CHAPTER 5 THE LYMPHOID TISSUES
CHAPTER 5 THE LYMPHOID TISSUES
THOMAS J. KIPPS
Thymic Immune Function
Lymph Node Anatomy
Lymph Node Structure
Lymph Node Function
Peripheral Lymphoid Tissues
Mucosa-Associated Lymphoid Tissues
The lymphoid tissues can be divided into primary and secondary lymphoid organs. Primary lymphoid tissues are sites where lymphocytes develop from progenitor cells into functional and mature lymphocytes. The major primary lymphoid tissue is the marrow, the site where all lymphocyte progenitor cells reside and initially differentiate. This organ is discussed in Chap. 4. The other primary lymphoid tissue is the thymus, the site where progenitor cells from the marrow differentiate into mature thymus-derived (T) cells. Secondary lymphoid tissues are sites where lymphocytes interact with each other and nonlymphoid cells to generate immune responses to antigens. These include the spleen, lymph nodes, and mucosa-associated lymphoid tissues (MALT). The structure of these tissues provides insight into how the immune system discriminates between self-antigens and foreign antigens and develops the capacity to orchestrate a variety of specific and nonspecific defenses against invading pathogens.
Acronyms and abbreviations that appear in this chapter include: CT, computed tomography; MALT, mucosa-associated lymphoid tissues; MHC, major histocompatibility complex; PALS, periarteriolar lymphoid sheath; T, thymus-derived; TCR, T-cell receptor.
The thymus is the site for development of thymic-dependent lymphocytes, or T cells. It is a primary lymphoid organ in that it is a major site of lymphopoiesis (lymphocyte development). In this organ, developing T cells, called thymocytes, differentiate from lymphoid stem cells derived from the marrow into functional, mature T cells. It is here that T cells acquire their repertoire of specific antigen receptors to cope with the antigenic challenges received throughout one’s life span. Once they have completed their maturation, the T cells leave the thymus and circulate in the blood and through secondary lymphoid tissues.
The thymus is located in the superior mediastinum, overlying, in order, the left brachiocephalic (or innominate) vein, the innominate artery, the left common carotid artery, and the trachea. It overlaps the upper limit of the pericardial sac below and extends into the neck beneath the upper anterior ribs. It receives its blood supply from the internal thoracic arteries. Venous blood from the thymus drains into the brachiocephalic and internal thoracic veins, which communicate above with the inferior thyroid veins.
Arising from the third and fourth brachial pouches as an epithelial organ populated by lymphoid cells, the thymus develops at about the eighth week of gestation. The thymus increases in size through fetal and postnatal life and remains ample into puberty,1 when it weighs about 40 g. Thereafter, the size progressively decreases with aging as a consequence of thymic involution.2,3
The volume of the thymus can be estimated by sonography. In one study of 149 healthy term infants within 1 week of birth, there was a significant correlation between the estimated thymic volume and the weight of the infant.4 However, no correlation was apparent between the estimated thymic volume and the infant’s sex, length, or gestational age. Also, there was no apparent correlation between estimated volume and the proportions of CD4+ T cells or CD8+ T cells found in the blood. The estimated thymic volume of healthy infants increases from birth to 4 and 8 months of age and then decreases.1 Most of the individual variation at 4 and 10 months of age appears to correlate with breast-feeding status, body size, and, to a lesser extent, illness. Breast-fed infants at 4 months of age have significantly larger estimated thymic volumes than do age-matched formula-fed infants with similar thymic volumes at birth.5
A longitudinal fissure divides the thymus into two asymmetrical lobes, a larger right and a smaller left, that are derived from the right and left brachial pouches, respectively. These two developmentally separate parts of the thymus are easily separated from each other by blunt dissection.
Each lobe of the thymus is divided into multiple lobules by fibrous septa. Each lobule consists of an outer cortex and an inner medulla. The cortex contains dense collections of thymocytes that appear as lymphocytes of slightly variable size with scattered, rare mitoses. The lighter-staining medulla is more sparsely populated with cells. It contains loosely arranged mature thymocytes and characteristic tightly packed whorls of squamous-appearing epithelial cells, called Hassall’s corpuscles. These appear to be remnants of degenerating cells and are rich in high-molecular-weight cytokeratins.
