Lymphoid organs are of two types:
• Primary (central) lymphoid organs (fetal liver, postnatal bone marrow, and thymus), where lymphocytes become immunocompetent
• Secondary (peripheral) lymphoid organs (lymph nodes, spleen, postnatal bone marrow, and mucosa-associated lymphoid tissue [MAlt]), where immunocompetent cells can interact with other cells and with antigens to initiate an immune response against pathogens and antigens
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Figure 12.3 Activation of ctls by th1 cells. the th1 cell and the ctl must be complexed to the same APc. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 286.)
TH1 cell TCR binds to MHC II–epitope complex of antigen-presenting cell.
The CD4 molecule of the TH1 cell recognizes MHC II. These two events cause the APC to express B7 molecules on its surface, which bind to CD28 of the TH1 cell, causing it to release IL-2, IFN-γ, and TNF.
The same APC also has MHC I–epitope complex expressed on its surface that is bound by a CTL’s CD8 molecule and T-cell receptor. Additionally, the CTL has CD28 molecules bound to the APC’s B7 molecule. The CTL also possesses IL-2 receptors, which bind the IL-2 released by the TH1 cell, causing the CTL to undergo proliferation, and IFN-γ causes its activation.
The newly formed CTLs attach to the MHC I–epitope complex via their TCR and CD8 molecules and secrete perforins and granzymes, killing the virus-transformed cells. Killing occurs when granzymes enter the cell through the pores established by perforins and act on the intracellular components to drive the cell into apoptosis.
B7 molecule IL-2
MHC II–epitope complex
MHC I–
epitope complex CD8 molecule CD4 molecule
T cell receptor
CD28 molecule TH1 cell
Cytotoxic T lymphocyte B7 CD28
Perforins Granzymes
Virus- transformed Antigen- cell
presenting cell
CTL
IFN-γ TNF
Figure 12.4 Activation of macrophages by th1 cells. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 287.)
TH1 cell IL-2
TH1 cell's TCR and CD4 molecules recognize the MHC II–epitope complex presented by a macrophage that was infected by bacteria. The TH1 cell becomes activated, expresses IL-2 receptors on its surface, and releases IL-2. Binding of IL-2 results in proliferation of the TH1 cells.
The newly formed TH1 cells contact infected macrophages (TCR and CD4 recognition of MHC II–epitope complex) and release inter- feron-γ (IFN-γ). IFN-γ activates the macrophage to express TNF-α receptors on its surface as well as to release TNF-α. Binding of IFN-γ and TNF-α on the macrophage cell membrane facilitates the production of oxygen radicals by the macrophage resulting in killing of bacteria.
Bacteria proliferating in phagosomes
Lysosomes Macrophage
Bacteria
IFN-γ TH1 cell
Macrophage Activated lysosome MHC II–epitope complex
CD4 molecule T-cell receptor
TNF-α
TNF-α receptor
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180 THyMuS
the thymus, a small endodermally derived organ lo- cated in the superior mediastinum, is divided into two lobes by its connective tissue capsule and functions in educating t cells to become immunocompetent.
Although around the time of puberty the thymus begins to involute (degenerate) and becomes infil- trated by adipocytes, it is still functional in adults. each lobe of the thymus is subdivided into incomplete lobules so that each lobule has its individual cortex, but shares the medulla with other lobules (Fig. 12.5).
the thymic cortex is occupied by numerous lym- phocytes whose large nuclei and scant cytoplasm impart a dark, basophilic image in histologic sec- tions. immunoincompetent T cell precursors from the bone marrow enter the cortex of the thymus to proliferate and become immunocompetent t cells.
to do this, they must contact various epithelial retic- ular cells of the cortex and develop some and elimi- nate other surface markers.
• T cell precursors from the bone marrow enter the corticomedullary junction of the thymus and migrate into the outer cortex, where they are known as thymocytes.
• Notch-1 receptors on the thymocyte
plasmalemma receive signaling molecules from the cortical epithelial reticular cells, causing them to become committed to the T cell lineage.
• thymocytes begin to express some T cell markers—cD2, but not cD3-tcR complex and not cD4 or cD8—therefore, they are known as double negative thymocytes.
• As the double negative thymocytes move deeper into the cortex (nearer the medulla), they express, and then suppress, other proteins on their surface.
• these double negative thymocytes express pre–T cell receptors (pre-TCRs) that cause the cells to proliferate.
• these newly formed thymocytes express cD4 and cD8 molecules and become known as double positive thymocytes.
• the double positive thymocytes rearrange their genes coding for the variable region of their TCR and express a low level of the cD3-tcR complex on their surface.
