THORLANDSVERK
The immune system comprises organs, aggregated lymphatic tissue, and cells that work to maintain the integrity of the body. Cells and tissues of the immune system identify and protect against pathogenic organisms and ensure that the body’s response to foreign substances is appropriate. The system has innate components that act rapidly but nonspecifically and adaptive components that act specifically but need a period of time to respond. Threats to the integrity of the individual are not limited to extrinsic sources. The processes of wear and tear and pathologic changes in tissues also result in an immune response.
CELLS OF THE IMMUNE SYSTEM
The cellular participants of the immune response can be categorized as either migratory cells or fixed cells. Lymphocytes are the principal migratory cells that are free to move anywhere in the body. Recirculation through the lymph or blood is a prominent feature of these leukocytes, ensuring effective surveillance of the tissues. The fixed cells are either mesenchymal or epithelial cells that form a scaffold for the stromal matrix in lymphatic tissue. These cells create a supportive framework that sustains the lymphocytes during different phases of development and function. The remarkable diversity of both migratory and fixed cells creates the unique character of lymphatic tissue.
Lymphocytes
The histology of lymphocytes is described in detail in Chapter 4. Lymphocytes are migratory cells of the immune system that control adaptive immunity by initiating a specific response after encountering antigens. Antigens are molecular components of exogenous agents, such as bacteria, viruses, protozoa, or toxins, and endogenous agents, such as tumor cells and virus-infected cells. The lymphocytic lineage gives rise to two major cell types: B cells (bone marrow–dependent) and T cells (thymus-dependent). B cells and T cells and their subpopulations are distinguished by different surface molecules that recognize antigens (i.e., antigen receptors [Fig. 8-1]) and are involved in signal transduction and cell cooperation (e.g., major histocompatibility markers). B and T cells cannot be identified using standard histologic stains such as hematoxylin and eosin.
B cells and T cells also differ in the way that they effect an immune response. After antigen stimulation, both lymphocyte types undergo proliferation and differentiation to become either memory cells or effector cells. Memory cells are long-lived cells that have the ability to mount an enhanced response upon a reencounter with antigen. Effector B-cell function is mediated by the secreted antigen receptor (immunoglobulin, also known as antibodies). In their active secretory phase, B effector cells typically are manifest as plasma cells (see Chapter 3 for the histology of plasma cells). Since antibodies circulate in the extracellular fluids (“humors”), B cells are said to be responsible for the humoral immune response. Antigen with attached antibody is more easily recognized by phagocytes and eliminated. The antigen–antibody complex also triggers a collection of plasma proteins, called the complement system. The complement system is an important component of innate defense with wide-ranging effects that include the ability to kill microorganisms.
FIGURE 8-1 Schematic drawing of lymphocyte surface antigen receptors. The B-cell receptor is an immunoglobulin (antibody) molecule that has two antigen-binding sites (dark segments), whereas the T-cell receptor has a single antigen-binding site.
Effector T cells, on the other hand, act more directly on adjacent cells within tissues. The two major subsets of effector T cells mediate their effects in different ways. T helper cells act through the secretion of soluble, local-acting molecules called cytokines, whereas the T cytotoxic cells attach to antigens on target cells to kill them (Fig. 8-2). Since these cell-killing actions require close cell-to-cell contact, T cells are said to be responsible for the cell-mediated immune response.
A third category of lymphocyte, the natural killer (NK) cell, lacks an antigen receptor that is typical for either B or T cells. NK cells appear to rely on an antigen recognition system that is less specific than that used by B cells and T cells; however, cell-mediated killing by NK cells is similar to the mechanism of T cyto-toxic cells. NK cells participate in the elimination of tumors and virus-infected cells or other cells that show altered expression of “self” molecules. In some species, these cells appear as large granular lymphocytes.