The thymus contains several other important cell types in addition to thymocytes. There are three types of specialized epithelial cells within the thymus: the medullary epithelial cells, which are organized into clusters; the cortical epithelial cells, which form an epithelial network; and the epithelial cells of the outer cortex.6 The epithelial cells in the cortex and medulla often have a stellate shape, display desmosomal connections to one another, and may function as nurse cells to developing thymocytes. In addition, the thymus contains marrow-derived antigen-presenting cells, primarily interdigitating dendritic cells and macrophages, particularly at the corticomedullary junction.
After puberty, thymic involution begins within the cortex. This region may disappear completely with aging, while medullary remnants persist throughout life. Corticosteroids also may induce atrophy of the cortex secondary to glucocorticoid-induced apoptosis of cortical thymocytes.7 This also may be seen in conditions that are associated with increases in circulating steroids, for example, pregnancy or stress.8,9
THYMIC IMMUNE FUNCTION
Prothymocytes originate in the marrow and migrate to the thymus, where they mature into T cells (see Chap. 82 and Chap. 84). Maturation of T cells is accompanied by the sequential acquisition by thymocytes of the various T-cell markers (Fig. 5-1). Terminal deoxynucleotidyl transferase is found in prothymocytes and immature thymocytes but is absent in mature T cells.
FIGURE 5-1 Structure of the thymus. The top half of the figure provides a cross section of a thymic lobule, indicating the outer cortex (left), inner medulla (center), and periphery (far right). The marked arrows indicate various structures and cell types. As thymocytes mature, they migrate from the cortex toward the medullary region and acquire phenotypic features that are outlined at the bottom of the figure, as described in the text (see Chap. 82).
Pre–T cells enter the cortex via small blood vessels and are double negative for CD4 and CD8 antigens. One of the earliest identifiable T-cell membrane antigens is CD2. As the thymocytes proliferate and differentiate in the cortex, they acquire CD4 and CD8 antigens. They subsequently acquire the CD3 antigen and the T-cell receptor for antigen as they migrate toward the medulla.
Positive and negative selection of maturing T cells takes place in the thymus. “Double-positive” (CD4+ and CD8+) thymocytes undergo an initial positive selection step that is mediated exclusively by thymic cortical epithelium.10 Thymocytes that have T-cell receptors (TCR) capable of interacting with the major histocompatibility complex (MHC) molecules expressed by thymic cortical epithelial cells will undergo expansion, while thymocytes with defective TCR will undergo apoptosis.11,12 As these positively selected cells migrate toward the medulla, they experience negative selection. Those thymocytes that have TCR that react too vigorously with the MHC molecules of the medullary epithelium and marrow-derived cells will undergo apoptosis.12,13 and 14 Most of the developing thymocytes are destroyed. In this way, only those T cells that have the right level of low affinity for self-MHC molecules will reach the final maturation stages and be allowed to exit the thymus.
The selected thymocytes enter the thymic medulla, where they further mature and differentiate to become “single positive” for either CD4 or CD8 and acquire the capacity for future helper and cytolytic functions, respectively. Here they also may interact with scattered B cells during their final stages of thymic education (see Chap. 15, Chap. 82, and Chap. 84). A small percentage of the lymphocytes produced in the thymus finally exit the medulla via efferent lymphatics as mature, naive T cells.
The spleen is a secondary lymphoid organ. Secondary lymphoid tissues provide an environment in which the cells of the immune system can interact with antigen and with one another to develop an immune response to antigen. The spleen is a major site of immune response to blood-borne antigens. In addition, the splenic red pulp contains macrophages that are responsible for clearing the blood of unwanted foreign substances and senescent erythrocytes, even in the absence of specific immunity. Thus, it acts as a filter for the blood.
