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Histology_Ross. in the wall of the longitudinally sectioned arteriole belong to the smooth muscle cells of the tunica media. Their round to ovoid shape indicates that these cells have been cut in cross section. The elongated nuclei (arrows) belong to endothelial cells. 320. Inset. The cross-sectioned arteriole is shown here at higher magnification and reveals the endothelial cell nuclei bulging into the lumen (arrows). They reflect a cross-sectional cut. The nuclei of the smooth muscle cells in the tunica media appear as elongate profiles reflecting their circular pattern around the vessel. 600.


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Histology_Ross. ﬂow to skeletal muscle is increased by dilation of arterioles, and blood ﬂow to the intestine is reduced by arteriolar constriction. After ingestion of a large meal, however, the reverse is true. Capillaries are the smallest diameter blood vessels, often smaller than the diameter of an erythrocyte.


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Histology_Ross. Capillaries form blood vascular networks that allow fluids containing gases, metabolites, and waste products to move through their thin walls. The human body contains approximately 50,000 miles of capillaries. Each consists of a single layer of endothelial cells and their basal lamina. The endothelial cells form a tube just large enough to allow the passage of red blood cells one at a time. In many capillaries the lumen is so narrow that the red cells literally fold on themselves to pass through the vessel (Fig. 13.20). The passing red blood cells fill virtually the entire capillary lumen, minimizing the diffusion path for gases and nutrients between the capillary and the extravascular tissue. In cross sections and with the TEM, the tube appears to be formed by only one cell or portions of several cells. Because of their thin walls and close physical association with metabolically active cells and tissues, capillaries are particularly well suited for the exchange of gases and


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Histology_Ross. of several cells. Because of their thin walls and close physical association with metabolically active cells and tissues, capillaries are particularly well suited for the exchange of gases and metabolites between cells and the bloodstream. The ratios of capillary volume to endothelial surface area and thickness also favor movement of substances across the vessel wall.


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Histology_Ross. Classification of Capillaries Capillary structure varies in different tissues and organs. On the basis of their morphology, three types of capillaries are described: continuous capillaries, fenestrated capillaries, and discontinuous capillaries. Continuous capillaries are typically found in muscle, lung, and the CNS. With the TEM, they appear in cross sections as two plasma membranes enclosing a ribbon of cytoplasm that may include the nucleus (Fig. 13.21). Occluding junctions can be seen in the typical cross section of a continuous capillary. They only allow the passage of relatively small molecules (less than 10,000 daltons) between adjacent endothelial cells.


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Histology_Ross. FIGURE 13.20 • Photomicrograph of the capillary network in the retina. This is a whole-mount preparation of retinal capillaries. After mild enzymatic digestion, retina was spread on a glass slide, stained with the periodic acid–Schiff (PAS) procedure, and counterstained with hematoxylin. Vertically crossing the image is an arterial (A) with a clearly visible layer of circularly arranged smooth muscle cells (SM). The arterial is crossed perpendicularly by a venule (V). Note the extensive network of capillaries connecting both vessels. Nuclei of endothelial cells (E) are clearly visible within capillaries. At this magnification, pericytes are difficult to discern. 560. (Courtesy Mr. Denifield W. Player.) Numerous pinocytotic vesicles underlie both the luminal and basal plasma membrane surfaces. The vesicles are approximately 70 nm in diameter and function in the transport of larger molecules between the lumen and the connective tissue and vice versa.


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Histology_Ross. In some continuous capillaries and postcapillary venules, pericytes (historically known as Rouget cells) may be associated with the endothelium (see Figs. 13.20 and 13.21). The pericyte, when present, intimately surrounds the capillary, with branching cytoplasmic processes, and is enclosed by a basal lamina that is continuous with that of the endothelium. Pericytes are contractile and are controlled by NO produced by endothelial cells. They provide vascular support and promote stability of capillaries and postcapillary venules through physical and chemical signaling with vascular endothelial cells. Histologically, pericytes display features of undifferentiated mesenchymal stem cells with large nuclei rich in heterochromatin. During embryonic development or angiogenesis (i.e., wound healing), pericytes give rise to both endothelial cells and smooth muscle cells. Pericytes are directly involved in the pathogenesis of vascular driven diseases (i.e., diabetic retinopathy and tumor


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Histology_Ross. healing), pericytes give rise to both endothelial cells and smooth muscle cells. Pericytes are directly involved in the pathogenesis of vascular driven diseases (i.e., diabetic retinopathy and tumor angiogenesis). In addition, uncontrolled divisions of pericytes give rise to the hemangiopericytoma, a rare vascular tumor that can originate in the body anywhere there are capillaries.


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Histology_Ross. Fenestrated capillaries are typically found in endocrine glands and sites of fluid and metabolite absorption such as the gallbladder, kidney, and intestinal tract. They are characterized by fenestrations, 80 to 100 nm in diameter, that provide channels across the capillary wall (Fig. 13.22). Fenestrated capillaries also have pinocytotic vesicles. Some research suggests that fenestrations are formed when a forming pinocytotic vesicle spans the narrow cytoplasmic layer and simultaneously opens on the opposite surface. A fenestration may have a thin, nonmembranous diaphragm across its opening. When viewed from the luminal surface, this diaphragm has a cartwheel-like shape with a central thickening and 14 wedge-shaped gaps. It is derived from the glycocalyx formerly enclosed in the pinocytotic vesicle from which the fenestration may have formed.


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Histology_Ross. Fenestrated capillaries in the gastrointestinal tract and gallbladder have fewer fenestrations and a thicker wall when no absorption is occurring. When absorption takes place, the walls thin, and the number of pinocytotic vesicles and fenestrations increases rapidly. The ionic changes in the perivascular connective tissue, caused by the absorbed solutes, stimulate pinocytosis. These observations support the suggested mode of formation of the fenestrations described above.


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Histology_Ross. Discontinuous capillaries (also called sinusoidal capillaries or sinusoids) are typically found in the liver, spleen, and bone marrow. They are larger in diameter and more irregularly shaped than other capillaries. Structural features of these capillaries vary from organ to organ and include specialized cells. Kupffer cells (stellate sinusoidal macrophages) and vitamin A–storing Ito cells (hepatic stellate cells) in the liver occur in association with the endothelial cells. In the spleen, endothelial cells exhibit a unique spindle shape with gaps between the neighboring cells; the basal lamina underlying the endothelium may be partially or even completely absent. Functional Aspects of Capillaries To understand capillary function, two important points— vasomotion (i.e., capillary blood flow) and the extent or density of the capillary network—should be considered.


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Histology_Ross. Blood flow is controlled through local and systemic signals. In response to vasodilating agents (e.g., NO, low O2 tension), the smooth muscle in the walls of the arterioles relaxes, resulting in vasodilation and increased blood ﬂow through the capillary system. Pressure within the capillaries increases, and much of the plasma ﬂuid is driven into the tissue. This process occurs in peripheral edema. Local endothelial-derived factors, systemic signals carried by the autonomic nervous system, and norepinephrine released by the adrenal gland cause the smooth muscle of the arterioles to contract (vasoconstriction), resulting in decreased blood ﬂow through the capillary bed. In this condition, capillary pressure can decrease and greatly increase absorption of tissue ﬂuid. This situation occurs during loss of blood volume and can add considerable amount of ﬂuid into the blood, preventing hypovolemic shock.


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Histology_Ross. FIGURE 13.21 • Electron micrograph and diagram of a continuous capillary. The endothelial cells that make up the wall of a continuous capillary contain numerous pinocytotic vesicles. The cell junctions are frequently marked by cytoplasmic (marginal) folds that protrude into the lumen. The endothelial cell nuclei are not included within the plane of section in the micrograph, but an endothelial cell with its nucleus is shown in the diagram. Similarly, the electron micrograph shows only a small amount of pericyte cytoplasm; a nucleus is not seen but is shown in the diagram (see the upper right and lower left of the micrograph). Note that the pericyte cytoplasm is enclosed by basal lamina. 30,000.


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Histology_Ross. The density of the capillary network determines the total surface area available for exchange between the blood and tissue. It is related to the metabolic activity of the tissue. The liver, kidney, cardiac muscle, and skeletal muscle have rich capillary networks. Dense connective tissue is less metabolically active and has less extensive capillary networks. Arteriovenous shunts allow blood to bypass capillaries by providing direct routes between arteries and veins.


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Histology_Ross. Generally, in a microvascular bed, arteries convey blood to the capillaries, and veins convey blood away from the capillaries. However, all the blood does not necessarily pass from arteries to capillaries and thence to veins. In many tissues, there are direct routes between the arteries and veins that divert blood from the capillaries. These routes are called arteriovenous (AV) anastomoses or AV shunts (see Fig. 13.11). AV shunts are commonly found in the skin of the fingertips, nose, and lips and in the erectile tissue of the penis and clitoris. The arteriole of AV shunts is often coiled, has a relatively thick smooth muscle layer, is enclosed in a connective tissue capsule, and is richly innervated. Contrary to the ordinary precapillary sphincter, contraction of the arteriole smooth muscle of the AV shunt sends blood to a capillary bed; relaxation of the smooth muscle sends blood to a venule, bypassing the capillary bed. AV shunts serve in thermoregulation at the body surface.


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Histology_Ross. muscle of the AV shunt sends blood to a capillary bed; relaxation of the smooth muscle sends blood to a venule, bypassing the capillary bed. AV shunts serve in thermoregulation at the body surface. Closing an AV shunt in the skin causes blood to ﬂow through the capillary bed, enhancing heat loss. Opening an AV shunt in the skin reduces the blood ﬂow to the skin capillaries, conserving body heat. In erectile tissue such as the penis, closing the AV shunt directs blood ﬂow into the corpora cavernosa, initiating the erectile response.


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Histology_Ross. FIGURE 13.22 • Electron micrograph and schematic diagram of a fenestrated capillary. The cytoplasm of the endothelial cells contains numerous fenestrations (small arrows). In some of the thicker regions of the endothelial cells where the fenestrations are absent, pinocytotic vesicles are present. Part of a pericyte is seen on the left side of the electron micrograph, including its nucleus in the upper left corner of the micrograph. 21,500. The inset shows to advantage the fenestrations and the diaphragm that spans the openings (large arrows). 55,000.


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Histology_Ross. Preferential thoroughfares, whose proximal segment is called a metarteriole (Fig. 13.23), also allow some blood to pass more directly from artery to vein. Capillaries arise from both arterioles and metarterioles. Although capillaries themselves have no smooth muscle in their walls, a sphincter of smooth muscle called the precapillary sphincter is located at their origin from either an arteriole or a metarteriole. These sphincters control the amount of blood passing through the capillary bed. The tunics of veins are not as distinct or well defined as the tunics of arteries. Traditionally, veins are divided into four types on the basis of size.  Venules are further subclassified as postcapillary and muscular venules. They receive blood from capillaries and have a diameter as small as 0.1 mm.  Small veins are less then 1 mm in diameter and are continuous with muscular venules.


