Molecules Cells and Tissues of the Immune Response

The generation of an immune response of either the innate or acquired variety requires the interaction of specific molecules, cells, and tissues. This chapter provides an overview of these structures with brief descriptions, enhanced by schematic representations and light and electron micrographs of those elements whose interactions yield a highly tailored immune response that is critical to survival of the species. Many of the molecules of immunity are described in subsequent chapters. Adhesion molecules that are important in bringing cells together in the generation of immune responses, of directing cellular traffic through vessels or interaction of cells with matrix are presented here.

All lymphocytes in the body are derived from stem cells in the bone marrow. Those cells destined to become T cells migrate to the thymus where they undergo maturation and education prior to their residence in the peripheral lymphoid tissues. B cells undergo maturation in the bone marrow following their release. Both B and T cells occupy specific areas in the peripheral lymphoid tissues. Depictions of the thymus, lymph nodes, spleen, and other lym-phoid organs are presented to give the reader a visual concept of immune system structure and development. The various cells involved in antigen presentation and development of an immune response are followed by a description of cells involved in effector immune functions. Understanding the molecules, cells, and tissues described in the pages that follow prepares the reader to appreciate the novel and fascinating interactions of these molecules and cells in the body tissues and organs which permit the generation of a highly specific immune response. Immunity may perform many vital functions; for example, the elimination of invading microbes, the activation of amplification mechanisms such as the complement pathway, or the development of protective antibodies or cytotoxic T cells that prevent the development of potentially fatal infectious diseases. By contrast, the immune system may generate responses that lead to hypersensitivity or tissue injury and disease. In either case, the process is fascinating and commands the attention and respect of the reader for Nature's incomparable versatility.

Immune: Natural or acquired resistance to a disease. Either a subclinical infection with the causative agent or deliberate immunization with antigenic substances prepared from it may render a host immune. Because of immunological memory, the immune state is heightened upon second exposure of individuals to an immunogen. A subject may become immune as a consequence of having experienced and recovered from an infectious disease.

CAM (cell adhesion molecules): Cell-selective proteins that promote adhesion of cells to one another and are calcium independent. They are believed to help direct migration of cells during embryogenesis. The majority of lymphocytes and monocytes express this antigen which is not found on other cells. The "humanized" antibodies specific for this epitope are termed Campath-IH. See CD52 in Chapter 11.

Cell adhesion molecules (CAMs) on the cell surface facilitate the binding of cells to each other in tissues as well as in cell-to-cell interaction. Most are grouped into protein families that include the integrins, selectins, mucin-like proteins, and the immunoglobulin superfamily.

Immune cell motility: Migration of immune cells is a principal host defense mechanism for the recruitment of leukocytes to inflammatory sites in the development of cell-mediated immunity. The induction of migratory responses follows the interaction of signal molecules with plasma membrane receptors, initiating cytoskeletal reorganization and changes in cell shape. Motile responses may be random, chemokinetic, chemotactic, or haptotactic. Random migration of unstimulated motility in chemoki-netic migration, i.e., stimulated random movement of cells without a stimulus gradient, are motile responses that are not consistently directional. By contrast, responses that are directional include those that are chemotactic and haptotac-tic. They take place when cells are subjected to a signal gradient, and the cells migrate toward an increasing concentration of the stimulus. The various motile responses may participate in the mobilization of immune cells to sites of inflammation.

The immune system includes the molecules, cells, tissues, and organs that are associated with adaptive immunity such as the host defense mechanisms.

Immune system anatomy: The lymphocyte is the cell responsible for immune response specificity. The human mature lymphoid system is comprised of 2 x 1012

lymphocytes together with various accessory cells that include epithelial cells, monocytes/macrophages, and other antigen-presenting cells. Accessory cells are a requisite for both maturation and effective functioning of lymphocytes. The thymus is the site of maturation of T cells and the bone marrow is the maturation site of B cells. These two tissues comprise the primary lymphoid organs. The secondary lym-phoid organs consist of the cervical lymph nodes, ancillary lymph nodes, spleen, mesenteric lymph nodes, and inguinal lymph nodes. Mature lymphocytes migrate from the central lymphoid organs by way of the blood vessels to the secondary or peripheral tissues and organs, where they respond to antigen. Peripheral lymphoid tissues comprise the spleen, lymph nodes, and mucosa-associated lymphoid tissue (MALT) which is associated with the respiratory, genitourinary, and gastrointestinal tracts, making up 50% of the lymphoid cells of the body. The mucosa-associated lym-phoid system consists of the adenoids, tonsils, and mucosa-associated lymphoid cells of the respiratory, genitourinary, gastrointestinal tracts, and Peyer's patches in the gut.

