Immunobiology of the Host Tumor Relationship | Kickoff

Immunobiology of the Host Tumor Relationship

1 Jun

For more than a century it has been evident that the various tissues of an organism are structur- ally different at both the morphological and molecular levels. In terms of immunobiology, this is reflected in the fact that tissues are antigenically distinct—that is, each tissue possesses unique macromolecules  capable of stimulating a specific immune response within a foreign host. This fact has certainly been obvious to the biochemist, as each tissue has a relatively unique enzy- matic content and thus would be expected to be antigenically distinct. An antigen may be de- fined as a substance capable of eliciting an immune response when the immune system of the organism is exposed to the antigen. An antibody is a circulating globulin specifically reactive with the antigen responsible for its production or with a comparable (cross-reactive)  antigenic species. Antigens that are relatively  specific to the tissue in which they are found have been termed tissue-specific antigens (Milgrom, 1966) or, in another context, differentiation antigens. A differentiation  antigen is operationally  defined as a determinant, detected in immunological tests (usually specific antibody-containing  sera), that is limited in its pattern of expression  to specific tissues (cf. Old et al., 1962; Old and Stockert, 1977). Lymphocyte populations express particular differentiation  antigens on their surfaces. When a number of monoclonal antibodies (Chapter 14) recognize or react with the same differentiation  antigen, these antibodies define clusters of differentiation, or CD. The nomenclature for some of these CD antigens is considered below.

ONTOGENY  AND PHYLOGENY  OF THE IMMUNE  RESPONSE

Many invertebrates exhibit cellular recognition and aggressive reaction against foreign cells and antigenic structures. Such organisms also exhibit innate constitutive mechanisms, such as cellu- lar engulfment or phagocytosis of foreign materials and the formation of bactericidal substances. Some relatively  primitive vertebrates  such as sharks have circulating serum immunoglobulins that have considerable structural similarity to the same types of molecules in mammals (March- alonis and Schluter, 1994). The evolution of the vertebrate immune system has been in the direc- tion of greater  diversity  and complexity  in relation  to the recognition  of “non-self,”  the specificity of the immune response, and the structures of the molecules involved (Du Pasquier,

1992). The immune response of vertebrates exhibits the highest degree of specificity in that all vertebrates are capable of generating an immunological response upon stimulation by an antigen (cf. Roitt, 1977). The immune response in vertebrates initially involves innate immunity, which is a rapid and nonspecific, more primitive response usually occurring on the initial exposure of the immune system to foreign substances.  Adaptive  or anticipatory  immunity  (Klein, 1997),

which is characteristic of higher vertebrates, involves specificity in the response by the forma- tion of specific immune globulins (antibodies) and cells that react specifically with certain anti- gens. Innate or nonanticipatory  immunity  is more characteristic  of invertebrates  (see above), many of which have little if any adaptive immunity. However, vertebrates also possess innate immunity, which depends on proteins directly encoded in the germline that identify potentially noxious substances  such as bacterial  surface proteins,  lipopolysaccharides,  and protozoan  as well as multicellular  parasitic organisms (Fearon and Locksley, 1996; Hoffmann et al., 1999). Innate immunity  is mediated  by several cell types including  macrophages  and natural killer cells, circulating proteins such as the complement system, and a number of antimicrobial pep- tides produced by secretory cells, especially of the gut (cf. Abbas and Janeway, 2000). It is also apparent that unmethylated DNA of such parasitic organisms may play a significant role in in- nate immunity (Krieg, 2000). However, it is the adaptive immune response that primarily con- cerns us in this chapter.

