Cells of the Immune System
The primary cells that participate in the immune response are lymphocytes, plasma cells, mast cells, neutrophils, eosinophils, and cells of the mononuclear phagocyte system. Antigen-presenting cells, a group of very diverse cell types, assist other cells in the immune response. This group includes, among other cells, lymphocytes, macrophages, and dendritic cells.
Lymphocytes are classified as B,T, or natural killer (NK) cells. The B and T cells are the only cells that have the ability to selectively recognize a specific epitope among a vast number of different epitopes (of the order of 1018). B and T cells differ based on their life history, surface receptors, and behavior during an immune response. Although B and T cells are morphologically indistinguishable in either the light or electron microscope, they can be distinguished by immunocytochemical methods because they have different surface proteins (markers). The precursors of all lymphocyte types originate in the bone marrow; some lymphocytes mature and become functional in the bone marrow, and after leaving the bone marrow enter the blood circulation to colonize connective tissues, epithelia, lymphoid nodules, and lymphoid organs. These are the B lymphocytes (Figure ,3). T lymphocyte precursors, on the other hand, leave the bone marrow, and through the blood circulation reach the thymus where they undergo intense proliferation and differentiation or die by apoptosis. After their final maturation, T cells leave the thymus and are distributed throughout the body in connective tissues and lymphoid organs (Figure ,3). Because of their function in lymphocyte production and maturation, the bone marrow and the thymus are called the primary or central lymphoid organs. The other lymphoid structures are the secondary or peripheral lymphoid organs (spleen, lymph nodes, solitary lymphoid nodules, tonsils, appendix, and Peyer's patches of the ileum). B and T cells are not anchored in the lymphoid organs; instead, they continuously move from one location to another, a process known as lymphocyte recirculation. B and T cells are not uniformly distributed in the lymphoid system but occupy preferential sites in these organs.
(Figure ,3):Origin of the main types of lymphocytes. B lymphocytes and natural killer lymphocytes are formed in the bone marrow and leave the bone marrow already mature, to seed the secondary lymphoid organs and transit through the blood, epithelia, and connective tissues. Immature CD4– and CD8– T lymphocyte precursors are transported by the blood circulation from the bone marrow to the thymus, where they complete their maturation and leave as either CD4+ or CD8+ cells.
Approximate Percentage of B and T Lymphocytes in Lymphoid Organs.
T Lymphocytes, (%)
B Lymphocytes, (%)
Each B lymphocyte that leaves the bone marrow or each T lymphocyte that leaves the thymus has just one type of surface receptor that recognizes a specific epitope.
In B lymphocytes, the surface receptors able to recognize antigens are monomeric molecules of IgM; each B cell is covered by about 150,000 molecules of IgM. The encounter of a B lymphocyte with the epitope it recognizes leads to several cycles of cell proliferation, followed by a redifferentiation of most of these lymphocytes into plasma cells. This population of plasma cells secretes antibodies against the same epitope as that of the B cell that originated them. In most cases, the activation of B cells requires the assistance of a subclass of T lymphocytes known as T-helper lymphocytes. Not all activated B cells, however, become plasma cells; some remain B memory lymphocytes, which react rapidly to a second exposure to the same epitope.
T cells constitute 65–75% of blood lymphocytes. To recognize epitopes, all T cells have on their surfaces a molecule called a T cell receptor (TCR). In contrast to B cells, which recognize soluble antigens or antigens present on cell surfaces, T lymphocytes recognize only epitopes (mostly small peptides) that form complexes with special proteins of the cell surface of other cells .
The two main subpopulations of T cells are helper and cytotoxic lymphocytes (CTLs). Helper cells play very important roles in the immune response, being responsible for cytokine production, interaction with B cells to promote their differentiation into plasma cells, activation of macrophages to phagocytose, activation of cytotoxic lymphocytes, and induction of an inflammatory reaction. Many of these actions are mediated by cytokines.