Immunity refers to a state of acquired or innate resistance or protection from a pathogenic microorganism or its products or from the effect of toxic substances such as snake or insect venom.

Cluster of differentiation (CD): The designation of antigens on the surface of leukocytes by their reactions with clusters of monoclonal antibodies. The antigens are designated as clusters of differentiation (CDs).

CD (cluster of differentiation): See cluster of differentiation. Molecular weights for the CD designations in this book are given for reduced conditions.

CD antigens are a cluster of differentiation antigens identified by monoclonal antibodies. The CD designation refers to a cluster of monoclonal antibodies, all of which have identical cellular reaction patterns and identify the same molecular species. Anti-CD refers to antiidiotype and should not be employed to name CD monoclonal antibodies. The CD designation was subsequently used to describe the recognized molecule but it had to be clarified by using the terms antigen or molecule. CD nomenclature is used by most investigators to designate leukocyte surface molecules. Provisional clusters are designated as CDw. CD antigen is a molecule of the cell membrane that is employed to differentiate human leukocyte subpopulations based upon their interaction with monoclonal antibody. The monoclonal antibodies that interact with the same membrane molecule are grouped into a common cluster of differentiation or CD.

CD molecules are cell surface molecules found on immune system cells that are designated "cluster of differentiation" or CD followed by a number such as CD33.

CMI is the abbreviation for cell-mediated immunity. Immunoblast: Lymphoblast.

Immunochemistry is that branch of immunology concerned with the properties of antigens, antibodies, complement, T cell receptors, MHC molecules, and all the molecules and receptors that participate in immune interactions in vivo and in vitro. Immunochemistry aims to identify active sites in immune responses and define the forces that govern antigen-antibody interaction. It is also concerned with the design of new molecules such as catalytic antibodies and other biological catalysts. Also called molecular immunology.

Immunocompetent is an adjective that describes a mature functional lymphocyte that is able to recognize a specific antigen and mediate an immune response. It also may refer to the immune status of a human or other animal to indicate that the individual is capable of responding immuno-logically to an immunogenic challenge.

Selectins are a group of cell adhesion molecules (CAMs) that are glycoproteins and play an important role in the relationship of circulating cells to the endothelium. The members of this surface molecule family have three separate structural motifs. They have a single N-terminal (extracellular) lectin motif preceding a single epidermal growth factor repeat and various short consensus repeat homology units. They are involved in lymphocyte migration. These carbohydrate-binding proteins facilitate adhesion of leukocytes to endothelial cells. There is a single-chain transmembrane glycoprotein in each of the selectin molecules with a similar modular structure that includes an extracellular calcium-dependent lectin domain. The three separate groups of selectins include L-selectin (CD62L), expressed on leukocytes, P-selectin (CD62P), expressed on platelets and activated endothelium, and E-selectin (CD62E), expressed on activated endothelium. Under shear forces their characteristic structural motif is comprised of an N-terminal lectin domain, a domain with homology to epidermal growth factor (EGF), and various complement regulatory protein repeat sequences. See also E-selectin, L-selectin, P-selectin, and CD62.

Immunocyte, literally immune cell, is a term sometimes used by pathologists to describe plasma cells in stained tissue sections, e.g., in the papillary or reticular dermis in erythema multiforme.

Mucins are heavily glycosylated serine- and threonine-rich proteins that serve as ligands for selectins.

Immunocytochemistry refers to the visual recognition of target molecules, tissues, and cells through the specific reaction of antibody with antigen by using antibodies labeled with indicator molecules. By tagging an antibody with a fluorochrome, color-producing enzyme, or metallic particle, the target molecules can be identified.

