Histology_Ross

Histology_Ross. When the TCR of a CTL recognizes and binds to an anti-gen–MHC I complex on the surface of a transformed or virusinfected cell, the activation process is triggered. First, CTLs undergo “clonal expansion” by entering the cell cycle and proceeding with cell divisions followed by differentiation into effector (“killer”) cells. During differentiation, a large number of secretory vesicles are formed containing specific proteins that include perforins and granzymes (fragmentins). As a result of interaction with antigen, CTLs secrete these proteins. Perforins are pore-forming proteins that enter the target cell by forming ringlike transmembrane channels in their cell membranes. These channels cause an increase in the permeability of the membrane that contributes to cell death. Granzymes are exogenous serine proteinases that are released from cytoplasmic granules and pass into the target cells through the pores created by perforins. Once inside the cell, granzymes activate caspases that induce


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Histology_Ross. serine proteinases that are released from cytoplasmic granules and pass into the target cells through the pores created by perforins. Once inside the cell, granzymes activate caspases that induce the cell to undergo apoptosis (Fig. 14.8). After killing the target cell, the majority of activated CTLs will die (of apoptosis), but some of them that interacted with helper T cells will become memory cells.


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Histology_Ross. CD4CD25FOXP3 suppressor T lymphocytes suppress the immune responses of other lymphocytes. Once the immune reactions are initiated by contact with antigen, the immune system is capable of controlling the


Histology_Ross

Histology_Ross. FIGURE 14.8 • Schematic diagram of T-cell activation leading to elimination of a virus-infected host cell. The TCR–CD3 complex on a helper CD4 T lymphocyte recognizes foreign antigen displayed on an MHC II molecule on the surface of a macrophage. This recognition triggers a rapid response from B lymphocytes and the release of interleukin 2 (IL-2). The same macrophage also expresses MHC I molecules (like every other cell in the body) that interact with the appropriate TCR on the surface of a cytotoxic CD8 T lymphocyte. The cytotoxic CD8 T lymphocyte also possesses IL-2 receptors. IL-2 binding to these receptors stimulates the cell to divide and differentiate. The newly formed cytotoxic CD8 T lymphocytes migrate to the site of viral infection. There the TCRs recognize the viral antigens displayed on the surface of MHC I molecules of infected cells. After successfully recognizing these “nonself” proteins, the cytotoxic CD8 T lymphocytes secrete perforins and granzymes, killing the


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Histology_Ross. displayed on the surface of MHC I molecules of infected cells. After successfully recognizing these “nonself” proteins, the cytotoxic CD8 T lymphocytes secrete perforins and granzymes, killing the infected cells.


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Histology_Ross. magnitude of this response and terminating it over time. Certain T lymphocytes called suppressor T cells diminish or suppress responses of the other lymphocytes to antigen. Characterization of these cells has proved to be difficult, but recent studies have convincingly shown that these cells belong to the population of CD4 T lymphocytes that coexpress the CD25 and FOXP3 marker proteins. CD4CD25FOXP3 suppressor T cells originate in the thymus and account for about 5% of the total population of T cells. They secrete cytokines such as IL-10 and transforming growth factor (TGF-), the latter a potent suppressor of proliferation of specific classes of T and B effector cells.


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Histology_Ross. Suppressor T cells diminish or suppress antibody formation by B cells, as well as lower the ability of CTLs to provide a cell-mediated immune response. They play important roles in delayed hypersensitivity reactions (allergic reactions) by downregulating responses to antigen that enter the body through the skin or mucosa. They are also important in the prevention of graft rejection. Suppressor T lymphocytes may also function in the regulation of erythroid cell maturation in bone marrow. Activated T lymphocytes synthesize a variety of cytokines.


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Histology_Ross. Cytokines are soluble polypeptide substances, synthesized mainly by activated T lymphocytes, which affect the function of immune system effector cells (T and B cells), monocytes, macrophages, and other APCs. In general, cytokines and growth factors are similar in nature; the distinction between them is related to their effects on their target cell populations. Cytokines are defined as substances that are involved in immune defense mechanisms and act on lymphocytes, whereas growth factors act on other somatic cells. Included among these substances are chemotactic and mitogenic agents, migration inhibitory factors, interferon, and interleukins. Cytokines serve as chemical messengers between cells of the immune system and act locally on the same cell that secreted them (autocrine control) or on neighboring cells (paracrine control). In a way similar to hormones, they may also communicate the state of the immune system to cells in other systems (e.g., central nervous system, endocrine


Histology_Ross

Histology_Ross. or on neighboring cells (paracrine control). In a way similar to hormones, they may also communicate the state of the immune system to cells in other systems (e.g., central nervous system, endocrine system, and hemopoietic system). Cytokines function through specific receptors. Therefore, cells regulated by cytokines possess cytokine receptors.


Histology_Ross

Histology_Ross. Interleukins are synthesized mainly by helper CD4 T lymphocytes and to a lesser extent by monocytes, macrophages, and endothelial cells. Interleukins promote growth and differentiation of T cells, B cells, and hematopoietic cells. Currently, more than 29 interleukins have been identified. Interleukin 2 was the first cytokine to be discovered and characterized. Mutations in the genes encoding several cytokine receptors have been identified in several immunodeficiency disorders, bacterial sepsis, certain lymphoid cancers, and diseases of autoimmunity. For instance, individuals with a mutation in the IL-12 receptor gene cannot mount an effective immune response against mycobacterial (fungal) infections. Cytokines have been used with promising results to prevent transplant rejection, reverse cellular deficiencies after chemotherapy and radiation therapy, and treat certain cancers. The major functions of selected interleukins are summarized in Table 14.3.


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Histology_Ross. APCs interact with helper CD4 T lymphocytes to facilitate immune responses. The interaction between most antigens and antibodies is insufficient to stimulate immune responses. The antigen must be broken into small peptides and presented in conjunction with MHC II molecules by specialized APCs to the appropriate helper CD4 T lymphocytes. Antigen can also be processed as a part of the B-cell activation pathway. Most APCs belong to the mononuclear phagocytotic system (MPS; described in Chapter 6, Connective Tissue, page 185). APCs include macrophages, perisinusoidal macrophages (Kupffer cells) of the liver, Langerhans’ cells in the epidermis, and dendritic cells of spleen and lymph nodes. Two APCs that do not belong to the MPS are B lymphocytes and type II and type III epithelioreticular cells of the thymus.


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Histology_Ross. To present an antigen to a helper T cell, the APC first processes the antigen intracellularly and then displays antigen peptides on its surface. Antigen processing begins when the APC endocytoses the antigen and breaks it down into 8 to 10 amino acid peptides. In the endosomal compartment of the APC, the peptides bind to MHC II molecules. The anti-gen–MHC II complex is then translocated to the plasma membrane of the APC and displayed on the cell surface (Fig. 14.9). In addition to acting as APCs, macrophages perform other crucial functions in the immune response. In addition to presenting antigens to both T and B lymphocytes, macrophages have other important, although nonspecific, functions in the immune response: conjunction with MHC II molecules to helper CD4 T lymphocytes.  They digest pathogenic microorganisms through lyso somal action in combination with the helper CD4


Histology_Ross

Histology_Ross. T lymphocytes.  They digest pathogenic microorganisms through lyso somal action in combination with the helper CD4 T lymphocytes. They secrete multiple cytokines including lymphokines, complement components, and interleukins, as well as acid hydrolases, proteases, and lipases. After contact with an antigen, macrophages undergo an activation process characterized by multiple functional and morphologic changes. The macrophage increases in size, as do the number of lysosomes and cytoplasmic vacuoles. The activated macrophage becomes avidly phagocytotic with a greater ability to lyse ingested pathogenic microorganisms (Fig. 14.10). Activated macrophages destroy phagocytosed bacteria and foreign antigens. Macrophages also play a vital role in sequestering and removing foreign materials and organisms that either do not provoke an immune response or are ingested but not digested.


Histology_Ross

Histology_Ross. Macrophages also play a vital role in sequestering and removing foreign materials and organisms that either do not provoke an immune response or are ingested but not digested. These include both organic and inorganic particulate materials (e.g., carbon particles), pigment (e.g., from tattoos), cellulose, and asbestos, as well as tuberculosis and leprosy bacilli and the organisms that cause malaria and other diseases. In these instances, macrophages often fuse to form multinucleate, foreign body giant cells called Langerhans’ giant cells that isolate these pathogens from the body. Lymphatic vessels are the route by which cells and large molecules pass from the tissue spaces back to the blood.


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Histology_Ross. Lymphatic vessels are the route by which cells and large molecules pass from the tissue spaces back to the blood. Lymphatic vessels begin as networks of blind capillaries in loose connective tissue. They are most numerous beneath the epithelium of skin and mucous membranes. These vessels remove substances and fluid from the extracellular spaces of the connective tissues, thus producing lymph. Because the walls of the lymphatic capillaries are more permeable than the walls of blood capillaries, large molecules, including antigens and cells, gain entry more readily into the lymphatic capillaries than into blood capillaries. As lymph circulates through the lymphatic vessels, it passes through lymph nodes. Within the lymph nodes, foreign substances (antigens) conveyed in the lymph are trapped by the follicular dendritic cells. The antigen exposed on the surface of follicular dendritic cells can be processed by APCs present within the lymph node.