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Histology_Ross.  Small veins are less then 1 mm in diameter and are continuous with muscular venules.  Medium veins represent most of the named veins in this category. They usually are accompanied by arteries and have a diameter of as much as 10 mm.  Large veins usually have a diameter greater than 10 mm. Examples of such veins include the superior and inferior vena cava and hepatic portal vein. Although large and medium veins have three layers— also designated tunica intima, tunica media, and tunica adventitia—these layers are not as distinct as they are in arteries. Largeand medium-sized veins usually travel with largeand medium-sized arteries; arterioles and muscular venules also sometimes travel together, thus allowing comparison in histologic sections. Typically, veins have thinner walls than their accompanying arteries, and the lumen of the vein is larger than that of the artery. The arteriole lumen


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Histology_Ross. FIGURE 13.23 • Diagram of microcirculation. This schematic diagram shows a metarteriole (initial segment of a thoroughfare channel) giving rise to capillaries. The precapillary sphincters of the arteriole and metarteriole control the entry of blood into the capillaries. The distal segment of the thoroughfare channel receives capillaries from the microcirculatory bed, but no sphincters are present where the afferent capillaries enter the thoroughfare channels. Blind-ended lymphatic vessels are shown in association with the capillary bed. Note the presence of anchoring filaments and the valve system within the lymphatic capillaries. is usually patent; that of the vein is often collapsed. Many veins, especially those that convey blood against gravity, such as those of the limbs, contain valves that allow blood to flow in only one direction, back toward the heart. The valves are semilunar flaps consisting of a thin connective tissue core covered by endothelial cells.


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Histology_Ross. Postcapillary venules collect blood from the capillary network and are characterized by the presence of pericytes. Postcapillary venules possess an endothelial lining with its basal lamina and pericytes (Plate 35, page 438). The endothelium of postcapillary venules is the principal site of action of vasoactive agents such as histamine and serotonin.


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Histology_Ross. Response to these agents results in extravasation of ﬂuid and emigration of white blood cells from the vessel during inﬂammation and allergic reactions. Postcapillary venules of lymph nodes also participate in the transmural migration of lymphocytes from the vascular lumen into the lymphatic tissue. Pericytes form umbrella-like connections with the endothelial cells. The relationship between endothelial cells and pericytes promote their mutual proliferation and survival. Both synthesize and share the basal lamina (see Fig. 13.21), synthesize growth factors, and communicate with each other through tight and gap junctions. Pericyte coverage is more extensive in the postcapillary venules than capillaries. The postcapillary venules in the lymph nodes are also called high endothelial venules (HEVs) because of the prominent cuboidal appearance of their endothelial cells and their ovoid nuclei.


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Histology_Ross. The postcapillary venules in the lymph nodes are also called high endothelial venules (HEVs) because of the prominent cuboidal appearance of their endothelial cells and their ovoid nuclei. Muscular venules are distinguished from postcapillary venules by the presence of a tunica media. Muscular venules are located distal to the postcapillary venules in the returning venous network and have a diameter of as much as 0.1 mm. Whereas postcapillary venules have no true tunica media, the muscular venules have one or two layers of smooth muscle that constitute a tunica media. These vessels also have a thin tunica adventitia. Usually, pericytes are not found in muscular venules.


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Histology_Ross. Medium veins have a diameter of as much as 10 mm. Most deep veins that accompany arteries are in this category (e.g., radial vein, tibial vein, popliteal vein). Valves are a characteristic feature of these vessels and are most numerous in the inferior portion of the body, particularly the lower limbs, to prevent retrograde movement of blood because of gravity. Often deep veins of lower limbs are the site of thrombus (blood clot) formation, a condition known as deep venous thrombosis (DVT). DVT is associated with immobilization of the lower limbs due to prolonged bed rest (after surgery or hospitalization), orthopedic casts, or restricted movement during long-haul ﬂights. DVT can be a life-threatening condition because of the potential for development of pulmonary embolism (blockage of the pulmonary arteries) by a dislodged blood clot originating from deep veins. The three tunics of the venous wall are most evident in medium-sized veins (Fig. 13.24).


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Histology_Ross. The three tunics of the venous wall are most evident in medium-sized veins (Fig. 13.24).  The tunica intima consists of an endothelium with its basal lamina, a thin subendothelial layer with occasional smooth muscle cells scattered in the connective tissue elements, and, in some cases, a thin internal elastic membrane.  The tunica media of medium-sized veins is much thinner than the same layer in medium-sized arteries. It contains several layers of circularly arranged smooth muscle cells with interspersed collagen and elastic fibers. In addition, longitudinally arranged smooth muscle cells may be present just beneath the tunica adventitia.  The tunica adventitia is typically thicker than the tunica media and consists of collagen fibers and networks of elastic fibers (Fig. 13.24b). In large veins, the tunica media is relatively thin, and the tunica adventitia is relatively thick. Veins with a diameter greater than 10 mm are classified as large veins.


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Histology_Ross. In large veins, the tunica media is relatively thin, and the tunica adventitia is relatively thick. Veins with a diameter greater than 10 mm are classified as large veins.  The tunica intima of these veins (Fig. 13.25 and Plate 34, page 436) consists of an endothelial lining with its basal lamina, a small amount of subendothelial connective tissue, and some smooth muscle cells. Often the boundary between the tunica intima and tunica media is not clear, and it is not always easy to decide whether the smooth muscle cells close to the intimal endothelium belong to the tunica intima or to the tunica media.


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Histology_Ross. FIGURE 13.24 • Schematic diagram and photomicrograph of a medium-sized vein. a. The cellular and extracellular components are labeled. Note that the tunica media contains a few layers of circularly arranged smooth muscle cells with interspersed collagen and elastic fibers. Also, longitudinally arranged smooth muscle cells are present at the junction with the tunica adventitia. b. This photomicrograph shows a section through the wall of a medium-sized vein in routine H&E preparation. The tunica intima consists of endothelium and a very thin subendothelial layer of connective tissue containing some smooth muscle cells. The tunica media contains a few layers of circularly and spirally arranged smooth muscle cells with collagen and elastic fibers. Note that the thickest layer is the tunica adventitia, which contains an abundance of collagen and some elastic fibers. The few nuclei seen in this layer belong to fibroblasts. 360.


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Histology_Ross.  The tunica media is relatively thin and contains circumferentially arranged smooth muscle cells, collagen fibers, and some fibroblasts. In some animals, but not in humans, cardiac muscle cells extend into the tunica media of the both superior and inferior vena cava and the pulmonary veins, near their junction with the heart.  The tunica adventitia of large veins (e.g., the subclavian veins, portal vein, and the venae cavae) is the thickest layer of the vessel wall. Along with the usual collagen and elastic fibers and fibroblasts, the tunica adventitia also contains longitudinally disposed smooth muscle cells (Fig. 13.26). In several locations in the body, blood vessels—both arteries and veins with an atypical structure are present. These include the following.


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Histology_Ross.  Coronary arteries, considered to be medium-sized muscular arteries, originate from the proximal part of the ascending aorta and lie on the surface of the heart in the epicardium surrounded by adipose tissue. The walls of coronary arteries are usually thicker than those of comparable arteries on the upper or lower limb because of the large amounts of circular smooth muscle layers in the tunica media. In routine H&E preparation, the subendothelial layer of the tunica intima of younger people is inconspicuous, but it progressively thickens by increasing amounts of smooth muscle cell and fibroelastic tissue with aging (Fig. 13.27). The internal elastic membrane is well developed, although it may be fragmented, duplicated, or focally lost in older individuals. The relatively “loose” consistency of the tunica adventitia is reinforced by the longitudinal bundles of collagen fibers that allow for continuous changes of the vascular diameter.


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Histology_Ross. Atherosclerotic changes in coronary arteries that restrict blood ﬂow and oxygen supply to cardiac muscle lead to ischemic heart disease (see Folder 13.3).  Dural venous sinuses represent venous channels in the cranial cavity. They are essentially broad spaces within the dura mater that are lined with endothelial cells and devoid of smooth muscles.  The great saphenous vein represents a long subcutaneous vein of the lower limb that originates in the foot and


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Histology_Ross. FIGURE 13.25 • Schematic diagram and photomicrograph of a large vein. a. The cellular and extracellular components are labeled. Note a thin layer of circumferentially arranged smooth muscles of tunica media and the tunica adventitia with a large amount of longitudinally arranged smooth muscle bundles. b. This photomicrograph shows a section through the wall of a human portal vein in a routine H&E preparation. The tunica intima is indiscernible at this magnification. The tunica media contains a layer of circumferentially arranged smooth muscle cells with collagen and elastic fibers. Note the thickest layer of this wall is the tunica adventitia. In addition to an extensive collagen and elastic fiber network, the tunica adventitia contains a broad layer of smooth muscle cells arranged in longitudinal bundles. These bundles are variable in size and separated from each other by connective tissue fibers. 125. (Courtesy of Dr. Donald J. Lowrie Jr., University of Cincinnati College of


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Histology_Ross. in longitudinal bundles. These bundles are variable in size and separated from each other by connective tissue fibers. 125. (Courtesy of Dr. Donald J. Lowrie Jr., University of Cincinnati College of Medicine.) drains into the femoral vein just below the inguinal ligament. This vein is often described as a muscular vein because of the presence of an unusual amount of smooth muscle (Fig. 13.28). In addition to the thick circular arrangement of smooth muscle in its tunica media, the great saphenous vein possesses numerous longitudinal smooth muscle bundles in the intima and in the well-developed adventitia. A thin, poorly developed internal elastic membrane separates the tunica intima from the media. The great saphenous vein is frequently harvested from the lower limb and used for autotransplantation in coronary artery bypass graft (CABG) surgery when arterial grafts (usually taken from internal thoracic artery) are not available or many grafts are required for multiple-bypass


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Histology_Ross. autotransplantation in coronary artery bypass graft (CABG) surgery when arterial grafts (usually taken from internal thoracic artery) are not available or many grafts are required for multiple-bypass anastomoses. CABG is one of the most commonly performed major surgical operations in the United States.


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Histology_Ross.  The central adrenomedullary vein that passes through the adrenal medulla and its tributaries have an unusual tunica media. It contains several longitudinally oriented bundles of smooth muscle cells that vary in size and apperance (Fig 13.29). These irregularly arranged smooth muscle bundles (also called muscle cushions) extend into larger tributaries of the central adrenomedullary vein. This unique eccentric arrangement of smooth muscle bundles results in the irregularity in the thickness of the vascular wall. In areas where muscle bundles are absent, cells of the adrenal medulla or sometimes adrenal cortex are separated from the lumen of the vein only by a thin layer of the tunica intima (see Fig. 13.29). Contraction of the longitudinally arranged smooth muscles in the tunica media enhances the efflux of hormones from the adrenal medulla into the circulation.


