Ii

Immature eosinophil Eosinophil

Monoblast

Monoblast

Monocyte

Monocyte

Pre-dendritic cell Dendritic cell Neutrophil

Pre-dendritic cell Dendritic cell Neutrophil

° 03^ Myeloblast

Self-renewal

CD34+ LIN-

FIGURE 2-9 Hematopoiesis. The development of the different lineages of blood cells is depicted in this "hematopoietic tree." Also shown are the principal cytokines that drive the maturation of different lineages. The development of lymphocytes forming the common lymphoid precursor is described later in this chapter and in Figure 8-2, Chapter 8. SCF, stem cell factor; Flt3L, Flt3 ligand; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; LIN-, negative for lineage-specific markers; M-CSF, macrophage colony-stimulating factor.

Lineage specific markers

FIGURE 2-9 Hematopoiesis. The development of the different lineages of blood cells is depicted in this "hematopoietic tree." Also shown are the principal cytokines that drive the maturation of different lineages. The development of lymphocytes forming the common lymphoid precursor is described later in this chapter and in Figure 8-2, Chapter 8. SCF, stem cell factor; Flt3L, Flt3 ligand; G-CSF, granulocyte colony-stimulating factor; GM-CSF, granulocyte-macrophage colony-stimulating factor; LIN-, negative for lineage-specific markers; M-CSF, macrophage colony-stimulating factor.

division of the HSCs. HSCs give rise to two kinds of multipotent cells, the common lymphoid and common myeloid progenitors. The common lymphoid progenitor is the source of committed single-lineage precursors of T cells, B cells, or NK cells. Most of the steps in B cell maturation take place in the bone marrow, but the final events may occur after the cells leave the marrow and enter secondary lymphoid organs, particularly the spleen. T cell maturation occurs entirely in the thymus and therefore requires that common lymphoid progenitors or some poorly characterized progeny of these cells migrate out of the marrow into the blood and then into the thymus. NK cell maturation is thought to take place entirely in the bone marrow. The common myeloid progenitors give rise to committed single-lineage progenitors of the ery-throid, megakaryocytic, granulocytic, and monocytic lineages, which give rise, respectively, to mature red cells, platelets, granulocytes (neutrophils, eosinophils, basophils), and monocytes. Most dendritic cells arise from the monocytic lineage.

The proliferation and maturation of precursor cells in the bone marrow are stimulated by cytokines (see

TABLE 2-4 Hematopoietic Cytokines

Cytokine

Size

Principal Cellular Sources

Principal Cellular Targets

Principal Cell Populations Induced

Stem cell factor (c-Kit ligand)

24 kD

Bone marrow stromal cells

Hematopoietic stem cells

All

Interleukin-7 (IL-7)

25 kD

Fibroblasts, bone marrow stromal cells

Immature lymphoid progenitors

B and T lymphocytes

Interleukin-3 (IL-3)

20-26 kD

T cells

Immature progenitors

All

Granulocyte-monocyte colony-stimulating factor (GM-CSF)

18-22 kD

T cells, macrophages, endothelial cells, fibroblasts

Immature and committed myeloid progenitors, mature macrophages

Granulocytes and monocytes, macrophage activation

Monocyte colony-stimulating factor (M-CSF)

Dimer of 70-90 kD; 40-kD subunits

Macrophages, endothelial cells, bone marrow cells, fibroblasts

Committed progenitors

Monocytes

Granulocyte colony-stimulating factor (G-CSF)

19 kD

Macrophages, fibroblasts, endothelial cells

Committed granulocyte progenitors

Granulocytes

Fig. 2-9). Many of these cytokines are called colony-stimulating factors because they were originally assayed by their ability to stimulate the growth and development of various leukocytic or erythroid colonies from marrow cells. Hematopoietic cytokines are produced by stromal cells and macrophages in the bone marrow, thus providing the local environment for hematopoiesis. They are also produced by antigen-stimulated T lymphocytes and cytokine-activated or microbe-activated macrophages, providing a mechanism for replenishing leukocytes that may be consumed during immune and inflammatory reactions. The names and properties of the major hema-topoietic cytokines are listed in Table 2-4.