The spleen is located within the peritoneum in the left upper quadrant of the abdomen between the fundus of the stomach and the diaphragm. It receives its blood supply from the systemic circulation via the splenic artery, which branches off the celiac trunk, and the left gastroepiploic artery.15 The blood returning from the spleen drains into the portal circulation via the splenic vein. Therefore, the spleen can become congested with blood and increase in size when there is portal hypertension.
About 10 percent of individuals have one or more accessory spleens. Accessory spleens are usually 1 cm in diameter and resemble lymph nodes. However, they usually are covered with peritoneum, as is the spleen itself. Accessory spleens typically lie along the course of the splenic artery or its gastroepiploic branch, but they may be elsewhere.16 The commonest location is near the hilus of the spleen, but approximately one in six accessory spleens can be found embedded in the tail of the pancreas, where they may be occasionally mistaken for a pancreatic mass lesion.17,18,19,20 and 21
The average weight of the spleen in the adult human is 135 g, ranging from 100 to 250 g. However, when emptied of blood it weighs only about 80 g. On autopsy of 539 subjects with normal spleens, there was a positive correlation between the spleen weight and both the degree of acute splenic congestion and the subject’s height and weight but not with the subject’s sex or age.22
The splenic volume can be estimated by computed tomography (CT) of the abdomen.23,24 In one study, the splenic volume was calculated from the linear and the maximal cross-sectional area measurements of the spleen, using the following formula: splenic volume = 30 cm3 + 0.58 × the product of the measured width, length, and thickness of the spleen.23 Using this formula, the mean value of the calculated splenic volume for 47 normal subjects was 214.6 cm3, with a range from 107.2 to 314.5 cm3. The calculated splenic volume did not appear to vary significantly with the subject’s age, gender, height, weight, body mass index, or the diameter of the first lumbar vertebra, the latter being considered representative of body habitus on CT.
The splenic volume also can be estimated by sonography. In one study of 32 normal spleens from adult corpses, the ultrasound measurements of maximal height, width, and breadth of the spleen were compared with the actual volume displaced by the excised organ.25 The mean actual splenic volume was approximately 148 cm3 (± 81 cm3 SD), whereas mean splenic volume estimated from ultrasound was 284 cm3 (± 168 cm3 SD). Despite the differences between the actual and estimated volumes, these investigators did find a roughly linear correlation between actual splenic volume and the estimated splenic volume measured by ultrasound. However, there may be operator-to-operator variation in measurement of the estimated splenic volume, making the use of sonography in longitudinal studies technically demanding.
The spleen has an “open” circulation, which lacks endothelial continuity from artery to vein.26 When isolated spleens are perfused in washout studies, erythrocytes that appear in the splenic vein appear to be flushed out from three compartments. The red cells that are flushed out first come from a compartment that presumably is formed by the splenic vessels. The erythrocytes that are flushed out next come from a second compartment, where they presumably are loosely held within the filtration beds. The erythrocytes that are flushed out last presumably were adherent to cells of the filtration beds. Although 90 percent of the blood flow passes through the splenic vessels, only about 10 percent of the total splenic red cells are found within this first compartment. The second compartment is perfused by 9 percent of the total inflow yet contains 70 percent of the splenic red cells. The last compartment is perfused by only 1 percent of the inflow but contains 20 percent of the splenic red cells.
These compartments reflect the anatomy of the spleen and its stroma. The stroma is composed of branched, fibroblast-like cells called reticular cells. These cells produce slender collagen fibers, the reticular fibers, which are rich in type IV collagen. The reticular cells and fibers form a meshwork, or reticulum, which filters the blood. Three major types of filtration beds can be distinguished by their structure and content: the white pulp, the marginal zone, and the red pulp.