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Histology_Ross. Veins in certain other locations (e.g., retina, placenta, trabeculae of the spleen) also have atypical walls and are discussed in the chapters that describe these organs. Lymphatic vessels convey fluids from the tissues to the bloodstream. In addition to blood vessels, another set of vessels circulates fluid called lymph through most parts of the body. These lymph-carrying vessels serve as adjuncts to the blood vessels. Unlike the blood vessels, which convey blood to and from tissues, the lymphatic vessels are unidirectional, conveying fluid


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Histology_Ross. FIGURE 13.26 • Photomicrograph of a large vein. This photomicrograph shows the three tunics in a section through the wall of the portal vein stained with H&E. The tunica intima consists of endothelium and a thin subendothelial layer of connective tissue containing a few smooth muscle cells. The tunica media contains relatively thin layer of circularly arranged smooth muscle cells. Tunica adventitia is the thickest layer of this vessel. It contains a thick layer of longitudinally arranged smooth muscle bundles (seen here in cross section) separated by collagen and elastic fibers. Note a layer of connective tissue containing coarse collagen and elastic fibers that separates longitudinal bundles of smooth muscle in the tunica adventitia from a layer of smooth muscles of the tunica media. 240. (Courtesy of Dr. Donald


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Histology_Ross. J. Lowrie Jr., University of Cincinnati College of Medicine.) only from tissues. The smallest lymphatic vessels are called lymphatic capillaries. They are especially numerous in the loose connective tissues under the epithelium of the skin and mucous membranes. The lymphatic capillaries begin as “blind-ended” tubes in the microcapillary beds (see Fig. 13.23). Lymphatic capillaries converge into increasingly larger vessels called lymphatic vessels. They ultimately unite to form two main channels that empty into the blood vascular system by draining into the large veins in the base of the neck. Lymph enter the vascular system at the junctions of the internal jugular and subclavian veins. The largest lymphatic vessel, draining most of the body and emptying into the veins on the left side, is the thoracic duct. The other main channel is the right lymphatic trunk. Lymphatic capillaries are more permeable than blood capillaries and collect excess protein-rich tissue fluid.


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Histology_Ross. Lymphatic capillaries are more permeable than blood capillaries and collect excess protein-rich tissue fluid. FIGURE 13.27 • Photomicrograph of the coronary artery. This photomicrograph of a cross section of the coronary artery obtained from adult human shows all three vascular tunics similar to those in muscular arteries. The subendothelial layer of the tunica intima (TI) is considerably thicker because of the aging process than a comparable muscular artery. The internal elastic membrane (IEM) is visible at the border with the tunica media (TM), which is also thicker than in other muscular-type arteries. Connective tissue of the tunica adventitia (TA) is loosely arranged and contains peripherally positioned longitudinal bundles of collagen fibers. There is an artificial separation between cardiac muscle (CM) and tunica adventitia. 175.


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Histology_Ross. Lymphatic capillaries are a unique part of the circulatory system, forming a network of small vessels within the tissues. Because of their greater permeability, lymphatic capillaries are more effective than blood capillaries in removing protein-rich fluid from the intercellular spaces. Once the collected fluid enters the lymphatic vessel, it is called lymph. Lymphatic vessels also serve to convey proteins and lipids that are too large to cross the fenestrations of the absorptive capillaries in the small intestine. Before lymph is returned to the blood, it passes through lymph nodes, where it is exposed to the cells of the immune system. Thus, the lymphatic vessels serve not only as an adjunct to the blood vascular system but also as an integral component of the immune system.


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Histology_Ross. Lymphatic capillaries are essentially tubes of endothelium that, unlike the typical blood capillary, lack a continuous basal lamina. This incomplete basal lamina can be correlated with their high permeability. Anchoring filaments extend between the incomplete basal lamina and the perivascular collagen. These filaments may help maintain the patency of the vessels during times of increased tissue pressure such as in inflammation.


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Histology_Ross. FIGURE 13.28 • Photomicrograph of the great saphenous vein. This photomicrograph shows a section through the wall of the greater saphenous vein. Tunica intima is usually thicker than in the other medium size veins and is characterized by a presence of numerous longitudinal smooth muscle bundles (SM) separated by connective tissue fibers. Tunica media contains relatively thick layer of circularly arranged smooth muscles. Tunica adventitia is well developed and contains additional layers of smooth muscle fibers arranged in spiral, oblique, and longitudinal bundles. 380. (Courtesy of Dr. Joseph J. Maleszewski, Mayo Clinic, Rochester, MN.)


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Histology_Ross. As lymphatic vessels become larger, the wall becomes thicker. The increasing thickness is because of connective tissue and bundles of smooth muscle. Lymphatic vessels possess valves that prevent backflow of the lymph, thus aiding unidirectional flow (Plate 35, page 438). There is no central pump in the lymphatic system. Lymph moves sluggishly, driven primarily by compression of the lymphatic vessels by adjacent skeletal muscles.


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Histology_Ross. FIGURE 13.29 • Photomicrograph of the central adrenomedullary vein. This photomicrograph of the human adrenal gland shows a large central adrenomedullary vein with its tributary stained with H&E. The wall of the vein is highly irregular, containing several longitudinally oriented bundles of smooth muscles (SM) that extend into the wall of a tributary. This unique eccentric arrangement of smooth muscles, sometimes called muscle cushions, results in the irregularity in the thickness of the vascular wall. Note that in the cleft between two smooth muscle bundles (asterisk), the lumen of the vein is separated from the chromaffin cells of the adrenal medulla only by the tunica intima. On the opposite side of the wall, muscle bundles are absent (arrowheads) and the cells of the adrenal cortex are in direct contact with the tunica intima. 120. (Courtesy of Dr. Donald J. Lowrie Jr., University of Cincinnati College of Medicine.)  FOLDER 13.3 Clinical Correlation: Ischemic Heart Disease


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Histology_Ross. Clinical Correlation: Ischemic Heart Disease Ischemic heart disease or ischemic cardiomyopathy is defined as the imbalance between supply and demand of the heart for oxygenated blood. Ischemic heart disease is the most common type of heart disease in the United States and affects approximately 1 in every 100 people. The most common cause of ischemic heart disease is atherosclerosis. The risk of developing atherosclerosis in-creases with age, family history, hypertension, cigarette smoking, hypercholesterolemia, and diabetes. In atheroscle-rosis, the lumina of the coronary arteries progressively narrow because of the accumulation of lipids, extracellular matrix, and cells, leading to the development of atheroma-tous plaques (Fig. F13.3.1). Plaques are formed by intra-cellular and extracellular lipid deposition, smooth muscle proliferation, and increased synthesis of proteoglycans and collagen within the intima of the vessel wall. Blood flow continued next page


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Histology_Ross. The cardiovascular system is a transport system that carries blood and lymph to and from the tissues of the body. The cardiovascular system includes the heart, blood vessels, and lymphatic vessels. Blood vessels provide the route by which blood circulates to and from all parts of the body. The heart pumps the blood. Lymphatic vessels carry tissue-derived fluid, called lymph, back to the blood vascular system. The heart is a four-chambered organ consisting of a right and left atrium and a right and left ventricle. Blood from the body is returned to the right atrium from which it enters the right ventricle. Blood is pumped from the right ventricle to the lungs for oxygenation and returns to the left atrium. Blood from the left atrium enters the left ventricle from which it is pumped to the rest of the body, i.e., the systemic circulation. The heart, which differentiates from a straight vascular tube in the embryo, has the same basic three-layered structure in its wall as do the blood


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Histology_Ross. rest of the body, i.e., the systemic circulation. The heart, which differentiates from a straight vascular tube in the embryo, has the same basic three-layered structure in its wall as do the blood vessels above the level of capillaries and postcapillary venules. In the blood vessels, the three layers are called the tunica intima, includ-ing the vascular endothelium and its underlying connective tissue; the tunica media, a muscular layer that varies in thickness in arteries and veins; and the tunica adventitia, the outermost layer of relatively dense connective tissue. In the heart, these layers are called the endo-cardium, the myocardium, and the epicardium, respectively.


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Histology_Ross. Atrioventricular septum, heart, human, H&E ×45; inset ×125.


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Histology_Ross. This micrograph of the field shows portions of the atrial (A) and ventricular (V) walls at the level of the atrioventricular septum and the root of the mitral valve (MV). Both chambers and the valve are lined with the squamous endothelium of the endocardium (En). Purkinje fibers (PF) of the cardiac conduction system are seen in the atrial wall between the relatively thin subendocardial connective tissue (CT) and the underlying modified cardiac muscle cells (CM) of the atrioventricular node (AVN). Dense fibrous connective tissue (DCT) that is continuous with that of the septum and the subendocardial layers of the atrium and ventricle extends from the root of the valve into the leaflet. Thin cardiac muscle fibers can also be seen extending from the wall of the atrium into the upper portion of the valve. Inset. This higher-magnification view of the field outlined by the rectangle (turned ~90°) shows more clearly the endothelial layer of the endocardium (En) and the dense fibrous


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Histology_Ross. portion of the valve. Inset. This higher-magnification view of the field outlined by the rectangle (turned ~90°) shows more clearly the endothelial layer of the endocardium (En) and the dense fibrous connective tissue of the endocardium (DCT) and subendocardial layer. A thin layer of smooth muscle (SM) appears between the more densely packed fibrous tissue immediately subjacent to the endothelium and the more loosely packed dense fibrous tissue of the subendocardium. Particularly evident are the longitudinally sectioned Purkinje fibers (PF) of the cardiac conduction system. These modified cardiac muscle cells contain the same fibrillar contractile system as their smaller counterparts in the myocardium, but the fibrils are fewer, are more loosely packed, and often surround what appear to be vacuolated areas. Intercalated discs (ID), typical of cardiac muscle cell organization, are evident in some areas.


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Histology_Ross. Coronary artery and cardiac vein, heart, human, H&E ×30. This micrograph shows cross sections of a coronary artery and cardiac vein in the coronary sulcus. The surrounding adipose tissue (AT) serves to cushion the blood vessels that run in the coronary sulcus. The coronary artery (CA) in the lower left of this micrograph is surrounded by small bundles of small cardiac muscle cells (CM) that are part of the atrioventricular node (AVN). A loop of the conduction bundle (CB) containing Purkinje fibers is evident to the right of the artery. The darkly stained tunica intima (TI) is delimited by an internal elastic membrane (IEM) that is easily distinguished even at this relatively low magnification. The thick muscular tunica media (TM) is also easily distinguished from the thinner, fibrous tunica adventitia (TA). A smaller arterial vessel (A ).