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Histology_Ross. Lymphocytes circulate through both lymphatic and blood vessels. The circulation of lymphocytes through the lymphatic vessels and the bloodstream enables them to move from one part of


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Histology_Ross. TABLE Characteristics of Interleukins14.3 Interleukin 12 IL-12 T cells Stimulates growth of NK cells, CD4T cells, and CD8T cells Interleukin 13 IL-13 T cells Modulates B-cell responses and promotes IgE synthesis Interleukin 14 IL-14 T cells, follicular dendritic cells Induces production of memory B cells Interleukin 15 IL-15 T cells, monocytes Induces proliferation and differentiation of CD8T cells Interleukin 16 IL-16 T cells Activates migration of CD8T cells, mono-cytes, and eosinophils Interleukin 17 IL-17 Memory CD4T cells Stimulates endothelial cells and fibroblasts to secrete cytokines Name Symbol Source Major Functions Interleukin 1 IL-1 Neutrophils, monocytes, macrophages, endothelial cells Stimulates various cells in inflammatory response Induces fever Facilitates proliferation of CD4T cells and proliferation and differentiation of B cells Interleukin 2 IL-2 CD4T cells Induces proliferation and differentiation of CD4T cells and to a lesser degree CD8T cells, B cells, and NK


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Histology_Ross. of CD4T cells and proliferation and differentiation of B cells Interleukin 2 IL-2 CD4T cells Induces proliferation and differentiation of CD4T cells and to a lesser degree CD8T cells, B cells, and NK cells Interleukin 3 IL-3 CD4T cells Induces proliferation of hematopoietic stem cells Interleukin 4 IL-4 CD4T cells, mast cells Induces proliferation and differentiation of B cells, CD4T cells Activates macrophages Promotes synthesis of IgE and IgG Interleukin 5 IL-5 CD4T cells Induces proliferation and differentiation of eosinophils Stimulates B cells to secrete IgA Interleukin 6 IL-6 Endothelial cells, neutrophils, macrophages, T cells Stimulates differentiation of hematopoietic cells Induces growth of activated B cells Interleukin 7 IL-7 Adventitial cells of bone marrow Stimulates growth and differentiation of progenitor B and T cells Interleukin 8 IL-8 Macrophages, endothelial cells Acts as chemotactic factor on T lymphocytes and neutrophils Interleukin 9 IL-9 CD4T cells Facilitates


Histology_Ross

Histology_Ross. and differentiation of progenitor B and T cells Interleukin 8 IL-8 Macrophages, endothelial cells Acts as chemotactic factor on T lymphocytes and neutrophils Interleukin 9 IL-9 CD4T cells Facilitates growth of CD4T cell (but not CD8T cells) Stimulates growth of hematopoietic cells Activates mast cells Interleukin 10 IL-10 Macrophages, T cells Acts on T cells as cytokine synthesis inhibitory factor Inhibits macrophage functions Interleukin 11 IL-11 Macrophages Facilitates growth of hematopoietic cells, mainly megakaryocytes  FOLDER 14.3 Clinical Correlation: Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency


Histology_Ross

Histology_Ross. Human immunodeficiency virus (HIV) is an RNA retro-helper CD4T cells, reducing the number of helper T cells virus; it contains an enzyme called reverse transcriptase. HIV is the virus that causes acquired immunodeficiency syndrome (AIDS). It has an incubation period that may be as long as 11 years before symptoms of clinical AIDS occur. The great majority of HIV-infected individuals eventually develop AIDS. HIV gains entry to helper T cells by binding to CD4 molecules. The virus then injects its own genetic information into the cell cytoplasm (Fig. F14.3.1). This injected genetic information consists of single-stranded RNA. The viral RNA is incorporated into the infected T-cell genome through reverse transcription of the RNA into DNA. The transcribed DNA is then incorporated into the host DNA. The T cell then makes copies of the virus, which are extruded from the T cell through exocytosis. These HIV particles then infect other helper T cells. The immune system responds to this


Histology_Ross

Histology_Ross. host DNA. The T cell then makes copies of the virus, which are extruded from the T cell through exocytosis. These HIV particles then infect other helper T cells. The immune system responds to this condition by generating cytotoxic CD8 T cells and antibodies directed against the virus particles. Cytotoxic CD8 T cells kill HIV-infected (the helper T-cell count is actually used as a clinical indicator of the progress of HIV infection). As the helper CD4 T-cell population becomes depleted, infected individuals eventually become incapable of generating an immune response against bacterial or viral infections. They usually die of secondary infections caused by opportunistic microorganisms or cancer.


Histology_Ross

Histology_Ross. Anti-HIV treatment is the major strategy against HIV infection and AIDS. Azidothymidine (AZT), an inhibitor of reverse transcriptase, was the first promising drug used to treat HIV infection. Currently, the most effective treatment is multiple drug therapy known as highly active antiretroviral therapy (HAART), which uses a combination of several chemotherapeutic agents. These include nucleoside and nonnucleoside reverse transcriptase inhibitors and HIV protease inhibitors. HAART offers several advantages over monotherapy such as synergistic dosage effects and reduced side effects as well as reduced drug resistance.


Histology_Ross

Histology_Ross. FIGURE F14.3.1 • Schematic diagram of the interaction between HIV and the helper CD4T cell. Human immu -nodeficiency virus (HIV) is the RNA virus that causes AIDS. It contains reverse transcriptase. HIV gains entry into the helper CD4T lymphocyte by binding to the CD4 molecule and injecting its genetic information into the cell cytoplasm. Accessory cell surface molecules such as gp 120 assist in viral entry into the cell. These proteins interact with CD4 molecules. The injected genetic information is incorporated into the host cell genome through reverse transcription of RNA into DNA. This DNA containing viral information is then incorporated into host DNA. HIV HIV gp 120 gp 120 CD4 CD4 chemokine receptor chemokine receptor gp 41 gp 41 RNA RNACD4T lymphocyte


Histology_Ross

Histology_Ross. FIGURE 14.9 • Schematic diagram of processing pathways for MHC I and MHC II synthesis and antigen presentation. During the processing and presentation of cytoplasmic antigen (Ag) for MHC I molecules (red pathway), cytoplasmic protein antigens are degraded by protease into 8 to 10 amino acid fragments that then enter the rough-surfaced endoplasmic reticulum (rER). In the rER, newly synthesized chains of MHC I molecules interact with both the processed antigen and 2 microglobulin (2M) and form a stable complex. This complex leaves the rER via the typical secretory pathway through the Golgi apparatus. The antigen–MHC I complex is displayed on the cell surface, where it is available for recognition by cytotoxic CD8 T lymphocytes. MHC II molecules are assembled in the rER and then bind to an invariant chain, which blocks the antigen-binding site. At this point, the MHC II molecule and the invariant chain are secreted to the cell surface (blue pathway). After a brief stay on the cell


Histology_Ross

Histology_Ross. an invariant chain, which blocks the antigen-binding site. At this point, the MHC II molecule and the invariant chain are secreted to the cell surface (blue pathway). After a brief stay on the cell surface, the MHC II molecule and invariant chain are endocytosed, and in an early endosome, the invariant chain is degraded. The foreign (exogenous) antigen is endocytosed and partially digested by proteolytic degradation in endosomes (white pathway). The MHC II molecule can now bind the processed foreign antigen and return with it to the cell surface. On the cell surface, the antigen–MHC II complex is recognized by helper CD4 T lymphocytes, which initiates the immune response. If the MHC II molecule fails to capture the antigen, it will be degraded in the lysosomal compartment (green pathway).


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Histology_Ross. the lymphatic system to another at different stages in their development and to reach sites within the body where they are needed. Lymphocytes conveyed in the lymph enter lymph nodes via afferent lymphatic vessels, whereas lymphocytes conveyed in the blood enter the node through the walls of postcapillary venules (high endothelial venules [HEVs]; Fig. 14.11). B and T cells migrate to and populate different regions within the lymph node. Some lymphocytes pass through the substance of the node and leave via the efferent lymphatic vessels, which lead to the right lymphatic trunk or to the thoracic duct. In turn, both of these channels empty into the blood circulation at the junctions of the internal jugular and subclavian veins at the base of the neck. The lymphocytes are conveyed to and from the various lymphatic tissues via the blood vessels. Diffuse lymphatic tissue and lymphatic nodules guard the body against pathogenic substances and are the site of the initial immune response.


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Histology_Ross. Diffuse lymphatic tissue and lymphatic nodules guard the body against pathogenic substances and are the site of the initial immune response. The alimentary canal, respiratory passages, and genitourinary tract are guarded by accumulations of lymphatic


Histology_Ross

Histology_Ross. The alimentary canal, respiratory passages, and genitourinary tract are guarded by accumulations of lymphatic FIGURE 14.11 • Diagram depicting circulation of lymphocytes in the body. Lymphocytes enter lymph nodes by two routes: afferent lymphatic vessels and through the wall of high endothelial venules (HEVs) in the deep cortex. Some lymph node lymphocytes move to the T and B domains of the lymph node; others efferent pass through the parenchyma of the lymphatic vessel. Ultimately, the lym phocytes enter a major lymphatic vessel—in this case, the right lymphatic trunk—that opens into the junction of the right internal jugular and right subclavian vein. The lymphocytes continue to the arterial side of the circulation and, via the arteries, to the lymphatic tissues of the body or to tissues where they participate in immune reactions. From the lymphatic tissues, lymphocytes again return to the lymph nodes to gain entry via the HEV.


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Histology_Ross. FIGURE 14.10 • Macrophage activation by a helper CD4 T cell. Helper CD4 T lymphocytes recognize the bacterial antigen expressed in the context of MHC II molecules on the surface of a macrophage that has phagocytosed the bacteria. The recognition of MHC II molecules activates the T cell, which in turn secretes IL-2. IL-2 acts as an autocrine hormone to stimulate T-cell division and differentiation. Newly formed helper CD4 T lymphocytes also interact with MHC II molecules and release interferon (IFN-). This cytokine stimulates the macrophage to destroy the bacteria inside its phagosomes. CD4 molecules on the surface of the T cell also potentiate antibacterial reactions.


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Histology_Ross. tissue that are not enclosed by a capsule. Lymphocytes and other free cells of this tissue are found in the lamina propria (subepithelial tissue) of these tracts. This form of lymphatic tissue is called diffuse lymphatic tissue or mucosa-associated lymphatic tissue (MALT) because of its association with mucous membranes (Fig. 14.12). These cells are strategically located to intercept antigens and initiate an immune response. After contact with antigen, they travel to regional lymph nodes, where they undergo proliferation and differentiation. Progeny of these cells then return to the lamina propria as effector B and T lymphocytes. The importance of diffuse lymphatic tissue in protecting the body from antigens is indicated by two factors:  The regular presence of large numbers of plasma cells, especially in the lamina propria of the gastrointestinal tract, a morphologic indication of local antibody secretion.


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Histology_Ross.  The presence of large numbers of eosinophils, also frequently observed in the lamina propria of the intestinal and respiratory tracts, an indication of chronic inflammation and hypersensitivity reactions. Lymphatic nodules are discrete concentrations of lymphocytes contained in a meshwork of reticular cells.


Histology_Ross

Histology_Ross. Lymphatic nodules are discrete concentrations of lymphocytes contained in a meshwork of reticular cells. In addition to diffuse lymphatic tissue, localized concentrations of lymphocytes are commonly found in the walls of the alimentary canal, respiratory passages, and genitourinary tract. These concentrations, called lymphatic nodules or lymphatic follicles, are sharply defined but not encapsulated (Fig. 14.13). A lymphatic nodule consisting chiefly of small lymphocytes is called a primary nodule. However, most nodules are secondary nodules and have distinctive features that include the following:  A germinal center is located in the central region of the nodule (Fig. 14.14) and appears lightly stained in histologic sections. The germinal center develops when a lymphocyte that has recognized an antigen returns to a primary nodule and undergoes proliferation. The lighter FIGURE 14.12 • Photomicrograph of diffuse lymphatic tissue.