In addition to self-renewing stem cells and their differentiating progeny, the marrow contains numerous antibody-secreting plasma cells. These plasma cells are generated in peripheral lymphoid tissues as a consequence of antigenic stimulation of B cells and then migrate to the marrow, where they may live and continue to produce antibodies for many years. Some long-lived memory T lymphocytes also migrate to and may reside in the bone marrow.

Thymus

The thymus is the site of T cell maturation. The thymus is a bilobed organ situated in the anterior mediastinum. Each lobe is divided into multiple lobules by fibrous septa, and each lobule consists of an outer cortex and an inner medulla (Fig. 2-10). The cortex contains a dense collection of T lymphocytes, and the lighter-staining medulla is more sparsely populated with lymphocytes. Bone marrow-derived macrophages and dendritic cells are found almost exclusively in the medulla. Scattered throughout the thymus are nonlymphoid epithelial cells, which have abundant cytoplasm. Thymic cortical epithelial cells provide IL-7 required early in T cell development. A subset of these epithelial cells found only in the medulla, called thymic medullary epithelial cells (often abbreviated as TMEC), play a special role in presenting self antigens to developing T cells and causing their deletion. This is one mechanism of ensuring that the immune system remains tolerant to self and is discussed in detail in Chapter 14. In the medulla are structures called Hassall's corpuscles, which are composed of tightly packed whorls of epithelial cells that may be remnants of degenerating cells. The thymus has a rich vascular supply and efferent lymphatic vessels that drain into mediastinal lymph nodes. The epithelial component of the thymus is derived from invaginations of the ectoderm in the developing neck and chest of the embryo, forming structures called branchial pouches. Dendritic cells, macrophages, and lymphocyte precursors are derived from the bone marrow.

Humans with DiGeorge syndrome suffer from T cell deficiency because of mutations in genes required for thymus development. In the "nude" mouse strain, which has been widely used in immunology research, a mutation in the gene encoding a transcription factor causes a failure of differentiation of certain types of epithelial cells that are required for normal development of the thymus and hair follicles. Consequently, these mice lack T cells and hair.

The lymphocytes in the thymus, also called thymocytes, are T lymphocytes at various stages of maturation. Cells that are committed to the T cell lineage are believed to develop in the bone marrow from common lymphoid progenitor cells, enter the circulation, and home to the thymic cortex through the blood vessels. Further maturation in the thymus begins in the cortex, and as thymo-cytes mature, they migrate toward the medulla, so that the medulla contains mostly mature T cells. Only mature T cells exit the thymus and enter the blood and peripheral lymphoid tissues. The details of thymocyte maturation are described in Chapter 8.

FIGURE 2-10 Morphology of the thymus. A, Low-power light micrograph of a lobe of the thymus showing the cortex and medulla. The darker blue-stained outer cortex and paler blue inner medulla are apparent. B, High-power light micrograph of the thymic medulla. The numerous small blue-staining cells are developing T cells called thymocytes, and the larger pink structure is Hassall's corpuscle, uniquely characteristic of the thymic medulla but whose function is poorly understood. C, Schematic diagram of the thymus illustrating a portion of a lobe divided into multiple lobules by fibrous trabeculae.

FIGURE 2-10 Morphology of the thymus. A, Low-power light micrograph of a lobe of the thymus showing the cortex and medulla. The darker blue-stained outer cortex and paler blue inner medulla are apparent. B, High-power light micrograph of the thymic medulla. The numerous small blue-staining cells are developing T cells called thymocytes, and the larger pink structure is Hassall's corpuscle, uniquely characteristic of the thymic medulla but whose function is poorly understood. C, Schematic diagram of the thymus illustrating a portion of a lobe divided into multiple lobules by fibrous trabeculae.