The cellular interrelations  of the immune system during embryonic  development  in the vertebrate follow similar pathways in a number of vertebrate species. The first systematic study of the developmental biology of the immune system was undertaken in the chicken. Stem cells from the yolk sac of the early embryo and the primitive bone marrow appeared to develop in this species along two general lines, one of which populated the thymus and the other a structure in the intestine of the bird known as the bursa. From this schema, cells that populated the thymus came to be known as T cells, while cells developing from the bursa were termed B cell. In mam- mals, that do not possess the anatomical structure known as the bursa, it has become apparent that several other tissues, predominantly  the bone marrow, appear to be the equivalent  of the bursa. Figure 19.1 shows a scheme for the development and migration of lymphocytes in fetal life and to some extent continuing into adult life. Stem cells derived from the yolk sac in the

Figure 19.1 Development  and migration  of lymphocytes.  Stem cells originating  in the yolk sac, fetal liver, or bone marrow are disseminated  in the bloodstream,  where some migrate to the thymus, ultimately differentiating  into T lymphocytes,  while others differentiate  within the bone marrow to produce B cells. Such T and B cells eventually circulate in blood and lymph and colonize the appropriate areas of lymphoid tissues. (From Miller, 1992, with permission of the author and publishers.)

embryo, as well as fetal liver and bone marrow—the latter in both the embryo and the adult— circulate and populate the thymus in the case of T cells and the follicles and medullary cords of the lymphocyte in the case of B cells (Miller, 1992). Within the thymus, T cells further differen- tiate into several varieties expressing CD (see above) antigens, specifically CD4 and CD8, each having specific functions, as discussed below (Weissman, 1994). In addition, later in life, T cell differentiation occurs extensively in extrathymic tissues such as liver, intestine, and omentum, as the thymus itself tends to atrophy with age (Abo, 1993).

MEDIATION  OF THE IMMUNE  RESPONSE

Differentiation  of the lymphocyte  population  also results in the differentiation  of function. T cells generally are involved in the mediation of responses that directly involve the interaction of the T cell with cells bearing antigenic components. B cells, in contrast, when activated directly or indirectly by a specific antigen, produce antibodies, which in turn circulate in the organism, reacting with antigen occurring at a distance from the cell and producing the antibody. This lat- ter response, characteristic of B cells, is termed the humoral immune response. Each is consid- ered separately below.

The Humoral Immune Response

Humoral immunity  is the result of the formation  of specific antibodies  reactive with specific antigens and the ultimate consequences of such a reaction either by eliminating foreign antigens or in producing abnormal reactions within the host itself (autoantibodies).  In order to consider the humoral immune response, however, it becomes necessary to understand the principal mo- lecular species involved in this response.

Structure and Function of Antibodies

Antibodies  are the proteins that form the basis for the humoral response to foreign antigens. Their structure has been known for some years and may be seen in schematic form in Figure 19.2. The upper portion of the figure gives a schematic structure of the basic immunoglobulin monomer (IgG). Each such structure consists of two identical heavy (H) chains and two identical light (L) chains. Segments of each of the molecules contain intrachain disulfide bonds within domains and homology regions. The domains marked VH and VL exhibit great variation in their amino acid sequence, especially in the hypervariable (HV) regions. Interspersed between the hy-pervariable regions are the less variable framework (FW) residues. The peptide chains are con- nected to each other by disulfide  bonds as shown. The “hinge” region is characterized  by a sequence of three prolines, which serve to give the molecule a specific confirmation in that re- gion (Putnam, 1969). The constant (C) regions of the heavy and light chains are shaded with diagonal lines. There are three domains, 1, 2, and 3, for the constant region of the heavy chain. The structures of the constant regions of the heavy chain differ among the five different types of immunoglobulins  as discussed below. The Fab and Fc fragments may be produced by treatment of the molecule with the enzyme, papain, which cleaves the structures near the hinge region, leaving two Fab molecules and a single Fc fragment. The Fc region contains carbohydrate as well as functional regions as shown in the figure.

The light chains consist of two classes or isotypes,  κ and λ,  for all immunoglobulin classes. The immunoglobulin  classes are shown in schematic form as units or multiples of the basic immunoglobulin  monomer in the figure. The class is determined by the type of the con-

Figure 19.2 The structure of immunoglobulins.  The upper portion of the figure details the structure of an individual antibody molecule. The different parts of the heavy chain V region are indicated on the right, and the segments of the gene that code for these nucleotides are shown in parentheses. The interchain disul- fide bonds are shown as –S-S–, whereas the amino (NH2) and carboxyl (COOH) ends of the molecule are as designated.  (Adapted  and modified  from Teillaud  et al., 1983,  with permission  of the authors  and publisher.)