• the double positive thymocytes that express low levels of cD3-tcR on their surface are tested by cortical epithelial reticular cells to see if they can recognize self-MHC–self-epitope complexes.
• Most double positive thymocytes (about 90%) do not recognize these complexes and are driven into apoptosis, and cortical macrophages phagocytose the dead cells.
• some double positive thymocytes (10%) recognize these complexes and are allowed to
mature, express higher levels of tcRs, and stop expressing both cD4 and cD8 molecules.
• When the t cells express either cD4 or cD8, they are known as single positive thymocytes, and they leave the cortex to enter the thymic medulla.
• single positive thymocytes contact medullary epithelial reticular cells and dendritic cells that challenge them to see if the thymocytes recognize self-epitopes that were not presented to them in the cortex.
• Single positive thymocytes that would mount an attack against the self are driven into apoptosis in the medulla, and the dead cells are eliminated by medullary macrophages (clonal deletion).
• Single positive thymocytes that would not initiate an immune response against the self are allowed to leave the thymus to populate secondary lymphoid organs as naïve T cells.
Epithelial Reticular cells
there are six types of epithelial reticular cells, three in the cortex and three in the medulla:
• type i cells isolate the cortex from the connective tissue capsule and trabeculae and form a sheath around blood vessels of the cortex.
• type ii cells are located in the midcortex and surround islands of thymocytes; they present self-antigens, Mhc i molecules, and Mhc ii molecules to thymocytes.
• type iii cells are located at the corticomedullary junction, they present self-antigens, Mhc i molecules, and Mhc ii molecules to thymocytes.
• type iV cells are located in the medulla at the corticomedullary junction; they assist type iii cells in isolating the cortex from the medulla.
• type V cells form the architectural framework of the medulla.
• type Vi cells form thymic (Hassall’s) corpuscles, release thymic stromal lymphopoietin that promotes clonal deletion, and assist in driving single positive t cells into apoptosis.
some individuals who are born without a thymus, a condition known as DiGeorge’s syndrome, are unable to generate t cells and are incapable of mounting a cell-mediated immune response. Because th cells are required in the initiation of most humor- ally mediated immune responses, these patients are mostly immunoincompetent. As long as patients with Digeorge’s syndrome are protected from infec- tion, they can survive; however, most die of infec- tions, or because many of these patients are also born without parathyroid glands, they die of calcium tetani (severe hypocalcemia).
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cLINIcAL coNSIDERATIoNS
The blood supply of the thymus first gains entry into the medulla and forms a capillary bed at the junction of the cortex and the medulla. Branches of these capillaries enter the cortex and
immediately become surrounded by a sheath of type I epithelial reticular cells that are held to one another by fasciae occludentes. These epithelial reticular cells form the blood thymus barrier in the thymic cortex, which ensures that
macromolecules carried in the bloodstream
cannot enter the cortex and interfere with the immunologic development of T cells. The endothelial cells of the cortical capillaries and the type I epithelial reticular cells possess their own basal lamina, which adds support to the barrier.
The space between the epithelial sheath and the endothelium is patrolled by macrophages that destroy macromolecules that manage to escape from the capillaries. The cortex of the thymus drains into the venous network of the medulla.
Medulla
Medulla Cortex
Cortex Capsule
Capsular vessels in capsule
Hassall’s
corpuscle Epithelial reticular cells
Capillaries in cortex LymphocytesSeptumSeptal vessels
Figure 12.5 Diagram of the thymus depicting its histology and vascular supply. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 288.)
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182 LyMPH NoDES
Lymph nodes are usually small, bean-shaped struc- tures (≤3 cm in diameter) with a convex surface and a concave surface (hilum) invested by a connective tissue capsule (Fig. 12.6) that is usually embedded in adipose tissue. Deep to the capsule, the paren- chyma is subdivided into:
• An outer cortex, housing B cells that form primary and secondary lymphoid nodules
• A middle paracortex, housing th cells
• Deeper medulla, whose predominant cells are lymphocytes, plasma cells, and macrophages
the capsule on the convex aspect sends trabeculae into the cortex, subdividing it into incomplete com- partments; as the trabeculae continue into the para- cortex and the medulla, they become more tortuous and less definite (see Fig. 12.6). lymph nodes house t cells, B cells, dendritic cells, macrophages, and APcs, and function in clearing lymph and initiating immunologic reactions against foreign antigens.