The white pulp contains the lymphocytes and other mononuclear cells that surround the arterioles branching off the splenic artery. After the splenic artery pierces the splenic capsule at the hilum, it divides into progressively smaller branches. Each branch is called a central artery because it runs through the central longitudinal axis of a distinctive filtration bed that surrounds each central artery (Fig. 5-2). This is composed of a cuff of lymphocytes called the periarteriolar lymphoid sheath (or PALS). The PALS is contained within a protective and supporting fibrous trabecula and is composed mostly of T lymphocytes, about two-thirds of which are CD4+ T cells. Attached to the PALS are lymphoid follicles, some of which contain pale kernels of activated lymphocytes interspersed with large, pale macrophages and dendritic cells called germinal centers.27 On gross inspection of the surface of a freshly cut spleen, these appear as white dots referred to as Malpighian corpuscles. These corpuscles predominantly contain a germinal center and have the same anatomic features and functions as secondary follicles in the lymph node (Fig. 5-3).
FIGURE 5-2 Structure of the spleen. A branch of the splenic artery enters the pulp and becomes a central artery. Surrounding the central artery is a PALS. At the circumference of the PALS is the marginal zone, which generally separates the white pulp of the PALS from the red pulp. Follicles of B cells with occasional germinal centers (Malpighian corpuscles) are located at the outer margins of the PALS for the depicted central artery and the PALS of central arteries that are in a different plane from that of the figure.
FIGURE 5-3 Structure of the lymph node. The lymph enters via afferent lymphatic channels and exits via the efferent lymphatic channel. The large arrows indicate the direction of the lymphatic flow into and out of the lymph node. The legend shows the symbols used for the T-cell zone (x) and the B-cell zone (shaded) of each follicle. The follicle in the lower left part of the node contains a primary follicle lacking a germinal center. The follicle immediately above this follicle contains a germinal center. Thus, the entire follicle delineated by the dashed lines is a secondary follicle. The cortex, paracortical area, and medulla are also shown.
Branches coming off the central artery deliver disproportionate amounts of plasma and lymphocytes to the rims of the PALS. These branches tend to run at acute angles, leading to a selective loss of plasma from the blood, a phenomenon referred to as skimming. After becoming relatively depleted of plasma, the arterioles then carry high-hematocrit blood into the filtration beds of the red pulp and marginal zone. As a result, the red pulp and marginal zone beds contain relatively high concentrations of red cells.
THE MARGINAL ZONE
The marginal zone surrounds the PALS and follicles. It is composed of reticulum, which forms a finely meshed filtration bed, serving as a vestibule for much of the blood that flows through the spleen. The marginal zone surrounds the white pulp and merges insensibly into the red pulp. It contains more lymphocytes than the red pulp. These are primarily memory B cells and CD4+ T cells.28,29 and 30 However, like the red pulp, the marginal zone may become congested and clear imperfect and senescent red cells and parasites.
THE RED PULP
The red pulp of the spleen is composed of a reticular meshwork, called the splenic cords of Billroth, and splenic sinuses. This region predominantly contains erythrocytes but has large numbers of macrophages and dendritic cells. There are relatively few lymphocytes and plasma cells in this area.
As the central arteries branch and decrease in size, the PALS also branches and decreases in diameter to but a few cells surrounding the arteriole. The small arteriole finally emerges from its sheath and then terminates in either the marginal zone or the red pulp. Here these vessels are suspended and anchored by adventitial reticular cells in the periarterial beds. They often terminate abruptly as arteriolar capillaries or as vessels with a trumpetlike flare with widened slits called interendothelial slits. The blood flows through these slits into filtration beds composed of large-meshed loculi that open to one another.
The blood in the red pulp and marginal zone drains into venous sinuses that form anastomosing, blind-ending vessels. These venous sinuses actually are specialized postcapillary venules. The endothelial cells are shaped as tapered rods that are stiffened by basal, longitudinal, intermediate cytoskeletal filaments and contractile filaments of actin and myosin. These intracellular contractile filaments can shorten the vein, causing the endothelium to buckle and form interendothelial gaps, favoring transmural passage.