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Histology_Ross. KEY A, atrium A, small artery AT, adipose tissue AVN, atrioventricular node B, blood CA, coronary artery CB, conduction bundle CM, cardiac muscle CT, connective tissue CV, cardiac vein DCT, dense connective tissue En, endothelium ID, intercalated disc IEM, internal elastic membrane LN, lymph node MV, mitral valve PF, Purkinje fibers SM, smooth muscle TA, tunica adventitia TM, tunica media TI, tunica intima V, ventricle


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Histology_Ross. PLATE 33 • AORTA The aorta, the main systemic artery of the body, is an elastic artery. The presence of numerous fenestrated elastic lamellae allows it to resist the pressure variations caused by rhythmic contraction of the left ventricle. The intima is comparatively much thicker than that seen in muscular arteries. The subendothelial layer of the in-tima consists of connective tissue with both collagen and elastic fibers. The cellular component consists of smooth muscle cells and fibroblasts. The external border of the intima is bounded by an internal elastic membrane that represents the first layer of the many concentric fenestrated laminae in the media of the vessel. The media constitutes the bulk of the wall. Between the elastic laminae are collagen fibers and smooth muscle cells. The latter are responsible for the synthesis of collagen and elastic fibers. With age, the number and thickness of elastic laminae in the wall in-creases. By 35 years as many as 60 laminae are found in


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Histology_Ross. latter are responsible for the synthesis of collagen and elastic fibers. With age, the number and thickness of elastic laminae in the wall in-creases. By 35 years as many as 60 laminae are found in the thoracic aorta. At ap-proximately 50 years, individual laminae begin to show signs of degeneration and gradually become replaced by collagen leading to a gradual loss of elasticity of the aortic wall. The adventitia consists of irregular dense connective tissue with intermixed elas-tic fibers that tend to be organized in a circumferential pattern. It also contains small blood vessels that supply the outer portion of the media. They are the vasa vasorum of the aorta. Also present in the adventitia are lymphatic capillaries. ORIENTATION MICROGRAPHS: The upper micrograph shows a cross section of an H&E stained human aorta from a child. The intima (I) stains considerably lighter than the adjacent media (M) The adventitia (A) contains an abundance of collagenous fibers and stains more


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Histology_Ross. of an H&E stained human aorta from a child. The intima (I) stains considerably lighter than the adjacent media (M) The adventitia (A) contains an abundance of collagenous fibers and stains more densely than that of either the media or intima. The lower micro-graph is from an adult and has been stained to reveal the elastic component of the vessel wall. The intima (I) is very lightly stained, in this case, due to the paucity of elastic material. The media (M) is heavily stained due to the presence of large amounts of elastic laminae. The adventitia (A) contains in addition to the dense connective tissue a moderate amount of elastic fibers. MMMMAAAAIIIIMMAAII


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Histology_Ross. Aorta, human, H&E, ×365; inset ×700. This micrograph shows the layers of the aortic wall. The intima consists of an endothelium (En) overlying loose connective tissue (LCT). The thickest portion of the vessel wall is the media (M). The wavy eosinophilic material is the collagenous fibers. The eosin stain does not reveal the elastic laminae. The nuclei are those of smooth muscle cells. Fibroblasts are absent. The outer Aorta, human, iron hematoxylin and aniline blue, ×255; inset ×350.


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Histology_Ross. Aorta, human, iron hematoxylin and aniline blue, ×255; inset ×350. The specimen shown here has been stained to distinguish collagen from elastic material. The intima (I) consists mostly of collagenous fibers. The endothelium (En) represented by several nuclei is just barely evident. The media (M) contains nu merous elastic lamellae that appear as the black wavy lines. The intervening blue stained material consists of collagen fibers. Careful examination of the layer of the vessel wall is the adventitia (A). The eosinophilic material here consists of dense connective tissue. The nuclei that are evident belong to fibroblasts. Also note the small blood vessel (BV) in the adventitia. The inset shows the intima at higher magnification and includes part of the media. Note the endothelium (En). The eosinophilic material in the intima consists of collagenous fibers (CF). The main cell type here is the smooth muscle cell (SMC).


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Histology_Ross. media reveals nuclei of smooth muscle cells dispersed between the elastic lamellae. The inset shows the intima at higher magnification. Note the nuclei of the endothelial cells (EnC) at the luminal surface. The remainder of the intima consists mostly of collagenous fibers (stained blue) with occasional elastic fibers (EF) identified by their darker coloration. The nuclei of the fibroblasts and occasional smooth muscle cells (SMC) appear randomly arranged. KEY A, adventitia BV, blood vessel CF, collagenous fibers EF, elastic fibers En, endothelium EnC, endothelial cells I, intima LCT, loose connective tissue M, media SMC, smooth muscle cells


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Histology_Ross. Muscular arteries have more smooth muscle and less elastin in the tunica media than do elastic arteries. Thus, as the arterial tree is traced fur-ther from the heart, the elastic tissue is considerably reduced and smooth muscle becomes the predominant component of the tunica media. The muscular arteries are characterized, however, by a refractile internal elastic membrane separating the tunica intima from the tunica media and, usually, by an external elastic membrane separating the tunica media from the tunica adventitia. Muscular arteries, or arteries of medium caliber, constitute the majority of the named arteries in the body. Veins usually accompany arteries as they travel in the loose connective tissue. The veins have the same three layers in their walls, but the tunica media is thinner than in the accompanying artery, and the tunica adventitia is the predominant layer in the wall. The veins usually have the same name as the artery they accompany.


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Histology_Ross. Muscular artery and medium vein, monkey, H&E ×365. In this photomicrograph, the lumen of the artery is at the left, the lumen of the vein is at the right. The arterial endothelium (AEn) is clearly seen on the corrugated surface of the tunica intima, whereas the venous endothelium (VEn) is somewhat harder to distinguish. The internal elastic membrane (IEM) is seen as a thin clear zone immediately beneath the endothelial layer, separating the tunica intima from the underlying smooth muscle (SM) of the tunica media (TM). It is evident here that the tunica media is almost twice as thick as the tunica adventitia (TA ). Muscular artery, monkey, H&E ×545. elastic membrane (IEM), which rests directly on the most luminal layer of smooth muscle cells (SM) of the thick tunica media (TM). The thinner tu- This is a higher-magnification micrograph of the portion of nica adventitia (TA ).


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Histology_Ross. This is a higher-magnification micrograph of the portion of nica adventitia (TA ). the figure above outlined by the rectangle turned 90°. At this magnification, it is evident that the flattened endothelial cells (EN) follow the contours of the refractile, corrugated internal M USCU LAR ARTERIES AND MEDIUM VEINS KEY AEn, arterial endothelium C, collagen bundles EF, elastic fibers EN, endothelial cells IEM, internal elastic membrane N, nuclei SM, smooth muscle SSm, small smooth muscle TA' tunica adventitia of artery TA, tunica adventitia of accompanying vein TI, tunica intima TM, tunica media VEn, venous endothelium Medium vein, monkey, H&E ×600.


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Histology_Ross. Medium vein, monkey, H&E ×600. In this higher-magnification view of a portion of the wall of the vein in the figure above, the endothelial cells (EN) are more easily recognized and are seen to be plumper than those of the arterial endothelium. The margin between the tunica intima (TI) and the thin tunica media (TM) is difficult to discern, but the smooth muscle cells (SM) in the thin media are more easily recognized than in the figure above because of the shape of their nuclei and the slight basophilia of their cytoplasm. The tunica adventitia (TA) is about twice as thick as the tunica media and appears to contain only bundles of collagen fibers and fibroblasts, with the latter recognizable by their nuclei (N). The collagen bundles of the loose connective tissue beneath the tunica adventitia are larger than those of the adventitia, and there are fewer cells in this portion of the specimen. PLATE 35 Arterioles, Venules, and Lymphatic Vessels


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Histology_Ross. PLATE 35 Arterioles, Venules, and Lymphatic Vessels The terminal components of the arterial tree just before a capillary bed or an arteriovenous shunt are the arterioles. Arterioles have an en-dothelial lining and smooth muscle in the wall but the smooth muscle is limited in thickness to one or two cells. There may or may not be an internal elastic membrane, according to the size of the vessel. Arterioles control blood flow into capillary networks. In the normal relationship between an arteriole and a capillary network, contraction of the smooth muscle of the arteriole wall reduces or shuts off the blood going to the capillaries. A precapillary sphincter is formed by a slight thickening of the smooth muscle at the origin of a capillary bed from an arteriole. Nerve impulses and hormonal stimulation can cause the muscle cells to contract, directing blood into capillary beds where it is most needed. Arteriole, venule, and small nerve, fngertip, human, H&E ×600.


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Histology_Ross. Arteriole, venule, and small nerve, fngertip, human, H&E ×600. This micrograph shows two cross-sectioned arterioles (A) and a venule (V). The arteriole on the left is identified as a large arteriole, based on the presence of two discrete layers of smooth muscle cells that form the tunica media of the vessel. The nu clei of the muscle cells appear in longitudinal profile as a result of the cir 438 cumferential arrangement of the cells. The endothelial cell nuclei of the vessel appear as small round profiles surrounding the lumen. These cells are elongate and oriented with their long axis in the direction of flow. Thus, Arteriole, fngertip, human, H&E ×350.


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Histology_Ross. Arteriole, fngertip, human, H&E ×350. This micrograph shows a longitudinal section of an arteriole. Because of its twisting path through the section, its wall has been cut such that the single layer of muscle cells of the tunica media is seen in different planes along its length. In the segment numbered 1, at the left, the vessel wall has been cut tan gentially. Thus, the vessel lumen is not included in the plane of section, but the smooth muscle cell nuclei of the tunica media are seen in longitudinal Lymphatic vessel, fngertip, human, H&E ×175.


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Histology_Ross. The lymphatic vessel shown in this figure shows a region where the vessel is making a U-shaped turn in the plane of the section, thus disappearing at the top and bottom of the micro-graph. The wall of the vessel consists of an endothelial lining and a small amount of connective tissue, with one being indis tinguishable from the other. A valve (Val), which is characteristic of their nuclei are seen here as cross-sectioned profiles. The arteriole on the right is a very small arteriole, having only a single layer of smooth muscle. Again, the muscle cell nuclei are seen in longitudinal profile. The endothelial cell nuclei appear as the small round profiles at the luminal surface. A venule is seen in proximity to the larger arteriole, and a cross section of peripheral nerve (N) is seen in proximity to the smaller arteriole. Compare the wall of the venule, consisting only of endothelium and a thin layer of connective tissue, with the arterioles. Also, note the relatively large lumen of the


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Histology_Ross. to the smaller arteriole. Compare the wall of the venule, consisting only of endothelium and a thin layer of connective tissue, with the arterioles. Also, note the relatively large lumen of the venule.