MEL-14 is a selectin on the surface of lymphocytes significant in lymphocyte interaction with endothelial cells of peripheral lymph nodes. Selectins are important for adhesion despite shear forces associated with circulating blood. MEL-14 is lost from the surface of both granulocytes and T lymphocytes following their activation. MEL-14 combines with phosphorylated oligosaccharides.

MEL-14 antibody identifies a gp90 receptor that permits lymphocyte binding to peripheral lymph node high endothelial venules. Immature double-negative thymocytes comprise cells that vary from high to low in MEL-14 content. The gp90 MEL-14 epitope is a glycoprotein on murine lymph node lymphocyte surfaces. MEL-14 antibody prevents these lymphocytes from binding to postcap-illary venules. The gp90 MEL-14 is apparently a lymphocyte homing receptor that directs these cells to lymph nodes in preference to lymphoid tissue associated with the gut.

Immunologic (or immunological) is an adjective referring to those aspects of a subject that fall under the purview of the scientific discipline of immunology.

An immunological reaction is an in vivo or in vitro response of lymphoid cells to an antigen they have never previously encountered or to an antigen for which they are already primed or sensitized. An immunological reaction may consist of antibody formation, cell-mediated immunity, or immunological tolerance. The humoral antibody and cell-mediated immune reactions may mediate either protective immunity or hypersensitivity, depending on various conditions.

A microenvironment is an organized, local interaction among cells that provides an interactive, dynamic, structural, or functional compartmentalization. The microenvironment may facilitate or regulate cell and molecular interactions through biologically active molecules. Microenvironments may exert their influence at the organ, tissue, cellular, or molecular levels. In the immune system, they include the thymic cortex and the thymic medulla, which are distinct; the microenvironment of lymphoid nodules; and a microenvironment of B cells in a lymphoid follicle, among others.

Microfilaments are cellular organelles that comprise a network of fibers of about 60 A in diameter present beneath the membranes of round cells, occupying protrusions of the cells, or extending down microprojections such as microvilli. They are found as highly organized and prominent bundles of filaments, concentrated in regions of surface activity during motile processes or endocytosis. Microfilaments consist mainly of actin, a globular 42-kDa protein. In media of appropriate ionic strength, actin polymerizes in a double array to form microfilaments which are critical for cell movement, phagocytosis, fusion of phagosome and lysosome, and other important functions of cells belonging to the immune and other systems.

An immunologically activated cell is the term for an immunologically competent cell following its interaction with antigen. This response may be expressed either as lymphocyte transformation, immunological memory, cellmediated immunity, immunologic tolerance, or antibody synthesis.

Bystander effects are indirect, nonantigen-specific phenomena that result in polyclonal responses. In contrast to antigen-specific interactions, bystander effects are the result of cellular interactions that take place without antigen recognition or under conditions where antigen and receptors for antigen are not involved. Bystander effects are phenomena linked to the specific immune response in that they do not happen on their own but only in connection with a specific response. Cells not directly involved in the antigen-specific response are transstimulated or "carried along" in the response.

Innocent bystander refers to a cell that is fatally injured during an immune response specific for a different cell type.

Bystander lysis refers to tissue cell lysis that is nonspecific. The tissue cells are not the specific targets during an immune response but are killed as innocent bystanders because of their close proximity to the site where nonspecific factors are released near the actual target of the immune response. Bystander lysis may occur by the Fas/FasL pathway depending on the polarity and kinetics of FasL surface expression and downregulation after TCR engagement. This cytotoxicity pathway may give rise to bystander lysis of Fas+ target cells.

An immunologically competent cell is a lymphocyte, such as a B cell or T cell, that can recognize and respond to a specific antigen.

An immunologist is a person who makes a special study of immunology.

Immunology is that branch of biomedical science concerned with the response of the organism to immunogenic (antigenic) challenge, the recognition of self from nonself, and all the biological (in vivo), serological (in vitro), physical, and chemical aspects of immune phenomena.

Immunophysiology refers to the physiologic basis of immunologic processes.

LCAM is the abbreviation for leukocyte cell adhesion molecule.

