Innate Immune System

The more primitive and evolutionarily older but faster-responding innate (natural) immune system consists of complement, antimicrobial peptides, cytokines, macrophages, neutrophils, natural killer (NK) cells, and Toll-like receptors. This system is nonspecific and does not establish an immunologic memory of the agent that elicited its attack. Table 12.1 lists acronyms used in this chapter.

Table 12.1 ACRONYMS AND ABBREVIATIONS

From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 274.

Table 12.2 TOLL-LIKE RECEPTORS AND THEIR PUTATIVE FUNCTIONS

LPS, lipopolysaccharide.

* Currently, TLR partner is unknown.

From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 275.

Adaptive Immune System

The adaptive (acquired) immune system is specific and composed of T and B lymphocytes (T and B cells) and antigen-presenting cells (APCs), although they also use the components of the innate immune system to perform their task of protecting the body. These cells not only release cytokines to communicate with each other, but also contact one another, and by recognizing particular membrane bound molecules, they induce specific responses in the other cells to combat foreign substances known as antigens. By definition:

The cells of the adaptive immune system release cytokines, recruiting cells of the innate immune system to assist in the response against the invading antigens. The adaptive immune system is typified by the following four characteristics: specificity, diversity, memory, and ability to distinguish between self and nonself. There are two types of immune reactions mounted by the adaptive immune system:

The cells of the adaptive immune system develop in the bone marrow where B cells mature and develop into immunocompetent cells. T cells have to leave the bone marrow and enter the thymic cortex, however, to develop into immunocompetent cells. Immunocompetent B and T cells leave their primary lymphoid organs (bone marrow and thymus) to enter diffuse lymphoid tissue, lymph nodes, and the spleen—collectively known as secondary lymphoid organs. Here they search out and contact antigens.

Clonal Selection and Expansion

To be able to recognize and eliminate all the possible antigens and pathogens that one may contact in a lifetime, during embryogenesis about 10¹⁵ lymphocytes are established. Each lymphocyte has the property of recognizing a particular foreign antigen, and each proliferates to form a cluster of identical cells, where each cluster is known as a clone. The members of each clone possess the same membrane-bound antibodies (surface immunoglobulins [sIgs]) or the same T cell receptor (TCR) for B cells and T cells, respectively. If the sIg or the TCR is against the macromolecules of the self, that clone is either eliminated during embryonic development (clonal deletion) or inactivated so that it cannot initiate an immune response (clonal anergy), protecting the individual from autoimmunity.

Immunoglobulins (Antibodies)

A special family of glycoproteins, known as antibodies (immunoglobulins), is manufactured in enormous numbers by plasma cells and in small quantities by B cells (that place them on their cell membranes as sIgs, B cell receptors). A representative antibody (IgG) resembles the letter Y and is composed of four polypeptide chains (Fig. 12.1).

• Two long, identical heavy chains, secured to each other by disulfide bonds, form the stem and arms of the Y (where the arm and stem are held to each other by a hinge region).

• Two short, identical light chains participate in the formation of the arms of the Y, each held to its heavy chain by disulfide bonds.

Figure 12.1 Drawing of a typical IgG.

(From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 278.)

Enzymatic cleavage of an antibody by papain occurs at the hinge region and forms an Fc fragment, the stem, whose amino acid sequence is constant, and two Fab fragments (antigen binding), each composed of a light chain and part of a heavy chain, whose distal portions are specific in their ability to bind only one particular epitope (the antigenic determinant region of an antigen). There are five different classes of immunoglobulins depending on various characteristic differences (Table 12.3).

  Page 171 

Table 12.3 IMMUNOGLOBULIN ISOTYPES

Cells of the Adaptive and Innate Immune Systems

The adaptive and innate immune systems rely on the following cells: B cells, T cells, macrophages and their subtype APCs, and NK cells.

B Lymphocytes (B Cells)

B cells develop and become immunocompetent in the bone marrow. These cells manufacture IgM and IgD antibodies and insert their Fc end into their plasmalemma (sIgs) so that the Fab end projects into the external milieu. The Fc portion is affixed to the cell membrane by two transmembrane proteins, Igβ and Igα, that, when the sIg contacts an epitope, transduce that information intracellularly, starting a sequence of steps whose consequence is:

• Activation of the B cell, whose responsibility is the humorally mediated immune system.

• Activated B cells proliferate to form plasma cells and B memory cells.

• Memory cells are responsible for clonal expansion.

• Plasma cells manufacture IgM and then switch to a different isotype (Table 12.4).

  Page 173 

Table 12.4 ISOTYPE SWITCHING FROM IgM

Certain polysaccharides, such as peptidoglycans of bacterial membranes, are thymic-independent antigens because they can initiate a humoral immune response without T cell intermediaries. Only IgM antibodies are produced, however, and B memory cells are not formed.

