This chapter should help you to:

· Know the functions of the lymphoid system.
· Know the names, locations, and functions of the cells, tissues, and organs of the lymphoid system and be able to identify them, as well as the named structural elements of the organs, on a slide or in a photomicrograph.
· Know the distinguishing features of the lymphoid organs.
· Know the difference between central and peripheral lymphoid organs. · Know the differences between cell-mediated and humoral immunity.
· Describe the steps in the differentiation of lymphocytes from stem cells to T or B memory and effector cells.
· Know the 5 classes of immunoglobulin and their distinguishing features.
· Describe the steps in lymphocyte activation by antigens.
· Describe the steps in antigen disposal by cell-mediated and humoral mechanisms.
· Describe the path taken by lymph as it flows through the lymph nodes.
· Describe the path taken by blood as it flows through the spleen according to the open and closed theories of splenic circulation.

I. GENERAL FEATURES OF THE LYMPHOID SYSTEM

A. Components: The lymphoid system's major functional components, lymphocytes, are of 2 main types, T and B lymphocytes. Lymphocytes circulate in the blood and lymph and are scattered in loose connective tissue. They also occur in clusters called lymphatic (or lymphoid) aggregates. These can be large and encapsulated, forming lymphoid organs such as the thymus, spleen, and lymph nodes. They also form small, partly encapsulated tonsils. Still smaller, unencapsulated aggregates often occur in the walls of the respiratory, digestive, and urinary tracts. In addition to lymphocytes, lymphoid tissues typically include a reticular con nective tissue stroma in whose meshwork lymphocytes, macrophages, and antigen-presenting cells are suspended. Lymphatic vessels and circulation are described in Chapter 11.

B, Classification of Lymphoid Tissues and Organs: In peripheral lymphoid organs (lymph nodes, spleen, tonsils) and unencapsulated lymphatic aggregates (V), lymphocyte pro duction is antigen-dependent and provides committed immunocompetent cells that respond to specific antigens. In central lymphoid organs (thymus, bone marrow, bursa of Fabricius fin birdsl), lymphocyte production is antigen-independent and supplies uncommitted T lymphocyte (thymus) or B lymphocyte (bone marrow, bursa) precursors that later move to peripheral organs and tissues. Mounting effective immune responses to new antigens requires ongoing production of uncommitted lymphocytes by the central lymphoid organs.

C, Lymphoid Nodules(Follicles): These occur in all lymphatic aggregates except the thymus. Active (lymphocyte-producing) nodules each have a dark-staining periphery, or mantle zone, that contains tightly packed small lymphocytes, and a light-staining core, or germinal center, that contains numerous immunoblasts (lymphoblasts), ie, lymphocytes stimulated by antigens to enlarge and proliferate. The lighter staining reflects the increased cytoplasmic volume and decreased nuclear heterochromatin that accompany lymphocyte activation.

D, General Functions of Lymphoid Tissues: All lymphoid tissues and organs produce lym phocytes. Lymph nodes also filter lymph and add antibodies to it, while the spleen filters and adds antibodies to blood and removes and destroys old red blood cells. Unencapsulated lym phoid aggregates filter and add antibodies to tissue fluid. The thymus has no significant filtering function, but supports the proliferation and programming of T lymphocyte precursors. The thymus also secretes hormones leg, thymosin, thymopoietin) that promote the function and maintenance of lymphoid tissues in general and T cells in particular. Lymphoid functions are all directed toward a single objective: antigen disposal, This involves 2 major mechanisms.

1. Cellular (cell-mediated) immunity. Activated T lymphocytes differentiate into specialized cell types, some of which contact and kill intruding cells, while others release lymphokines, substances that enhance various aspects of the immune response.
2. Humoral immunity Activated B lymphocytes differentiate into plasma cells that secrete the antigen-binding immunoglobulins (antibodies) which circulate in the blood and lymph.

E, Immunoglobulins: There are 5 major classes of circulating antibodies, or immunoglobulins (Igs): IgM, IgA, IgD, IgG, and IgE (easily recalled with the mnemonic MADGE). All are secreted by plasma cells, but each class has distinguishing features (II.B). Each Ig binds with great specificity to its antigen to inactivate toxic substances and to mark (opsonize) them for removal by macrophages, neutrophils, and eosinophils.