The Lymphatic System

The lymphatic system, which consists of specialized vessels that drain fluid from tissues into and out of lymph nodes and then into the blood, is essential for tissue fluid homeostasis and immune responses (Fig. 2-11). Interstitial fluid is constitutively formed in all vascularized tissues by movement of a filtrate of plasma out of capillaries, and the rate of local formation can increase dramatically when tissue is injured or infected. The skin, epithelia, and parenchymal organs contain numerous lymphatic capillaries that absorb this fluid from spaces between tissue cells. The lymphatic capillaries are blind-ended vascular channels lined by overlapping endothelial cells without the tight intercellular junctions or basement membrane that are typical of blood vessels. These distal lymphatic capillaries permit free uptake of interstitial fluid, and the overlapping arrangement of the endothelial cells and one-way valves within their lumens prevents backflow of the fluid. The absorbed fluid, called lymph once it is within the lymphatic vasculature, is pumped into convergent, ever larger lymphatic vessels by the contraction of perilymphatic smooth muscle cells and the pressure exerted by movement of the musculoskeletal tissues.

Cervical nodes

Thoracic duct

Draining lymph node

Infection site

Cervical nodes

Thoracic duct

Draining lymph node

Infection site

Intercostal vessels

Axillary nodes

FIGURE 2-11 The lymphatic system. The major lymphatic vessels, which drain into the inferior vena cava (and superior vena cava, not shown), and collections of lymph nodes are illustrated. Antigens are captured from a site of infection and the draining lymph node to which these antigens are transported and where the immune response is initiated.

Intercostal vessels

Axillary nodes

Cisterna chyli

Para-aortic nodes

Vessels from intestines

Inguinal nodes

FIGURE 2-11 The lymphatic system. The major lymphatic vessels, which drain into the inferior vena cava (and superior vena cava, not shown), and collections of lymph nodes are illustrated. Antigens are captured from a site of infection and the draining lymph node to which these antigens are transported and where the immune response is initiated.

These vessels merge into afferent lymphatics that drain into lymph nodes, and the lymph drains out of the nodes through efferent lymphatics. Because lymph nodes are connected in series by lymphatics, an efferent lymphatic exiting one node may serve as the afferent vessel for another. The efferent lymph vessel at the end of a lymph node chain joins other lymph vessels, eventually culminating in a large lymphatic vessel called the thoracic duct. Lymph from the thoracic duct is emptied into the superior vena cava, thus returning the fluid to the blood stream. Lymphatics from the right upper trunk, right arm, and right side of the head drain into the right lymphatic duct, which also drains into the superior vena cava. About 2 liters of lymph are normally returned to the circulation each day, and disruption of the lymphatic system may lead to rapid tissue swelling.

The lymphatic system collects microbial antigens from their portals of entry and delivers them to lymph nodes, where they can stimulate adaptive immune responses. Microbes enter the body most often through the skin and the gastrointestinal and respiratory tracts. All these tissues are lined by epithelia that contain dendritic cells, and all are drained by lymphatic vessels. The dendritic cells capture some microbial antigens and enter lymphatic vessels. Other microbes and soluble antigens enter the lymphatics independently of dendritic cells. In addition, soluble inflammatory mediators, such as che-mokines, produced at sites of infection enter the lymphatics. The lymph nodes are interposed along lymphatic vessels and act as filters that sample the soluble and dendritic cell-associated antigens in the lymph before it reaches the blood and permit the antigens to be seen by the adaptive immune system.

Lymph Nodes

Lymph nodes are encapsulated, vascularized secondary lymphoid organs with anatomic features that favor the initiation of adaptive immune responses to antigens carried from tissues by lymphatics (Fig. 2-12). Lymph nodes are situated along lymphatic channels throughout the body and therefore have access to antigens encountered at epithelia and originating in interstitial fluid in most tissues. A lymph node is surrounded by a fibrous capsule, beneath which is a sinus system lined by reticular cells, cross-bridged by fibrils of collagen and other extracellular matrix proteins and filled with lymph, macrophages, dendritic cells, and other cell types. Afferent lymphatics empty into the subcapsular (marginal) sinus, and lymph may drain from there directly into the connected medullary sinus and then out of the lymph node through the efferent lymphatics. Beneath the inner floor of the subcapsular sinus is the lymphocyte-rich cortex. The outer cortex contains aggregates of cells called follicles. Some follicles contain central areas called germinal centers, which stain lightly with commonly used histologic stains. Follicles without germinal centers are called primary follicles, and those with germinal centers are secondary follicles. The cortex around the follicles is called the parafollicular cortex or paracortex and is organized into cords, which are regions with a complex microanatomy of matrix proteins, fibers, lymphocytes, dendritic cells, and mononuclear phagocytes.