Histology_Ross

Histology_Ross. FIGURE 14.12 • Photomicrograph of diffuse lymphatic tissue. This photomicrograph shows the diffuse lymphatic tissue in the lamina propria (LP) of the large intestine. The lower portion of two intestinal glands (Gl) is also evident. The highly cellular, diffuse lymphatic tissue includes fibroblasts, plasma cells, and eosinophils. However, the most abundant cell component, whose presence characterizes diffuse lymphatic tissue, is the lymphocyte, which can be identified by its small, round, dark-staining nucleus. 320.


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Histology_Ross. 320. FIGURE 14.13 • Photomicrograph of a lymphatic nodule. This photomicrograph shows a section of the wall of the small intestine (duodenum). Short villi and intestinal glands are present in the upper part of the micrograph. A lymphatic nodule (LN) occupies most of the remainder of the micrograph. The lighter central region of the nodule is the germinal center. The lymphocytes in the germinal center are larger than those in the denser region of the nodule. They have more cytoplasm, so, their nuclei are more dispersed, giving the appearance of a less compact cellular mass. 120.


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Histology_Ross. staining is attributable to the large immature lymphocytes (lymphoblasts and plasmablasts) that it contains. These lymphocytes have large amounts of dispersed euchromatin in their nuclei rather than the dense heterochromatin of small lymphocytes. Follicular dendritic cells (FDCs) are also present in germinal centers interdispersed between populations of B lymphocytes. The germinal center is a morphologic indication of lymphatic tissue response to antigen. The presence of a germinal center represents a cascade of events that includes activation and proliferation of lymphocytes, differentiation of plasma cells, and antibody production. Mitotic figures are frequently observed in the germinal center, reflecting the proliferation of new lymphocytes at this site. The number of FDCs and macrophages in the germinal center often increases dramatically after a period of intense response to an antigen.


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Histology_Ross.  A mantle zone or corona is present that represents an outer ring of small lymphocytes that encircles the germinal center. Lymphatic nodules are usually found in structures associated with the alimentary canal such as the tonsils, ileum, and vermiform appendix.


Histology_Ross

Histology_Ross. Generally, nodules are dispersed singly in a random manner. In the alimentary canal, however, some aggregations of nodules are found in specific locations. These include the following:  Tonsils form a ring of lymphatic tissue at the entrance of the oropharynx. The pharyngeal tonsils (adenoids) (located in the roof of the pharynx), the palatine tonsils (or simply the tonsils, located on either side of the pharynx and between the palatopharyngeal and palatoglossal arches), and the lingual tonsils at the base of the tongue all contain aggregates of lymphatic nodules. The palatine tonsils consist of dense accumulations of lymphatic tissue located in the mucous membrane. The squamous epithelium that forms the surface of the tonsil dips into the underlying connective tissue in numerous places, forming tonsillar crypts (Fig. 14.15). The walls of these crypts usually possess numerous lymphatic nodules. Like other aggregations of lymph nodules, tonsils do not possess afferent lymphatic


Histology_Ross

Histology_Ross. forming tonsillar crypts (Fig. 14.15). The walls of these crypts usually possess numerous lymphatic nodules. Like other aggregations of lymph nodules, tonsils do not possess afferent lymphatic vessels; however, lymph drains from the lymphatic tissue of the tonsil via efferent lymphatic vessels.


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Histology_Ross.  Peyer’s patches are located in the ileum (distal portion of the small intestine) and consist of numerous aggregations of lymphatic nodules containing T and B lymphocytes (Fig. 14.16). In addition, numerous isolated single (solitary) lymph nodules are located along both large and small intestines.  The vermiform appendix arises from the cecum. The lamina propria is heavily infiltrated with lymphocytes and contains numerous lymphatic nodules. Although the appendix is often described as a vestigial organ, the abundant lymphatic tissue that it contains during early life suggests that it is functionally associated with bursa-equivalent organs.


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Histology_Ross. FIGURE 14.14 • Photomicrograph of a lymph node. This photomicrograph shows the superficial cortex (SC), deep cortex (DC), and medulla (M) of the lymph node in a routine H&E preparation. The capsule (Cap) is composed of dense connective tissue from which trabeculae (T) penetrate into the organ. Below the capsule is the subcapsular sinus (SCS). It receives lymph from afferent lymphatic vessels that penetrate the capsule. The subcapsular sinus is continuous with the trabecular sinuses that course along the trabeculae. The superficial cortex contains the lymphatic nodules (LN). The deep cortex is nodule free. It consists of densely packed lymphocytes and contains the unique high endothelial venules (not visible at this magnification). The medulla consists of narrow strands of anastomosing lymphatic tissue called medullary cords (MC), which are separated by light-appearing spaces, the medullary sinuses (MS). The medullary sinuses receive lymph from the trabecular sinuses as well as lymph


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Histology_Ross. tissue called medullary cords (MC), which are separated by light-appearing spaces, the medullary sinuses (MS). The medullary sinuses receive lymph from the trabecular sinuses as well as lymph that has filtered through the cortical tissue. 140.


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Histology_Ross. FIGURE 14.15 • Photomicrograph of a palatine tonsil. a. This low-magnification photomicrograph shows an H&E–stained palatine tonsil. The stratified squamous epithelium that forms the surface of the tonsil dips into the underlying connective tissue in numerous places, forming tonsillar crypts. 25. b. This higher-magnification photomicrograph of the rectangular area in a shows the stratified squamous epithelium (SSE) lining the tonsillar crypt. In the portion of the photomicrograph below the lumen of the crypt, SSE is well defined and separated by a connective tissue layer (CT) from the lymphatic nodule (LN). In the upper portion of the photomicrograph, the SSE is just barely recognized because of the heavy infiltration of lymphocytes; the epithelial cells are present, however, although they are difficult to identify. In effect, the lymphatic nodule has literally grown into the epithelium, distorting it and resulting in the disappearance of the more typical, well-defined


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Histology_Ross. although they are difficult to identify. In effect, the lymphatic nodule has literally grown into the epithelium, distorting it and resulting in the disappearance of the more typical, well-defined epithelial–connective tissue boundary. 450.


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Histology_Ross. With age, the amount of lymphatic tissue within the organ regresses and is diffcult to recognize. As noted, diffuse lymphatic tissue and lymphatic nodules are named according to the region or organ in which they appear. In the alimentary canal, they are collectively referred to as gut-associated lymphatic tissue (GALT); in the bronchial tree, they are known as bronchus-associated lymphatic tissue (BALT). The term mucosa-associated lymphatic tissue (MALT) includes GALT and BALT. Diffuse lymphatic tissue and lymphatic nodules of MALT are present in many other regions of the body (e.g., female reproductive tract) where the mucosa is exposed to the external environment. All lymphatic nodules become enlarged as a consequence of encounters with antigen. Lymph nodes are small encapsulated organs located along the pathway of lymphatic vessels.


Histology_Ross

Histology_Ross. Lymph nodes are small encapsulated organs located along the pathway of lymphatic vessels. Lymph nodes are small, bean-shaped, encapsulated lymphatic organs. They range in size from about 1 mm (barely visible with the unaided eye) to about 1 to 2 cm in their longest dimension. Lymph nodes are interposed along lymphatic vessels (Fig. 14.17) and serve as filters through which lymph percolates on its way to the blood vascular system. Although widely distributed throughout the body, they are concentrated in certain regions such as the axilla, groin, and mesenteries.


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Histology_Ross. Two types of lymphatic vessels serve the lymph node:  Afferent lymphatic vessels convey lymph toward the node and enter it at various points on the convex surface of the capsule. Efferent lymphatic vessels convey lymph away from the node and leave at the hilum, a depression on the concave surface of the node that also serves as the entrance and exit for blood vessels and nerves. Note that activated lymphocytes, which remain in the lymph node to proliferate and differentiate, are carried to the node primarily by blood vessels. The supporting elements of the lymph node are:  capsule, composed of dense connective tissue that surrounds the node;


Histology_Ross

Histology_Ross. FIGURE 14.16 • Photomicrograph of aggregated nodules in the wall of the ileum. This low-magnification photomicrograph provides an example of aggregated nodules. The multiple lymphatic nodules (indicated by a dashed line) with visible germinal centers are typically found in the ileum. This accumulation of lymphatic tissue is known as a Peyer’s patch. The nodules originate in the lamina propria and extend into the submucosa of the ileum. 5.  trabeculae, also composed of dense connective tissue, which extend from the capsule into the substance of the node, forming a gross framework; and  reticular tissue composed of reticular cells and reticular fibers that form a fine supporting meshwork throughout the remainder of the organ (Fig. 14.18). The reticular meshwork of lymphatic tissues and organs (except the thymus) consists of cells of mesenchymal origin and reticular fibers and ground substance produced by those cells. Cells of the Reticular Meshwork


Histology_Ross

Histology_Ross. Cells of the Reticular Meshwork The reticular meshwork of the lymph node contains several types of cells that perform different functions in generating immune responses. The cells of the reticular meshwork appear as stellate or elongated cells with an oval euchromatic nucleus and a small amount of acidophilic cytoplasm. These cells can take up dyes and colloidal materials. Using immunocytochemistry and transmission electron microscopy, several populations of cells have been identified.


Histology_Ross

Histology_Ross.  Reticular cells are indistinguishable from typical fibroblasts. These cells synthesize and secrete type III collagen (reticular fibers) and the associated ground substance that forms the stroma observed with the light microscope (Plate 38, page 481). Elongated cytoplasmic processes of these cells wrap around the bundles of reticular fibers, effectively isolating these structural components from the parenchyma of the lymphatic tissue and organs (Fig. 14.19). Besides their supporting role, they express surface molecules and produce substances that attract T cells, B cells, and dendritic cells.


Histology_Ross

Histology_Ross.  Dendritic cells (DCs) are unique bone marrow–derived APCs. DCs monitor the local environment for foreign substances that they then process and present to antigen-specific T cells. They are much more efficient in antigen presentation than other APCs and can present virtually any form of protein antigen on both MHC I and MHC II molecules. They express an exceptionally high level of MHC II and costimulatory molecules necessary for activation of T cells. In the lymph node, DCs are usually localized in T lymphocyte–rich areas.


Histology_Ross

Histology_Ross.  Macrophages are both phagocytic and antigen-presenting cells that express MHC I, MHC II, and costimulatory molecules. However, the expression levels of MHC II and costimulatory molecules are much lower than those of the dendritic cells, making them less efficient APCs. Instead, they have an immense capacity for endocytosis and digestion of internalized materials. The structure, microscopic characteristics, and functions of macrophages are described in Chapter 6, Connective Tissue.