F. Lymphocyte Programming and Activation: This is a multistep process, as outlined below.

I. Cells of mesodermal origin are programmed in the bone marrow or thymus as B or T lymphocyte precursors, respectively.
2. They next move to peripheral organs, where each encounters a specific antigen (I.G) to which it becomes programmed (committed) to respond. Concentration of antigens on the surfaces of special antigen-presenting cells (III.E), or the delivery of processed antigens to lymphocytes by macrophages (III.B), improves the efficiency of this step over that available from random lymphocyte-antigen collisions 3. Contact with an antigen (activation) stimulates lymphocytes to enlarge and form lympho- blasts (blast transformation) and then proliferate (clonal expansion).
4. The products of this division then undergo differentiation into 2 basic cell types: effector cells which immediately begin to dispose of the antigen (primary immune response), and memory cells, which are held in reserve for subsequent encounters with the antigen (second ary immune response). T lymphocyte derivatives form 3 types of effector cells (III.A.2), which enter the circulation and search the body for their antigens, providing cellular immu nity. B lymphocyte derivatives form only one effector cell type, plasma cells. These usually remain in the tissue or organ where they differentiated and secrete into the body fluids Igs that circulate to provide humoral immunity.
5. When the antigen is next encountered, memory cells (either T or B) undergo the same process--blast transformation, clonal expansion, and differentiation--as in the primary response, but more rapidly and effectively than before. This is the secondary response.

G, Antigens: These are foreign (nonself) substances able to elicit an immune response (cellular, humoral, or both). They can be entire cells leg, bacteria, tumor cells) or large molecules leg, proteins, polysaccharides, nucleoproteins). Their antigenicity is determined by several factors: Larger and more complex leg, branched or folded) molecules are more potent antigens than smaller, simpler ones; proteins are more antigenic than carbohydrates; and lipids are nonan tigenic unless complexed with a more potent antigen. The site of entry of an antigen into the body can also affect its antigenicity. The specific part of an antigen that elicits the immune response (and to which the antibodies bind) is called an antigenic determinant, or epitope, which can consist of a monosaccharide or as few as 4-6 arnino acids. Thus a bacterium can have many antigenic determinants and elicit many cellular and humoral responses.

II. IMMUNOGLOBULINS

These antibodies are proteins secreted by plasma cells into the body fluids (blood, lymph, tissue fluid, saliva, tears, milk, mucus) in response to antigenic stimulation. They bind with high affinity to the antigenic determinants that elicited their production and make up most of the gamma g]obulins of blood plasma.

A. Immunoglobulin Structure: Familiarity with the Y-shaped structure common to all Igs and the positions of their components (Fig 14-1) will improve understanding of the lymphoid system.

1. Heavy and light chains. Each IgG has 2 heavy chains (MW 50,000 each) and 2 light chains (MW 23,000 each). The heavy chains form the stem and part of each arm of the Y. The light chains lie in the arms, parallel to the heavy chains.
2. Constant and variable domains. Each chain (heavy or light) includes both a region of constant structure that varies little from one IgG to another and a region of variable structure that determines the binding specificity of the antibody. The variable domains occupy the distal ends of the arms, while the constant regions are in the stem and proximal parts of the arms.
3. Fe and Fab regions. The proteolytic enzyme papain cleaves each Ig into 3 fragments at the branch point of the Y (hinge region). The single crystallizable fragment (Fc region) includes part of the constant domain that occupies the stem. It is crystallizable because only a pure preparation of a single protein crystallizes and because even in a mixture of antibodies with different binding affinities, the stem structure is constant. There are 2 antigen-binding frag ments (Fab regions), which include the entire light chain and variable and constant portions of the heavy chain. Since the combined variable regions of the light and heavy chains determine antigen-binding specificity, these fragments retain the binding specificity of the original Ig. Since they vary from one antibody to another, Fab fragments from a mixture of Igs are not crystallizable.
4. Carboxyl and amino termini. The carboxyl termini are the free ends of the constant portions and the amino termini are the free ends of the variable portions of both the light and heavy chains.
5. Antigen-binding and cell-binding regions. The amino-terminal region of the variable portions of each arm of the Y is the antigen-binding site. Thus there are 2 antigen-binding sites on each Ig. The cell-binding region is the carboxyl terminus at the base of each heavy chain. Thus the Fc fragment harbors the cell-binding region.
6. Disulfide bonds. Interchain disulfide bonds link the heavy chains to each other and to the light chains near the hinge region. Inrrachain disulfide bonds occur at various sites along both the light and heavy chains.

B, Characteristics of Immunoglohulin Types: Human Igs are divided into 5 major groups:

1. IgG, The most abundant type in blood (75% of serum Ig), IgG occurs mainly as a monomer. It takes longer to appear after an initial antigenic challenge than IgM and is a bit less effective in complement activation, but shows greater antigen-binding specificity. It constitutes most of the secondary humoral immune response and can remain active in blood for many weeks (6 times as long as IgM). IgG can cross the placenta to confer passive immunity on the fetus; it is also found in human milk.
2. IgA. The secretory antibody, this is the main Ig in body secretions (saliva, tears mucus, colostrum, milk, semen, vaginal fluid), but makes up only 0.2% of serum Ig. Secrctory IgA includes 2 IgA monomcrs linked by protein J and another protein, the secretory, or trans port, component. The IgA monomers and protein J are plasma cell products; the transport component is produced by mucosal epithelial cells.
3. IgM. Although it constitutes only 10% of the serum Ig, IgM is the major Ig in the primary immune response. Secreted soon after a new antigenic challenge, it is less antigcn-specitic than IgG. It is found, along with IgD, on the surface of B lymphocytes. When antigen binds to these surface antibodies, B cells differentiate into plasma cells. IgM is effective in complement activation (II.C.I); in solution it usually occurs as a pentamer.
4. IgE, Normally, IgE occurs as a monomer in very small amounts in the serum. Its Fc portion binds avidly to cell surface receptors on mast cells and basophils, leaving its antigen-binding sites extending away from the cell surface. The binding of antigcns to IgE cross-links the receptors and stimulates the release of such substances as histamine, heparin, Icukotricncs (including slow-reacting substance of anaphylaxis [SRS-A1), and eosinophil chemotactic factor of anaphylaxis (ECF-A) from the cytoplasmic granules. Antigens that bind to IgE or stimulate its production are termed allergens, and IgE plays a major role in allergic reactions. Elevated IgE levels are also found in the blood of patients infested with para sites.
5. IgD. The least understood of the immunoglobulins, IgD may function as an embryonic or fetal Ig. Its concentration in plasma is low (0.2C/o of serum Ig), and it is found on the surface of B lymphocytes along with IgM.

C, General Mechanisms of Immunoglobulin Action:

1. Opsonization. Foreign cells and molecules to which antibodies have bound are more easily recognized as intruders by antigen-disposing cells (macrophages, cytotoxic T cells, neu trophils, eosinophils). Antibody-labeled antigens are thus opsonized (marked for disposal). IgC, IgM, and some components of the complement system act as opsonins,
2. Complement activation. The complement system is a complex of plasma enzymes that catalyze a cascade of reactions when activated (both IgG and IgM can initiate the cascade). Effects of complement activation include (1) increased blood flow to the affected area (inflammation), (2) cbemotaxis of the inflammatory cells (eosinophils, basophils, neu trophils, cytotoxic T cells), (3) opsonization, and (4) lysis of the invading cells tie, compo nents of the system act together to puncture the plasma membrane of the invading cells).
3. Formation of antigen-antibody complexes. Antigenic molecules in body fluids precipitate when antibodies bind them. In the process, the antigens may be inactivated; ie, their toxicity is diminished or eliminated. The antigen-antibody complexes are then phagocytosed by macrophages, neutrophils, or eosinophils.

III. CELLS OF THE LYMPHOID SYSTEM

A. Lymphocytes: These are the principal cells of the lymphoid system. Their ability to recog nize and respond to foreign cells and substances is the basis for initiating an immune response, but lymphocytes are not phagocytic. The functional classes of lymphocytes differ in cell surface composition and in their response to antigenic challenges, but they are indistinguishable with standard histologic stains. (The appearance of lymphocytes in connective tissues and blood is described in Chapters 5 and 12, respectively, and the origin of lymphocyte precursors in bone marrow is described in Chapter 13.) Bone marrow-derived precursors enter the circulation and then populate central lymphoid organs. Those in the thymus become T lymphocyte precursors. Although the precise B lymphocyte programming site (called the bursa equivalent or bursa analogue in humans) is unclear, evidence favors specific microenvironments in bone marrow.

1. B lymphocytes (B cells). Primarily responsible for humoral immunity (I.D.2), B cells carry IgM and IgD on their membranes as antigen receptors. When antigens bind to these Igs, B lymphocytes undergo blast transformation and clonal expansion (I.F). Most of the resulting daughter cells differentiate into plasma cells (III.C), while others become memory cells that react to the same antigen in subsequent encounters. B cells require assistance from helper T cells to respond to many antigens; these antigens are called T-dependent (thymus dependent) antigens.
2. T lymphocytes (T cells). Primarily responsible for cell-mediated immunity (I.D.I), T cells carry antibodylike antigen receptors (but not Igs) on their surfaces. When antigens bind to these receptors, T lymphocytes undergo blast transformation and proliferation and produce both effector and memory cells (I.F); they may require the aid of macrophages for an optimal response. There are 3 major types of T lymphocyte effector cells: (1) Helper T cells aid B lymphocytes in mounting a humoral immune response to T-dcpendcnt antigcns; (2) sup pressor T cells moderate helper cell activity, thereby helping to regulate humoral immune responses; and (3) cytotoxic (killer)T cells recognize, adhere to, and kill--by cell lysis- invading bacteria, virus-infected cells, transplanted cells, and tumor cells. These are the main graft rejection cells. Their killing activity requires activation by their specific antigen. Antigen-stimulated T cells and macrophages also release lymphokines, the proteins leg, blastogenic factor, migration-inhibiting factor, proliferation-inhibiting factor) that control B and T cell proliferation and macrophage activity. T lymphocyte precursors programmed in the thymus enter the circulation and populate T-dependent regions of the lymph nodes (paracortical zone) and spleen (periarterial lymphatic sheaths). T lymphocyte effector cells reenter the circulation more readily than do B lymphocyte effecters (plasma cells).
3. Natural killer (NK) cells. These are circulating lymphocytes that cannot be classed as either T or B cells tie, they lack both T and B surface antigens). Like cytotoxic T cells, they are able to attack and lyse invading cells leg, tumor cells) through direct cell-cell contact. On the other hand, the killing activity of NK cells appears to be independent of antigenic activation tie, it is natural or innate). The mechanism whereby these cells target nonsclf cells for destruction is not yet clear.