Anatomic Organization of B and T Lymphocytes

B and T lymphocytes are sequestered in distinct regions of the cortex of lymph nodes, each region with its own unique architecture of reticular fibers and stromal cells (Figs. 2-13 and 2-14). Follicles are the B cell zones. They are located in the lymph node cortex and are organized around FDCs, which have processes that interdigitate to form a dense reticular network. Primary follicles contain mostly mature, naive B lymphocytes. Germinal centers develop in response to antigenic stimulation. They are sites of remarkable B cell proliferation, selection of B cells producing high-affinity antibodies, and generation of memory B cells and long-lived plasma cells. The T lymphocytes are located mainly beneath and more central to the follicles, in the paracortical cords. These T cell-rich zones contain a network of fibroblastic reticular cells (FRCs), which are arranged to form the outer layer of tube-like structures called FRC conduits. The conduits range in diameter from 0.2 to 3 |jm and contain organized arrays of extracellular matrix molecules, including innermost parallel bundles of collagen fibers embedded in a meshwork of fibrillin microfibers, all tightly

B cell zone (follicle)

High endothelial venule (HEV)

Antigen

Antigen i} Afferent lymphatic

Subcapsular sinus

B cell zone (follicle)

High endothelial venule (HEV)

i} Afferent lymphatic

Subcapsular sinus

Germinal' Medulla sinus center Medullar/ Efferent lymphatic Vein vessel ■''30I Lymphocytes

T cell zone

Germinal' Medulla

Capsule Trabecula sinus center Medullar/ Efferent lymphatic Vein vessel ■''30I Lymphocytes

Primary lymphoid follicle (B cell zone)

Primary lymphoid follicle (B cell zone)

Secondary

Parafollicular' follicle with cortex (T cell zone) germinal center

FIGURE 2-12 Morphology of a lymph node. A, Schematic diagram of a lymph node illustrating the T cell-rich and B cell-rich zones and the routes of entry of lymphocytes and antigen (shown captured by a dendritic cell). B, Light micrograph of a lymph node illustrating the T cell and B cell zones. (Courtesy of Dr. James Gulizia, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.)

Secondary

Parafollicular' follicle with cortex (T cell zone) germinal center

FIGURE 2-12 Morphology of a lymph node. A, Schematic diagram of a lymph node illustrating the T cell-rich and B cell-rich zones and the routes of entry of lymphocytes and antigen (shown captured by a dendritic cell). B, Light micrograph of a lymph node illustrating the T cell and B cell zones. (Courtesy of Dr. James Gulizia, Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts.)

surrounded by a basement membrane produced by a continuous sleeve of FRCs. These conduits begin at the subcapsular sinus and extend to both medullary sinus lymphatic vessels and cortical blood vessels, called high endothelial venules (HEVs). Naive T cells enter the T cell zones through the HEVs, as described in detail in Chapter 3. T cells are densely packed around the conduits in the lymph node cortex. Most (~70%) of the cortical T cells are CD4+ helper T cells, intermingled with relatively sparse CD8+ cells. These proportions can change dramatically during the course of an infection. For example, during a viral infection, there may be a marked increase

Dendritic cell

High endothelial venule

Naive B cell

B cell specific chemokine

Dendritic cell

High endothelial venule

Naive B cell

B cell specific chemokine

B cell zone

T cell zone

Afferent lymphatic vessel

B cell zone

T cell zone

T cell and dendritic cell specific chemokine

Artery T cell]

B cell

T cell and dendritic cell specific chemokine

Artery T cell]

B cell

T cell zone

(parafollicular cortex)

B cell zone

(lymphoid follicle)

T cell zone

(parafollicular cortex)

B cell zone

(lymphoid follicle)