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Histology_Ross.  Follicular dendritic cells (FDCs) have multiple, thin, hairlike branching cytoplasmic processes that interdigitate between B lymphocytes in the germinal centers (Fig. 14.20). Antigen–antibody complexes adhere to the dendritic cytoplasmic processes by means of the antibody’s Fc receptors, and the cell can retain antigen on its surface for weeks, months, or years. Although this mechanism is similar to the adhesion of antigen–antibody complexes to macrophages, the antigen is not generally endocytosed, as it is by the macrophage. FDCs are thus not APCs because they lack MHC II molecules. General Architecture of the Lymph Node


Histology_Ross

Histology_Ross. General Architecture of the Lymph Node The parenchyma of the lymph node is divided into a cortex and medulla (Fig. 14.21). The cortex forms the outer portion of the node except at the hilum. It consists of a dense mass of lymphatic tissue (reticular framework, dendritic cells, follicular dendritic cells, lymphocytes, macrophages, and plasma cells) and lymphatic sinuses, the lymph channels. The medulla is the inner part of the lymph node.


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Histology_Ross. FIGURE 14.17 • Structure of a lymph node. a. This diagram depicts the general features of a lymph node as seen in a section. The substance of the lymph node is divided into a cortex, including a deep cortex, and a medulla. The cortex, the outermost portion, contains spherical or oval aggregates of lymphocytes called lymphatic nodules. In an active lymph node, nodules contain a lighter center called the germinal center. The medulla, the innermost region of the lymph node, consists of lymphatic tissue that appears as irregular cords separated by lymphatic medullary sinuses. The dense population of lymphocytes between the superficial cortex and the medulla constitutes the deep cortex. It contains the high endothelial venules. Surrounding the lymph node is a capsule of dense connective tissue from which trabeculae extend into the substance of the node. Under the capsule and adjacent to the trabeculae are, respectively, the subcapsular sinus and the trabecular lymphatic sinuses. Afferent


Histology_Ross

Histology_Ross. from which trabeculae extend into the substance of the node. Under the capsule and adjacent to the trabeculae are, respectively, the subcapsular sinus and the trabecular lymphatic sinuses. Afferent lymphatic vessels (arrows) penetrate the capsule and empty into the subcapsular sinus. The subcapsular sinus and trabecular sinuses communicate with the medullary sinuses. The upper portion of the lymph node shows an artery and a vein and the location of the high endothelial venules of the lymph node. b. Photomicrograph of a lymph node in a routine H&E preparation. The dense outer portion of the lymph node is the cortex. It consists of aggregations of lymphocytes organized as nodules and a nodule-free deep cortex. The innermost portion of the lymph node, the medulla, extends to the surface at the hilum, where blood vessels enter or leave and where efferent lymphatic vessels leave the node. Surrounding the lymph node is the capsule, and immediately beneath it is the subcapsular sinus. 18.


Histology_Ross

Histology_Ross. FIGURE 14.18 • Photomicrograph of a lymph node. This silver preparation shows the connective tissue capsule (at the top), subcapsular sinus, and the superficial cortex of the lymph node (at the bottom). The reticular fibers (arrows) form an irregular anastomosing network throughout the stroma of the lymph node. Note elongated oval nuclei of reticular cells (arrowheads), which are in intimate contact with reticular fibers in the sinus. 640. FIGURE 14.19 • Electron micrograph of a reticular cell. The body of a reticular cell and its processes (arrows) are evident. The arrangement of the reticular cells contains and isolates the collagen fibrils from exposure to the lymphocytes. Note the adjacent lymphocytes on the right. In the light microscope and using a silver staining method, these collagen fibrils are recognized as a reticular fiber. 12,600. Lymphocytes in the superficial cortex are organized into nodules.


Histology_Ross

Histology_Ross. Lymphocytes in the superficial cortex are organized into nodules. As elsewhere, the lymphatic nodules of the cortex are designated primary nodules if they consist chiefly of small lymphocytes and secondary nodules if they possess a germinal center. Lymphatic nodules are found in the outer part of the cortex, called the superficial (nodular) cortex (Plate 37, page 479). The portion of the cortex between the medulla and superficial cortex is free of nodules; it is called the deep cortex (paracortex). This region contains most of the T cells in the lymph node (Fig. 14.22a). Because of its dependence on the thymus, perinatal thymectomy in animals results in a poorly developed deep cortex. On the basis of this


Histology_Ross

Histology_Ross. FIGURE 14.20 • Diagram of a follicular dendritic cell. This cell, usually found in germinal centers, has multiple, thin, hairlike cytoplasmic processes that interdigitate between B lymphocytes. Antigen–antibody complexes adhere to the dendritic cytoplasmic processes by means of Fc receptors. Follicular dendritic cells are not antigen-presenting cells because they lack MHC II molecules. observation, the deep cortex is also called the thymus-dependent cortex. The medulla of the lymph node consists of the medullary cords and medullary sinuses.


Histology_Ross

Histology_Ross. observation, the deep cortex is also called the thymus-dependent cortex. The medulla of the lymph node consists of the medullary cords and medullary sinuses. The medulla, the inner part of the lymph node, consists of cords of lymphatic tissue separated by lymphatic sinuses called medullary sinuses. As described above, a network of reticular cells and fibers traverses the medullary cords and medullary sinuses and serves as the framework of the parenchyma. In addition to reticular cells, the medullary cords contain lymphocytes (mostly B lymphocytes), macrophages, dendritic, and plasma cells (Fig. 14.22b). The medullary sinuses converge near the hilum, where they drain into efferent lymphatic vessels. Filtration of lymph in the lymph node occurs within a network of interconnected lymphatic channels called sinuses.


Histology_Ross

Histology_Ross. Filtration of lymph in the lymph node occurs within a network of interconnected lymphatic channels called sinuses. There are three types of lymphatic channels called sinuses in the lymph node. Just beneath the capsule of the lymph node is a sinus interposed between the capsule and the cortical lymphocytes called the subcapsular (cortical) sinus


Histology_Ross

Histology_Ross. FIGURE 14.21 • Schematic diagram of lymphocyte circulation within a lymph node. The green arrows indicate the circulation pathway of lymphocytes that enter the lymph node with the flow of lymph. Afferent lymphatic vessels carry lymph from the surrounding tissues and neighboring lymph nodes into the elaborate network of lymphatic sinuses. The wall of the sinuses allows lymph to percolate freely into the superficial and deep cortex, allowing lymphocytes to engage in immunosurveillance. The lymphocytes that enter the tissue next migrate back to the sinuses and leave the lymph node with the flow of the lymph. Lymphocytes that migrate to the lymph node from the blood (blue arrows) enter the deep cortex via high endothelial venules (HEVs) and also migrate to the superficial cortex. Here lymphocytes perform the same functions as lymphocytes that enter via lymphatic vessels. They also leave the lymph node by the efferent lymph vessels.


Histology_Ross

Histology_Ross. (Plate 38, page 481). Afferent lymphatic vessels drain lymph into this sinus. Trabecular sinuses that originate from the subcapsular sinuses extend through the cortex along the trabeculae and drain into medullary sinuses. Lymphocytes and macrophages or their processes readily pass back and forth between the lymphatic sinuses and the parenchyma of the node. The sinuses have a lining of endothelium that is continuous where it is directly adjacent to the connective tissue of the capsule or trabeculae but discontinuous where it faces the lymphatic parenchyma. Although a macrophage may reside in the lymphatic parenchyma, it often sends pseudopods (long cytoplasmic processes) into the sinus through these endothelial discontinuities. These pseu


Histology_Ross

Histology_Ross. FIGURE 14.22 • Distribution of T and B lymphocytes in the superficial cortex of the lymph node. a. Distribution of T lymphocytes in the lymph node of a marmoset monkey was visualized using an immunocytochemical method employing antibodies against CD3 protein, a specific marker for T lymphocytes. Tissue sections were initially treated with primary rabbit antihuman antibodies against a CD3 marker and later exposed to biotinylated secondary swine antirabbit antibodies. After incubation with avidin-biotin-peroxidase complex, the positive response was then visualized with diaminobenzidine (DAB) solution (brown-colored reaction). Cell nuclei were counterstained with hematoxylin. Note that the majority of T cells are distributed within the deep cortex (DP), a small number of T cells is present in the superficial cortex (SC), mainly around germinal centers (GC). b. Using the same immunoperoxidase DAB reaction described above, B cells were localized using primary monoclonal antibodies against


Histology_Ross

Histology_Ross. the superficial cortex (SC), mainly around germinal centers (GC). b. Using the same immunoperoxidase DAB reaction described above, B cells were localized using primary monoclonal antibodies against human CD20 protein (specific marker for B lymphocytes). Subsequently, secondary rabbit antimouse antibodies were used to visualize location of B cells, which the accumulations are found within germinal centers (GC) of the superficial cortex (SC). Cap, capsule. 200. (Courtesy of Dr. Douglas F. Paulsen.) dopods monitor the lymph as it percolates through the sinus.


Histology_Ross

Histology_Ross. Lymphatic sinuses are not open spaces, as are blood sinuses. Particularly in the medulla, macrophage processes, along with the reticular fbers surrounded by reticular cell processes, span the lumen of the sinus and form a crisscrossing meshwork that retards the free fow of lymph and enhances its fltration. Antigenic material and transformed cells of metastatic cancer are trapped by this mechanical flter and then phagocytosed by macrophages. In metastatic cancer, the system can be overwhelmed by an excessive number of cancer cells fowing through the lymphatic sinuses; as a result, the cells may establish a new metastatic site in the lymph node. Specialized high endothelial venules (HEVs) are the site of fluid absorption and the entrance for circulating lymphocytes into the lymph node.


Histology_Ross

Histology_Ross. In addition to lymph, lymphocytes also circulate through the lymph nodes. Although some lymphocytes enter nodes through afferent lymphatic vessels as components of lymph, most (about 90%) enter the node through the walls of postcapillary venules located in the deep cortex (see Fig. 14.21 and Plate 38, page 481). Because the postcapillary venules are lined by cuboidal or columnar endothelial cells, they are referred to as high endothelial venules (HEVs); Fig. 14.23). Cells of HEVs play an important role in circulating and concentrating lymph by transporting approximately 35% of fluid and electrolytes entering via afferent lymph vessels directly into the bloodstream. The cells of HEVs express a high concentration of water channels (aquaporin-1 [AQP-1] molecules). The rapid resorption of the interstitial fluid via water channels into the bloodstream causes lymph entering through the afferent lymph vessels to be drawn into the deep cortex by solvent drag.


Histology_Ross

Histology_Ross. These specialized endothelial cells also possess receptors for antigen-primed lymphocytes. They signal lymphocytes to leave the circulation and migrate into the lymph node. Both B and T cells leave the bloodstream through HEVs, crossing the endothelium by diapedesis—that is, by migrating between the endothelial cells in a manner similar to that described for neutrophils (see Fig. 10.6, page 277). The T cells remain in the thymus-dependent deep cortex; the B cells migrate to the nodular cortex (see Fig. 14.22). Most lymphocytes leave the lymph node by entering lymphatic sinuses from which they flow to an efferent lymphatic vessel. The lymph node is an important site for phagocytosis and initiation of immune responses.