Helper cells have a marker called CD4 on their surfaces and are, hence, called CD4+ T cells. Cytotoxic, or CD8+ T cells, can act against foreign cells or virus-infected cells by means of two main mechanisms. In one, they attach to the cells to be killed and release proteins called perforins that create holes in the cell membrane of the target cell, with consequent cell lysis. In the other, they attach to a cell and kill it by triggering mechanisms that induce programmed cell death, or apoptosis. The first encounter of a CD4+ or CD8+ T cell with its specific epitope is followed by amplification of that clone; some of the cells of this increased population become effector cells and some remain memory helper or memory cytotoxic T cells, reacting rapidly to the next presentation of the same epitope.
Natural Killer Cells
The natural killer lymphocytes lack the marker molecules characteristic of B and T cells. They comprise about 10–15% of the lymphocytes of circulating blood. Their name derives from the fact that they attack virus-infected cells, transplanted cells, and cancer cells without previous stimulation; for this reason they are involved in what is called an innate immune
Antigen-Presenting Cells (APCs)
APCs are found in many tissues and constitute a heterogeneous cell population that includes B lymphocytes, macrophages, and dendritic cells. The dendritic cells (not to be confused with cells of the nervous tissue) are present within the epidermis (where they are called Langerhans cells), within other epithelia, and within lymphoid organs. A common feature of APCs is the presence of class II MHC molecules on their surfaces. CD4+ T (helper) cells interact with complexes formed by peptides and class II MHC molecules on APCs, whereas CD8+ T (cytotoxic) cells interact with complexes of peptides with class I MHC molecules that can be presented by any nucleated cell. APCs, being recognized by helper lymphocytes, are, thus, essential for the triggering and development of a complex immune response.
The Langerhans cells of the epidermis constitute a very efficient system for trapping antigens that happen to enter the epidermis. These cells have many processes and upon capturing antigens, they retract the processes, move toward the dermis, and may enter a lymphatic vessel.
Types of Immune Responses
The two basic types of immune responses are the innate response and the adaptive response. The innate response, which occurs through the action of neutrophils, macrophages, mast cells, and natural killer cells, is fast, nonspecific, and older from an evolutionary point of view. It does not produce memory cells. The adaptive response, which depends on the initial recognition of antigens by B and T cells, is much more complex, is slower and specific, produces memory cells, and is a more recent evolutionary development.
The adaptive mechanisms that lead to the elimination of antigens are classified as humoral or cellular responses. Humoral immunity is accomplished by antibodies produced by plasma cells derived from clones of activated B lymphocytes. Cellular immunity is mediated by T lymphocytes that
(1) secrete cytokines that act on B lymphocytes, on other T cells, and on inflammatory cells such as macrophages and neutrophils.
(2) attack foreign cells or cells that exhibit foreign epitopes on their surfaces, such as cells infected by viruses or parasites, and tumor cells. With few exceptions, both types of immune response are activated when foreign epitopes are recognized by lymphocytes.
Lymphoid Organs: Introduction
The cells of the immune system
(1) Are distributed throughout the body in the blood, lymph, and epithelial and connective tissues.
(2) Are organized as differently sized organs called lymphoid organs—the lymph nodes, the spleen, the thymus, and the bone marrow.
(3) Diffuse lymphoid tissue is especially prominent in the mucosa of the gastrointestinal and respiratory systems. It is organized as non encapsulated clusters of lymphoid cells or as lymphoid (lymphatic) nodules. Diffuse lymphoid tissue is collectively called mucosa-associated lymphoid tissue (MALT).
MALT consists of two major types, bronchus-associated lymphoid tissue (BALT) and gutassociated lymphoid tissue (GALT). Both types possess lymphoid nodules that are isolated from one another, except in the case of Peyer patches.
C. Lymphoid (lymphatic) nodules are transitory dense spherical accumulations of lymphocyte (mostly B cells). The dark, peripheral region of nodules (corona) is composed mainly of small, newly formed lymphocytes. Lymphoid nodules of the GALT are isolated from the lumina of their respective tracts by microfold (M) cells, which transfer antigens from the lumen and present them (without processing them into epitopes) to lymphocytes and macrophages lying in deep invaginations of their basal cell surfaces. From here, an appropriate immune response is mounted by lymphoid tissue in the underlying lamina propria.