The endothelial cells are attached to a basement membrane. While this appears to be fashioned of fibers, the basement membrane actually is an extracellular membranous wall with large, regular defects that expose considerable basal endothelial surface. This includes the interendothelial slits, through which blood may flow from the filtration bed and into the vein. Ordinarily the interendothelial slits are narrow or even closed unless forced apart by cells in transmural transit or by endothelial contraction.
Splenic arterioles terminate at varied distances from the walls of venous vessels. Blood flowing from arterioles that terminate at the venous vessel wall may flow directly into the splenic vein. However, blood flowing from arterioles that terminate at a distance from a vein must traffic through the spleen. In so doing, the blood either may pass quickly through a nonsinusal venous aperture or slowly through sinusal interendothelial slits and the fibroblast stroma.
The fibroblast stroma contains reticular cells and myofibroblast cells, also called barrier cells.31 The latter may fuse with each other to form a syncytial membrane that connects the arterial terminals with venous interendothelial slits or apertures. Like other myofibroblasts, these cells contain actin and myosin and may contract, thereby approximating splenic arterial and venous vessels with one another. Thus, the fibroblast stroma may affect the relative proportion of blood that flows through the sinusal interendothelial slits and the stroma itself.
RED CELL CLEARANCE
Mixed within the stroma of the red pulp and marginal zone are monocytes and macrophages. As the blood passes through the stroma, monocytes may be held on the stroma, where the microenvironment is conducive to their maturation into macrophages and large, dendritic, lysosome-rich phagocytes. These cells may assist the reticular cells in mechanical filtration. More important, these cells have phagocytic activity that allows them to ingest imperfect erythrocytes, store platelets, and remove infectious agents, such as Plasmodia, from the circulation. In addition, these cells have nonphagocytic functions, such as the presentation of antigens to T cells or the elaboration of certain cytokines.
Collectively, the anatomy of the spleen allows the marginal zone and red pulp to cull defective erythrocytes. As the blood passes slowly through the sinusal interendothelial slits and the fibroblast stroma, the erythrocytes must undergo alterations in shape to squeeze through the mechanical barrier generated by this filtration compartment. Normal red cells that are supple may pass through readily because the interendothelial slits can open to about 0.5 µm. However, blood cells containing large, rigid inclusions, such as plasmodium-containing erythrocytes, are delayed or sequestered. Moreover, splenic macrophages residing within these filtration beds can sequester erythrocytes that are coated with antibody.
When these filtration beds sequester imperfect red cells, the blood pools inside the spleen, causing stasis and congestion. This stimulates sphincterlike contraction of the distal vein, resulting in proximal plasma transudation that produces a viscous luminal mass of high-hematocrit blood. During episodes of enhanced red cell sequestration, as occur during malarial crises or hemolytic episodes in sickle cell disease, the splenic volume and weight may increase ten- to twenty-fold.32,33 Although the white pulp may enlarge, particularly in germinal centers, the marginal zones and red pulp become greatly widened with pooled erythrocytes and macrophages in this setting.
SPLENIC IMMUNE FUNCTION
The spleen and its responses to antigens are similar to those of lymph nodes, the major difference being that the spleen is the major site of immune responses to blood-borne antigens, while lymph nodes are involved in responses to antigens in the lymph. Antigens and lymphocytes enter the spleen through the vascular sinusoids, since the spleen lacks high endothelial venules. Upon entry, the lymphocytes home to the white pulp. T cells migrate to the PALS and B cells to the lymphoid nodules. T cells and B cells migrate within these compartments for about 5 and 7 h, respectively. In the absence of an immune response, these cells migrate through a reticulum arranged around the circumference of the central artery.
Upon immune activation in response to antigen, the lymphocytes may remain in the spleen to sustain a primary or secondary immune response. Activation of B cells is initiated in the marginal zones that are adjacent to CD4+ T cells in the PALS. Activated B cells then migrate into germinal centers or into the red pulp.34 Lymphoid nodules appear and expand by recruiting lymphocytes from the blood and the peripheral zone of the follicles, termed the mantle zone. These cells then proliferate and differentiate in the center of a lymphoid nodule, forming a germinal center.35 In their path from the marginal zone to the follicles, B cells pass the PALS, where they remain in contact with T lymphocytes for a few hours, allowing ample time for T-B cell interaction in response to antigens. If they are not recruited in an immune response to antigen, both T and B lymphocytes exit the spleen via deep efferent lymphatics, not the splenic veins.