B, Macrophages: These are commonly monocyte derivatives, ie, components of the mono nuclear phagocyte system (the morphologic characteristics of these large, often migratory phagocytic cells are described in Chapter 5). In both cellular and humoral immunity, they phagocytose complex antigens and enhance their antigenicity by breaking them into a multitude of antigenic determinants for presentation to the lymphocytes. They also phagocytose antigen antibody complexes. Macrophages interact with T lymphocytes primarily through direct cell contact. The T cells thus activated differentiate into T lymphocyte effector cells (for cellular immunity). Activated helper T cells cooperate with B cells to stimulate their differentiation into Ig-secreting plasma cells (for humoral immunity). Macrophages are found lining vascular si nuses, distributed among the lymphocytes of lymphoid organs and tissues, and dispersed in loose connective tissues.

C. Plasma Cells: These differentiated B lymphocyte effector cells secret the Igs primarily re sponsible for humoral immunity. (Their morphologic characteristics, including a "clock face" nucleus and abundant RER typical of protein-secreting cells, are described in Chapter 5.) Plasma cells, found in all lymphoid tissues, occur in high concentration in the medullary cords of lymph nodes, the red pulp cords in the spleen, and the lamina propria underlying mucosal and glandular epithelia. They are rare in the thymus, occurring only in the medulla. Each plasma cell secretes only one class of Ig that will bind only one antigen.

D. Reticular Cells: Usually stellate, these cells have long processes that form a meshwork in which lymphocytes, plasma cells, and other tissue components are suspended. Lymphoid organs contain either of 2 major types of reticular cells:

1. Mesenchymal reticular cells. Reticular cells of lymph nodes, spleen, tonsils, and bone marrow are of mesodermal origin. Each has a central nucleus with a prominent nucleolus and pale, sparse cytoplasm that contains RER, a Golgi complex, free ribosomes, lysosomes, glycogen granules, and intermediate filaments composed of vimentin. They produce a reticu lar fiber network (Chapter 5) on which they are suspended and which they partly surround with their long filopodia. Other functions ascribed to these cells and their derivatives include (1) phagocytosing antigenic organisms, inert foreign matter, dead cells, and cell debris; (2) trapping antigens on their surfaces and subsequently stimulating adjacent lymphocytes; and (3) acting as hematopoietic (lymphoid and myeloid) stem cells.
2. Epithelial reticular cells. Reticular cells of the thymus are of endodermal origin (the lining of the third pharyngeal pouch). Like the mesoderm-derived reticular cells, these may be stellate, but they differ in that they do not secrete reticular fibers. They form their reticular meshwork by attaching to one another at the tips of their long cell processes with desmo somes, Their intermediate filaments consist of cytokeratins. The cells have large, pale, oval nuclei with prominent nucleoli; the cytoplasm contains a Golgi complex, RER, and ribo somes. They also contain small (O.l-CLm), dense granules thought to be secretory granules that contain thymic hormones leg, serum thymic factor, thymic humoral factor, thy mopoietin, thymosin). In the thymic medulla, these cells assume many shapes; some become flattened to form tight concentric bodies called Hassall's corpuscles. In the cortex, they are mainly stellate and help form the blood-thymus barrier (VI.A.2.b).

E. Antigen-Presenting Cells: These cells, many of which derive from mesenchymal reticular cells, bind antigen-antibody complexes on their surfaces for long periods without phagocytosmg them. In this way, they collect and concentrate antigens for presentation to, and stimulation of, lymphocytes. Antigen-presenting cells appear in the lymph nodes as follicular dendritic cells of the cortex and dendritic cells of the paracortical zone; in the spleen they are the dendritic cells of the marginal zone; in the skin (Chapter 18) they are Langerhans' cells; and in the liver (Chapter 16) they are Kupffer's cells. Although macrophages (III.B) also have important antigen-presenting functions, their first task is usually to phagocytose the antigen.