FIGURE 2-13 Segregation of B cells and T cells in a lymph node. A, The schematic diagram illustrates the path by which naive T and B lymphocytes migrate to different areas of a lymph node. The lymphocytes enter through an artery and reach a high endothelial venule, shown in cross section, from where naive lymphocytes are drawn to different areas of the node by chemokines that are produced in these areas and bind selectively to either cell type. Also shown is the migration of dendritic cells, which pick up antigens from the sites of antigen entry, enter through afferent lymphatic vessels, and migrate to the T cell-rich areas of the node. B, In this section of a lymph node, the B lymphocytes, located in the follicles, are stained green; the T cells, in the parafollicular cortex, are red. The method used to stain these cells is called immunofluorescence (see Appendix IV for details). (Courtesy of Drs. Kathryn Pape and Jennifer Walter, University of Minnesota School of Medicine, Minneapolis.) The anatomic segregation of T and B cells is also seen in the spleen (see Fig. 2-15).

in CD8+ T cells. Dendritic cells are also concentrated in the paracortex of the lymph nodes, many of which are closely associated with the FRC conduits.

The anatomic segregation of B and T lymphocytes in distinct areas of the node is dependent on cytokines that are secreted by lymph node stromal cells in each area and that direct the migration of the lymphocytes (see Fig. 2-13). Naive T and B lymphocytes are delivered to a node through an artery and leave the circulation and enter the

Sinus lining cell

Subcapsular sinus

Fibroblastic reticular cell (FRC) conduit Reticular fiber

Fibroblastic reticular cell Subcapsular macrophage or dendritic cell

Trabecular sinus

Capsule

Sinus lining cell

Subcapsular sinus

Laminin Collagen1

FIGURE 2-14 Microanatomy of the lymph node cortex.

A, Schematic of the microanatomy of a lymph node depicting the route of lymph drainage from the subcapsular sinus, through fibroreticular cell conduits, to the perivenular channel around the high endothelial venule (HEV). B, Transmission electron micrograph of an FRC conduit surrounded by fibroblast reticular cells (arrowheads) and adjacent lymphocytes (L). (From Gretz JE, CC Norbury, AO Anderson, AEI Proudfoot, and S Shaw. Lymph-borne chemokines and other low molecular weight molecules reach high endothelial venules via specialized conduits while a functional barrier limits access to the lymphocyte microenvironments in lymph node cortex. The Journal of Experimental Medicine 192:1425-1439, 2000.) C, Immunofluorescent stain of an FRC conduit formed of the basement membrane protein laminin (red) and collagen fibrils (green). (From Sixt M, K Nobuo, M Selg, T Samson, G Roos, DP Reinhardt, R Pabst, M Lutz, and L Sorokin. The conduit system transports soluble antigens from the afferent lymph to resident dendritic cells in the T cell area of the lymph node. Immunity 22:19-29, 2006. Copyright ©2005 by Elsevier Inc.)

stroma of the node through the HEVs, which are located in the center of the cortical cords. The type of cytokines that determine where B and T cells reside in the node are called chemokines (chemoattractant cytokines), which bind to chemokine receptors on the lymphocytes. Chemokines include a large family of 8- to 10-kD cyto-kines that are involved in a wide variety of cell motility functions in development, maintenance of tissue architecture, and immune and inflammatory responses. We will discuss the general properties of chemokines and their receptors in Chapter 3. Naive T cells express a receptor called CCR7 that binds the chemokines CCL19 and CCL21 produced by stromal cells in the T cell zones of the lymph node. These chemokines attract naive T cells to move from the blood, through the HEVs, into the T cell zone. Dendritic cells that drain into the node through lymphatics also express CCR7, and this is why they migrate from the subcapsular sinus to the same area of the node as do naive T cells (see Chapter 6). Naive B cells express another chemokine receptor, CXCR5, that recognizes a chemokine, CXCL13, produced only in follicles by FDCs. Thus, B cells are attracted into the follicles, which are the B cell zones of lymph nodes. Another cytokine (which is not a chemokine) called lymphotoxin plays a role in stimulating CXCL13 production, especially in the follicles. The functions of chemokines and other cytokines in regulating where lymphocytes are located in lymphoid organs and in the formation of these organs have been established by numerous studies in mice. For example, CXCR5 knockout mice lack B cell-containing follicles in lymph nodes and spleen. Similarly, CCR7 knockout mice lack T cell zones.