Lymphocytes circulate continuously from the blood through lymphatic and nonlymphatic tissues and subsequently return to the blood either directly or via the lymph. This process, called lymphocyte recirculation, facilitates the dissemination of an immune response throughout the body and enables effective immune surveillance for foreign invaders and alterations in the body’s own cells. Most lymphocytes enter organs such as the lungs, liver, and bone marrow and return to the blood via venules, whereas some lymphocytes leave these organs via the lymph and drain to lymph nodes via afferent lymph vessels. Tissue fluid from large peripheral areas also drains into regional lymph nodes, further enhancing the likelihood of an encounter between a lymphocyte and its target antigen. A proportion of lymphocytes migrates from blood directly into lymphatic tissues through specialized postcapillary venules called high endothelial venules (see Lymph Node section below [FIg. 8-18]). High endothelial venules have lining cells that are cuboidal, in contrast to the flattened endothelial cells of other blood vessels. These specialized venules are abundant in lymphatic tissue and serve as the sites of entry for both T cells and B cells from the blood circulation. The spleen is an exception, because it does not possess specialized postcapillary venules or afferent lymphatics. Lymphocytes migrate into the spleen via blood capillaries in the marginal zone (see Spleen section below). Normally, relatively few lymphocytes migrate into organs such as the skin, synovia, muscle, and brain; however, during acute and chronic inflammation, an influx of large numbers of lymphocytes can occur.
FIGURE 8-2 Schematic drawing of antigen–antigen receptor interaction. The B-cell receptor (BCR) can interact directly with native antigen (Ag), either while bound to the plasma membrane of a B cell or as secreted antibody. The B-cell receptor also recognizes antigen presented by the follicular dendritic cell. The T-cell receptor recognizes processed antigen presented by a major histocompatibility complex (MHC-II) molecule on the surface of the interdigitating dendritic cell. The B cell can present antigen to T cells by binding the antigen, processing it, and presenting it in the context of MHC II (black arrow). Macrophages are also capable of presenting antigen to T cells.
Stromal Cells
Stromal cells are fixed cells of the lymphatic system that form a tissue reticulum and support the immune response. Either mesenchymal reticular cells or epithelial reticular cells form a supportive mesh or stroma for the lymphocytes that constitute the parenchyma of lymphatic organs.
Reticular Cells
Reticular cells of mesenchymal origin and fibroblastlike structure form a reticulum in all lymphatic organs except the thymus and cloacal bursa (see Lymph Node section below [Fig. 8-16]). Because of their numerous long and branching processes, reticular cells have a stellate appearance. These cells synthesize reticular fibers that are closely associated with or invaginated into their cell surface.
Epithelial Reticular Cells
In the thymus and cloacal bursa, stellate epithelial reticular cells form a reticulum that supports developing lymphocytes and macrophages (see Thymus section below [Fig. 8-8]). Unlike reticular cells, epithelial reticular cells do not produce reticular fibers.
Antigen-Presenting Cells
For antigen recognition and the initiation of an immune response to occur, B cells recognize antigen either directly or as complexes presented by an antigen-presenting cell such as the follicular dendritic cell (Fig. 8-2). T cells require antigen to be presented on the surface of an antigen-presenting cell, such as the inter-digitating dendritic cell, in association with a major histo-compatibility complex (MHC) molecule.
Dendritic Cells
Most dendritic cells (DCs), including the interstitial dendritic cell, interdigitating dendritic cell, veiled cell, and intraepidermal macrophage, are derived from hematopoietic stem cells. The origin of follicular dendritic cells is unclear. Typical dendriticcells have numerous long cytoplasmic processes (Fig. 8-2). Functionally, dendritic cells bind antigens and cluster lymphocytes on their surface in tissues throughout the body. Once antigens are bound and processed, the dendritic cell then becomes an antigen-presenting cell. In the stratified squamous epithelia, dendritic cells localize in the upper spinous layer and are termed intra-epidermal macrophages (Langerhans cells) (see Chapter 16). When they are in lymph and blood, dendritic cells possess prominent surface folds and have been called veiled cells. Interstitial dendritic cells are located in the heart, kidney, gut and lung. Follicular dendritic cells and interdigitating dendritic cells are found in lymphatic tissues.
Follicular dendritic cells
Follicular dendritic cells are specialized stromal cells localized within the B-cell areas of lymphatic tissue. Receptors on the follicular dendritic cell surface bind to antigen and present it to B cells that induce a humoral immune response (Fig. 8-2). In contrast to other dendritic cells, follicular dendritic cells can trap and maintain antigen in a complex for long periods of time. Follicular dendritic cells lack the MHC-II surface molecules found in interdigitating dendritic cells.
Interdigitating dendritic cells
Interdigitating dendritic cells are found in lymph nodes, thymic medulla, and spleen. Cytoplasmic granules are characteristic features of these dendritic cells, which also have numerous MHC-II molecules on their surface that are associated with antigen presentation (Fig. 8-2). The interdigitating dendritic cell presents antigen to T lymphocytes (helper cells), which induce a cellular immune response.