These efferent lymphatics are not distinguished as separate structures within the PALS, being quite thin-walled and often packed with efferent lymphocytes. However, they are important in moving nonreactive lymphocytes out of the spleen and in producing high-hematocrit pulp blood. After leaving the spleen, the efferent lymphocytes become the afferent lymphatics of the perisplenic mesenteric lymph nodes or empty into the thoracic duct. This duct empties into the left subclavian vein, thus returning the lymphocytes to the venous circulation.
The lymphoid nodes are secondary lymphoid tissues. They form part of a network that filters antigens from the interstitial tissue fluid and lymph during its passage from the periphery to the thoracic duct. Thus, the lymph nodes are the primary sites of immune response to tissue antigens.
LYMPH NODE ANATOMY
The lymph nodes are round or kidney-shaped clusters of mononuclear cells that normally are less than 1 cm in diameter. A collagenous capsule surrounds a typical lymph node and has an indentation called the hilus where blood vessels enter and leave.
Lymph nodes typically are present at the branches of the lymphatic vessels and form part of the extensive network of lymphatic channels that extends throughout the body. Several afferent lymphatic channels that drain lymph from regional tissues into the lymph node perforate the capsule of each lymph node. The lymph draining from the node leaves through one efferent lymphatic vessel at the hilus. The lymph from the node, in turn, empties into efferent lymphatic vessels that eventually drain into larger lymphatic channels leading eventually to the thoracic duct. The thoracic duct in turns drains into the left subclavian vein, thus returning lymph into the systemic circulation.
Clusters of lymph nodes are placed strategically in areas that drain various superficial and deep regions of the body, such as the neck, axillae, groin, mediastinum, and abdominal cavity. The lymph nodes that receive lymph that drains from the skin, termed somatic nodes, are superficial. The lymph nodes that receive their lymph from the mucosal surface of the respiratory, digestive, or genitourinary tract, termed visceral nodes, are usually deep within body cavities.
LYMPH NODE STRUCTURE
Beneath the collagenous capsule is the subcapsular sinus, into which the afferent lymphatic channels drain (see Fig. 5-3). This sinus is lined with phagocytic cells. Fibrous trabeculae radiate from the medulla adjacent to the hilus of the node to the subcapsular sinus, thus breaking the node into several follicles, called cortical follicles. These trabeculae, together with the capsule and a network of reticulin fibers, support the various cellular components of the node and serve as the scaffolding for lymphatic spaces, namely, the subcapsular and cortical sinuses. These lymphatic spaces are continuous with medullary sinuses and the solitary efferent lymphatic channel exiting the hilus.
Each cortical follicle contains dense collections of small, mature, recirculating lymphocytes. These consist of a B-cell area (cortex), a T-cell area (paracortex), and a central medulla with cellular cords that contain T cells, B cells, plasma cells, and macrophages. Some follicles contain lightly staining areas of 1- to 2-mm in diameter, called germinal centers. Germinal centers are the specialized sites for the generation of memory B cells and antibody affinity maturation via the process of immunoglobulin variable-region somatic hypermutation.36,37 Follicles without germinal centers are called primary follicles, and those with germinal centers are called secondary follicles. Primary lymphoid follicles contain nodules that consist predominantly of small, mature, recirculating B lymphocytes.
Within 1 week after antigenic stimulation, secondary follicles develop a germinal center, which contains proliferating B cells and macrophages.27,38 The small, nonreactive B cells are apparently forced to the periphery of the follicle, where they form a dense follicular mantle. The B cells within the germinal center, on the other hand, are highly activated, typically forming blasts that have abundant cytoplasm and round, cleaved, or convoluted shapes. Follicular dendritic cells also are found within the germinal centers. These cells can trap and retain antigens for months, possibly in the form of immune complexes.39 The germinal centers of the secondary follicle may gradually regress after the antigenic stimulus is eliminated.
