activation
1. Receptors - not immunoglobulins, but rather some other protein having the required specificity.
2. Activation - only occurs when the appropriate antigen is presented by an antigen-presenting cell (APC)
C. Results of activation
1. Memory cells - many small lymphocytes bearing the specific binding proteins.
2. Effector cells - cytotoxic cells act directly or indirectly.
a. Directly - T-cells make direct contact with the foreign cells and release factors (perforin) that punch holes their membrane so that they are lysed.
b. Indirectly - cells release lymphokines, some of which are:
1. lymphotoxin - causes cell lysis
2. migration inhibiting factor (MIF) causes macrophages to accumulate at the site
3. blastogenic factor (BF) causes nonspecific transformation of other T-cells, that amplifies the response
4. osteoclast activating factor (OAF), Interleukin 1 beta causes mobilization of bone calcium
5. ACTH-like factor that may link the immune and neuroendocrine systems
D. T-cells subclasses
1. Helper - have CD4 on their surface (CD4+); they are greatly suppressed or absent in AIDS - facilitate production of antibody by B-cells.
2. Cytotoxic and Suppressor - have CD8 on their surface (CD8+); they are not reduced in AIDS - they kill virus-infected and other aberrant cells or inhibit production of antibody by B-cells.
3. Macrophage arming - activate macrophages to enhance their phagocytic and bacteriolytic activities.
IV. Natural Killer (NK) CELLS
A. Those with Fc receptors.
These cells react with the non-variable part (Fc) of immunoglobulin molecules. On contact with foreign cells that have antibody attached to them, these T cells cause them to lyse by releasing an enzyme that has been named perforin.
V. LYMPHOCYTIC CIRCULATION - lymph to blood and back to lymph.
Small memory cells, mostly T-cells, leave blood stream in thymic dependent areas of lymphoid tissue (post-capillary venules of lymph nodes) and reenter via the lymph. Memory and effector cells from a primary or secondary immune response also leave the lymph nodes by way of the lymph, and seed other lymphoid tissues. There is some organ specificity in this seeding. For example: medium to large lymphocytes in the thoracic duct lymph, come largely from gut associated lymphoid tissue and mesenteric lymph nodes, and are rapidly concentrated in the lamina propria of the gut, where they produce secretory immunoglobulin (IgA).
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Last Revised: Tue, Nov 14, 2006