The diagrams in the lower portion of the figure are the comparative structures of the several immu- noglobulins. IgG is the most commonly found immunoglobulin,  while IgM is the immunoglobulin  charac- teristically  formed as an immediate  response to the administration  of a new foreign antigen. The overall structure of the IgD, IgG, and IgE is comparable to the upper figure, with the individual peptide chains and interchain disulfides shown as single lines. The IgA and IgM molecules are polymers of this monomeric structure  held together  by a joining piece (J) and, in the case of IgA, an additional  piece, the secretory component  (SC), which seems to be necessary  to allow IgA entrance  into mucosal  secretions.  (Lower portion  of the figure modified  from Goldman  and Goldman,  1984, with permission  of the authors  and publisher.)

stant regions (C) of the heavy chains (µ, δ, γ, α, and ε) corresponding respectively to IgM, IgD, IgG, IgA, and IgE. Any individual immunoglobulin molecule possesses only one type of heavy chain and one type of light chain.

In the case of the multimeric IgA and IgM immunoglobulins, the individual monomers are covalently interactive through a separate polypeptide, termed the J chain, whose synthesis oc- curs within B cells (cf. Mestecky et al., 1974). In addition, IgA molecules may be secreted into saliva, milk, sweat, and other body secretions. The secreted dimeric IgA molecule contains a separate glycoprotein termed the secretory component (SC), which it obtains during the transcy- tosis of the IgA from the basal to the luminal surface of the secretory  cell through which it passes. Figure 19.3 is a schematic representation of the uptake of both IgA and IgM by secretory mucosal cells following the interaction of these immunoglobulins secreted by plasma cells in the immediate adjacent tissue, termed the lamina propria. SC is synthesized as an inherent plasma

Figure 19.3 Steps in the production of human secretory IgA (right, top) and secretory IgM (right, bot- tom) via SC-mediated  epithelial  transport  of J chain–containing  polymeric  IgA (IgA-J)  and pentameric IgM (IgM-J) secreted by local plasma cells (left). Transmembrane  SC is synthesized in the rough endoplas- mic reticulum  (RER) of secretory  epithelial  cell and matures by terminal  glycosylation  (●) in the Golgi complex. After sorting through the trans-Golgi network (TGN), SC is phosphorylated  (  ) and expressed as polymeric Ig (pIg) receptor at the basolateral plasma membrane. Endocytosis of noncovalently ligand-com- plexed and unoccupied pIg receptor is followed by transcytosis to apical endosomes and finally by cleavage and release of secrtory Ig molecules with bound SC as well as excess of free SC at the luminal cell face. During the external  translocation,  covalent  stabilization  of the IgA-SC  complexes  regularly  occurs (two disulphide bridges indicated in secretory IgA), whereas free SC in the secretion apparently serves to stabi- lize the noncovalent  IgM-SC  complexes  (dynamic  equilibrium  indicated  for secretory  IgM).  (From Brandtzaeg, 1995, with permission of the author and publisher.)

membrane protein, which also acts as a receptor for these immunoglobulins.  Following interac- tion, the IgA or IgM complexed with the plasma membrane receptor FC is transcytosed through the cytoplasm of the cell to be secreted through its luminal surface. Either prior to or at the time of secretion, the SC molecule loses its membrane interactive component (Solari and Kraehen- buhl, 1985). In this way the secretory component has been termed the sacrificial receptor, since the molecule is utilized only once, partially cleaved, and secreted in association with the immu- noglobulin. The association of the glycoprotein SC with the immunoglobulin protects the mole- cules against  proteolytic  attack  (Brandtzaeg,  1985).  These  mucosal  immunoglobulins  are considered the first line of defense against infectious agents coming in contact with various mu- cous membranes (Mestecky, 1987).

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