1-Secondary nodules, formed in response to an antigenic challenge, have a lightly staining central area called the germinal center, which is composed of B lymphocytes (lymphoblasts [centroblasts] as well as centrocytes). A darker region, known as the mantle (corona), is composed of resting B cells that are being displaced from the germinal center by the newly formed B cells. In addition to centroblasts and centrocytes, the germinal center houses B memory cells, plasma cells, migrating dendritic cells, follicular dendritic cells, macrophages, and reticular cells.
2. Primary nodules lack germinal centers and are composed of resting B memory cells,
Lymphatic nodules are usually found in structures associated with the alimentary canal such as the tonsils, ileum and vermiform appendix. Generally, nodules are dispersed singly in a random manner. In the alimentary canal, however, some aggregations of nodules are found in specific locations. These include the following:
• Tonsils form a ring of lymphatic tissue at the entrance of the oropharynx. The pharyngeal tonsils (adenoids)(located in the roof of the pharynx), the palatine tonsils (or simply the tonsils, located on either side of the pharynx and between the palatopharyngeal and palatoglossal arches), and the lingual tonsils at the base of the tongue all contain aggregates of lymphatic nodules.
The palatine tonsils consist of dense accumulations of lymphatic tissue located in the mucous membrane. The squamous epithelium that forms the surface of the tonsil dips into the underlying connective tissue in numerous places, forming tonsillar crypts .The walls of these crypts usually possess numerous lymphatic nodules. Like other aggregations of lymph nodules, tonsils do not possess afferent lymphatic vessels; however, lymph drains from the lymphatic tissue of the tonsil via efferent lymphatic vessels.
• Peyer’s patches are located in the ileum (distal portion of the small intestine) and consist of numerous aggregations of lymphatic nodules containing T and B lymphocytes.In addition, numerous isolated single (solitary) lymph nodules are located along both large and small intestines.
• The vermiform appendix arises from the cecum. The lamina propria is heavily infiltrated with lymphocytes and contains numerous lymphatic nodules.
Lymph nodes are small encapsulated organs located along the pathway of lymphatic vessels. Lymph nodes are small, bean-shaped, encapsulated lymphatic organs. They range in size from about 1 mm (barely visible with the unaided eye) to about 1 to 2 cm in their longest dimension. Lymph nodes are interposed along lymphatic vessels and serve as filters through which lymph percolates on its way to the blood vascular system. Although widely distributed throughout the body, they are concentrated in certain regions such as the axilla, groin, and mesenteries.
Two types of lymphatic vessels serve the lymph node:
• Afferent lymphatic vessels convey lymph toward the node and enter it at various points on the convex surface of the capsule.
• Efferent lymphatic vessels convey lymph away from the node and leave at the hilum, a depression on the concave surface of the node that also serves as the entrance and exit for blood vessels and nerves.
The supporting elements of the lymph node are:
• capsule, composed of dense connective tissue that surrounds the node;
The cells of the reticular meshwork appear as stellate or elongated cells with an oval euchromatic nucleus and a small amount of acidophilic cytoplasm. These cells can take up dyes and colloidal materials. Using immunocytochemistry and transmission electron microscopy, several populations of cells have been identified.
• Reticular cells are indistinguishable from typical fibroblasts. These cells synthesize and secrete type III collagen (reticular fibers) and the associated ground substance that forms the stroma observed with the light microscope . Besides their supporting role, they express surface molecules and produce substances that attract T cells, B cells, and dendritic cells.
• Dendritic cells (DCs) are unique bone marrow–derived APCs. DCs monitor the local environment for foreign substances that they then process and present to antigen specific T cells. Costimulatory molecules necessary for activation of T cells. In the lymph node, DCs are usually localized in T lymphocyte–rich areas.
• Macrophages are both phagocytic and antigen-presenting cells costimulatory molecules are much lower than those of the dendritic cells, making them less efficient APCs. Instead, they have an immense capacity for endocytosis and digestion of internalized materials. The
• Follicular dendritic cells (FDCs) have multiple, thin, hairlike branching cytoplasmic processes that interdigitate between B lymphocytes in the germinal centers
General Architecture of the Lymph Node
The parenchyma of the lymph node is divided into a cortex and medulla . The cortex forms the outer portion of the node except at the hilum. It consists of a dense mass of lymphatic tissue (reticular framework, dendritic cells, follicular dendritic cells, lymphocytes, macrophages, and plasma cells) and lymphatic sinuses, the lymph channels. The medulla is the inner part of the lymph node.