A neural cell adhesion molecule-L1 (NCAM-L1) is a member of the Ig gene superfamily. Although originally identified in the nervous sytem, NCAM-L1 is also expressed in hematopoietic and epithelial cells. It may function in cell-cell and cell-matrix interactions. NCAM-L1 can support homophilic NCAM-L1-NCAM-L1 and integrin cell-binding. It can also bind with high affinity to the neural proteoglycan eurocan. NCAM-L1 promotes neurite outgrowth by functioning in neurite extension.

Activated leukocyte cell adhesion molecule (ALCAM/ CD166) is a member of the immunoglobulin (Ig) gene superfamily. It is expressed by activated leukocytes and lymphocyte antigen CD6. The extracellular region of ALCAM contains five Ig-like domains. The N-terminal Ig domain binds specifically to CD6. ALCAM-CD6 interactions have been implicated in T cell development and regulation of T cell function. ALCAM may also play a role in progression of human melanoma.

Ligand refers to a molecule or part of a molecule that binds or forms a complex with another molecule such as a cell surface receptor. A ligand is any molecule that a receptor recognizes.

Cell surface receptors and ligands: Activation of caspases via ligand binding to cell surface receptors involves the TNF family of receptors and ligands. These receptors contain an 80-amino acid death domain (DD) that through homophilic interactions recruits adaptor proteins to form a signaling complex on the cytosolic surface of the receptor. The signaling induced by the ligand binding to the receptor appears to involve trimerization. Based on x-ray crystallography, the trimeric ligand has three equal faces; a receptor monomer interacts at each of the three junctions formed by the three faces. Thus, each receptor polypeptide contacts two ligands. The bringing together of three receptors, thereby orienting the intracel-lular DDs, appears to be the critical feature for signaling by these receptors. The adaptor proteins recruited to the aligned receptor DDs recruit either caspases or other signaling proteins. The exact mechanism by which recruitment of caspases-8 to the DD-induced complex causes activation of caspases-8 is not clear.

Homing receptors are molecules on a cell surface that direct traffic of that cell to a precise location in other tissues or organs. For example, lymphocytes bear surface receptors that facilitate their attachment to high endothe-lial cells of postcapillary venules in lymph nodes. Adhesion molecules present on lymphocyte surfaces enable lymphocytes to recirculate and home to specific tissues.

Homing receptors bind to ligands termed addressins found on endothelial cells in affected vessels.

Adhesion molecules are extracellular matrix proteins that attract leukocytes from the circulation. For example, T and B lymphocytes possess lymph node homing receptors on their membranes that facilitate passage through high endothelial venules. Neutrophils migrate to areas of inflammation in response to endothelial leukocyte adhesion molecule-1 (ELAM-1) stimulated by TNF and IL-1 on the endothelium of vessels. B and T lymphocytes that pass through high endothelial venules have lymph node homing receptors. Adhesion molecules mediate cell adhesion to their surroundings and to neighboring cells. In the immune system, adhesion molecules are critical to most aspects of leukocyte function, including lymphocyte recirculation through lymphoid organs, leukocyte recruitment into inflammatory sites, antigen-specific recognition, and wound healing. The five principal structural families of adhesion molecules are (1) integrins, (2) immunoglobulin superfamily (IgSF) proteins, (3) selectins, (4) mucins, and (5) cadherins.

Neuropilin is a cell-surface protein that is a receptor for the collapsin/semaphorin family of neuronal guidance proteins.

Adhesion molecule assays: Cell adhesion molecules are cell-surface proteins involved in the binding of cells to each other, to endothelial cells, or to the extracellular matrix. Specific signals produced in response to wounding and infection control the expression and activation of the adhesion molecule. The interactions and responses initiated by the binding of these adhesion molecules to their receptors/ligands play important roles in the mediation of the inflammatory and immune reaction. The immediate response to a vessel wall injury is the adhesion of platelets to the injury site and the growth, by further aggregation of platelets, of a mass which tends to obstruct (often incompletely) the lumen of the damaged vessel. This platelet mass is called a hemostatic plug. The exposed basement membranes at the sites of injury are the substrate for platelet adhesion, but deeper tissue components may have a similar effect. Far from being static, the hemostatic plug has a continuous tendency to break up with new masses reformed immediately at the original site.