The development of lymph nodes as well as of other peripheral lymphoid organs requires the coordinated actions of several cytokines, chemokines, transcription factors, and lymphoid tissue inducer cells. During fetal life, lymphoid tissue inducer cells, which are cells of hematopoietic origin with phenotypic features of both lymphocytes and NK cells, stimulate the development of lymph nodes and other secondary lymphoid organs. This function is mediated by various proteins expressed by the inducer cells, the most thoroughly studied being the cytokines lymphotoxin-a (LTa) and lymphotoxin-P (LTP). Knockout mice lacking either of these cytokines do not develop lymph nodes or secondary lymphoid organs in the gut. Splenic white pulp development is also disorganized in these mice. The LTP produced by the inducer cells acts on stromal cells in different locations of a developing secondary lymphoid organ, and these stromal cells are activated to produce the chemokines CXCL13 or CCL19 and CCL21. In areas where CXCL13 is induced, circulating B cells are recruited into nascent B cell follicles; and in the areas where CCL19 and CCL21 are induced, T cells and dendritic cells are recruited to form T cell zones. There are several other proteins expressed by lymphoid tissue inducer cells that are required for their function, including transcription factors, but their roles in lymphoid organogenesis are not well defined.

The anatomic segregation of T and B cells ensures that each lymphocyte population is in close contact with the appropriate APCs, that is, T cells with dendritic cells and B cells with FDCs. Furthermore, because of this precise segregation, B and T lymphocyte populations are kept apart until it is time for them to interact in a functional way. As we will see in Chapter 11, after stimulation by antigens, T and B cells lose their anatomic constraints and begin to migrate toward one another. Activated T cells may either migrate toward follicles to help B cells or exit the node and enter the circulation, whereas activated B cells migrate into germinal centers and, after differentiation into plasma cells, may home to the bone marrow.

Antigen Transport Through Lymph Nodes

Lymph-borne substances that enter the subcapsular sinus of the lymph node are sorted by molecular size and delivered to different cell types to initiate different types of immune responses. The floor of the subcapsular sinus is constructed in a way that permits cells in the sinus to contact or migrate into the underlying cortex but does not allow movement of soluble molecules in the lymph to freely pass into the cortex. Viruses and other high-molecular-weight antigens are taken up by sinus macrophages and presented to cortical B lymphocytes just beneath the cortical sinus. This is the first step in antibody responses to these antigens. Low-molecular-weight soluble antigens are transported out of the sinus through the FRC conduits and passed to resident cortical dendritic cells located adjacent to the conduits. The resident dendritic cells extend processes between the cells lining the conduits and into the lumen and capture and pino-cytose the soluble antigens inside the conduits. The contribution of this pathway of antigen delivery may be important for initial T cell immune responses to some microbial antigens, but larger and sustained responses require delivery of antigens to the node by tissue dendritic cells, as discussed in Chapter 6. In addition to antigens, there is evidence that soluble inflammatory mediators, such as chemokines and other cytokines, are transported in the lymph that flows through the conduits; some of these may act on the penetrating dendritic cells, and others may be delivered to HEVs into which the conduits drain. This is a possible way in which tissue inflammation can be sensed in the lymph node and thereby influence recruitment and activation of lymphocytes in the node.

Spleen

The spleen is a highly vascularized organ whose major functions are to remove aging and damaged blood cells and particles (such as immune complexes and opsonized microbes) from the circulation and to initiate adaptive immune responses to blood-borne antigens. The spleen weighs about 150 g in adults and is located in the left upper quadrant of the abdomen. The splenic parenchyma is anatomically and functionally divided into the red pulp, composed mainly of blood-filled vascular sinusoids, and the lymphocyte-rich white pulp. Blood enters the spleen through a single splenic artery, which pierces the capsule at the hilum and divides into progressively smaller branches that remain surrounded by protective and supporting fibrous trabeculae (Fig. 2-15). Some of the arteriolar branches of the splenic artery end in extensive vascular sinusoids, which form the red pulp, lined by macrophages and filled with large numbers of eryth-rocytes. The sinusoids end in venules that drain into the splenic vein, which carries blood out of the spleen and into the portal circulation. The red pulp macrophages serve as an important filter for the blood, removing microbes, damaged cells, and antibody-coated (opso-nized) cells and microbes. Individuals lacking a spleen are highly susceptible to infections with encapsulated bacteria such as pneumococci and meningococci. This may be because such organisms are normally cleared by