Histology_Ross

Histology_Ross. The lymph node is an important site for phagocytosis and initiation of immune responses. Phagocytosis of particulate material by phagocytotic cells within the lymph nodes is an important step in initiating an immune response. The physical accumulation of microorganisms and particulate substances conveyed in the lymph and phagocytosis of the particulate material help to concentrate antigen, thus enhancing its presentation to lymphocytes. Antigens conveyed in the lymph percolate through the sinuses and penetrate the lymph nodules to initiate an immune response. Some antigens become trapped on the surface of the follicular dendritic cells, whereas others are processed by macrophages, dendritic cells, and B cells, leading to activation and differentiation of B cells into antibody-producing plasma cells and memory B cells.


Histology_Ross

Histology_Ross. The plasma cells then migrate to the medullary cords where they synthesize and release specific antibodies into the lymph flowing through the sinuses. Plasma cells account for 1% to 3% of the cells in resting lymph nodules. Their number increases dramatically during an immune response, thereby increasing the amount of circulating immunoglobulins. Memory B cells may leave the lymph nodes and circulate to various regions throughout the body, where they can proliferate in response to subsequent exposure to their specific antigen. The presence of memory cells in various sites


Histology_Ross

Histology_Ross. FIGURE 14.23 • Photomicrograph of the deep cortex of a lymph node. This photomicrograph shows several longitudinally sectioned high endothelial venules (HEVs) as well as several that are seen in cross section (arrows). These vessels are lined by cuboidal endothelial cells. In some preparations, the walls of an HEV may be infiltrated with migrating lymphocytes, making it difficult to recognize. 400. Inset. The cross section of an HEV shown here at higher magnification reveals several lymphocytes (arrowheads) in the process of migrating from the HEV into the parenchyma of the lymph node. 640. throughout the body ensures a more rapid response to an antigen, the secondary response.


Histology_Ross

Histology_Ross. throughout the body ensures a more rapid response to an antigen, the secondary response. Lymph nodes in which lymphocytes are responding to antigens often enlarge, refecting formation of germinal centers and proliferation of lymphocytes. This phenomenon is often seen in the lymph nodes of the neck in response to nasal or oropharyngeal infection, and in axillary and inguinal regions because of infection in extremities. Lymphadenitis, a reactive (infammatory) lymph node enlargement, is a common complication of microbial infections. These enlarged lymph nodes are commonly referred to as swollen glands (see Folder 14.4).  FOLDER 14.4 Clinical Correlation: Reactive (Inflammatory) Lymphadenitis


Histology_Ross

Histology_Ross.  FOLDER 14.4 Clinical Correlation: Reactive (Inflammatory) Lymphadenitis Reactive (inﬂammatory) lymphadenitis refers to enlargement of the lymph nodes that is often secondary to bacterial and other microbial infections. Lymph nodes enlarge because of edema and hyperplasia of lymphatic nodules and their cellular components (Fig. F14.4.1). These include B lymphocytes, T lymphocytes, macrophages, and other antigen-presenting cells. In addition, infiltration of lymphatic sinuses by neutrophils is also prominent. In severe bacterial infections, lymphadenitis may be accompanied by lymphangitis, an inflammation of afferent lymphatic vessels that carry infected lymph into regional lymph nodes. Inflamed lymph vessels may be visible as red streaks under the skin in the affected area of lymphatic drainage. Common symptoms of acute lymphadenitis are swollen lymph nodes that are tender to palpation, fever, chills, loss of appetite, tachycardia, and general weakness. Lymph


Histology_Ross

Histology_Ross. Common symptoms of acute lymphadenitis are swollen lymph nodes that are tender to palpation, fever, chills, loss of appetite, tachycardia, and general weakness. Lymph FIGURE F14.4.1 • Photomicrograph of a lymph node with nodes are usually palpable and tender, with red discol reactive lymphadenitis. Section though a superficial cortex oration on the overlying skin. In severe cases of suppura-of the lymph node shows a hyperplastic germinal center (GC) tive necrosis (necrosis with pus formation), a fistula (false projecting toward the connective tissue capsule. The majority opening) may develop that allows pus to drain from the of pale staining cells within the germinal center are enlarged lymph node to the surface. represented by B lymphocytes and macrophages;


Histology_Ross

Histology_Ross. The most common microbial organisms that cause lym-accumulation of T lymphocytes forms a distinct mantle zone phadenitis are streptococcal and staphylococcal bacteria. that encircles the germinal center. 120. (Reproduced from Other less common organisms are viruses (as in mononu-Schwarting R, McKenzie S, Rubin R. Hematopathology. cleosis or rubella), protozoa, rickettsiae, fungi, and the In: Rubin R, Strayer DS [eds]: Rubin’s Pathology: Clinicotuberculosis bacilli. Tonsillitis, infections originating from pathologic Foundations of Medicine, 5th ed. Baltimore: Lippincott Williams & Wilkins, 2008.) teeth, and bacterial pharyngitis (sore throats) are the most common causes of lymphadenitis in the neck area. Generalized lymphadenopathy is typical for rheumatoid arthritis and is detected as an early sign of HIV infection. In chronic lymphadenitis, lymph nodes are enlarged, but they are usuxally not tender. The thymus is a lymphoepithelial organ located in the superior mediastinum.


Histology_Ross

Histology_Ross. The thymus is a lymphoepithelial organ located in the superior mediastinum. The thymus is a bilobed organ located in the superior mediastinum, anterior to the heart and great vessels. It develops bilaterally from the third (and sometimes also the fourth) branchial (oropharyngeal) pouch. During development, the epithelium invaginates, and the thymic rudiment grows caudally as a tubular projection of the endodermal epithelium into the mediastinum of the chest. The advancing tip proliferates and ultimately becomes disconnected from the branchial epithelium. Multipotential lymphoid stem cells (CFU-Ls) from the bone marrow are destined to develop into immunocompetent T cells that invade the epithelial rudiment and occupy spaces between the epithelial cells so that the thymus develops into a lymphoepithelial organ.


Histology_Ross

Histology_Ross. The thymus is fully formed and functional at birth. It persists as a large organ until about the time of puberty, when T-cell differentiation and proliferation are reduced and most of the lymphatic tissue is replaced by adipose tissue (involution). The organ can be restimulated under conditions that demand rapid T-cell proliferation. General Architecture of the Thymus Connective tissue surrounds the thymus and subdivides it into thymic lobules. The thymus possesses a thin connective tissue capsule from which trabeculae extend into the parenchyma of the organ. The capsule and trabeculae contain blood vessels, efferent (but not afferent) lymphatic vessels, and nerves. In addition to collagen fibers and fibroblasts, the connective tissue of the thymus contains variable numbers of plasma cells, granulocytes, lymphocytes, mast cells, adipose cells, and macrophages.


Histology_Ross

Histology_Ross. The trabeculae establish domains in the thymus called thymic lobules. They are not true lobules, but cortical caps over portions of the highly convoluted but continuous inner FIGURE 14.24 • Photomicrograph of an infant human thymus. This H&E preparation reveals multiple lobules separated by connective tissue trabeculae that extend into the organ from the surrounding capsule. Each lobule is composed of a dark-staining basophilic cortex and a lighter-staining and relatively eosinophilic medulla. The medulla is actually a continuous branching mass surrounded by the cortex. The cortex contains numerous densely packed lymphocytes, whereas the medulla contains fewer lymphocytes. Note that in some instances the medulla may bear a resemblance to germinal centers of lymphatic nodules (upper right and center left). Such isolated medullary profiles are continuous with the overall medullary tissue, but this continuity may not be seen within the plane of section. 25.


Histology_Ross

Histology_Ross. medullary tissue (Fig. 14.24 and Plate 41, page 487). In some planes of section, the “lobular” arrangement of the cortical cap and medullary tissue superficially resembles a lymphatic nodule with a germinal center, which often confuses students. Other morphologic characteristics (described below) allow positive identification of the thymus in histologic sections. The thymic parenchyma contains developing T cells in an extensive meshwork formed by epithelioreticular cells.


Histology_Ross

Histology_Ross. The thymic parenchyma contains developing T cells in an extensive meshwork formed by epithelioreticular cells. The outer portion of the parenchyma, the thymic cortex, is markedly basophilic in hematoxylin and eosin (H&E) preparations because of the closely packed developing T lymphocytes with their intensely staining nuclei. These T lymphocytes, also called thymocytes, occupy spaces within an extensive mesh-work of epithelioreticular cells (Fig. 14.25). Macrophages are also dispersed among the cortical cells. The developing T cells arise from CFU-Ls, which originate in bone marrow. As development proceeds in the thymus, the cells derived from CFU-Ls pass through a series of developmental stages that are reflected by their expression of different CD molecules.


Histology_Ross

Histology_Ross. As their name implies, epithelioreticular cells have features of both epithelial and reticular cells. They provide a framework for the developing T cells; thus, they correspond to the reticular cells and their associated reticular fibers in other lymphatic tissues and organs. Reticular connective tissue cells and their fibers, however, are not present in the thymic parenchyma. Epithelioreticular cells exhibit certain features characteristic of epithelium such as intercellular junctions and intermediate filaments. Six types of epithelioreticular cells are recognized on the basis of function: Three types in the cortex and three types in the medulla. Each type is designated by roman numerals. In the cortex, the following cell types are recognized.


Histology_Ross

Histology_Ross.  Type I epithelioreticular cells are located at the boundary of the cortex and the connective tissue capsule as well as between the cortical parenchyma and the trabeculae. They also surround the adventitia of the cortical blood vessels. In essence, type I epithelioreticular cells serve to separate the thymic parenchyma from the connective tissue of the organ. The occluding junctions between these cells reflect their function as a barrier that isolates developing T cells from the connective tissue of the organ—that is, capsule, trabeculae, and perivascular connective tissue.


Histology_Ross

Histology_Ross.  Type II epithelioreticular cells are located within the cortex. The transmission electron microscope (TEM) reveals maculae adherents (desmosomes) that join long cytoplasmic processes of adjacent cells. The cell body and cytoplasmic processes contain abundant intermediate filaments. Because of their processes, these cells are stellate. They have a large nucleus that stains lightly with H&E because of its abundant euchromatin. This nuclear feature allows the cell to be easily identified in the light microscope. Type II cells compartmentalize the cortex into isolated areas for the developing T cells. Unlike type I cells, type II cells express MHC I and MHC II molecules, which are involved in thymic cell education.