Macrophages
Macrophages, also known as mononuclear phagocytes, exist in various tissues and are active in the phagocytosis and degradation of foreign substances (see Chapter 3 for the histology of macrophages). The processing of foreign substances into short peptides is essential for presentation of antigen to T cells in the peptide-binding groove of the MHC-II molecule (Fig. 8-2).
B Cells
B cells express MHC-II molecules and are very efficient in the presentation of antigen to T helper cells. In contrast to macrophages, which will ingest most foreign substances, B cells bind a specific single antigen through surface immunoglobulin. The bound molecule is then endocytosed, fragmented, and presented by MHC-II molecules.
ORGANIZATION OF CELLS TO FORM LYMPHATIC TISSUES AND ORGANS
As the fetus develops, the immune system is molded into two principal types of tissues: the diffuse and the organized lymphatic tissues. Diffuse lymphatic tissues are found scattered throughout loose connective tissues of the gut, respiratory tract, urogenital system, and skin and in extranodular areas of lymphatic organs. The organized lymphatic tissues include encapsulated organs such as the lymph nodes and spleen.
Diffuse Lymphatic Tissue
Diffuse lymphatic tissue contains a variable number of small lymphocytes, mingled with lymphoblasts (often seen in mitosis) and macrophages. The stroma of diffuse lymphatic tissue consists of a three-dimensional network of dendritic cells and connective tissue.
Lymphatic Nodules
Primary Lymphatic Nodules
Primary lymphatic nodules consist of a stromal network of connective tissue and immature follicular dendritic cells (Fig. 8-3). Small, tightly packed lymphocytes and some medium lymphocytes are distributed throughout the stromal network and represent predominantly naive recirculating B cells. Primary nodules do not contain germinal centers.
Secondary Lymphatic Nodules
Secondary lymphatic nodules are characterized by a light-staining germinal center within the nodule (Fig. 8-4). Formation of the germinal center begins in a primary nodule with an accumulation of large, euchromatic lymphoblasts and tingible body macrophages. Differentiated follicular dendritic cells form the stroma of the secondary nodules. An established germinal center consists of a central light zone and an adjacent dark zone. The light zone is populated by B lymphocytes with euchromatic, light-staining nuclei. Along the periphery of the light zone is a thin layer of small heterochromatic lymphocytes that often form a thicker cap, called the mantle, over the apex of the germinal center. The dark zone is composed of B-cell lymphoblasts engaged in intense mitotic activity. The germinal center is usually oriented such that the light zone is closest and the dark zone is farthest from the subcapsular sinus in lymph nodes, the surface epithelium in mucosal nodules, or the marginal zone in the spleen. The germinal center regresses when cellular activity declines late in an immune response.
PRIMARY LYMPHATIC ORGANS
During the development of the fetus, the unique identity of T and B lymphocytes first becomes established within primary lymphatic organs. The primary lymphatic organs include the bone marrow (mammals), aggregated lymphatic nodules of the distal small intestine (sheep, cattle), cloacal bursa (birds), and thymus (both mammals and birds). Stem cells in these organs are located in a specialized environment that is isolated from antigen and suitable for cellular differentiation and development. Intense cell proliferation is accompanied by random rearrangement of the genes responsible for the antigen receptor and expression of accessory molecules that allow interaction with other cells and that also confer effector functions. Lymphocytes leaving a primary lymphatic organ are classified as naive or virgin cells because they have not been exposed to antigen. Scrutiny of the emerging lymphocytes is followed by elimination of more than 90% of the cells that are identified as unsuitable, largely because of their reaction with the body’s own molecules (autoreactivity). These lymphocytes are eliminated by apoptosis, a mechanism that involves activation of a genetic pathway ensuring rapid disintegration of the selected cells with minimal harm to the surrounding tissues.
FIGURE 8-3 Lymph node (fetal lamb 140 days of gestation). Primary lymphatic nodule (N) in the outer cortex consists of an aggregate of small to medium-sized lymphocytes and some follicular dendritic cells (arrowheads). Note the presence of a capillary network outlining the primary nodule (arrows). Subcapsular sinus (S); capsule (C). Hematoxylin and eosin.