Surrounding the lymphoid follicles of the superficial cortex are sheets of lymphocytes that extend to the deep cortex, the so-called paracortex, that blend into medullary cords of cells. The paracortical zones are formed mostly of T cells. The ratio of T cells to B cells in these zones is about 3:1. The medulla, however, contains scattered B cells, dendritic cells, macrophages, and, during an immune response, plasma cells. The superficial cortex and medulla of the lymph nodes are the thymic-independent areas, while the deep cortex is particularly enriched with T cells, forming an area that sometimes is referred to as the thymic-dependent area. The major T-cell population found within the lymph node consists of CD4+ T cells. The scattering of CD4+ T cells in the follicles, and in more prominent numbers in the interfollicular zones, reveals the proximity of CD4+ T and B cells important for T-B cooperation during proliferation and maturation of antigen-stimulated B cells.40
Lymphocytes primarily enter lymphatic tissues from the blood by migrating across the tall, active endothelium of specialized post-capillary venules called high endothelial venules.41 Cellular adhesion molecules and various chemokines are responsible for the pattern of lymphocyte trafficking and determine the microanatomy of the lymphoid tissues.42
LYMPH NODE FUNCTION
The lymph node is the site where different types of lymphocytes, macrophages, and dendritic cells can interact with one another to generate an immune response to antigens carried within the lymph. As the lymph passes across the nodes from afferent to efferent lymphatic vessels, particulate antigens are removed by the phagocytic cells and transported into the lymphoid tissue of the lymph node. Abnormal cells within the lymph, such as neoplastic cells, also can be trapped within the lymph node.
Within the lymph node, antigen is presented to T cells as processed peptides by MHC molecules of antigen-presenting cells (see Chap. 84). Various T-cell subsets comprise a network of interactive cells. CD4+ and CD8+ cell-mediated contacts, as well as T cell–derived soluble factors, induce and regulate the immune response (see Chap. 15). T-cell recognition is mediated by the TCR for antigen (see Chap. 84). Which T cells are activated is determined by the specificity of the TCRs (see Chap. 86), the structure of MHC molecules, and the nature of antigen-presenting cells, including the dendritic reticular cells, macrophages, and B cells.
However, along with TCR recognition of processed antigen presented in the MHC of the antigen-presenting cell, adequate T-cell activation requires second signals, or costimulation, delivered through accessory molecules, such as CD28 on T cells (see Chap. 84).43 Without these second signals, the T cells may become anergic, or specifically nonresponsive to antigen stimulation. This specific suppression is thought to play an important regulatory role in the maintenance of self-tolerance.44,45
T-cell recognition of specific antigen may induce release of soluble factors, such as the interleukins, that can activate T cells, B cells, and/or monocytes.46,47,48 and 49 Also, the activated T cells express surface molecules, such as CD40 ligand, that also can activate B cells, dendritic cells, or macrophages.50,51
The T-dependent immune response includes the formation of early germinal centers within days after antigen exposure. There is a mixture of B cells and activated CD4+ T cells in the lymphoid follicles. T-B cooperation involves the accessory B-cell antigen CD40 and the CD40 ligand expressed on activated T cells (see Chap. 15). Activated B cells become blasts and comprise the largest numbers of cells in the early germinal center.27 Subsequently, B-cell blasts give rise to smaller B cells, the centrocytes. B cells undergo affinity maturation within the germinal center. During this process, the genes encoding the surface immunoglobulin of B cells undergo high rates of mutation, called somatic hypermutation.35,52 B cells, including the centrocytes, that express immunoglobulin with little or no affinity for antigen undergo apoptosis.53 The resulting cellular debris is tingible, or capable of being stained, and is found prominently within macrophages specifically designated tingible body macrophages. On the other hand, B cells expressing surface immunoglobulin with high affinity for antigen are selected to proliferate and differentiate to memory B cells or plasma cells.38 As well as promoting activation of B cells, CD4+ T cells, and CD8+ T cells, the T-cell limb of the primary immune response may generate circulating CD4+ and CD8+ memory T cells.54,55