T Lymphocytes (T Cells)

T cells develop in the bone marrow but have to enter the cortex of the thymus to express the necessary plasmalemma-bound molecules to become immunocompetent (see later in the section on the thymus). In contrast to B lymphocytes, T cells:

• Possess TCRs rather than sIgs.

• TCRs resemble antibodies in that their constant region is embedded in the plasmalemma, and their variable region, projecting into the intercellular space, binds to epitopes.

• Do not recognize epitopes unless APCs proffer it to them.

• Express cluster of differentiation proteins (CD molecules) on their plasmalemma (Table 12.5).

• About 200 different CD molecules have been identified. The TCR complex, consisting of TCR, CD3, and either CD4 or CD8, recognizes and binds to epitopes presented by APCs.

• Are able to act only in their immediate vicinity.

• Ignore nonprotein antigens.

• Recognize epitopes only if they are associated with one of the two classes of MHC molecules of APCs. These molecules are genetically determined and are unique to each individual, characterizing the self.

• MHC class I are on the cell membranes of nucleated cells.

• MHC class II (and MHC class I) are on the cell membranes of APCs.

Table 12.5 SELECTED SURFACE MARKERS INVOLVED IN THE IMMUNE PROCESS

T cells can become activated only if they recognize not only the epitope but also the MHC molecule. If the T cell does not recognize the MHC molecule, it cannot mount an immune response; therefore, T cells are said to be MHC-restricted. T lymphocytes are classified into three broad categories:

• Naïve T cells

• Memory T cells

• Effector T cells

Naïve T cells are immunologically competent and have CD45RA molecules on their plasmalemma, but have not as yet been challenged immunologically. When they are challenged, they proliferate to form memory and effector T lymphocytes.

Memory T cells possess CD45R0 molecules on their plasmalemma and are of two types: central memory T cells (TCMs), whose cell membrane sports CR7⁺ molecules, and effector memory T cells (CR7⁻ cells, TEMs), which do not have CR7 molecules on their surface. These cells establish the immunologic memory of the immune system. TCMs reside in the paracortex of lymph nodes where they bind to APCs, inducing the APCs to release IL-12. This cytokine causes TCMs to proliferate and form TEMs. The newly formed TEMs travel to the site of inflammation, differentiate into effector T cells, and respond to the antigenic challenge.

CLINICAL CONSIDERATIONS

IgM is the first antibody to be formed by B cells until T_H cells instruct them to switch to IgG synthesis. Individuals who have defective CD40 ligands are unable to switch isotypes and have excess blood levels of IgM, a condition known as hyper-IgM syndrome, resulting in humoral immunodeficiency–induced chronic infections.

All nucleated cells possess MHC I molecules, and these have to be recognized by CTLs to mount an immune response. Many tumor cells and virally altered cells stem the synthesis of MHC I molecules to avoid being recognized and destroyed by CTLs. NK cells are able to destroy these cells, however, because they do not need to recognize MHC I molecules.

  Page 174 

Effector T Cells

Effector memory T cells give rise to effector T cells, three different groups of immunocompetent cells that have the ability to mount an immune response. The three categories are T_H cells, CTLs and T killer cells, and T reg cells.

All T_H cells display CD4 molecules on their plasmalemma and have the ability to work with cells that belong to the innate and the adaptive immune systems. T_H cells also function in activating CTLs to kill foreign and virally altered cells and in activating B cells to differentiate into plasma cells to form antibodies. There are four subcategories of T_H cells (a fifth one was placed into the T reg cell category), and they all secrete various cytokines (Table 12.6):

• T_H0 cells, precursors of the other three classes of T_H cells, are able to release many cytokines.

• T_H1 cells:

• Direct responses against pathogens that invade the cytosol.

• Initiate cell-mediated immune responses.

• Secrete IL-2, which induces mitosis in CD4 and CD8 T cells and CTL cytotoxicity.

• Secrete IFN-γ, which induces macrophages to destroy phagocytosed microorganisms and activates NK cells. Macrophages secrete IL-12, which causes formation of more T_H1 cells and restrains production of T_H2 cells.

• Secrete tumor necrosis factor-β, which promotes acute inflammation by neutrophils.

• T_H2 cells function in prompting humoral responses against parasites and infection of the mucosa and secrete:

• IL-4, which encourages B cells to switch to IgE production for allergic responses and, with IL-10, impedes the development of T_H1 cells.

• IL-5, which prompts eosinophil formation.

• IL-6, which encourages formation of T and B cells to battle asthma and systemic lupus erythematosus.

• IL-9 which augments mast cell responses and T_H2 cell proliferation

• IL-13, which encourages B cell formation and retards formation of T_H1 cells.

• T_H17 cells secrete IL-17 and boost neutrophil response by facilitating their recruitment; they also develop from naïve T cells if IL-6 and transforming growth factor-β are present.