IV. LYMPHOID NODULES

These spheric collections of lymphocytes constitute the primary functional subunits of all cncapsulated and unencapsulated lymphoid aggregates except the thymus. B lymphocytcs predominate, but smaller numbers of helper T cells may also be present. Primary nodules lack germinal centers and contain only small lymphocytes. They are present prenatally and in the absence of antigens leg, in animals housed in sterile surroundings). Secondary nodules, which appear after birth, are primary nodules activated by exposure to antigens; their size and number are proportionate to the degree of antigenic stimulation. Structurally, they have a narrow, dark-staining halo of small lymphocytes surrounding a larger, lighter-staining germinal center that contains mainly lymphoblasts. The dark periphery often shows a cap, a localized crescent-shaped thickening of the mantle zone where memory cells (I.F.4) typically collect. The size of the germinal center decreases when antigenic stimuli are removed. Thin sections through the periphery of a secondary nodule may resemble primary nodules, but the presence of primary nodules is doubtful if nearby nodules contain germinal centers.

V. UNENCAPSULATED LYMPHATIC AGGREGATES

These are lymphoid nodules that occur singly or in small clusters. The classic example is Peyer's patches, clusters of lymphoid nodulcs in the lamina propria of the small intestine (ileum; Chapter15). Nodule clusters also occur in the appendix, and there are scattered solitary nodules beneath the epithelium in the walls of the digestive, respiratory, urinary, and genital passages. These occur especially at branch points and the sites at which 2 organs join leg, esophageal-cardiac stomach junction). Nodules may be covered by a layer of flattened reticular cells, but they lack the connective tissue capsule that surrounds lymphoid organs.

VI. THYMUS

This is the only discrete central lymphoid organ in humans. It produces only T lymphocyte precursors and has no lymphoid nodules. Its reticular cells derive from endoderm and produce no reticular fibers. It is the only organ containing Hassali's corpuscles. Its age-dependent structural atrophy or involution (VI.B.6) is also unique among lymphoid organs.

A. Structure: Major structural features that allow rapid identification of the lymphoid organs are shown in Table 14-1. The thymus lies in the mediastinum anterior to the large vessels emerging from the heart. Its 2 lobes are joined and covered by a thin loose connective tissue capsule that penetrates the lobes as septa, dividing each lobe into incomplete lobules. Each lobule has a peripheral dark-staining cortex, adjacent to the capsule and septa, and a central light-staining medulla. The septa penetrate only to the corticomedullary junction, so that the medulla of each lobule is continuous with that of adjacent lobules.

1. Cortex. This is the dark-staining periphery of each lobule. Small lymphocytes predominate, but large and medium-sized lymphocytes are also present. The dark color reflects the tight packing of lymphocyte nuclei, which are suspended in a meshwork of long epithelial reticu lar cell processes. The reticular cells, which are stellate and less numerous than in the medulla, form a boundary between the cortex and the connective tissue of the capsule and septa. They also ensheathe the cortical capillaries, the only blood vessels found in the cortex. The cortex is the site of T lymphocyte precursor proliferation and of the blood-thymus barrier (VI.B.2).
2. Medulla. In effect, each thymic lobe has a single medulla that extends into the core of each of the lobules. The light staining of the medulla reflects the presence of more epithelial reticular cells and fewer lymphocytes than in the cortex. Medullary reticular cells assume many shapes and sizes; some have granules containing thymic hormones. The lymphocytes, which are more mature than in the cortex, enter the circulation from the medulla to populate the T-dependent areas of other lymphoid organs. The spheric Hassall's corpuscles (30 150 um in diameter) are composed of concentric layers of flattened epithelial reticular cells. With age, cells in the core of the corpuscles may die and calcify; the function of these structures is unknown.