Germinal center of lymphoid follicle

Marginal sinus

Follicular arteriole

T cell zone (periarteriolar lymphoid sheath PALS)

B cell zone (follicle)

Germinal center of lymphoid follicle

^sheathfPALSV'^

%iP1p

B cell zone

(lymphoid follicle)

T cell zone (periarteriolar lymphoid sheath)

FIGURE 2-15 Morphology of the spleen. A, Schematic diagram of the spleen illustrating T cell and B cell zones, which make up the white pulp. B, Photomicrograph of a section of human spleen showing a trabecular artery with adjacent periarteriolar lymphoid sheath and a lymphoid follicle with a germinal center. Surrounding these areas is the red pulp, rich in vascular sinusoids. C, Immunohistochemical demonstration of T cell and B cell zones in the spleen, shown in a cross section of the region around an arteriole. T cells in the periarteriolar lymphoid sheath are stained red, and B cells in the follicle are stained green. (Courtesy of Drs. Kathryn Pape and Jennifer Walter, University of Minnesota School of Medicine, Minneapolis.)

opsonization and phagocytosis, and this function is defective in the absence of the spleen.

The function of the white pulp is to promote adaptive immune responses to blood-borne antigens. The white pulp consists of many collections of densely packed lymphocytes, which appear as white nodules against the background of the red pulp. The white pulp is organized around central arteries, which are branches of the splenic artery distinct from the branches that form the vascular sinusoids. Several smaller branches of each central artery pass through the lymphocyte-rich area and drain into a marginal sinus. A region of specialized cells surrounding the marginal sinus, called the marginal zone, forms the boundary between the red and white pulp. The architecture of the white pulp is analogous to the organization of lymph nodes, with segregated T cell and B cell zones. In the mouse spleen, the central arteries are surrounded by cuffs of lymphocytes, most of which are T cells. Because of their anatomic location, morphologists call these T cell zones periarteriolar lymphoid sheaths. B cell-rich follicles occupy the space between the marginal sinus and the periarteriolar sheath. As in lymph nodes, the T cell areas in the spleen contain a network of complex conduits composed of matrix proteins lined by FRC-like cells, although there are ultrastructural differences between the conduits in nodes and spleen. The marginal zone just outside the marginal sinus is a distinct region populated by B cells and specialized macrophages. The B cells in the marginal zone, known as marginal zone B cells, are functionally distinct from follicular B cells and have a limited repertoire of antigen specificities. The architecture of the white pulp is more complex in humans than in mice, with both inner and outer marginal zones and a perifollicular zone. Antigens in the blood are delivered into the marginal sinus by circulating dendritic cells or are sampled by the macrophages in the marginal zone. The anatomic arrangements of the APCs, B cells, and T cells in the splenic white pulp promote the interactions required for the efficient development of humoral immune responses, as will be discussed in Chapter 11. The segregation of T lymphocytes in the periarteriolar lymphoid sheaths and B cells in follicles and marginal zones is a highly regulated process, dependent on the production of different cytokines and chemokines by the stromal cells in these different areas, analogous to the case for lymph nodes. The chemokine CXCL13 and its receptor CXCR5 are required for B cell migration into the follicles, and CCL19 and CCL21 and their receptor CCR7 are required for naive T cell migration into the periarteriolar sheath. The production of these chemo-kines by nonlymphoid stromal cells is stimulated by the cytokine lymphotoxin.

Regional Immune Systems

Each major epithelial barrier of the body, including the skin, gastrointestinal mucosa, and bronchial mucosa, has its own system of lymph nodes, nonencapsulated lym-phoid structures, and diffusely distributed immune cells, which work in coordinated ways to provide specialized immune responses against the pathogens that enter at those barriers. The skin-associated immune system has evolved to respond to a wide variety of environmental microbes. The components of the immune systems associated with the gastrointestinal and bronchial mucosa are called the mucosa-associated lymphoid tissue (MALT) and are involved in immune responses to ingested and inhaled antigens and microbes. The skin and MALT

contain a major proportion of the cells of the innate and adaptive immune systems. We will discuss the special features of these regional immune systems in Chapter 13.

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