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Histology_Ross. PLATE 35 • ARTERIOLES, VENULES, AND LYMPHATIC VESSELS profile. After the arteriole makes an acute turn (segment numbered 2), the vessel wall is cut to reveal the lumen. Here, the smooth muscle nuclei appear as round profiles and the nuclei of the endothelial cells lining the lumen appear in longitudinal profile. In the segment numbered 3, the vessel wall is again only grazed. In the segment numbered 4, the cut is deeper, again showing the lumen and some of the endothelial cells in face view (arrowheads). The structure below the vessel is a Pacinian corpuscle (P).


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Histology_Ross. lymphatic vessels, is seen within the vessel. It is formed of a miniscule layer of connective tissue that is covered on both sides by endothelium. The arrows indicate nuclei that are just barely visible at this magnification; most of them belong to endothelial cells. Typically, the lumen contains precipitated lymph material (L); sometimes, lymphocytes may be present. Adjacent to the vessel, on the right, is adipose tissue (AT) and on the upper left is dense irregular connective tissue (DCT). Lymphatic vessel, fngertip, human, Mallory ×375.


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Histology_Ross. Lymphatic vessel, fngertip, human, Mallory ×375. The lymphatic vessel shown here is contained within dense irregular connective tissue (DCT). The lumen is irregular, appearing relatively narrow below the valve (Val). A few endothelial cell nuclei are evident (arrows). A thin layer of connective tissue that is present outside of the endothelium blends with the dense connective tissue beyond the wall of the vessel. A venule (V) is also present; it can readily be distinguished from the lymphatic vessel by the presence of red blood cells in the lumen. KEY A, arteriole Ad, adipocyte AT, adipose tissue DCT, dense irregular connective tissue L, lymph material N, nerve P, Pacinian corpuscle V, venule Val, valve arrowheads, endothelial cells arrows, endothelial cell nuclei PLATE 35 • ARTERIOLES, VENULES, AND LYMPHATIC VESSELS VVV NNN AAA ATATDCTDCTPP11223344AT DCT P 1 2 3 4 ValValVal DCTDCTATAT LLDCT AT L AdAdDCTDCTDCTDCTVVAALLLLAd DCT DCTV ValValVal A L L


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Histology_Ross. PLATE 35 • ARTERIOLES, VENULES, AND LYMPHATIC VESSELS VVV NNN AAA ATATDCTDCTPP11223344AT DCT P 1 2 3 4 ValValVal DCTDCTATAT LLDCT AT L AdAdDCTDCTDCTDCTVVAALLLLAd DCT DCTV ValValVal A L L OVERVIEW OF THE LYMPHATIC SYSTEM / 440 CELLS OF THE LYMPHATIC SYSTEM / 441 Overview / 441 Lymphocytes / 444 Antigen-Presenting Cells / 453 LYMPHATIC TISSUES AND ORGANS / 453 Lymphatic Vessels / 453 Diffuse Lymphatic Tissue and Lymphatic Nodules / 456 Lymph Nodes / 460 Cells of the Reticular Meshwork / 461 Thymus / 466 Spleen / 471 Folder 14.1 Functional Considerations: Origin of the Names T Lymphocyte and B Lymphocyte / 447 Folder 14.2 Clinical Correlation: Hypersensitivity Reactions / 447 Folder 14.3 Clinical Correlation: Human Immunodeficiency Virus (HIV) and Acquired Immunodeficiency Syndrome (AIDS) / 455 Folder 14.4 Clinical Correlation: Reactive (Inflammatory) Lymphadenitis / 466


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Histology_Ross. Throughout history, it has been noted that people who recover from certain diseases such as chickenpox, measles, and mumps become resistant (i.e., immune) to the same disease. Another longstanding observation is that immunity is specific—that is, immunity to chickenpox does not prevent infection with measles. We also now recognize that the immune system can react against itself, causing autoimmune diseases such as lupus erythematosus, autoimmune hemolytic anemia, some forms of diabetes mellitus, and autoimmune thyroiditis (Hashimoto’s thyroiditis).


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Histology_Ross. The lymphatic system consists of groups of cells, tissues, and organs that monitor body surfaces and internal fluid compartments and react to the presence of potentially harmful substances. Lymphocytes are the definitive cell type of the lymphatic system and the effector cells in the response of the immune system to harmful substances. Included in this system are the diffuse lymphatic tissue, lymphatic nodules, lymph nodes, spleen, bone marrow, and thymus (Fig. 14.1). The various lymphatic organs and lymphatic tissues are often collectively referred to as the immune system. Lymphatic vessels connect parts of the system to the blood vascular system.


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Histology_Ross. Lymphatic vessels connect parts of the system to the blood vascular system. Lymphatic tissues serve as sites where lymphocytes proliferate, differentiate, and mature. In addition, in the thymus, bone marrow, and gut-associated lymphatic tissue (GALT), lymphocytes are “educated” to recognize and destroy specific antigens. These are now immunocompetent cells that can distinguish between “self” (molecules normally present within an organism) and “nonself” (foreign molecules—i.e., those not normally present). An antigen is any substance that can induce a specific immune response.


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Histology_Ross. An antigen is any substance that can induce a specific immune response. The body is constantly exposed to pathogenic (diseasecausing) organisms and hazardous substances from the external environment (infectious microorganisms, toxins, and foreign cells and tissues). In addition, changes may occur in cells (such as transformation of normal cells into cancerous cells) that give them characteristics of foreign cells. An immune response is generated against a specific antigen, which can be a soluble substance (e.g., a foreign protein, polysaccharide, or toxin) or an infectious organism, foreign tissue, or transformed tissue. Most antigens must be “processed” by cells of the immune system before other cells can mount the immune response.


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Histology_Ross. FIGURE 14.1  Overview of the structures constituting the lymphatic system. Because lymphatic tissue is the main component of some organs, they are regarded as organs of the lymphatic system (spleen, thymus, lymph nodes). Lymphatic tissue is present as part of other organs such as red bone marrow, lymphatic nodules of the alimentary canal: tonsils, vermiform appendix, gut-associated lymphatic tissue (GALT) and of the respiratory system (bronchus-associated lymphatic tissue, or BALT ), and, not shown in the illustration, diffuse lymphatic tissue of mucous membranes (mucosa-associated lymphatic tissue, or MALT). The lymph nodes are interspersed along the superficial lymphatic vessels (associated with the skin and superficial fascia) and deep lymphatic vessels (associated with main arteries). Ultimately, the lymphatic vessels empty into the bloodstream by joining the large veins at the base of the neck. The thoracic duct is the largest lymphatic vessel.


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Histology_Ross. The immune responses can be divided into nonspecific (innate) and specific (adaptive) defenses. The body has two lines of immune defenses against foreign invaders and transformed cells: nonspecific immunity and specific immunity.  In nonspecific (innate) immunity, preexisting nonspecific defenses constitute the innate immune response. In all living organisms, the innate immunity represents the frst line of defense against microbial aggression. It consists of (1) physical barriers (e.g., the skin and mucous membranes) that prevent foreign organisms from invading the tissues, (2) chemical defenses (e.g., low pH ) that destroy many invading microorganisms, (3) various secretory substances (e.g., thiocyanate in saliva, lysozymes, interferons, fbronectin, and complement in serum) that neutralize foreign cells, and (4) phagocytic cells (e.g., macrophages, neutrophils, and monocytes) and natural killer (NK) cells.


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Histology_Ross.  With specific (adaptive) immunity, if nonspecific defenses fail, the immune system provides specific, or adaptive, defenses that target specific invaders. The initial contact with a specific antigen or foreign agent initiates a chain of reactions that involve effector cells of the immune system and frequently leads to a state of immune “memory.” Adaptive immunity induces acquired resistance against microbial aggression through random somatic rearrangements of genes that encode immunoglobulins and specifc receptors on T lymphocytes (i.e., T-cell receptors, or TCRs). During adaptive immune responses, specifc B and T lymphocytes become activated to destroy invading organisms. Two types of specific defenses have been identified: Humoral response results in the production of proteins called antibodies that mark invaders for destruction by other immune cells, and the cellular immune response targets transformed and virus-infected cells for destruction by specific “killer” cells.


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Histology_Ross. Therefore, shortly after invasion by bacteria or other pathogenic agents, the immune system becomes activated (inflammatory response) to destroy infectious agents and generate long-term memory against pathogens. Cells of the immune system include lymphocytes and various supporting cells.


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Histology_Ross. Cells of the immune system include lymphocytes and various supporting cells. Lymphocytes and a variety of supporting cells make up the cells of the immune system. Three major types of lym phocytes are recognized: B cells, T cells, and NK cells. Supporting cells interact with lymphocytes and play important roles in the presentation of antigen to lymphocytes and the regulation of immune responses. These cells include monocytes, macrophages, neutrophils, basophils, eosinophils, reticular cells, dendritic cells, follicular dendritic cells, Langerhans’ cells, and epithelioreticular cells. In addition, a series of specialized epithelial and stromal cells provide the environment for many immune reactions to occur by secreting specific substances that regulate growth, migration, and the activation of effector and supporting cells. Supporting cells in the lymphatic organs are organized into loose meshworks.


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Histology_Ross. Supporting cells in the lymphatic organs are organized into loose meshworks. In lymph nodules, lymph nodes, and the spleen, reticular cells and the reticular fibers produced by these cells form elaborate meshworks. Lymphocytes, macrophages, dendritic cells, follicular dendritic cells, and other cells of the immune system reside in these meshworks and in the loose connective tissue of the body; Langerhans’ cells are found only in the middle layers of epidermis. At these sites, they carry out their mission of surveillance and defense. In the thymus, epithelioreticular cells form the structural meshwork within the tissue. Despite their name, these cells neither produce nor are related to reticular fibers. Different types of cells in lymphatic tissue are identified by specific cluster of differentiation (CD) markers on their surface.


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Histology_Ross. Different types of cells in lymphatic tissue are identified by specific cluster of differentiation (CD) markers on their surface. Different lymphatic and hematopoietic tissue cells possess unique cell surface molecules. These specific markers, called cluster of differentiation (CD) molecules, are designated by numbers according to an international system that relates them to antigens expressed at different stages of their differentiation. CD molecules can be visualized by immunohistochemical methods using monoclonal antibodies and are useful in identifying specific subtypes of lymphatic or hematopoietic cells. Some CD markers are expressed by cells throughout their entire life; others are expressed only during one phase of differentiation or during cell activation. Table 14.1 lists the most clinically useful markers.