Histology_Ross

Histology_Ross.  Type III epithelioreticular cells are located at the boundary of the cortex and medulla. The TEM reveals occluding junctions between sheetlike cytoplasmic processes of adjacent cells. Like type I cells, type III epithelioreticular cells create a functional barrier—in this case, between the cortex and medulla. Like type II cells, they possess MHC I and MHC II molecules.  Macrophages reside within the thymic cortex and are responsible for phagocytosis of T cells that do not fulfill thymic education requirements. These T cells are programmed to die before leaving the cortex. Approximately 98% of the T cells undergo this apoptosis and are then phagocytosed by the macrophages. The macrophages in the cortex are difficult to identify in H&E preparations. However, the periodic acid– Schiff (PAS) reaction readily defines them because of the


Histology_Ross

Histology_Ross. FIGURE 14.25 • Photomicrograph of a human thymus. a. The cortex contains a dense population of small, maturing T cells that creates the dark staining of this region of the thymus. The medulla, in contrast, appears lighter. The medulla also contains the thymic corpuscles that stain with eosin and give it a further distinction. 120. b. This higher-magnification photomicrograph shows the medulla with a thymic corpuscle (left) and surrounding cells. Thymic corpuscles are isolated masses of closely packed, concentrically arranged type VI epithelioreticular cells; these cells exhibit flattened nuclei. The more central mass of the corpuscle contains fully keratinized cells. In addition to numerous lymphocytes, the micrograph also shows type V epithelioreticular cells (arrows), with their eosinophilic cytoplasm and large, pale-staining nuclei. 600. staining of their numerous large lysosomes. Accordingly, these macrophages are called PAS cells.


Histology_Ross

Histology_Ross. staining of their numerous large lysosomes. Accordingly, these macrophages are called PAS cells. Although the epithelioreticular cells of the thymic cortex play an important role in the development of immunocompetent T cells, recent evidence shows that T cells at the different stages of differentiation control the microarchitecture of the thymic epithelioreticular cells, a phenomenon called crosstalk. The developing lymphocytes and epithelioreticular cells thus influence each other during T-cell development. Thymic or Hassall’s corpuscles (derived from type VI epithelioreticular cells) are a distinguishing feature of the thymic medulla.


Histology_Ross

Histology_Ross. Thymic or Hassall’s corpuscles (derived from type VI epithelioreticular cells) are a distinguishing feature of the thymic medulla. The thymic medulla, the inner portion of the parenchyma, contains a large number of epithelioreticular cells and loosely packed T cells (Fig. 14.25). The medulla stains less intensely than the cortex because, like the germinal centers of lymph nodules, it contains mostly large lymphocytes. These lymphocytes have pale-staining nuclei and quantitatively more cytoplasm than small lymphocytes. Like the cortex, the medulla also contains three types of epithelioreticular cells:  Type IV epithelioreticular cells are located between the cortex and the medulla close to type III cells. They possess sheetlike processes with occluding junctions between adjacent cells as well as between them and type III cells. In cooperation with type III cells, they create the barrier at the corticomedullary junction.


Histology_Ross

Histology_Ross.  Type V epithelioreticular cells are located throughout the medulla. Like the type II cells located in the cortex, processes of adjacent cells are joined by desmosomes to provide the cellular framework of the medulla and to compartmentalize groups of lymphocytes. These nuclei contrast markedly with the densely staining lymphocyte nuclei.  Type VI epithelioreticular cells form the most characteristic feature of the thymic medulla, the thymic (Hassall’s) corpuscles (Fig. 14.26 and Plate 41, page 487). Thymic corpuscles are isolated masses of closely packed, concentrically arranged type VI epithelioreticular cells that exhibit flattened nuclei. TEM studies of these cells reveal keratohyalin granules, bundles of cytoplasmic intermediate filaments, and lipid droplets. The cells are joined by desmosomes. The center of a thymic corpuscle


Histology_Ross

Histology_Ross. FIGURE 14.26 • Electron micrograph of a thymic (Hassall’s) corpuscle. This relatively low-magnification electron micrograph shows some of the nuclei (N) and cytoplasm of the concentrically arranged epithelioreticular cells of a thymic (Hassall’s) corpuscle. Bundles of intermediate filaments, keratohyalin granules, and lipid droplets are also evident within the cytoplasm of the epithelioreticular cells. Fully keratinized cells (black layer) are present in the center of the thymic corpuscle. 5,000. (Courtesy of Dr. Johannes A. G. Rhodin.) may display evidence of keratinization, not a surprising feature for cells developed from oropharyngeal epithelium. Thymic corpuscles are unique, antigenically distinct, and functionally active multicellular components of the medulla. Although the function of thymic corpuscles is not fully understood, it is thought that thymic corpuscles produce interleukins (IL-4 and IL-7) that function in thymic differentiation and education of T lymphocytes.


Histology_Ross

Histology_Ross. Blood vessels pass from the trabeculae to enter the parenchyma of the thymus. Typically, the blood vessels enter the medulla from the deeper parts of the trabeculae and carry a sheath of connective tissue along with them. This perivascular connective tissue sheath varies in thickness. It is thicker around larger vessels and gradually becomes thinner around smaller vessels. Where it is thick, it contains reticular fibers, fibroblasts, macrophages, plasma cells, and other cells found in loose connective tissue; where it is thin, it may contain only reticular fibers and occasional fibroblasts. The blood–thymus barrier protects developing lymphocytes in the thymus from exposure to antigens.


Histology_Ross

Histology_Ross. The blood–thymus barrier protects developing lymphocytes in the thymus from exposure to antigens. Lymphocytes reaching the thymic cortex are prevented from contact with antigen by a physical barrier called the blood– thymus barrier (Fig. 14.27). The following components constitute the blood–thymus barrier between the T cells and the lumen of cortical blood vessels, from the lumen outward:  The endothelium lining the capillary wall is of the continuous type with occluding junctions. It is highly impermeable to macromolecules and is considered a major structural component of the barrier within the cortical parenchyma. The underlying basal lamina of endothelial cells and occasional pericytes are also part of the capillary wall.


Histology_Ross

Histology_Ross. FIGURE 14.27 • Schematic diagram of the blood–thymus barrier. The blood–thymus barrier consists of three major elements: (1) capillary endothelium and its basal lamina, (2) perivascular connective tissue space occupied by macrophages, and (3) type I epithelioreticular cells with their basal lamina. The perivascular connective tissue is enclosed between the basal lamina of the epithelioreticular cells and the endothelial cell basal lamina. These layers provide the necessary protection to the developing immature T cells and separate them from mature immunocompetent lymphocytes circulating in the bloodstream.  Macrophages residing in the surrounding perivascular connective tissue may phagocytose antigenic molecules that escape from the capillary lumen into the cortical parenchyma.


Histology_Ross

Histology_Ross.  Macrophages residing in the surrounding perivascular connective tissue may phagocytose antigenic molecules that escape from the capillary lumen into the cortical parenchyma.  Type I epithelioreticular cells with their occluding junctions provide further protection to the developing T cells. The epithelioreticular cells surround the capillary wall in the cortex; with their basal lamina, they represent another major structural component of the blood–thymus barrier. The thymus is the site of T-cell education. During fetal life, the thymus is populated by multipotential lymphoid stem cells that originate from the bone marrow and are destined to develop into immunocompetent T cells. Stem cell maturation and differentiation into immunocompetent T cells is called thymic cell education (Fig. 14.28). This process is characterized by the expression and deletion of specific surface CD antigens.


Histology_Ross

Histology_Ross. immunocompetent T cells is accomplished by the expression and deletion of specific surface CD DO NOT selection antigens. The CFU-L stem cells enter the medulla PASS of the thymus via a postcapillary venule and then type migrate to the periphery of the thymic lobule. The II erc presence of CD2 and CD7 molecules on the cell surface indicates an early stage of differentiation. This is followed by expression of the CD1


Histology_Ross

Histology_Ross. The expression of CD2 and CD7 molecules on the T-cell surface indicates an early stage of differentiation (doublenegative stage). The double-negative term refers to lack of both CD4 and CD8 molecules. This early stage is followed by the expression of the CD1 molecule, which indicates the middle stage of T-cell differentiation. As maturation progresses, the T-cells express TCRs, CD3, and both CD4 and CD8 molecules. This is the double-positive stage of T-cells differentiation. These cells are then presented with selfand foreign antigens by type II and III epithelioreticular cells. If the lymphocyte recognizes self-MHC molecules and selfor foreign antigen, it will survive, a process called positive selection. If not, the cell will die. Cells that pass the positive-selection test leave the cortex and enter the medulla. Here, they undergo another selection process in which cells that recognize self-antigen displayed by self-MHC are eliminated, a process called negative selection. The cells


Histology_Ross

Histology_Ross. and enter the medulla. Here, they undergo another selection process in which cells that recognize self-antigen displayed by self-MHC are eliminated, a process called negative selection. The cells that survive become either


Histology_Ross

Histology_Ross. FIGURE 14.28 • Schematic drawing of the major steps in thymic education. The process of multipotential lymphatic stem cell (CFU-L) molecule, indicating the middle stage of T-cell differentiation. As maturation progresses, the cells express TCRs, CD3, CD4, and CD8 molecules. These cells are then presented with epithelioreticular (erc) cells. If the lymphocyte recognizes self MHC and self or foreign antigen, then it will survive the selection (positive TCR selection); if not, death of the cell will occur. Cells that pass the positive selection test leave the cortex and enter the medulla. Here they undergo to self-antigen displayed by self MHC are typeV eliminated (negative selection). Cells that survive erc that selection then become either cytotoxic CD8 T lymphocytes or helper CD4 T lymphocytes.


Histology_Ross

Histology_Ross. CD8 These cells are now ready for the immune response; they leave the thymus from the medulla and enter the blood circulation. Hormonal substances secreted by type VI epithelioreticular cells within the thymic (Hassall’s) corpuscle promote the process of thymic cell education. Note the distribution of all six types of epithelioreticular cells. cytotoxic CD8 T lymphocytes (by losing CD4 and retaining CD8) or helper CD4 T lymphocytes (by losing CD8 and retaining CD4). This stage is called the single-positive stage of T-cells differentiation. Now the cells leave the thymus by passing from the medulla into the blood circulation. The process of thymic cell education is promoted by substances secreted by the epithelioreticular cells, including interleukins (IL-4 and IL-7), colony-stimulating factors, and interferon .