FIGURE 8-4 Lymph node (goat). Secondary lymphatic nodule with germinal center. Dark area (D); light area (L); mantle (M); capsule (C); deep cortex (DC). Hematoxylin and eosin (×150).
Even with the elimination of most of their cells, primary lymphatic organs still produce vast numbers of B and T cells that have a diverse repertoire of antigen specificities. The released cells are disseminated throughout the body to diffuse lymphatic tissue, secondary lymphatic tissue (i.e., mucosa-associated lymphoid tissue), and secondary lymphatic organs (e.g., lymph nodes), where they will encounter antigen.
Bone Marrow
The structure and major hematopoietic functions of the bone marrow are presented in Chapter 4. In mammals, the bone marrow is the source of pluripotent stem cells (e.g., B-cell and T-cell precursors) and B-cell differentiation. B cells are located adjacent to the endosteum of bone and undergo differentiation and selection as they migrate centrally toward the venous sinuses in the hematopoietic space. B-cell maturation occurs in close association with stromal reticular cells and macrophages of the bone marrow.
Aggregated Lymphatic Nodules in the Distal Small Intestine
Most organized lymphatic tissue associated with the gut has been attributed with functions related to mucosal and systemic immunity (see Gut-Associated Lymphoid Tissue below). In young ruminants, pigs, and carnivores, a single large aggregate of lymphatic nodules (the ileal Peyer’s patch) is present in the distal jejunum/ileum. A specific role for the ileal Peyer’s patch in the diversification of the preimmune antigen-receptor repertoire and expansion of early B-cell populations has recently been defined in sheep and cattle (Fig. 8-5).
Removal of the ovine ileal Peyer’s patch before birth results in a marked decline in the number of mature, circulating B cells. At 2 months of age, the weight of the ileal Peyer’s patch is more than twice that of the thymus.
FIGURE 8-5 A. Jejunal aggregated lymphatic nodules (lamb). A large saclike lymphatic nodule (n) is separated from other nodules in the submucosa by wide internodular (T-cell) regions (i). A prominent corona (c) is interposed between the nodule and a broad dome region (d) that extends into the gut lumen. Villus (v); lymphatic sinuses (arrows); capsule of nodule (arrowheads). Hematoxylin and eosin. B. Jejunal Peyer’s patch (3-week-old calf). Short microfolds are present on an M cell (m) at the dome surface; adjacent absorptive cells have densely packed microvilli (×10,000). C. Jejunal Peyer’s patch (3-week-old calf). An M cell (m) with microfolds is wedged between two microvilli-bearing (mv) absorptive cells (a) and envelops lymphocytes (ly). Lumen (lu) (×7500).
The intense cell division in the aggregated nodules is independent of foreign antigen. Similar to the avian bursa described below, the processes of positive and negative lymphocyte selection likely occur, ensuring the suitability of the lymphocytes that are permitted to exit into the blood and lymphatic circulations.
It should be noted that the earliest immigrants to both the single large aggregate of lymphatic nodules in the distal small intestine of sheep and the avian bursa are already committed to the B-cell lineage. Thus, neither organ is strictly a primary lymphatic organ; that is, B cells do not develop de novo from uncommitted precursors.
Cloacal Bursa of Birds
The dichotomy of the T- and B-cell lineages was first revealed in birds. B cells were discovered in association with the avian cloacal bursa. The cloacal bursa (bursa of Fabricius) is a lymphatic organ located in the dorsal wall of the cloaca (Fig. 8-6). The bursa is considered to be functionally equivalent to the mammalian bone marrow in regard to the differentiation of B cells.
From day c08 to day 15 of chicken embryo development, precursor cells committed to the B-cell lineage migrate into the developing organ. Lymphatic nodules develop as invaginations of the cloacal epithelium into underlying tissues of the cloaca at approximately day 12 of incubation. Longitudinal folds containing the nodules and a stroma of epithelial reticular cells then protrude into the bursal lumen, followed by the formation of light central and dark peripheral zones and the initiation of lymphocyte differentiation within the nodules. Simple columnar or pseudostratified epithelium overlying the nodules within the folds has a remarkable capacity for transcytosis of macromolecules, including antigens, from the bursal lumen into the nodules.
FIGURE 8-6 Cloacal bursa (chicken). A modified epithelium (between arrows) overlies a lymphatic nodule that contains a dark peripheral zone (pz) and a light central zone (cz). Bursal lumen (BL). Hematoxylin and eosin.
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