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Histology_Ross. TABLE Most Common CD Markers Used in Clinical Practice 14.1 Marker Main Cellular Expression Function/Identity Molecular Weight (kDa) CD1 T cells in the midstage of development Interact with MHC I molecules Developmental markers for T cells and Langerhans’ cells of the skin 49 CD2 T cells Adhesion molecules Used as clinical markers for T cells 50 CD3 T cells Form complex with T-cell receptor (TCR) 100 CD4 Helper T cells, monocytes, macrophages Members of immunoglobulin superfamily Interact with MHC II molecules Bind viral protein gp120 of HIV-1 and HIV-2 56 CD5 T cells, some B cells Costimulatory molecules High levels in chronic lymphocytic leukemia 67 CD7 T cells Members of immunoglobulin superfamily Bind the PI-3 kinase Useful clinical markers for T-cell leukemia stem cells 40 CD8 Cytotoxic T cells Members of immunoglobulin superfamily Interact with MHC I molecules 34 CD9 B cells, T cells, monocytes, eosinophils, basophils, platelets, endothelial cells Facilitate aggregation of


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Histology_Ross. T cells Members of immunoglobulin superfamily Interact with MHC I molecules 34 CD9 B cells, T cells, monocytes, eosinophils, basophils, platelets, endothelial cells Facilitate aggregation of platelets, cell adhesion, and cell migration 24 CD10 Pre-B cells, pre-T cells Zinc metalloproteas Common markers for acute lymphoblastic leukemia 100 CD16a NK cells, granulocytes, monocytes Clinical markers for NK cells Function as Fc receptors for aggregated IgG Mediate phagocytosis and antibody-dependent cell-mediated cytotoxicity 27 CD19 B cells, dendritic cells Coreceptors with CD21 Clinical markers for all stages of B-cell development 90 continued next page chapter 14 Lymphatic System CE LLS OF TH E LYM PHATIC SYSTE M CD20 B cells Form Ca2channels Markers for late stage of B-cell development 37 CD21 B cells, follicular dendritic cells Receptors for C3d complement protein and for Epstein-Barr virus 145 CD22 B cells B-lymphocyte cell adhesion molecules Mediate B-cell to T-cell adhesion 140


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Histology_Ross. 37 CD21 B cells, follicular dendritic cells Receptors for C3d complement protein and for Epstein-Barr virus 145 CD22 B cells B-lymphocyte cell adhesion molecules Mediate B-cell to T-cell adhesion 140 CD24 B cells, granulocytes, epithelial cells Expressed in late stage of B-cell differentiation 41 CD28 T cells T-cell costimulatory molecule interacts with CD80 (B7.1) and CD86 (B7.2); the costimulatory signal induces T-cell activation and IL-2 production 44 CD34 Hemopoietic stem cells (HSCs) Clinical markers for HSCs and ligand for CD62L Mediate attachment of stem cells to bone marrow extracellular matrix 120 CD35 T cells, B cells, monocytes, dendritic cells, granulocytes, erythrocytes Complement receptor 1 Promote phagocytosis of complement-coated particles Bind C3b and C4b complement protein 250 CD38 Activated T cells NAD glycohydrolase Used as markers for T-cell activation and proliferation 45 CD40 B cells, macrophages, dendritic cells Active in proliferating B cells Costimulatory


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Histology_Ross. 250 CD38 Activated T cells NAD glycohydrolase Used as markers for T-cell activation and proliferation 45 CD40 B cells, macrophages, dendritic cells Active in proliferating B cells Costimulatory molecules for CD40L (CD154) Facilitate cytokine production in macrophages and dendritic cells 48 CD40L Activated CD4T cells; known as CD154 Facilitate interaction between T and B cells Regulate B-cell function Costimulatory molecules for CD40 39 CD45 All human leukocytes Thyrosine phosphatase Leukocyte common antigen 220 CD56 NK cells Clinical markers for NK cells Isoforms of neural adhesion molecules (N-CAM) 135 CD62L Leukocytes Bind CD34 Represent L-selectins, leukocyte adhesion molecules that allow lymphocytes to roll along the endothelial surface 150 CD80 B cells, macrophages, dendritic cells, monocytes, macrophages APC costimulatory molecule interacts with CD28 45 CD86 Activated B cells, macrophages, monocytes, dendritic cells, endothelial cells APC costimulatory molecule interacts with


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Histology_Ross. monocytes, macrophages APC costimulatory molecule interacts with CD28 45 CD86 Activated B cells, macrophages, monocytes, dendritic cells, endothelial cells APC costimulatory molecule interacts with CD28 70 CD94 NK cells Clinical markers for NK cells 43 TABLE Most Common CD Markers Used in Clinical Practice (Cont.)14.1 Marker Main Cellular Expression Function/Identity Molecular Weight (kDa) APC, antigen-presenting cell; NK, natural killer.


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Histology_Ross. Circulating lymphocytes are the chief cellular constituents of lymphatic tissue. To understand the function of lymphocytes, one must realize that most lymphocytes (approximately 70%) in blood or lymph represent a circulating pool of immunocompetent cells. These cells participate in a cycle during which they exit the systemic circulation to enter the lymphatic tissue. While there, they are responsible for immunologic surveillance of surrounding tissues. The cells then return to the systemic circulation. This population of cells is represented mainly by long-lived, mature lymphocytes (mainly T cells) that have developed the capacity to recognize and respond to foreign antigens and are in transit from one site of lymphatic tissue to another.


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Histology_Ross. The remaining 30% of lymphocytes in the blood vessels do not circulate between the lymphatic tissues and the systemic circulation. This population comprises mainly short-lived, immature cells or activated cells destined for a specific tissue. These cells leave the capillaries and migrate directly to the tissues, especially into the connective tissue that underlies the lining epithelium of the respiratory, gastrointestinal, and urogenital tracts as well as into the intercellular spaces of these epithelia. Functionally, three major types of lymphocytes are present in the body: T lymphocytes, B lymphocytes, and NK cells. The functional classifcation of lymphocytes is independent of their morphologic (size) characteristics. T lymphocytes differentiate in the thymus and account for the majority of circulating lymphocytes.


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Histology_Ross. T lymphocytes differentiate in the thymus and account for the majority of circulating lymphocytes. T lymphocytes (T cells) are named for the thymus, where they differentiate. They have a long lifespan and are involved in cell-mediated immunity. They account for 60% to 80% of circulating lymphocytes. T cells express CD2, CD3, CD5, and CD7 markers and T-cell receptors (TCRs); however, they are subclassified according to the presence or absence of two other important surface markers: CD4 and CD8.  Helper CD4 T lymphocytes are T cells that also express CD4 markers. These cells are further subdivided by their ability to secrete cytokines (see page 454). Helper T cells that synthesize interleukin 2 (IL-2), interferon (IFN-), and tumor necrosis factor (TNF-) are called TH1 cells.


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Histology_Ross. These cells interact with cytotoxic CD8 T lymphocytes (CTLs), NK cells, and macrophages in cell-mediated im mune responses and are essential for controlling intracellu lar pathogens such as viruses and certain microorganisms. The other group of helper T cells synthesize IL-4, IL-5, IL 10, and IL-13 and are called TH2 cells. They interact with B lymphocytes and are essential for initiating antibody-me pathogens.  Cytotoxic CD8 T lymphocytes (CTLs) are T cells that also express CD8 markers. They kill other target cells such as virus-infected cells, cancer-transformed cells, cells infected with intracellular microorganisms, parasites, and transplanted cells.


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Histology_Ross.  Regulatory (suppressor) T lymphocytes represent a phenotypically diverse population of T lymphocytes that can functionally suppress an immune response to foreign and self-antigen by influencing the activity of other cells in the immune system. For example, T lymphocyte with CD4 CD25FOXP3 markers represent a classical example of the regulatory cells that can diminish the ability of T lymphocytes to initiate immune responses. The FOXP3 marker indicates an expression of forkhead family transcription factors that are characteristic of many T cells. Another tumor-associated T lymphocyte with CD8CD45RO markers is able to suppress T-cell activation. Other suppressor T cells may also function in suppressing B-cell differentiation and in regulating erythroid cell maturation in the bone marrow.


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Histology_Ross.  Gamma/delta (/) T lymphocytes represent a small population of T cells that possess a distinct TCR on their surface made of one -chain and one -chain. Most other TCRs are composed of two glycoprotein chains called -and -TCR chains. These cells develop in the thymus and migrate into various epithelial tissues (e.g., the skin, oral mucosa, intestines, and vagina). Once they colonize an epithelial tissue, they do not recirculate between blood and lymphatic organs. Gamma/delta (/) T cells are strategically positioned at the interfaces of the external and internal environments and function as the first line of defense against invading organisms. They encounter antigen on the surface of the epithelial cells even before it enters the body. B lymphocytes differentiate in the bursa-equivalent organs and participate in humoral immunity.


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Histology_Ross. B lymphocytes (B cells) are so named because they were first recognized as a separate population in the bursa of Fabricius in birds (page 447) or bursa-equivalent organs such as bone marrow and GALT in mammals. They have variable life spans and are involved in the production and secretion of the various circulating antibodies, also called immunoglobulins (Ig), the immune proteins associated with humoral immunity (Fig. 14.2 and Table 14.2). B cells account for 20% to 30% of the circulating lymphocytes. In addition to secreting circulating immunoglobulins, B cells express membrane-bound forms of immunoglobulin called B-cell receptors (BCRs) that serve as the antigen-specific binding site. During diff erentiation, the BCR isotope switches from immunoglobulin M (IgM) in immature B cells to immu noglobulin D (IgD) in mature B cells. B cells also express the major histocompatibility complex II (MHC II) molecules on the cell surface. Their CD markers are CD9, CD19, and CD20.


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Histology_Ross. tion in the primary lymphatic organs. In humans and other mammals, the bone marrow and GALT region (together called the bursa-equivalent organ) and the thy mus have been identified as primary (central) lymphatic organs. Lymphocytes differentiate into immunocompetent cells in these organs. Initially, lymphocytes are genetically programmed to recognize a single antigen out of virtually an infinite number of possible antigens, a process called These immunocompetent cells then enter the blood or lymph antigen-independent proliferation and differentiation. region of IgG, IgM carboxy terminus FIGURE 14.2 • Schematic diagram of an antibody molecule.