Integrins are a family of cell membrane glycoproteins that are heterodimers comprised of a and P chain subunits. They serve as extracellular matrix glycoprotein receptors. They identify the RGD sequence of the P subunit, which consists of the arginine-glycine-aspartic acid tripeptide that occasionally also includes serine. The RGD sequence serves as a receptor recognition signal. Extracellular matrix glycoproteins, for which integrins serve as receptors, include fibronectin, C3, and lymphocyte function-associated antigen 1 (LFA-1), among other proteins. Differences in the P chain serve as the basis for division of integrins into three categories. Each category has distinctive a chains. The P chain provides specificity. The same 95-kDa P chain is found in one category of integrins that includes LFA-1, p150,95, and complement receptor 3 (CR3). The same 130-kDa P chain is shared among VLA-1, VLA-2, VLA-3, VLA-4, VLA-5, VLA-6, and integrins found in chickens. A 110-kDa P chain is shared in common by another category that includes the vitronectin receptor and platelet glycoprotein IIb/IIIa. There are four repeats of 40 amino acid residues in the P chain extracellular domains. There are 45 amino acid residues in the P chain intracel-lular domains. The principal function of integrins is to link the cytoskeleton to extracellular ligands. They also participate in wound healing, cell migration, killing of target cells, and in phagocytosis. Leukocyte adhesion deficiency syndrome occurs when the P subunit of LFA-1 and Mac-1 is missing. VLA proteins facilitate binding of cells to collagen (VLA-1, VLA-2, and VLA-3), laminin (VLA-1, VLA-2, and VLA-6), and fibronectin (VLA-3, VLA-4, and VLA-5). The cell-to-cell contacts formed by integrins are critical for many aspects of the immune response such as antigen presentation, leukocyte-mediated cytotoxicity, and myeloid cell phagocytosis. Integrins comprise an essential part of an adhesion receptor cascade that guides leukocytes from the bloodstream across endothelium and into injured tissue in response to chemotactic signals.

Substrate adhesion molecules (SAM) are extracellular molecules that share a variety of sequence motifs with other adhesion molecules. Most prominent among these are segments similar to the type III repeats of fibronectin and immunoglobulin-like domains. In contrast to other morphoregulatory molecules, SAMs do not have to be made by the cells that bind them. SAMs can link and influence the behavior of one another. Examples include glycoproteins, collagens, and proteoglycans.

During chemokine-induced lymphocyte polarization, the cytoskeletal protein moesin is important for the redistribution of adhesion molecules to the cellular uropod.

Homing-cell adhesion molecule (H-CAM) is also known as CD44, gp90 hermes, GP85/Pgp-1, and ECMRIII. It is a lymphocyte transmembrane glycoprotein with a molecular weight of 85 to 95 kDa and is expressed in macrophages, granulocytes, fibroclasts, endothelial cells, and epithelial cells. H-CAM has been found to bind to extracellular matrix molecules such as collagen and hyaluronic acid. H-CAM is also an important signal transduction protein during lymphocyte adhesion as it has been demonstrated that phosphorylation by kinase C

and acylation by acyl-transferases enhance H-CAM's interaction with cytoskeletal proteins.

Immunoreceptor tyrosine-based activation motif (ITAM): Amino acid sequences in the intracellular portion of signal-transducing cell surface molecules that are sites of tyrosine phosphorylation and of association with tyrosine kinases and phosphotyrosine-binding proteins that participate in signal transduction. Examples include Iga, IgP, CD3 chains, and several Ig Fc receptors. Following receptor-ligand binding and phosphorylation, docking sites are formed for other molecules that participate in maintaining cell-activating signal transduction mechanisms.

ITAMs: Abbreviation for immunoreceptor tyrosine-based activation motifs.

Immunoreceptor tyrosine-based inhibition motif (ITIM): Motifs with effects that oppose those of immunoreceptor tyrosine-based activation motifs (ITAMs). These amino acids in the cytoplasmic tail of transmembrane molecules bind phosphate groups added by tyrosine kinases. This six-amino acid (isoleucine-X-tyrosine-X-X-leucine) motif is present in the cytoplasmic tails of immune system inhibitory receptors that include Fc RIIB on B lymphocytes and the killer inhibitory receptor (KIR) on the NK cells. Following receptor-ligand binding and phosphorylation on their tyrosine residue, a docking site is formed for protein tyrosine phosphatases that inhibit other signal transduction pathways, thereby negatively regulating cell activation.