B. Functions:

1. T lymphocyte production. This is the primary function of the thymus. T lymphocyte precursors populate the thymic cortex. The cortical environment influences these thymic lymphocytes (thymocytes) to proliferate and acquire the ability to become T lymphocytes. For unknown reasons, most cortical thymocytes undergo cell death and fragmentation (up optosis) followed by phagocytosis by macrophages; this may be a mechanism to eliminate cells prematurely activated or targeted toward "self" antigens. Maturing survivors move toward the medulla, where they enter the circulation through postcapillary venules or efferent lymphatic vessels. They populate the T-dependent regions of secondary lymphoid organs leg, lymph nodes, spleen). Here they further differentiate into functional T lymphocytes. The vast majority of thymocytes in the thymus are functionally inert and cannot respond to antigens. Therefore, thymocytes-especially those in the cortex--should be considered distinct from, but precursors to, the T lymphocytes that carry out the cellular immune response.
2. Blood supply and blood-thymus barrier. The arterial supply enters the thymus through the capsule, penetrating the organ through the septa. Branches of septal vessels extend along the border between the cortex and medulla, feeding capillaries that penetrate both regions. The cortical capillaries arch through the cortex and empty into postcapillary venules in the medulla, as do the medullary capillaries. The venous drainage follows the arterial course in reverse. The thymus contains continuous (nonfenestrated) capillaries surrounded by a thick basal lamina. In the cortex, processes of capillary endothelial cells may penetrate the basal lamina and contact processes of epithelial reticular cells that ensheathe the cortical capil laries. This 3-layered structure (nonfenestrated capillary endothelium, thick basal lamina, and reticular cell sheath) forms the blood-thymus barrier. This barrier, found only in the cortex, separates proliferating thymocytes from the blood. Together with the disposition of the blood vessels (directing blood flow toward the medulla and away from the cortex), the barrier limits the antigenic material to which the thymocytes are exposed in the thymus. This helps maintain a supply of uncommitted stem cells for later programming during encounters with new antigens.
3. Hormone production. Epithelial reticular cells of the thymic medulla have cytoplasmic granules thought to contain thymic hormones leg, thymopoietin thymosin). These humoral factors have a trophic effect on the entire lymphoid system and promote thymocyte prolifera tion and T cell differentiation.
4. Effects of exogenous hormones. Adrenocorticosteroids and ACTH slow thymocyte pro liferation and reduce the thickness of the thymic cortex. Androgens· and estrogens accelerate thymic involution; castration has the opposite effect. Growth hormone stimulates thymic growth in general.
5. Effects of thymectomy, Destruction or removal of the thymus at birth results in complete failure of T lymphocyte production. It reduces the number of circulating lymphocytes, and T-dependent regions of the spleen and lymph nodes remain unpopulated. There is no cell mediated immune response--and consequently, no delayed hypersensitivity or graft rejec tion. Neither is there any T-dependent humoral immune response, and the lack of thymic hormones causes general atrophy of other lymphoid organs. By 3-4 months after postnatal thymectomy, the animal becomes weaker; it loses weight and finally dies. Thymectomy in adults has less dramatic effects because many thymocytes have already left the thymus. Functional T lymphocytes are already distributed in the tissues and T-dependent regions of the secondary lymphoid organs. The number of circulating lymphocytes is reduced, how ever, and the response to new and unusual antigens may be compromised. At any age, grafting thymic tissue into thymectomized animals reverses the effects of thymectomy. The graft is repopulated with thymocyte precursors from the host bone marrow, and thymic function is restored.
6. Histogenesis and involution. The thymus arises from the ventral portion of the paired third pharyngeal pouches, whose endodermal lining gives rise to the epithelial rcticular cells. After the sixth week of gestation, the thymic rudiments detach from the pharyngeal wall and migrate to the mediastinum, where they partially fuse to form the 2 lobes of the thymus. The thymus is populated by hematopoietic stem cells of mesodermal origin from the liver and bone marrow during hepatosplenothymic and medullary hematopoiesis, respectively; the stem cells divide and fill the cortex with thymocytes. The thymus increases in size until puberty, but it reaches its maximum size (relative to body weight) shortly after birth. At puberty, involution begins. The cortex thins as the rate of thymocyte proliferation slows and more cells leave the thymus. The relative area of the medulla increases, and the Hassall's corpuscles enlarge, sometimes becoming calcified. Even in adults, the thymus can produce large numbers of thymocytes when needed. In the elderly, much of the active thymic tissue is replaced by connective and adipose tissue.

VII. LYMPH NODES

These are the smallest but most numerous encapsulated lymphoid organs. Scattered in groups along lymphatic vessels in the neck, axilla, groin, thorax, and abdomen, they act as in-line filters of the lymph, removing antigens and cellular debris and adding Igs.

A. Structure: Lymph nodes are bean-shaped structures with convex and concave surfaces (Fig 14-2). The parenchyma consists of a peripheral cortex, adjacent to the convex surface, and a central medulla lying near the depression (hilum) in the concave surface. The connective tissue capsule gives off traheculae that penetrate between the cortical nodules and subdivide the cortex. Blood vessels enter and leave through the hilum.