Following release of specific antibody, antigen-antibody complexes may form and become sequestered on the surface of follicular dendritic cells within the germinal centers. These antigen-antibody complexes produce a coating of small, beadlike, immune complex–coated bodies called iccosomes. Iccosomes may be presented to CD4+ T cells by B cells and dendritic cells. Iccosomes also appear to assist in anamnestic recall of high levels of antibody following reentry of antigen in the host.56 T-cell and B-cell memory functions and self-tolerance depend upon persistence of antigen.54,57,58 and 59
PERIPHERAL LYMPHOID TISSUES
MUCOSA-ASSOCIATED LYMPHOID TISSUES
The MALT are diffusely organized aggregates of lymphocytes that protect the respiratory and gastrointestinal epithelium. The lymphoid aggregates associated with the respiratory epithelium are sometimes referred to as the bronchial-associated lymphoid tissue. The lymphoid aggregates associated with the intestinal epithelium are sometimes referred to as the gut-associated lymphoid tissue.60 These tissues include the tonsils, adenoids, appendix, and specialized structures called Peyer’s patches found in the ileum, and they collect antigen from the epithelial surfaces of the gastrointestinal tract.
Solitary lymph nodules with follicular and germinal center structures occur in the mucosa and submucosa of the respiratory tract, the gastrointestinal tract (particularly within the ileum), the urinary tract, and the vagina. During states of chronic inflammation, lymphoid nodules may form as a localized center of lymphocytes with marked follicular activity. Waldeyer’s ring of pharyngeal lymphoid tissues and Peyer’s patches in the ileum contain prominent aggregated nodular lymphoid tissue. No capsule or efferent or afferent lymphatic vessels are present in these accessory lymphoid tissues.
These MALT are rich in plasma cells and eosinophils. The plasma cells are a source of secretory immunoglobulin that is transferred into the lumina of the bronchi and gastrointestinal tract. The majority of plasma cells in the mucosa of the bronchi and gut contain IgA. IgA is released from the plasma cell and then combines with a secretory piece synthesized within the mucosal epithelium to become secretory IgA (see Chap. 83). Secretory IgA then is secreted across the microvilli of mucosal epithelium into the lumen, where it may prevent colonization of mucosal membranes by pathogens. Lymphoid nodules along mucosa-lined tracts serve as precursors of IgA-producing cells. These nodules form a barrier against many microorganisms and antigens. Microfolds overlying specialized epithelial cells in the gut transport antigenic material by pinocytosis, with subsequent immunization and IgA secretion.
Peyer’s patches are the most important and highly organized of the gut-associated lymphoid tissues. They are found in the lamina propria of the small intestine (beneath the mucosa near the ileocolonic junction) and consist of up to 50 or more lymphoid nodules covered by a single layer of columnar epithelium. They are well developed in youth and regress with age. Antigens from the intestinal epithelium are collected by specialized epithelial cells called M cells, allowing for generation of specific immune responses against intestinal pathogens.61 Peyer’s patches are the sites at which B cells differentiate, in response to these antigens, into the plasma cells found within the intestine.62
The tonsils are the major component of Waldeyer’s ring of pharyngeal lymphoid tissues. They are covered by variable epithelial surfaces that have deep, branching depressions called crypts. Fused lymphatic nodules lie adjacent to the crypts, and germinal centers are prominent. A pseudocapsule of condensed connective tissue surrounds the tonsils, and septae within the structures form lobulations. Together with the other lymphoid tissues of Waldeyer’s ring, the tonsils provide the initial barrier to pathogens entering the oral pharynx.
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Ernest Beutler, Marshall A. Lichtman, Barry S. Coller, Thomas J. Kipps, and Uri Seligsohn