Histology_Ross

Histology_Ross. The spleen is about the size of a clenched fist and is the largest lymphatic organ. It is located in the upper left quadrant of the abdominal cavity and has a rich blood supply. The spleen filters blood and reacts immunologically to blood-borne antigens. The spleen has both morphologic and immunologic filtering functions. In addition to large numbers of lymphocytes, it contains specialized vascular spaces or channels, a meshwork of reticular cells and reticular fibers, and a rich supply of macrophages and dendritic cells. These contents allow the spleen to monitor the blood immunologically, much as the macrophages and dendritic cells of the lymph nodes monitor the lymph. The spleen is enclosed by a dense connective tissue capsule from which trabeculae extend into the parenchyma of the organ (Fig. 14.29). The connective tissue of the capsule


Histology_Ross

Histology_Ross. FIGURE 14.29 • Schematic diagram and photomicrograph of splenic structure. a. The substance of the spleen is divided into white pulp and red pulp. White pulp consists of a cylindrical mass of lymphocytes arranged around a central artery that constitutes the periarterial lymphatic sheath (PALS). Splenic nodules occur along the length of the PALS. When observed in cross section through part of the sheath that contains a nodule, the central artery appears eccentrically located with respect to the lymphatic mass. The red pulp consists of splenic sinuses surrounded by splenic cords (cords of Billroth). A capsule surrounds the spleen; trabeculae project from it into the substance of the spleen. Both capsule and trabeculae give the appearance of dense connective tissue infiltrated by numerous myofibroblasts. Blood vessels traverse the capsule and trabeculae before and after passage within the substance of the spleen. Lymphatic vessels originate in the white pulp near the trabeculae. b. This


Histology_Ross

Histology_Ross. Blood vessels traverse the capsule and trabeculae before and after passage within the substance of the spleen. Lymphatic vessels originate in the white pulp near the trabeculae. b. This low-magnification photomicrograph of the spleen reveals the same components shown in the previous drawing. Note the capsule with several trabeculae projecting into the substance of the spleen. In the center, there is a trabecula containing a trabecular vein through which blood leaves the organ. The red pulp constitutes the greater bulk of the splenic tissue. The white pulp contains lymphatic tissue that follows and ensheathes the central artery. Expansion of the white pulp creates the splenic nodules. 45.


Histology_Ross

Histology_Ross. and trabeculae contains myofibroblasts. These contractile cells also produce extracellular connective tissue fibers. In many mammals, the spleen holds large volumes of red blood cells in reserve. In these species, contraction in the capsule and trabeculae helps discharge stored red blood cells into the systemic circulation. The human spleen normally retains relatively little blood, but it has the capacity for contraction by means of the contractile cells in the capsule and trabeculae. The hilum, located on the medial surface of the spleen, is the site for the passage of the splenic artery and vein, nerves, and lymphatic vessels. The lymphatic vessels originate in the white pulp near the trabeculae and constitute a route for lymphocytes leaving the spleen.


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Histology_Ross. Most of the spleen consists of splenic pulp. Splenic pulp, in turn, is divided into two functionally and morphologically different regions: white pulp and red pulp, based on the color of fresh sections. White pulp appears as circular or elongated whitish gray areas surrounded by red pulp. White pulp consists of a thick accumulation of lymphocytes surrounding an artery.


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Histology_Ross. The white pulp consists of lymphatic tissue, mostly lymphocytes. In H&E–stained sections, white pulp appears basophilic because of the dense heterochromatin in the nuclei of the numerous lymphocytes (Plate 39, page 483). Branches of the splenic artery course through the capsule and trabeculae of the spleen and then enter the white pulp. Within the white pulp, the branch of the splenic artery is called the central artery. Lymphocytes that aggregate around the central artery constitute the periarterial lymphatic sheath (PALS). The PALS has a roughly cylindrical configuration that conforms to the course of the central artery. In cross sections, the PALS appears circular and may resemble a lymphatic nodule. The presence of the central artery, however, distinguishes the PALS from typical lymphatic nodules found in other sites. Nodules appear as localized expansions of the PALS and displace the central artery so that it occupies an eccentric rather than a central position.


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Histology_Ross. The nodules are the territory of B lymphocytes; other lymphocytes of the PALS are chiefly T lymphocytes that surround the nodules. Thus, the PALS may be considered a thymus-dependent zone similar to the deep cortex of a lymph node. The nodules usually contain germinal centers, which, as in other lymphatic tissues, develop as B cells proliferate after their activation. In humans, germinal centers develop within 24 hours after antigen exposure and may become extremely large and visible with the naked eye. These enlarged nodules are called splenic nodules or Malpighian corpuscles (not to be confused with the renal corpuscles that have the same name). Red pulp contains large numbers of red blood cells that it filters and degrades.


Histology_Ross

Histology_Ross. Red pulp contains large numbers of red blood cells that it filters and degrades. Red pulp has a red appearance in the fresh state as well as in histologic sections because it contains large numbers of red blood cells (Plate 40, page 485). Essentially, red pulp consists of splenic sinuses separated by splenic cords (cords of Billroth). Splenic cords consist of the now-familiar loose meshwork of reticular cells and reticular fibers that contain large numbers of erythrocytes, macrophages, lymphocytes, dendritic cells, plasma cells, and granulocytes. Splenic macrophages phagocytose damaged red blood cells. The iron from destroyed red blood cells is used in the formation of new red blood cells; splenic macrophages begin the process of hemoglobin breakdown and iron reclamation. Megakaryocytes are also present in certain species, such as rodents and the cat, but not in humans except during fetal life.


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Histology_Ross. The splenic or venous sinuses are special sinusoidal vessels lined by rod-shaped endothelial cells. The endothelial cells that line the splenic sinuses are extremely long. Their longitudinal axis runs parallel to the direction of the vessel (Fig. 14.30). There are few contact points between adjacent cells, thus producing prominent intercellular spaces. These spaces allow blood cells to pass readily into and out of the sinuses. Processes of macrophages extend between the endothelial cells and into the lumen of the sinuses to monitor the passing blood for foreign antigens.


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Histology_Ross. The sinuses do not possess a continuous basal lamina. Strands of basal lamina loop around the outside of the sinus much like the hoops that loop around the staves of a barrel. These strands are at right angles to the long axes of the endothelial cells. This material stains with silver-containing reagents or with the PAS reaction (Plate 40, page 485). Neither smooth muscle nor pericytes are present in the wall of splenic sinuses. Reticular cell processes may extend to the basal side of the endothelial cells and are probably associated with the reticular fibers that appear to merge with the perisinusoidal loops of basal lamina. Blood fills both the sinuses and cords of the red pulp, often obscuring the underlying structures and making it difficult to distinguish between the cords and the sinuses in histologic sections. Circulation within red pulp allows macrophages to screen antigens in the blood.


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Histology_Ross. Branches of the splenic artery enter the white pulp from the trabeculae. The central artery sends branches to the white pulp itself and to the sinuses at the perimeter of the white pulp called marginal sinuses (see Fig. 14.29). The central artery continues into the red pulp, where it branches into several relatively straight arterioles called penicillar arterioles. The penicillar arterioles then continue as arterial capillaries. Some arterial capillaries are surrounded by aggregations of macrophages and are thus called sheathed capillaries. Sheathed capillaries then empty directly into the reticular meshwork of the splenic cords rather than connecting to the endothelium-lined splenic sinuses. Blood entering the red pulp in this manner percolates through the cords and is exposed to the macrophages of the cords before returning to the circulation by squeezing through the walls of the splenic sinuses (Fig. 14.31). This type of circulation is referred to as open circulation, and it is the


Histology_Ross

Histology_Ross. of the cords before returning to the circulation by squeezing through the walls of the splenic sinuses (Fig. 14.31). This type of circulation is referred to as open circulation, and it is the only route by which blood returns to the venous circulation in humans. In other species such as the rat and dog, some of the blood from the sheathed capillaries passes directly to the splenic sinuses of the red pulp. This type of circulation is referred to as closed circulation.


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Histology_Ross. FIGURE 14.30 • Splenic sinus and splenic cord structure. a. This scanning electron micrograph shows a cross section of a splenic sinus (SS), revealing the lattice structure of its wall. Through the multiple openings in the wall, processes of macrophages (arrows) are inserted into the sinus lumen. The remainder of the micrograph shows characteristically smooth-surfaced processes of reticular cells (RC). The spaces of the reticular cell framework contain neutrophils (N), macrophages (M), and blood platelets (P). 4,400. b. Schematic diagram of the reconstructed structure of splenic sinus. Note the direction of blood flow in open and closed circulations. c.


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Histology_Ross. b. Schematic diagram of the reconstructed structure of splenic sinus. Note the direction of blood flow in open and closed circulations. c. Scanning electron micrograph of the splenic sinus, showing the architecture of the sinus wall as seen from its luminal side. Rodlike endothelial cells run in parallel and are intermittently connected to each other by side processes. A nuclear swelling is shown at lower right. The tapered ends of a few of the rod cells are seen. The macrophage, neutrophil, and lymphocyte are outside the sinus. 5,300. (Reprinted with permission from Fujita T, Tanaka K, Tokunga J. SEM Atlas of Cells and Tissues. Tokyo: Igaku-Shoin, 1981.)


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Histology_Ross. 5,300. (Reprinted with permission from Fujita T, Tanaka K, Tokunga J. SEM Atlas of Cells and Tissues. Tokyo: Igaku-Shoin, 1981.) FIGURE 14.31 • Schematic diagram of open and closed splenic circulations. In the open circulation, which occurs in humans, penicillar arterioles empty directly into the reticular meshwork of the cords rather than connect to the endotheliumlined splenic sinuses. Blood entering the red pulp then percolates through the cords and is exposed to the macrophages residing there. In the closed circulation, which occurs in other species, the penicillar arterioles empty directly into the splenic sinuses of the red pulp. PALS, periarterial lymphatic sheath.


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Histology_Ross. Open circulation exposes the blood more efficiently to the macrophages of the red pulp. Both transmission and scanning electron micrographs often show blood cells in transit across the endothelium of the sinus, presumably reentering the vascular system from the red pulp cords. The blood collected in the sinuses drains to tributaries of the trabecular veins that converge into larger veins and eventually leaves the spleen by the splenic vein. The splenic vein in turn joins the drainage from the intestine in the hepatic portal vein. The spleen performs both immune and hemopoietic functions.


Histology_Ross

Histology_Ross. The spleen performs both immune and hemopoietic functions. Because the spleen filters blood as the lymph nodes filter lymph, it functions in both the immune and the hemopoietic systems. Immune system functions of the spleen include  antigen presentation by APCs (mostly dendritic cells and macrophages) and initiation of immune response;  activation and proliferation of B and T lymphocytes;  production of antibodies against antigen present in circu lating blood; and removal of macromolecular antigens from the blood. Activation and proliferation of T cells and differentiation of B cells and plasma cells, as well as secretion of antibodies, occur in the white pulp of the spleen; in this regard, the white pulp is the equivalent of other lymphatic organs.


Histology_Ross

Histology_Ross. Hemopoietic functions of the spleen include:  removal and destruction of senescent, damaged, and abnormal erythrocytes and platelets;  retrieval of iron from erythrocyte hemoglobin;  formation of erythrocytes during early fetal life; and  storage of blood, especially red blood cells, in some species.