• CTLs, in contrast to T_H cells, have CD8 molecules on their plasmalemma. The TCRs of CTLs binds to epitopes on the plasma membranes of foreign, virally altered tumor cells; additionally, CTLs:

• Insert perforins into the target cell plasmalemma, inducing creation of pores in the membrane.

• Secrete granzymes that enter the target cell’s cytosol through the newly formed pores, driving the cell into apoptosis.

• Possess CD95L (death ligand) on their plasmalemma and bind to and activate CD95 (death receptor) on the target cell membrane, inducing the cascade of apoptotic death in the target cell.

• T reg cells also have CD4 molecules on their plasmalemma and function in suppressing the immune response. The two categories of T reg cells, which may function together to curtail autoimmune responses, are:

• Natural T reg cells, which stem an immune response in a non–antigen-specific fashion by binding to APCs.

• Inducible T reg cells (previously known as T_H3 cells), which secrete IL-10 and TGF-β to prevent the formation of T_H1 cells.

• In contrast to the other T cells, natural T killer cells are able to respond against lipid antigens that APCs with CD1 molecules on their cell surface present to them. Natural T killer cells are similar to NK cells in that they can be activated without intermediate steps, although only after they spent time in the thymic cortex where they become immunocompetent. These cells release IL-4, IL-10, and IFN-γ.

  Page 175 

Table 12.6 ORIGIN AND SELECTED FUNCTIONS OF SOME CYTOKINES

CLINICAL CONSIDERATIONS

Occasionally, the immune system develops a dysfunction, as in Graves’ disease, in which the thyroid follicular cells’ receptors for thyroid- stimulating hormone are no longer recognized as part of the self. Instead, these receptors become viewed as if they were antigens. Conditions where the self is viewed as if it were foreign are known as autoimmune diseases. Antibodies bind to the TSH receptors, causing the follicular cells to secrete an overabundance of thyroid hormone. Patients with Graves’ disease present with an enlarged thyroid gland and exophthalmos (protruding eyeballs).

T_H2 Cell–Mediated Humoral Immune Response

For all thymus-dependent antigens, B cells internalize and disassemble their antigen-sIg complex, load the MHC II, and place the MHC II–epitope complex on its plasmalemma to present it to a T_H2 cell (Fig.12.2).

• Step 1: T_H2 cell recognizes the epitope with its TCR and the MHC II with its CD4 molecule.

• Step 2: T_H2 cell’s CD40 receptor and CD28 molecule have to bind to the B cell’s CD40 molecule and CD80 molecule, resulting in the formation of B memory cells and plasma cells.

Figure 12.2 Activation of B cells by T_H2 cells to produce B memory cells and antibody-forming plasma cells. The humoral response to thymus-independent antigens and the interaction with T_H2 cells are not required.

(From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 285.)

  Page 177 

CLINICAL CONSIDERATIONS

Acquired immunodeficiency syndrome (AIDS) is caused by human immunodeficiency virus (HIV), which has the ability to bind to the CD4 molecules of T_H cells. After binding to the CD4 molecules, the virus introduces its core into the T_H cell, debilitating it. As the virus increases in number and infects additional T_H cells, the number of T_H cells diminishes, and the patient is unable to mount an immune response and succumbs to opportunistic infections.

T_H1 Cell–Mediated Killing of Virally Transformed Cells

The ability of a CTL to kill a virally transformed cell depends on two conditions:

1. It must receive signaling molecules from an activated T_H1 cell.

2. It must be bound to the same APC that is in the process of activating the T_H1 cell (Fig. 12.3).

• Activation of the T_H1 cell occurs when the following two steps are achieved:

• Step 1: T_H1 cell TCR and CD4 molecules must be able to bind to the epitope–MHC II complex of the APC, inducing the APC to place a B7 molecule on its plasmalemma.

• Step 2: T_H1 cell’s CD28 molecule has to bind to the APC’s B7 molecule, and the T_H1 cell releases IL-2, IFN-γ, and TNF.

• Activation of the CTL occurs when the following two steps are achieved:

• Step 1: CTL’s CD8 molecule and TCR must recognize the APC’s epitope–MHC II complex, and the CTL’s CD28 molecule must bind to the APC’s B7 molecule.

• Step 2: T_H1 cell releases IL-2, which must bind to the IL-2 receptor of the CTL. The activated CTL proliferates because of the influence of IFN-γ.

Figure 12.3 Activation of CTLs by T_H1 cells. The T_H1 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.)