1. Cortex. The cortex is dark-staining owing to the presence of tightly packed lymphocytes. These are suspended in a reticular connective tissue network and arranged as a layer of typical secondary lymphoid nodules (containing primarily B lymphocytes) with germinal centers. The cortex also contains reticular cells, antigen-presenting follicular dendritic cells, macrophages, a few plasma cells, and some helper T cells.
2. Medulla. Lighter staining than the cortex, the medulla is composed of cords of lymphoid tissue (medullary cords) separated by medullary sinuses. The lymphocytes are mainly small, less numerous than in the cortex, and concentrated in the cords. The cords are also rich in reticular cells and fibers and contain many plasma cells that have migrated from the cortex.
3. Paracortical zone. This is the T-dependent region, lying between the cortical lymphoid nodules and the medulla. It contains mainly T lymphocytes suspended in a reticular connec tive tissue network. B lymphocytes, plasma cells, macrophages, and antigen-presenting interdigitating dendritic cells may also be present. This zone is also characterized by the presence of many high-endothelial postcapillary venules. T lymphocytes leave the blood to enter the paracortical zone by passing between the cuboidal endothelial cells lining these vessels.
4. Lymphatic vessels. Lymphatic vessels associated with lymph nodes are of 2 types. Both contain valves to ensure a unidirectional flow of lymph through the node. Afferent lym phatic vessels deliver lymph by penetrating the capsule at several points on the convex surface. Efferent lymphatic vessels carry filtered lymph away from the node, exiting through the hilum on the concave surface.
5. Sinuses. The sinuses of the lymph nodes filter the lymph passing through them and direct its Row. Partly lined with reticular cells and many macrophages, they are not simply open spaces, but are traversed by a meshwork of reticular cells and fibers, macrophages, and follicular dendritic cells. The complex sieving action slows lymph flow to facilitate the removal of antigens. Lymph is delivered by the afferent vessels to the cuplike suhcapsular sinus between the capsule and the cortical parenchyma. From here it passes directly into the peritrabecular sinuses surrounding the trabeculae. It then flows through the anastomotic network of medullary sinuses that converge on the efferent lymphatic vessels exiting through the hilum.

B. Functions:

1. Filtration of lymph. Cellular debris and antigens carried by incoming lymph are removed by the macrophages and follicular dendritic cells of the sinuses (similar cells are found in the cortical nodules and medullary cords). Lymphocytes carried by the lymph may flow through the nodes, contacting antigen-presenting cells and macrophages in the sinuses, or leave the sinuses and enter the parenchyma. By the time the lymph reaches the efferent lymphatic vessels, more than 90% of the antigens and cellular debris have been removed. More than 99% of the lymph remains in the sinuses as it passes through the nodes.
2. Lymphocyte production (lymphopoiesis). Stimulated by antigens removed from the lymph, T lymphocytes undergo blast transformation and clonal expansion and then differ entiate into effector and memory cells that recognize and respond to a specific antigen. T lymphocyte effector cells may leave the paracortical zone to seek and destroy the antigen, entering the sinuses and leaving the node through efferent vessels. The cells typically reenter the blood at the point where the lymphatic vascular system empties into the venous system. Similarly stimulated, B lymphocytes move to the germinal centers of cortical nodules to undergo the blast transformation that yields memory and effector (plasma) cells. Differenti ated plasma cells migrate to the medullary cords. Memory B lymphocytes either return to the nodule's peripheral mantle zone or leave the node by migrating into the sinuses. 3. Immuuoglobulin production. Most plasma cells remain in the medullary cords, secreting Igs into the lymph as it flows through the medullary sinuses and exits through the efferent lymphatic vessels. These Igs reach the blood as the lymph empties into the venous system in the neck.

VIII. SPLEEN

The largest of the lymphoid organs, the spleen lies in the upper left quadrant of the abdominal cavity. Its functions include lymphopoiesis, Ig production, and filtration of blood for cellular debris and antigens. Because it serves as the immunologic filter of the blood, its blood supply and circulation are especially important. Unlike other lymphoid organs, the spleen lacks a definitive cortex and medulla. The parenchyma (splenic pulp) lacks true lobules; however, the dense connective tissue capsule, which contains a small amount of smooth muscle, gives rise to trabeculae that divide the splenic pulp into incomplete compartments.