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Histology_Ross. Antibodies are Y-shaped molecules produced by plasma cells. They consist of two heavy (H) and two light (L) polypeptide chains connected by disulfide bonds (SOS). Both H and L chains are composed of domains of amino acids that are constant (at the carboxy terminus) or variable (at the amino terminus) in their sequence. The five different immunoglobulin (Ig) isotypes (see Table 14.2) are determined by the type of heavy chain present. An antibody molecule binds an antigen (Ag) at the two sites of the amino terminus, where the heavy and light chains are associated with each other. Digestion of an antibody molecule by the proteolytic enzyme papain cleaves the antibody into two Fab fragments and one crystallizable Fc fragment. The Fab fragments impart the specific antigen binding, whereas the Fc fragment, which is composed of two carboxy-terminus heavy-chain segments (CH2 and CH3), fulfills the effector functions (e.g., in complement activation). Many cells express Fc receptors on their


Histology_Ross

Histology_Ross. Fc fragment, which is composed of two carboxy-terminus heavy-chain segments (CH2 and CH3), fulfills the effector functions (e.g., in complement activation). Many cells express Fc receptors on their surfaces, which anchor antibodies at the Fc fragment.


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Histology_Ross. Natural killer lymphocytes (NK cells) are neither T nor B cells and are specialized to kill certain types of target cells. Natural killer (NK) cells, which develop from the same precursor cell as B and T cells, are named for their ability to kill certain types of target cells. They constitute about 5% to 10% of circulating lymphocytes. They do not mature in the thymus; however, during their development, they are genetically programmed to recognize transformed cells (i.e., cells infected with a virus or tumor cells). NK cells kill target cells in a similar fashion to that of cytotoxic CD8 T lymphocytes. After recognition of a transformed cell, they release perforins and granzymes (fragmentins), substances that create channels in the cell’s plasma membrane, which induces them to self-destruct (a process known as apoptosis). Their specific markers include CD16a, CD56, and CD94. and are transported throughout the body, where they are dispersed in the connective tissue.


Histology_Ross

Histology_Ross. and are transported throughout the body, where they are dispersed in the connective tissue. Lymphocytes undergo antigen-dependent activation in the secondary lymphatic organs. Immunocompetent lymphocytes (together with plasma cells derived from B lymphocytes and with macrophages) organize around reticular cells and their reticular fibers to form the adult effector lymphatic tissues and organs (i.e., lymphatic nodules, lymph nodes, tonsils, and spleen). Within these secondary (peripheral) lymphatic organs, T and B lymphocytes undergo antigen-dependent activation into effector lymphocytes and memory cells. Immune Responses to Antigens Inflammation is the initial response to an antigen. The initial reaction of the body to invasion by an antigen, either a foreign molecule or a pathogenic organism, is the nonspecific defense known as the inﬂammatory response.


Histology_Ross

Histology_Ross. The initial reaction of the body to invasion by an antigen, either a foreign molecule or a pathogenic organism, is the nonspecific defense known as the inﬂammatory response. The infammatory response may either sequester the antigen, physically digest it with enzymes secreted by neutrophils, or phagocytose and degrade the antigen in the cytoplasm of macrophages. Degradation of antigens by macrophages may lead to subsequent presentation of a portion of the antigen to immunocompetent lymphocytes to elicit a specifc immune response. Specific immune responses are either primary or secondary. When immunocompetent cells encounter a foreign antigen (e.g., antigen associated with pathogenic microorganisms, tissue transplants, or toxins), a specific immune response to the antigen is generated.


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Histology_Ross. A primary immune response refers to the body’s first encounter with an antigen. This response is characterized by a lag period of several days before antibodies (mostly IgM) or specific lymphocytes directed against the invading antigen can be detected in the blood. The initial response to an antigen is initiated by only one or a few B lymphocytes that have been genetically programmed to respond to that specifc antigen. After this initial immune response, a few antigen-specifc B lymphocytes remain in circulation as memory cells. The secondary immune response is usually more rapid and more intense (characterized by higher levels of secreted antibodies, usually of the IgG class) than the primary


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Histology_Ross. TABLE Characteristics of Human Immunoglobulins14.2 Isotype Molecular Weight (kDa) Serum Level (mg/mL) Percentage of all Ig in Adult Blood Cells to Which Bind via Fc Region Major Functions IgG 145 12.0 85 Macrophages, B cells, NK cells, neutrophils, eosinophils Principal Ig in secondary immune response Longest half-life (23 days) of all five Igs Activates complement Stimulates chemotaxis Crosses placenta, providing newborn with passive immunity IgM 190 (950)a1.5 5–10 B cells Principal Ig produced during primary immune response Most efficient Ig in fixing complement Activates macrophages Serves as Ag receptor of B lymphocytes IgA 160 (385)b2.0 5–15 B cells Ig present in body secretions, including tears, colostrum, saliva, and vaginal fluid, and in secretions of nasal cavity, bronchi, intestine, and prostate Provides protection against proliferation of microorganisms in these fluids and aids in defense against microbes and foreign molecules penetrating body via cell linings of these


Histology_Ross

Histology_Ross. and prostate Provides protection against proliferation of microorganisms in these fluids and aids in defense against microbes and foreign molecules penetrating body via cell linings of these cavities IgD 185 0.03 1 B cells Acts as an antigen receptor (together with IgM) on surface of mature B lymphocytes (only traces in serum) IgE 190 3 × 10 5 1 Mast cells, basophils Stimulates mast cells to release histamine, heparin, leukotrienes, and eosinophil chemotactic factor of anaphylaxis Responsible for anaphylactic hypersensitivity reactions Increased levels in parasitic infections a IgM found in serum as a pentameric molecule. b IgA found in serum as dimeric molecule. Ag, antigen; Ig, immunoglobulin; NK, natural killer.


Histology_Ross

Histology_Ross. response because of the presence of specific memory B lymphocytes already programmed to respond to that specific antigen. The secondary response is the basis of most immunizations for common bacterial and viral diseases. Some antigens, such as penicillin and insect venoms, may trigger an intense secondary immune response that produces a hypersensitivity reaction or even anaphylaxis (see Folder 14.2). However, antibodies themselves do not kill or destroy invading antigens; they simply mark them for destruction by cells of the immune system. The two types of specific immune responses are the humoral and cell-mediated responses. In general, an encounter with a given antigen triggers a response characterized as either a humoral immune response (antibody production) or a cell-mediated immune response.  FOLDER 14.2 Clinical Correlation: Hypersensitivity Reactions


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Histology_Ross.  FOLDER 14.2 Clinical Correlation: Hypersensitivity Reactions When an individual has been immunologically sensitized by exposure to antigen, subsequent exposure may lead not only to secondary response but also to tissue-damaging reactions called hypersensitivity reactions. Such reac-tions are observed in sensitized humans after insect bites or injections of penicillin. One common type of hypersen-sitivity reaction is the allergic reaction. Certain aspects of a hypersensitivity reaction are caused by the antibody-induced discharge of mast cell granules. These granules contain histamine, which accounts for the distressing fea-tures of hypersensitivity reactions. Eosinophils are  FOLDER 14.1 Functional Considerations: Origin of the Names T Lymphocyte and B Lymphocyte


Histology_Ross

Histology_Ross. In the early 1960s, investigators using chicken embryos demonstrated that the bursa of Fabricius, a mass of lym-phatic tissue associated with the cloaca of birds, was one of the anatomic sites of lymphocyte differentiation. When this tissue was destroyed in the chicken embryos (by either surgical removal or administration of high doses of testos-terone), the adult chickens were unable to produce antibod-ies, leading to impaired humoral immunity. The chickens also demonstrated a marked reduction in the number of lymphocytes found in specific bursa-dependent areas of the spleen and lymph nodes. These affected lymphocytes were therefore named B lymphocytes or B cells. The bursa-equivalent organs in mammals (including humans) are the GALT and the bone marrow, where B lymphocytes differentiate into immunocompetent cells. Thus, the “B” refers to the bursa of Fabricius or the bursa-equivalent organs of mammals. Investigators studying newborn mice found that removal of the thymus results in


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Histology_Ross. into immunocompetent cells. Thus, the “B” refers to the bursa of Fabricius or the bursa-equivalent organs of mammals. Investigators studying newborn mice found that removal of the thymus results in profound deficiencies in cell-mediated immune responses. The rejection of transplanted skin from a heterologous donor is an example of cell-medi-ated immune response. Thymectomized mice demonstrate a marked reduction in the number of lymphocytes found in specific regions of the spleen and the lymph nodes (thymus-dependent areas). The areas of depletion differ from those identified after removal of the bursa of Fabricius in the chicken. These affected lymphocytes were therefore named T lymphocytes or T cells; T refers to thymus.


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Histology_Ross. attracted to the site of mast cell degranulation, where they neutralize the effects of histamine. Thus, eosinophils are frequently seen in connective tissue at allergic or other hypersensitivity reaction sites. Typically, however, both cellular and humoral immune systems are involved, although one system generally predominates, depending on the stimulus.  Humoral (antibody-mediated) immunity is mediated by antibodies that act directly on an invading agent. These antibodies are produced by B lymphocytes and by plasma cells derived from B lymphocytes. In some diseases (e.g., tetanus), a nonimmune person can be rendered immune by receiving an injection of antibody purifed from the blood of an immune person or animal. The effectiveness of this passive transfer proves that it is the antibody that is responsible for the protection.


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Histology_Ross.  Cell-mediated immunity is mediated by specific T lymphocytes that attack and destroy virus-infected host cells or foreign cells. Cell-mediated immunity is important in the defense against viral, fungal, and mycobacterial infections, as well as tumor cells. Cell-mediated immunity is also responsible for transplant rejection. Helper T and cytotoxic T lymphocytes ( CTLs) recognize and bind to antigens that are bound to MHC molecules.


Histology_Ross

Histology_Ross. Helper T and cytotoxic T lymphocytes ( CTLs) recognize and bind to antigens that are bound to MHC molecules. To understand how the specific immune responses (hu-moral and cell-mediated responses) are initiated, one must grasp the central role played by the helper and cytotoxic T lymphocytes. Helper T and cytotoxic lymphocytes act as the immune system “patrols.” Both kinds of lymphocytes have a T-cell receptor (TCR), a transmembrane protein whose exposed portion is on the T-cell membrane in close proximity to the CD3 marker (Fig. 14.3). The TCR recognizes antigen only when it is attached to “identification molecules,” the MHC molecules. In addition, helper T lymphocytes can only recognize an antigen when it is “presented” to them by cells called antigen-presenting cells (APCs). Cytotoxic T lymphocytes can only recognize antigen on other body cells such as those transformed by cancer or infected with a virus. The two classes of MHC molecules display peptides on the surface of cells.