The activated CTLs bind, via TCR and CD8, to the epitope–MHC I complex of the virally transformed cells and kill the transformed cells by:

• Inserting perforins into the transformed cells’ plasmalemma, which cause the formation of large pores through which the components of the cytosol leak out of the cell

• Inserting perforins into the transformed cells’ plasmalemma and releasing granzymes into the cytosol, driving the cell to apoptosis

• Alternatively, the CTL’s Fas ligand (CD95L molecule, death ligand) can bind with the transformed cells’ Fas protein (CD95, death receptor), which drives the transformed cells to apoptosis.

T_H1 Cells Assist Macrophages in Killing Phagocytosed Bacteria

Macrophages have to be activated by T_H1 cells before they can destroy bacteria that they phagocytosed. This process requires that first the T_H1 cell become activated; the activated T_H1 cell then instructs the macrophage to destroy the bacteria in its phagosomes (Fig. 12.4). The activation of the T_H1 cell requires two steps:

• Step 1: T_H1 cell’s CD4 molecule and TCR have to recognize the epitope–MHC II complex of the macrophage.

• Step 2: T_H1 cell activates itself by expressing IL-2 receptors and releasing IL-2, which binds to the newly expressed receptors and induces mitotic activity of the T_H1 cells.

Figure 12.4 Activation of macrophages by T_H1 cells.

(From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 287.)

The newly formed, activated T_H1 cells bind to the macrophages with bacteria in their phagosomes.

• Step 1: T_H1 cell’s CD4 molecule and TCR have to recognize the epitope–MHC II complex of the macrophage, and the T_H1 cell releases IFN-γ.

• Step 2: Macrophage is activated by IFN-γ and releases TNF-α, which also binds to the macrophage; these two signaling molecules initiate the destruction of the phagocytosed bacteria by the formation of oxygen radicals.

Thymus

The thymus, a small endodermally derived organ located 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 infiltrated 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).

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.)

The thymic cortex is occupied by numerous lymphocytes whose large nuclei and scant cytoplasm impart a dark, basophilic image in histologic sections. 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 reticular cells of the cortex and develop some and eliminate other surface markers.

Lymph Nodes

Lymph nodes are usually small, bean-shaped structures (≤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 parenchyma is subdivided into:

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.)

The capsule on the convex aspect sends trabeculae into the cortex, subdividing it into incomplete compartments; as the trabeculae continue into the paracortex 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 connective tissue capsule and laterally by trabeculae derived from the capsule (see Fig. 12.6). As the afferent 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 particulate matter.

The cortical compartments display dark, spherical secondary or primary lymphoid nodules.

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 medullary 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.

Spleen

The spleen has a dense, irregular, and collagenous connective tissue capsule that is covered by the peritoneum, 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, paracortex, and medulla; instead, it comprises white pulp, the marginal zone, and red pulp (sporting an abundance of tortuous sinusoids) that are intermingled (Fig. 12.7) to serve the functions of the spleen:

Figure 12.7 Diagram of the spleen.

(From Gartner LP, Hiatt JL: Color Textbook of Histology, 3rd ed. Philadelphia, Saunders, 2007, p 294.)

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.

Figure 12.8 Diagram of the closed and open circulation in the spleen.

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  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.

  Page 185 

  Page 186 

The functions of the spleen are intimately interconnected with the design of its vascular supply.

• The first region where blood entering the spleen contacts the splenic parenchyma is at the marginal sinusoids, where APCs search for antigens, and macrophages attack microorganisms traveling in the bloodstream. T and B cells leave the bloodstream through the walls of the marginal sinusoids and enter the PALS and the lymphoid nodules.

• At the marginal zone, interdigitating dendritic cells present their MHC-epitope complex to T cells. B cells recognize thymus-independent antigens to initiate an immune response; they differentiate into plasma cells, most of which migrate to the bone marrow and make antibodies.

• Material that is not eliminated in the marginal zone enters the sinusoids of the red pulp to be eliminated there by macrophages. This material includes old platelets and senescent erythrocytes. Old erythrocytes are recognized because they lose sialic acid residues and have galactose moieties on their cell membranes.

Mucosa-Associated Lymphoid Tissue

The mucosae of the respiratory, digestive, and urinary tracts display nonencapsulated clusters of lymphoid nodules and lymphocyte infiltrations known as MALT; examples are gut-associated lymphoid tissue (GALT), bronchus-associated lymphoid tissue (BALT), and tonsils.

Figure 12.9 Transmission electron micrographs. A, ALPA vessel (L) of the interfollicular area full of lymphocytes that has an intraendothelial channel that includes lymphocytes (arrow) in the endothelial wall (×3000). B–D, Ultrathin serial sections that document various stages through an intraendothelial channel composed of one (1) and two (2) endothelial cells (×9000). l, lymphocyte.

(From Azzali G, Arcari MA: Ultrastructural and three-dimensional aspects of the lymphatic vessels of the absorbing peripheral lymphatic apparatus in Peyer’s patches of the rabbit. Anat Rec 258:76, 2000.)