As elsewhere, the lymphatic nodules of the cortex are designated primary nodules if they consist chiefly of small lymphocytes and secondary nodules if they possess a germinal center. Lymphatic nodules are found in the outer part of the cortex, called the superficial (nodular) cortex . The portion of the cortex between the medulla and superficial cortex is free of nodules; it is called the deep cortex (paracortex). This region contains most of the T cells in the lymph node. Because of its dependence on the thymus, perinatal thymectomy in animals results in a poorly developed deep cortex. On the basis of this observation, the deep cortex is also called the thymus dependent cortex. The medulla of the lymph node consists of the medullary cords and medullary sinuses. The medulla, the inner part of the lymph node, consists of cords of lymphatic tissue separated by lymphatic sinuses called medullary sinuses. As described above, a network of reticular cells and fibers traverses the medullary cords and medullary sinuses and serves as the framework of the parenchyma. In addition to reticular cells, the medullary cords contain lymphocytes (mostly B lymphocytes), macrophages, dendritic, and plasma cells. The medullary sinuses converge near the hilum, where they drain into efferent lymphatic vessels.
Filtration of lymph in the lymph node occurs within a network of interconnected lymphatic channels called sinuses.
There are three types of lymphatic channels called sinuses in the lymph node. Just beneath the capsule of the lymphnode is a sinus interposed between the capsule and the cortical lymphocytes called the subcapsular (cortical) sinus Afferent lymphatic vessels drain lymph into this sinus. Trabecular sinuses that originate from the subcapsular sinuses extend through the cortex along the trabeculae and drain into medullary sinuses. Lymphocytes and macrophages or their processes readily pass back and forth between the lymphatic sinuses and the parenchyma of the node. The sinuses have a lining of endothelium that is continuous where it is directly adjacent to the connective tissue of the capsule or trabeculae but discontinuous where it faces the lymphatic parenchyma. Although a macrophage may reside in the lymphatic parenchyma, it often sends pseudopods (long cytoplasmic processes) into the sinus through these endothelial discontinuities. These pseuAfferent lymphatic vessels drain lymph into this sinus. Trabecular sinuses that originate from the subcapsular sinuses extend through the cortex along the trabeculae and drain into medullary sinuses. Lymphocytes and macrophages or their processes readily pass back and forth between the lymphatic sinuses and the parenchyma of the node. The sinuses have a lining of endothelium that is continuous where it is directly adjacent to the connective tissue of the capsule or trabeculae but discontinuous where it faces the lymphatic parenchyma. Although a macrophage may reside in the lymphatic parenchyma, it often sendspseudopods (long cytoplasmic processes) into the sinus through these endothelial discontinuities. These pseudopods monitor the lymph as it percolates through the
The thymus is a lymphoepithelial organ located in the superior mediastinum. The thymus is a bilobed organ located in the superior mediastinum. It develops bilaterally from the third (and sometimes also the fourth) branchial (oropharyngeal) pouch. During development, the epithelium invaginates, and the thymic rudiment grows caudally as a tubular projection of the endodermal epithelium into the mediastinum of the chest. The advancing tip proliferates and ultimately becomes disconnected from the branchial epithelium. Multipotential lymphoid stem cells from the bone marrow are destined to develop into immunocompetent T cells that invade the epithelial rudiment and occupy spaces between the epithelial cells so that the thymus develops into a lymphoepithelial organ. The thymus is fully formed and functional at birth. It persists as a large organ until about the time of puberty,
when T-cell differentiation and proliferation are reduced and most of the lymphatic tissue is replaced by adipose tissue (involution). The organ can be restimulated under conditions that demand rapid T-cell proliferation. General Architecture of the Thymus Connective tissue surrounds the thymus and subdivides it into thymic lobules. The thymus possesses a thin connective tissue capsule from which trabeculae extend into the parenchyma of the organ. The capsule and trabeculae contain blood vessels, efferent (but not afferent) lymphatic vessels, and nerves. In addition to collagen fibers and fibroblasts, the connective tissue of the thymus contains variable numbers of plasma cells, granulocytes, lymphocytes, mast cells, adipose cells, and macrophages, the trabeculae establish domains in the thymus called thymic lobules.