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Histology_Ross. The two classes of MHC molecules display peptides on the surface of cells. MHC molecules display short fragments of digested foreign proteins on the surface of cells. These proteins bind to MHC molecules inside the cell and are then transported to the cell FIGURE 14.3 • Schematic diagram of the molecular structure of the CD3– TCR complex. The CD3 molecule consists of five different polypeptide chains with molecular weights ranging from 16 to 28 kilodaltons. This molecule is closely associated with the T-cell receptor (TCR), which has two polypeptide chains ( and ). The T cell may be activated after the interaction of the TCR with antigen (Ag) displayed on the surface of a major histocompatability complex (MHC) molecule. This interaction transmits the signals to the interior of the cell through the CD3 molecule. This signal stimulates the T cell to secrete interleukins, which in turn stimulate T cells to divide and differentiate.


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Histology_Ross. surface. MHC I and MHC II molecules are products of a “supergene” located on chromosome 6 in humans known as the major histocompatibility gene complex. The expression of this gene complex produces molecules that are specific not only to the individual cell that produces them but also to the tissue type and degree of cellular differentiation. MHC I is expressed on the surface of all nucleated cells and platelets. MHC I molecules act as a target to allow the elimination of abnormal host cells (e.g., virus-infected or transformed cancer cells). MHC I molecules perform this function by displaying on their surface short fragments of all peptides that are actively synthesized by the cell. Therefore, all endogenous “self ” peptides are displayed on the surface of every cell in the body, but viral or cancer-specific peptides are displayed only on the surface of infected or transformed cells (Fig. 14.4). The MHC I molecules present peptides fragments to cytotoxic CD8 T lymphocytes.


Histology_Ross

Histology_Ross. MHC II is limited in its distribution (see Fig. 14.4). It is expressed on the surface of all APCs and is critical in immune interactions. The MHC II molecules present partially digested, endocytosed foreign peptides to helper CD4 T lymphocytes. Activation of T and B Cells Activation of T cells requires the presence of costimulatory signals. become fully activated and to subsequently differentiate and proliferate. The interaction of the TCR and the CD4 or CD8 molecules with the antigen–MHC complex is referred to as a first signal. The second signal, which is called the costimulatory signal, is delivered by the interaction of membrane molecules on T cells and molecules on the APC. The most important interactions are between the CD28 molecule expressed on the T-cell membrane and the B7 (CD86) molecule expressed on the APC membrane. Another pair of costimulatory signals is generated by the interaction of CD40 (on APC cells) with CD40L (CD154), on T cells.


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Histology_Ross. When a helper (CD4) T lymphocyte recognizes an antigen bound to an MHC molecule, the TCR attaches to the antigen–MHC II complex. The binding of the TCR to the antigen–MHC II complex in the presence of a costimulatory signal (derived from the CD28–B7 interaction) activates the helper T lymphocyte to release immune chemicals, or cytokines. Cytokines are immune substances (proteins) that are biologic modulators of immune responses. The specific cytokines secreted by helper CD4 T lymphocytes are called interleukins (ILs). Interleukins stimulate other T cells, B cells, and NK cells to differentiate and proliferate. When a cytotoxic CD8 T lymphocyte (CTL) recognizes an antigen–MHC I complex, the TCR attaches to it. If a costimulatory signal is present (derived from the interaction of CD40 and CD40L), the CTL is activated. Once activated,


Histology_Ross

Histology_Ross. FIGURE 14.4 • Schematic diagram of the molecular structure of MHC I and MHC II molecules. The MHC I molecule is a glycoprotein that is expressed on the surface of all nucleated cells of the body and on platelets. MHC I molecules present endogenously synthesized peptides for recognition by cytotoxic CD8 T lymphocytes. Therefore, the MHC I molecule acts as the target for the elimination of abnormal host cells producing abnormal proteins (e.g., cells infected by an intracellular agent such as a virus, or cells that have been transformed such as cancer cells). MHC I consists of an heavy chain (45 kilodaltons) and a smaller, noncovalently attached 2 microglobulin polypeptide (12 kilodaltons). The 2 microglobulin promotes maturation of T cells and acts as a chemotactic factor. The MHC II molecule is also a glycoprotein but is expressed only on a restricted population of cells known as antigen-presenting cells (APCs). MHC II molecules present exogenous (foreign) peptides to helper CD4 T


Histology_Ross

Histology_Ross. is also a glycoprotein but is expressed only on a restricted population of cells known as antigen-presenting cells (APCs). MHC II molecules present exogenous (foreign) peptides to helper CD4 T lymphocytes. They consist of two chains–an chain (33 kilodaltons) and a chain (29 kilodaltons)—each of which possesses oligosaccharide groups.


Histology_Ross

Histology_Ross. the CTL also releases cytokines that stimulate cells to proliferate and destroy the abnormal host cells. CD8 T lymphocytes are MHC I restricted, and CD4 T lymphocytes are MHC II restricted. MHC molecules are recognized by helper CD4 T lymphocytes or CTLs, depending on the class of the MHC molecule engaged. This restricted presentation of foreign antigens by MHC molecules to either cytotoxic or helper T lymphocytes is a key component of immune surveillance. The MHC I molecule with the peptide antigen displayed on its surface interacts only with the TCR and CD8 molecule expressed on cytotoxic CD8 T lymphocytes; these cells are therefore described as MHC I restricted. This interaction allows cytotoxic T lymphocytes to recognize infected or transformed target cells (Fig. 14.5a).


Histology_Ross

Histology_Ross. In contrast, the MHC II molecule with the peptide antigen displayed on its surface interacts only with the TCR and CD4 molecule expressed on helper CD4 T lymphocytes (Fig. 14.5b); these cells are therefore described as MHC II restricted. MHC II molecules are found on APCs, such as macrophages, whose main function is to present antigen to T lymphocytes. For B cells to become activated and differentiate into plasma cells, they require interactions with helper T lymphocytes.


Histology_Ross

Histology_Ross. Each B lymphocyte reacts only with a single antigen or type of antigenic site that it has been genetically programmed to recognize. Activation of B cells requires two signals. One is derived from interaction between BCRs and antigen. The bound antigen molecules are engulfed into B cells by receptor-mediated endocytosis, and fragments of the antigen are then displayed at the cell surface with the help of MHC II molecules. Helper T cells with complementary TCRs bind B cells and provide the second costimulatory signal. The binding usually involves a reaction between CD40 molecules on a B-cell surface with their ligands (CD40L or CD154) residing at the surface of a helper T cell. These interactions complete the activation process of a B lymphocyte and induce an involved T cell to secrete specific cytokines that stimulate divisions and differentiation of B cells. Details of B-cell activation are illustrated in Figure 14.6.


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Histology_Ross. FIGURE 14.5 • Schematic diagram of the molecular interactions that occur during antigen presentation. To become activated, both cytotoxic and helper T lymphocytes need to identify presented antigens as “nonself” as well as recognize the appropriate class of MHC molecules. Note that each interaction between an antigen–MHC complex with its specific T-cell receptor (TCR) requires a costimulatory signal from the interaction of CD28 with B7 molecules. Without a costimulatory signal, the T cell cannot be fully activated. a. In all nucleated cells of the body, viral antigen or cancer (tumor-specific) proteins are displayed in the context of MHC I molecules to interact with cytotoxic CD8 T lymphocytes. b. On antigen-presenting cells (e.g., macrophages), the foreign antigen is displayed in the context of MHC II molecules to interact with a helper CD4 T lymphocyte. FIGURE 14.6 • Schematic diagram of B lymphocyte activation leading to plasma cell and B memory cell formation.


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Histology_Ross. FIGURE 14.6 • Schematic diagram of B lymphocyte activation leading to plasma cell and B memory cell formation. B cells are activated by the binding of antigen (Ag) to B-cell receptors (BCRs; membrane-bound antibodies) expressed on their surface. As an antigen-presenting cell, a B cell internalizes the BCR–antigen complex, partially digests the antigen, and then displays parts of it on the surface of its own MHC II molecules. The T-cell receptor (TCR) on a helper CD4 T lymphocyte (TH2 cell) recognizes both the antigen and the MHC II molecule, activating the helper CD4 T lymphocyte. The activated helper CD4 T lymphocyte releases interleukins IL-2, IL-4, IL-5, IL-10, and IL-13, which promote division and differentiation of the B lymphocyte into plasma cells and memory B cells. Note the presence of a costimulatory molecule complex between the B and T cells. Ab, antibody.


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Histology_Ross. FIGURE 14.7 • Schematic diagram of activation of natural killer cells leading to destruction of a transformed tumor cell by antibody-dependent, cell-mediated cytotoxicity (ADCC). The ADCC reaction involves (1) activation of natural killer (NK) cells by the binding of interferon (IFN-), the powerful NK cell activator, to its cell surface receptor (IFNreceptor) and (2) the binding of an antibodyor an antibodyand complement-coated target cell to an NK cell bearing Fc receptors. These reactions induce apoptosis, or lysis, of the target cell, usually through the action of tumor-specific antibodies or the action of perforins and granzymes (fragmentins) secreted by activated NK cells. Activated B lymphocytes differentiate into plasma cells and memory B cells.  Plasma cells synthesize and secrete a specific antibody.


Histology_Ross

Histology_Ross. Activated B lymphocytes differentiate into plasma cells and memory B cells.  Plasma cells synthesize and secrete a specific antibody. During this process, activated B cells switch from synthe sizing their BCRs as integral membrane proteins to form ing a soluble version, which are called antibodies.  Memory B cells respond more quickly to the next encounter with the same antigen. The specific antibody produced by the plasma cell binds to the stimulating antigen, forming an antigen–antibody complex. These complexes are eliminated in a variety of ways, including destruction by NK cells and phagocytosis by macrophages and eosinophils. In antibody-dependent cell-mediated cytotoxicity (ADCC), IgG molecules direct NK cells to their target.


Histology_Ross

Histology_Ross. In antibody-dependent cell-mediated cytotoxicity (ADCC), IgG molecules direct NK cells to their target. The membranes of a number of cells, including NK cells, macrophages, neutrophils, and eosinophils, possess immunoglobulin Fc receptors and can kill certain target cells. NK cells recognize the Fc region of antibodies and preferentially attack and destroy target cells, usually those coated with IgG antibodies (Fig. 14.7). The recognition and subsequent destruction of antibody-coated target cells by NK cells is called antibody-dependent cell-mediated cytotoxicity (ADCC). The antibodies in ADCC that coat the target cells often include tumor-specifc antibodies. This binding (through the Fc region) results in the apoptosis and lysis of the target cell.


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Histology_Ross. If the antigen is a bacterium, the antigen–antibody complex may also activate a system of plasma proteins called the complement system and cause one of its components, usually C3, to bind to the bacterium and act as a ligand for its phagocytosis by macrophages. Complement-bound foreign cells are also targets of ADCC. The cell-mediated immune response: Cytotoxic CD8 T lymphocytes (CTLs) target and destroy transformed and virus-infected cells.