Histology_Ross

Histology_Ross. The role of the red pulp is primarily blood filtration (i.e., removal of particulate material, macromolecular antigens, and aged, abnormal, or damaged blood cells and platelets from the circulating blood). These functions are accomplished by the macrophages embedded in the reticular mesh-work of the red pulp. Senescent, damaged, or abnormal red cells are broken down by the lysosomes of the macrophages; the iron of the hemoglobin is retrieved and stored as ferritin or hemosiderin for future recycling. The heme portion of the molecule is broken down to bilirubin, which is transported to the liver via the portal system and there conjugated to glucuronic acid. Conjugated bilirubin is secreted into the bile, giving it a characteristic color. Macrophages recognize senescent or abnormal blood cells by several different mechanisms: become more rigid and are thus more easily trapped in the mesh of the red pulp.


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Histology_Ross. Macrophages recognize senescent or abnormal blood cells by several different mechanisms: become more rigid and are thus more easily trapped in the mesh of the red pulp. Specific mechanisms include opsonization of the cell membrane with anti-band 3 IgG antibodies, which trigger Fc receptor–dependent phagocytosis of erythrocytes. In addition, specific changes in glycosylation of glycophorins (see page 274) in aging erythrocytes act as a recognition signal that triggers the elimination of senescent erythrocytes by macrophages. Despite these important functions, the spleen is not essential for human life. It can be removed surgically, which is often done after trauma that causes intractable bleeding from the spleen. The removal and destruction of aging red blood cells then occurs in the bone marrow and liver. This page intentionally left blank.


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Histology_Ross. The palatine tonsils are paired structures consisting of masses of lymphatic tissue lo-cated on either side of the pharynx. They, along with the pharyngeal tonsils (adenoids) and lingual tonsils, form a ring at the entrance to the oropharynx (Waldeyer’s ring). Structurally, the tonsils contain numerous lymphatic nodules located in the mucosa. The stratified squamous epithelium that covers the surface of the palatine tonsil (and pharyngeal) dips into the underlying connective tissue forming many crypts, the tonsi-lar crypts. The walls of these crypts contain lymphatic nodules. The epithelial lining of the crypts is typically infiltrated with lymphocytes and often to such a degree that the epithelium may be difficult to discern. While the nodules principally occupy the con-nective tissue, the infiltration of lymphocytes into the epithelium tends to mask the ep-ithelial connective tissue boundary. The tonsils guard the opening of the pharynx, the common entry to the respiratory and


Histology_Ross

Histology_Ross. the infiltration of lymphocytes into the epithelium tends to mask the ep-ithelial connective tissue boundary. The tonsils guard the opening of the pharynx, the common entry to the respiratory and digestive tracts. The palatine and pharyngeal tonsils can become enflamed due to repeated infection in the oropharynx and na-sopharynx and can harbor bacteria that cause repeated infections if they are over-whelmed. When this occurs, the enflamed tonsils are removed surgically (tonsillectomy and adenoidectomy). Tonsils, like other aggregations of lymphatic nodules, do not possess afferent lymphatic vessels. Lymph, however, does drain from the tonsular lymphatic tissue through efferent lymphatic vessels. ORIENTATION MICROGRAPH: This low magnification micrograph is a section through a palatine tonsil. The hematoxylin staining areas represent the lymphatic tis-sue (L). The tonsil is surfaced by stratified squamous epithelium (SSE) which dips into the underlying connective tissue forming the


Histology_Ross

Histology_Ross. tonsil. The hematoxylin staining areas represent the lymphatic tis-sue (L). The tonsil is surfaced by stratified squamous epithelium (SSE) which dips into the underlying connective tissue forming the tonsilar crypts (TC). At the base of one of the crypts are a number of mucous secreting glands (MG). LLLLLLMGMGTCTCTCTCSSESSELLLMGTCTCSSE


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Histology_Ross. Tonsil, human, H&E, ×47. This micrograph is from the area in the rectangle of the orientation micrograph. At this higher magnification, part of the surface epithelium (SE) of the tonsil can be readily identified. In other sites, the lymphocytes (Ly) have infiltrated the epithelium to such an extent that the epithelium is difficult to identify. The body of the nodules (N) lie within the mucosa and because of Tonsil, human, H&E, ×365.


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Histology_Ross. Tonsil, human, H&E, ×365. At the higher magnification of this micrograph, the characteristic invasiveness of the lymphocytes into the overlying epithelium is readily evident. Note on the lower left side of the micrograph a clear boundary between the epithelium and the underlying lamina propria. The basal cells (BC) of the stratified squamous epithelium can be recognized. The underlying lamina propria is occupied by numerous lymphocytes; only a few have entered the epithelial compartment. Also note the thin band of collagen fibers (CF) that their close proximity, they tend to merge. Several of the nodules have been cut in a plane that includes their germinal center (GC). Note the eosinophilic staining in these areas. Beneath the nodules is the submucosa (S) consisting of dense connective tissue, which is continuous with the dense connective tissue beyond the tonsilar tissue.


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Histology_Ross. can be seen at the boundary between the epithelium and lamina propria. In contrast, the lower right side of the micrograph displays numerous lymphocytes that have invaded the epithelium. More striking is the presence of what appear as isolated islands of epithelial cells (Ep) within the periphery. The thin band of collagen (C) lying at the interface of the epithelium is so disrupted in this area that it appears as small fragments. In effect, the small portion of the nodule seen in the right side of the micrograph has literally grown into the epithelium with the consequent disappearance of the well-defined epithelial-connective tissue boundary. KEY BC, basal cells C, collagen CF, collagen fibers Ep, islands of epithelial cells GC, germinal center L, lymphatic tissue Ly, lymphocytes MG, mucous secreting glands N, nodule S, submucosa SE, surface epithelium SSE, stratified squamous epithelium TC, tonsilar crypts


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Histology_Ross. PLATE 37 • LYM PH NODE I Lymph nodes are small, encapsulated lymphatic organs that are located in the path of the lymph ves-sels. They serve as filters of the lymph and as the principal site in which T and B lymphocytes undergo antigen-dependent proliferation and differentiation into effector lymphocytes (plasma cells and T cells) and memory B cells and T cells. A low-magnification (×14) micrograph of a section through a human lymph node is shown on this page for orientation. The capsule appears as a thin connective tissue covering. The parenchyma of the node is composed of a mass of lymphatic tissue, arranged as a cortex (C) that surrounds a less dense area, the medulla (M). The cortex is interrupted at the hilum of the organ (H), where there is a recognizable concavity. It is at this site that blood vessels enter and leave the lymph node; the efferent lymphatic vessels also leave the node at the hilum. Afferent lymphatic vessels penetrate the capsule at multiple sites to empty into


Histology_Ross

Histology_Ross. that blood vessels enter and leave the lymph node; the efferent lymphatic vessels also leave the node at the hilum. Afferent lymphatic vessels penetrate the capsule at multiple sites to empty into an endothelium-lined space, the cortical or subcapsular sinus. This sinus drains into the trabecular sinuses that extend through the cortex alongside the trabeculae and then supply the medullary sinuses. These, in turn, drain to the efferent lymphatics that leave the node at the hilum. MM CC H


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Histology_Ross. Cortex of lymph node, human, H&E ×120. An area from the cortex is shown here at higher magnification. The capsule (Cap) is composed of dense connective tissue from which trabeculae (T) penetrate into the organ. Immediately below the capsule is the cortical or subcapsular sinus (CS), which receives lymph from the afferent lymphatic vessels after they penetrate the capsule. The cortical sinus is continuous with the trabecular sinuses (TS) that course along the trabeculae. The cortex contains the lymphatic nodules (LN) and a deeper component that lacks nodules, known as the deep cortex. Whereas lymph nodules Lymphatic nodule, lymph node, human, H&E ×400; inset ×640.


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Histology_Ross. This higher-magnification micrograph of a lymphatic nodule from figure above illustrates the germinal center (GC) containing medium and large lymphocytes. Germinal centers also contain plasma cells. Dividing lymphocytes are shown at slightly higher magnification in the inset (arrows), which corresponds to the area in the circle in this figure. The inset also reveals nuclei of the reticular cells (RC) that form the connective tissue stroma throughout the organ. The and their lighter-staining germinal centers characterize the outer cortex, a more dense mass of lymphocytes, which impart a distinct basophilia, characterize the deep cortex. In contrast to these areas, the medulla is characterized by narrow strands of anastomosing lymphatic tissue containing numerous lymphocytes, the medullary cords (MC), separated by light-appearing areas known as the medullary sinuses (MS). The medullary sinuses receive lymph from the trabecular sinuses and lymph filtered through the cortical tissue.


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Histology_Ross. ovoid reticular cell has a large pale-staining nucleus, and its cytoplasm forms long processes that surround the reticular fibers. In H&E preparations, the reticular fibers and the surrounding cytoplasm are difficult to identify. Reticular cells are best seen in the sinuses, where they extend across the lymphatic space and are relatively unobscured by other cells. A unique vessel, the high endothelial venule (HEV), is found in relation to the lymphatic nodules, particularly in the deep cortex. These vessels have an endothelium composed of tall cells between which lymphocytes migrate from the vessel lumen into the parenchyma. KEY C, cortex Cap, capsule CS, cortical or subcapsular sinus GC, germinal center H, hilum LN, lymphatic nodule M, medulla MC, medullary cords MS, medullary sinus HEV, high endothelial venule RC, reticular cells T, trabecula TS, trabecular sinus arrows, dividing lymphocytes


Histology_Ross

Histology_Ross. Immunocompetent B cells that have been exposed to an antigen that they can recognize and bind migrate to a lymph node, where they undergo activation and begin a series of mitotic divisions that produce large numbers of immature lymphocytes. They proliferate further in superficial cortex into a clone of lymphocytes that differentiate into antibody-secreting plasma cells and memory cells. B cell proliferation and differentiation take place in germinal centers in the superficial cortex of the lymph node. T cell activation and differentiation take place in the deep cortex. Newly differentiated plasma cells migrate to the medulla, where they release antibodies into the lymph leaving the node. They may also leave the node, enter the blood vascular system at the thoracic duct, and travel to localized sites in the connective tissue where they may continue to produce antibodies. Deep cortex, lymph node, human, H&E ×365.


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Histology_Ross. Deep cortex, lymph node, human, H&E ×365. This micrograph shows the lymph node deep cortex. As noted in the previous plate, it lies below the region containing the lymph nodules and consists of closely packed lymphocytes. A number of blood vessels can be seen in this region. Whereas typical small blood vessels such as capillaries (Cap) and480 venules are present, the more unusual postcapillary venule called high endothelial venule (HEV) is also found in this region. A small vessel that can be identified as a venule (Ven), based on lumen size and wall thickness, is seen at a point of transition to become a high endothelial venule (arrowheads). The endothelial cell nuclei at this point of juncture have become Hilar region, lymph node, human, H&E ×250.