The thymus possesses no lymphoid nodules; instead, it is divided into an
• outer darker staining cortex, composed of epithelial reticular cells, macrophages, and small T lymphocytes (thymocytes), and an
• inner lighter staining medulla consisting of large T lymphocytes, epithelial reticular cells, and thymic (Hassall’s) corpuscles
The thymic medulla is continuous between adjacent lobules and contains large numbers of epithelial reticular cells and mature T cells, which are loosely packed, causing the medulla to stain lighter than the cortex.
It also contains whorl-like accretions of epithelial reticular cells called Hassall corpuscles (thymic corpuscles). These structures display various stages of keratinization and increase in number with age. Their function is unknown, although it has been shown that these epithelial reticular cells manufacture thymic stromal lymphopoietin (TSLP), a cytokine that facilitates dendritic cell maturation.
Mature T cells exit the thymus via venules and efferent lymphatic vessels from the thymic medulla. The T cells then migrate to secondary lymphoid structures.
A simple squamous epithelium (peritoneum) covers the dense irregular collagenous connective tissue capsule of the spleen, which sends trabeculae into the substance of the spleen to form a supportive framework. The spleen is similar to lymph nodes in that it possesses a hilum but differs from both the thymus and lymph nodes in that it lacks a cortex and medulla. It further differs from lymph nodes because it has no afferent lymphatic vessels.The spleen is divided into red pulp and white pulp; the latter contains lymphoid elements. These two regions are separated from each other by the marginal zone.
Function—Spleen. The spleen filters blood, stores erythrocytes, phagocytoses damaged and aged erythrocytes, and is a site of proliferation of B and T lymphocytes and the production of antibodies by plasma cells.
Vascularization of the spleen is derived from the:
a. splenic artery, which enters the hilum and gives rise to trabecular arteries. Trabecular arteries leave the trabeculae, become invested by a periarterial lymphatic sheath (PALS, described later), and are known as central arteries.
b. Central arteries branch but maintain their lymphatic sheath until they leave the white pulp to form several straight penicillar arteries.
c. Penicillar arteries enter the red pulp. They have three regions: pulp arterioles, macrophage-sheathed arterioles, and terminal arterial capillaries. These last named vessels either drain directly into the splenic sinusoids (closed circulation) or terminate as open-ended vessels within the splenic cords of the red pulp (open circulation).
d. Splenic sinusoids are drained by pulp veins, which are tributaries of the trabecular veins; these in turn drain into the splenic vein, which exits the spleen at the hilum.
a. White pulp of the spleen includes all of the organ’s lymphoid tissue (diffuse and nodular), such as lymphoid nodules (mostly B cells) and PALS (mostly T cells) around the central arteries. It also contains macrophages and other APCs.
b. The marginal zone of the spleen
(1) is a sinusoidal region between the red and white pulps at the periphery of the PALS.
(2) receives blood from capillary loops derived from the central artery and thus is the first site where blood contacts the splenic parenchyma.
(3) is richly supplied by avidly phagocytic macrophages and other APCs.
(4) is the region where circulating T and B lymphocytes enter the spleen before
becoming segregated to their specific locations within the organ and where interdigitating dendritic cells are able to display their MHC-epitope complex for recognition by T cells.
c. Red pulp of the spleen (Figure 12.4) is composed of an interconnected network of sinusoids supported by a loose type of reticular tissue (splenic cords).
(a) are lined by long fusiform endothelial cells separated by relatively large bloodcontaining intercellular spaces.
(b) have a discontinuous basal lamina underlying the endothelium and circumferentially arranged ribs of reticular fibrils.
(2) Splenic cords (cords of Billroth) contain plasma cells, stellate reticular cells, blood cells, and macrophages enmeshed within the spaces of the reticular fiber network. Processes of the macrophages enter the lumina of the sinusoids through the spaces between the endothelial cells.