lymph enters the lymph node via afferent lymph vessels that pierce the convex surface and whose valves prevent the lymph from flowing out of the node. the lymph percolates through the node and exits, via efferent lymph vessels, which also have valves to prevent the lymph from reentering the node at the hilum. Arteries enter and veins leave the lymph node at the hilum; these vessels use trabeculae to penetrate the parenchyma of the node. in the paracortex, the veins form high endothelial venules (HEVs).
the incomplete compartments of the cortex of a lymph node are bounded superiorly by the con- nective tissue capsule and laterally by trabeculae derived from the capsule (see Fig. 12.6). As the affer- ent lymph vessels pierce the capsule, they deliver their lymph into the subcapsular sinus, from which the lymph travels into paratrabecular sinuses that follow the trabeculae and deliver their lymph into the very tortuous medullary sinuses that are drained by efferent lymph vessels. these lymphatic sinuses are lined by simple squamous endothelial cells, and their lumina are spanned by an interdigitating complex of stellate reticular cells that not only slow the flow of lymph but also are used as scaffoldings by macrophages that phagocytose antigenic particu- late matter.
the cortical compartments display dark, spherical secondary or primary lymphoid nodules.
• Secondary nodules (see Fig. 12.6) are formed as a reaction to an antigenic stimulation, and they actively produce B cells (centroblasts) that have not as yet expressed sigs. Proliferation of these cells occurs initially in the dark zone and later in the light zone of the central, clear area (the germinal center); the centroblasts displace the resting B cells, pushing them away to form the dense mantle (corona) that fashions a cap over the germinal center toward the subcapsular sinus. Additional cells that are located in a secondary follicle are:
• Migrating dendritic cells, such as Langerhans cells of the skin, are bone marrow–derived and are distributed throughout the body; when they detect foreign antigens, they migrate to the nearest lymph node to initiate an immune response.
• Follicular dendritic cells are not derived from bone marrow and reside in the lymph node;
they present antigens to centrocytes, newly formed B cells that have expressed sigs.
Follicular dendritic cells force B cells with improper sigs into apoptosis and permit the other B cells to differentiate into B memory cells and plasma cells, which enter the medulla and leave the lymph node.
• Reticular cells synthesize type iii collagen (reticular fibers), which forms the architectural framework of lymph nodes.
• Macrophages destroy apoptotic cells.
• Primary nodules (see Fig. 12.6) are resting nodules in that they do not have germinal centers or a mantle until B cells that were activated by t helper cells at the border of the cortex and paracortex migrate into the primary nodule to form a germinal center, transforming the primary into a secondary nodule.
the paracortex (see Fig. 12.6) is the t cell–rich region of the lymph node. here heVs permit the entry of B and t cells into the lymph node. B cells migrate to the cortex, and t cells remain in the paracortex.
the medulla (see Fig. 12.6) is composed of med- ullary sinusoids, trabeculae, and medullary cords, structures formed by reticular fibers, reticular cells, and macrophages, and B cells and plasma cells that were formed in secondary lymphoid follicles.
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cLINIcAL coNSIDERATIoNS
In a healthy individual, lymph nodes are too soft to be able to be palpated. If the patient has a regional infection, however, the lymphocytes of the node draining that particular area proliferate;
the node swells, becomes hard and painful, and may be palpated with ease. Each area of the body is drained by a series of lymph nodes that are connected to one another by lymph vessels. This formation of chains of lymph nodes is frequently responsible for the spread of infections or the metastasis of malignancy from one part of the body to another. As lymph percolates throughout the sinusoids of the lymph node, macrophages remove approximately 99% of foreign or
undesirable particulate matter by phagocytosing it.
aPcs that contacted antigens make their way to the lymph node nearest to their location, present the MHC-epitope complex to T helper cells, and initiate an immune response. When in the lymph node, these APCs are known as migrating dendritic cells.
antigens that enter the lymph node via the afferent lymph vessels are picked up by follicular dendritic cells, which present the epitope to
resident lymphocytes. When the antigen is recognized, a B cell becomes activated at the interface of the paracortex and cortex, it migrates into a primary lymphoid nodule, and begins to undergo rapid mitosis, forming a germinal center, transforming the primary into a secondary lymphoid nodule. If the activated B cells express improper sIgs, they are driven into apoptosis by the follicular dendritic cells; if they present proper sIgs, they are permitted to continue to differentiate into B memory cells and plasma cells. The newly differentiated cells migrate into the medulla of the lymph node and form medullary cords.
Approximately 90% of the plasma cells leave the lymph node via the efferent lymph vessels and migrate to the bone marrow, where they
manufacture and release antibodies until they die.