Adhesion receptors (Figure 2.1) are proteins in cell membranes that facilitate the interaction of cells with

Antigen Presenting Cell

Antigen Presenting Cell

T Cell

FIGURE 2.1 Adhesion receptors.

T Cell

FIGURE 2.1 Adhesion receptors.

matrix. They play a significant role in adherence and chemoattraction in cell migration. They are divided into three groups that include the immunoglobulin super-family which contains the T cell receptor/CD3, CD4, CD8, MHC class I, MHC class II, sCD2/LFA-2, LFA-3/CD58, ICAM-1, ICAM-2, and VCAM-2. The second group of adhesion receptors is made up of the integrin family which contains LFA-1, Mac-1, p150,95, VLA-5, VLA-4/LPAM-1, LPAM-2, and LPAM-3. The third family of adhesion receptors consists of selectin molecules that include Mel-14/LAM-1, ELAM-1, and CD62.

Heparin is a glycosaminoglycan comprised of two types of disaccharide repeating units. One is comprised of D-glucosamine and D-glucuronic acid, whereas the other is comprised of D-glucosamine and L-iduronic acid. Heparin is extensively sulfated and is an anticoagulant. It unites with an antithrombin III which can unite with and block numerous coagulation factors. It is produced by mast cells and endothelial cells. It is found in the lungs, liver, skin, and gastrointestinal mucosa. Because of its anticoagulant properties, heparin is useful for treatment of thrombosis and phlebitis.

Heparan sulfate is a glycosaminoglycan that resembles heparin and is comprised of the same disaccharide repeating unit. Yet, it is a smaller molecule and less sulfated than heparin. An extracellular substance, heparan sulfate is present in the lungs, arterial walls, and on numerous cell surfaces.

Reactive oxygen intermediates (ROIs) are highly reactive compounds that include superoxide anion (O2), hydroxyl radicals (OH), and hydrogen peroxide (H2O2) that are produced in cells and tissues. Phagocytes use ROIs to form oxyhalides that injure ingested microorganisms. Release from cells may induce inflammatory responses leading to tissue injury.

4-1BB is a TNF receptor family molecule that binds specifically to 4-1BB ligand.

4-1BB ligand (4-1BBL) is a TNF family molecule that binds to 4-1BB.

Integrin family of leukocyte adhesive proteins: The

CD11/CD18 family of molecules.

Integrins, HGF/SF activation of: Integrins and growth factor receptors can share common signaling pathways. Each type of receptor can impact the signal and ultimate response of the other. An example of a growth factor that has been shown to influence members of the integrin family of cell adhesion receptors is hepatocyte growth factor/scatter factor (HGF/SF). HGF/SF is a multifunctional cytokine that promotes mitogenesis, migration, invasion, and morphogenesis. HGF/SF-dependent signaling can modulate integrin function by promoting aggregation and cell adhesion.

Morphogenic responses to HGF/SF are dependent on adhesive events. HGF/SF-induced effects occur via signaling of the MET tyrosine kinase receptor, following ligand binding. HGF/SF binding to MET leads to enhanced integrin-mediated B cell and lymphoma cell adhesion. Blocking experiments with monoclonal antibodies directed against integrin subunits indicate that a4 p1 and a5 p1 integrins on hematopoietic progenitor cells are activated by HGF/SF to induce adhesion to fibronectin. The HGF/SF-dependent signal transduction pathway can also induce ligand-binding activity in functionally inactive av P3 integrins. These effects elicited by HGF/SF highlight the importance of growth factor regulation of integrin function in both normal and tumor cells.

LFA-1, LFA-2, LFA-3: See leukocyte functional antigens.

Lymphocyte function-associated antigen-1 (LFA-1)

(Figure 2.2) is a glycoprotein comprised of a 180-kDa a chain and a 95-kDa P chain expressed on lymphocyte and phagocytic cell membranes. LFA-1's ligand is the intercellular adhesion molecule 1 (ICAM-1). It facilitates natural killer cell and cytotoxic T cell interaction with target cells. Complement receptor 3 and p150,95 share the same specificity of the 769-amino acid residue P chain found

Adhesion to Artificial Membranes T cell

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