A. Structure:

1. Splenic pulp is composed of many erythrocytes, leukocytes, and macrophages, as well as a variety of blood vessels, all suspended within a meshwork of mesenchymal reticular cells and fibers. Unstained slices of splenic pulp exhibit many whitish islands of lymphoid tissue (white pulp) embedded in a sea of dark red, erythrocyte-rich tissue (red pulp). a. White pulp consists of the lymphoid tissue surrounding each of the many central arteries (VIII.A.2); it has 2 major components. The sleeves of lymphoid tissue immediately surrounding each central artery are called periarterial lymphatic sheaths (PALS). These contain mainly T lymphocytes and constitute the T-dependent regions of the spleen. Surrounding each PALS, or appended to one side, is the second component, the peripheral white pulp (PWP). PWP contains mainly B lymphocytes and usually in cludes a typical secondary lymphoid nodule with a germinal center. b. Red pulp makes up most of the spleen and also has 2 major components: the red pulp cords and the splenic sinusoids that lie between them. The red pulp (Billroth's) cords are irregular sheets of reticular connective tissue that branch and anastomose to surround the sinuses. The cords vary in thickness according to the distention of the adjacent sinusoids. In addition to reticular cells and fibers, the cords contain many cell types. including all the formed elements of blood, dendritic cells, macrophages, plasma cells. and lymphocytes. Splenic sinusoids differ from common capillaries: the lumen is wider and more irregular; there are 2-3-um spaces between the lining endothelial cells; and there is a sparse, discontinuous basal lamina that is composed largely of reticular fibers arranged in bands that run roughly perpendicular to the length of the vessel. The overall arrangement resembles a barrel, with the endothelial cells (elongated on the sinusoids long axis) as the wooden staves and the bands of basal lamina as the hoops. The slitlike spaces between the endothelial cells permit extensive exchange of fluids, solutes, and flexible cells between the sinusoids and cords. Macrophages in the cords extend their processes through the slits and phagocytose material in the sinusoid lumen. c, The marginal zone forms a border between the white and red pulp; it consists of a moatlike arrangement of blood sinuses and loose lymphoid tissue containing few lym phocytes. Blood-bome antigens delivered to the marginal sinuses are phagocytosed by the many macrophages and trapped by intcrdigitating dendritic cells in the zone. Its rich blood supply, cellular composition, and location next to the white pulp make the mar ginal zone important in concentrating blood-borne antigens for presentation to the splenic lymphocytes .
2. Splenic circulation (Fig 14-3) a. Arterial supply. The spleen receives blood from the splenic artery (a branch of the celiac trunk off the abdominal aorta). Near the hilum, the splenic artery branches to form several trahecular arteries. These enter the spleen through the trabeculae and branch to enter the parenchyma as the numerous central arteries around which the white pulp is organized. After passing through the white pulp, the arteries give rise to many penicillar arterioles, which in turn give off many capillaries and sheathed arterioles, Near their termination, the sheathed arterioles have localized wall thickenings consisting of mac rophages. Many of the capillaries arising from the central artery loop back toward the white pulp to feed the marginal sinuses. Others, including those arising from the penicil lar and sheathed arterioles, feed the sinuses of the red pulp. b. Open and closed theories of splenic circulation. How blood in the capillaries reaches the sinusoid lumens is not clear. The closed theory holds that the capillary walls are continuous with the walls of the sinusoids and that the capillaries empty directly into the sinusoid lumens. The open theory holds that the capillaries end abruptly in the red pulp cords and that blood reaches the sinusoid lumens by percolating through the cords and passing through openings in the sinusoid walls. For humans, current evidence favors the open theory. c. Venous drainage. From the sinusoids, blood flows into red pulp veins that converge on the trabeculae and empty into trabecular veins; these are unusual in that their walls lack a distinct tunica media. At the hilum, trabecular veins empty into the splenic vein, which joins the inferior mesenteric vein and empties into the hepatic portal vein just before it enters the liver.

B. Functions:

1. Filtration of blood. Removal of antigenic material and cellular debris from blood involves several aspects of splenic structure and function. Antigens carried by capillaries to the marginal sinuses are removed by macrophages and dendritic cells; they are concentrated and processed for presentation to lymphocytes in the white pulp. Other macrophages lie in red pulp cords and in the sheaths surrounding sheathed arterioles. Antigenic material in the sinusoids can be removed by macrophage processes that extend into the lumen; in the cords, such materials are cleared by macrophages and dendritic cells
2. Lymphocyte production (lymphopoiesis). Both T and B lymphocytcs are activated in the spleen. Lymphocyte-antigen interactions are more intense in the white pulp, particularly near the marginal zone, but they also occur in the red pulp. T lymphocyte effector cells formed in the PALS migrate through the pulp cords to the sinusoids to enter the circulation. B lymphocytes stimulated in the marginal zone move to germinal centers of the PWP, where they divide. Plasma cells generated in this way migrate from the white pulp into the red pulp cords, where they remain, producing Igs that percolate into the sinusoids and leave the spleen in the venous blood.
3. Destruction of worn red blood cells occurs in both the spleen and the bone marrow. Toward the end of their average 120-day lifespan, erythrocytes become less flexible; they can frag ment before or during their passage through the spleen. Fragments trapped in red pulp cords are phagocytoscd and digested by macrophages there. The hemoglobin is degraded into several components (13.III.A.3). 4, Extramedullary hematopoiesis, In pathologic conditions such as leukemia, in which bone marrow function (medullary hematopoiesis) is compromised, the spleen may resume its embryonic erythropoietic or granulopoietic activity. In some cases, the liver and lymph nodes resume similar functions.

IX. TONSILS

These incompletely encapsulated lymphoid aggregates contain many lymphoid nodules; they underlie the mucous membranes (epithelial lining) of the mouth and pharynx. Together with the diffuse subepithelial lymphoid tissue that connects them to form a ring, they guard the common entrance to the digestive and respiratory tracts. The 3 types, palatine tonsils, the pharyngeal tonsil, and lingual tonsils, differ in number, epithelial covering, presence (or absence) and number of epithelial Invaginations or crypts, and presence (or absence) of a definitive partial capsule (Table 14-2).

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