The remaining 10% of plasma cells stay in the medullary cord and manufacture antibodies until they also die. Most B memory cells also leave their lymph node of origin to seed other
secondary lymphatic organs, where they set up small clones in case the same antigen invades the body again. A few B memory cells remain in their lymph node of origin and establish a small clone there.
Figure 12.6 Diagram of a typical lymph node. (From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 291.)
Afferent lymph vessel Lymphoid nodule Cortex
Capsule
Subcapsular sinus
Medulla Paracortex
Medullary sinus Lymph Lymph Arterial blood Venous blood Artery
Vein
Efferent lymphatic vessels
Subcapsular sinus
Capillary bed Postcapillary venules
Trabecula Trabecular sinus
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184 SPLEEN
the spleen has a dense, irregular, and collagenous connective tissue capsule that is covered by the peri- toneum, a simple squamous epithelium. the largest lymphoid organ, the spleen has a convex surface and a concave area, the hilum, where the capsule sends connective tissue trabeculae, bearing blood vessels and nerve fibers into the substance of the spleen. Attached to the capsule and the trabeculae is a three-dimensional complex of type III collagen fibers with their associated reticular cells that form the physical framework of the spleen. in contrast to lymph nodes, the spleen is not divided into a cortex, paracor tex, and medulla; instead, it comprises white pulp, the marginal zone, and red pulp (sporting an abundance of tortuous sinusoids) that are inter- mingled (Fig. 12.7) to serve the functions of the spleen:
• Filtering blood and destroying senescent erythrocytes
• Forming t and B cells and mounting immune responses
• hematopoiesis in the fetus and, if the need arises, in adults
vascular Supply of the Spleen
the large artery supplying the spleen, the splenic artery, forms several branches before it enters the substance of the spleen at its hilum (Figs. 12.7 and 12.8).
• the vessels travel via trabeculae as trabecular arteries that provide numerous, ever smaller branches in correspondingly smaller trabeculae.
• When the arteries are 200 µm or smaller in diameter, they leave their respective trabeculae, and their tunica adventitia unravels and becomes mired in a sheath of t cells, known as the periarterial lymphatic sheath (PALS). the artery occupying the center of the PAls is referred to as the central artery.
• As the central artery becomes smaller in diameter, it loses its PAls, and it forms a series of small, straight arterioles that parallel each other as they enter the red pulp, known as the penicillar arteries, each of which has three sections:
• Pulp arteriole
• sheathed arteriole that possesses a coat of macrophages (schweigger-seidel sheath)
• terminal arterial capillary, which delivers blood directly into a sinusoid (closed
circulation) or into the red pulp tissue in the vicinity of a sinusoid (open circulation) or, as believed by most investigators, in open and closed circulations.
• Veins of the pulp (see Fig. 12.8) receive blood from the sinusoids and are drained by larger veins that accompany arteries of corresponding sizes in trabeculae that lead the larger veins to the hilum, where they form the large splenic vein.
White Pulp, Marginal zone, and Red Pulp
the three components of the spleen are white pulp, marginal zone, and red pulp.
• White pulp is the sheath of T lymphocytes, the PALS, whose center is delineated by the central artery. often a lymphoid nodule, composed of B cells, is formed within the PAls so that the t cells surround a spherical accumulation of B cells. if the nodule is responding to an immunologic challenge, a germinal center is also present. in the spleen, as in lymph nodes, t and B cells occupy prescribed regions (see Figs.
12.7 and 12.8).
• Marginal zone, a region approximately 110 mm wide, is the interface between the white pulp and red pulp (see Fig. 12.7). the cells of the marginal zone are interdigitating dendritic cells (APCs), macrophages, plasma cells, T cells, and B cells.
Additionally, small sinusoids, marginal sinuses, abound in this region. capillaries, derived from the central artery, enter the red pulp for a short distance, recur, and empty into the marginal sinuses.
• the red pulp (see Figs. 12.7 and 12.8) is composed of vascular spaces, the sinusoids, surrounded by the stroma of the red pulp, the splenic cords, consisting of a network of reticular fibers that are invested by stellate reticular cells to prevent the collagen fibers from contacting the extravasated blood that percolates through its interstices and precipitating the coagulation cascade. the endothelial cells of the sinusoids are unusual in that they are fusiform cells whose longitudinal axes parallel the long axis of the sinusoids. the endothelium is quite leaky with wide spaces between adjacent cells through which blood cells can easily escape from the lumen into the splenic cords. sparse,
threadlike reticular fibers, coated with
discontinuous basal lamina–like material, wrap around the endothelial lining of the sinusoids.