T CELLS AND THEIR RECEPTORS

Each T cell is also committed to a given antigen and recognizes it by one of two TCRs. They may have TCR2s composed of gamma (γ) and delta (δ) chains or TCR2s composed of another heterodimer of alpha (α) and beta (β) chains. These TCR2s are associated with a group of transmembrance proteins on the CD3 molecule, which takes the antigen recognition signal inside the cell. Signal transduction via the CD3 complex is regulated by a series of kinases, which are associated with the tails of the CD3–TCR complex and regulate phosphorylation. Defi ciencies or blocks in the T-cell signaling pathways either at the cell-surface complex or at the level of the kinases may result in various forms of immunodefi ciency. Two other important antigens present on TCR2 cells recognize histocompatibility antigens and will be discussed later. The genes for TCR chains are on different chromosomes with the β and α molecules on chromosome 7, while the α and δ are on chromosome 14. As seen in Figure 1.5, the four chains are made up of a variable region and a constant region similar to those observed with the immunoglobulins. The variable regions are also numerous and joined at D and J regions by RAG1 and RAG2. This permits a diversity of antigen recognition similar to that observed with immunoglobulin, but additional somatic mutation is not involved in T cells. These similarities have led to the concept that genes for antigen-specifi c T cells evolved in the same manner as immunoglobulin from a parent gene, and both are members of a superantigen family. 

The TCR complex recognizes small peptides presented to it by the MHC class I and II and depends on the type of T cell.  Helper T cells (CD4) recognize class II antigens while suppressor cytotoxic T cells (CD8) recognize class I antigens. Because of the rather low affi nity of the reactions, recognition of processed antigen alone is not suffi cient to activate T cells. Soluble interleukins are needed to complete the picture and are generated during the antigen processing.

The genetics of antibody production

The major mucosal immunoglobulin, IgA, consists of two basic units joined by a J chain. The addition of a secretion molecule prevents its digestion by enzymes present in mucosal and intestinal secretions. Thus, IgA2 is the major IgA molecule in secretions and is quite effective in neutralizing antigens that enter via these mucosal routes. IgA1, the main IgA molecule in serum, is, however, susceptible to inactivation by serum proteases and is thus less active for defense. Its function is unclear at present. 

Two other classes are worthy of note. IgD is synthesized by antigen-sensitive B cells and is involved in the activation of these cells by antigen. IgE is produced by plasma cells and binds to specifi c IgE receptors on most cells and basophiles. This molecule (see Chapter 9) plays an extremely important role in allergic reactions and expelling intestinal parasites, which is accomplished by increasing vascular permeability and inducing chemotactive factors following mast cell degranulation. 

Given this extraordinary ability to generate large numbers of antibody molecules, how does the immune system recognize all pathogens, including past, present, and future? This diversity is achieved by the way in which the genetics of antibody production is arranged (see Figure 1.3). The light and heavy chains are carried on different chromosomes. The heavy chain genes are carried on chromosome 14. These genes are broken up into coding systems called exons with intervening segments of silent segments called entrons. The exons represent the central region of the heavy chain and a large number of V regions. Between the V and D genes are two small sets of exons called the D and J. With each single B cell, one V gene is joined to one D and J in the chromosome. The product, the VH domain, is then joined at the level of RNA processing to Cu and the B cell makes an IgM molecule. By omitting the Cu gene and joining VHDJ to a Cλ an IgG molecule is produced. This enormous versatility allows the cell to make IgM, IgD, IgG, IgA, or IgE in sequence while using the same variable regions (see Figure 1.4). The heavy chain gene recombinations are controlled by two recombination activity genes called RAG1 and RAG2. If these genes are eliminated by “knock-out” techniques in mice, profound immunodefi ciency status occurs in these animals, characterized by absent mature B and T cells. 

Thus, the diversity of antigen binding is achieved by the large number of V genes available and their combination with different D and L genes to provide different antibodies. Furthermore, the inherited set of genes may be increased by somatic mutation during multiple divisions of lymphoid cells, thereby increasing the number of antibody specifi cities to 1014, which far exceeds the number of B cells (1010) in the body. 

Once a given B cell is preselected to produce a particular VH and VL domain, all the ensuing progeny of that B cell will produce the same VH or VL domain. The sequence of events is as follows: initially, the B cell produces intracellular antigen-specific IgM, which becomes bound to the cell surface. The B cell is now antigen responsive with exposure to a given antigen. The committed B cell begins producing a certain isotype or class of immunoglobulins and begins dividing, and all the progeny will produce the identical immunoglobulin molecules. These B cells will later mature into either plasma cells or long-term memory B cells.

ANTIGENS

Antigens are any substances that are capable, under appropriate conditions, of inducing the formation of antibodies and reacting specifi cally with the antibodies so produced. They react with both T-cell recognition receptors and with antibodies. These antigenic molecules may have several antigenic determinants, called epitopes, and each epitope can bind with a specifi c antibody. Thus, a single antigen can bind to many different antibodies with different binding sites.

Some low-molecular-weight molecules called haptens are unable to evoke an immune response but can react with existing antibodies. These molecules need to be coupled to a carrier molecule to be antigenic. 

For some molecules such as drugs, the molecule needs to be conjugated to a carrier. The carrier may be a host protein. The tertiary structure of the molecule as well as the amino acid sequence is important in determining antigenicity. Certain structures such as lipids and DNA are generally poor antigens. 

Most antigens are either thymusdependent or thymus-independent antigens. Thymus-dependent antigens require T-cell participation: Most proteins and foreign red cells are examples of these molecules. Thymus-independent antigens do not require T-cell participation for antibody production. Instead, they directly stimulate specifi c B lymphocytes by crosslinking antigen receptors on the surface of B cells. These molecules produce primarily IgM and IgG2 antibodies and do not stimulate long-lasting memory cells. Most bacterial polysaccharides (found in bacterial cell walls) fall into this category. Certain polysaccharides, such as LPS (lipopolysaccharide), not only induce specifi c B-cell activation but also can act as a polyclonal B-cell stimulant.

ANTIBODY

It consists of a four-chain structure divided into two identical heavy (H) chains with a molecular weight of 25 kDa. Each chain is composed of domains of 110 amino acids and is connected in a loop by a disulfide bond between two cysteine residues in the chain. 

The amino acid N-terminal domains of the heavy and light chains include the antigen-binding site. The amino acids of these variable domains vary between different antibody molecules and are thus known as the variable (V) regions. Most of these differences reside in the hypervariable areas of the molecule and are usually only six to ten amino acid residues in length. When the hypervariable regions in each chain come together along with the counterparts on the other pair of H and L chains, they form the antigen-binding site. This part of the molecule is unique to the molecule and is known as the idiotype determinant. In any individual, 106 to 107 different antibody molecules can be composed from 103 different heavy and light chains of the variable regions. The part of the molecule next to the V region is called the constant (C) region made up of one domain in the light chain (C1) and three or four in a heavy chain (CH). A Cl chain may consist of either two kappa (κ) or two lambda (λ) chains but never one of each. Of all the human antibody molecules, approximately 60%, are κ chains and 40% contain λ chains. Although there are no known differences in the functional properties of κ and λ chains, there are several different types of the CH domain. These differences are refl ected in determining the class (isotype) of the antibody and thereby the physiological function of a particular antibody molecule.

The IgM molecule is the oldest class of immunoglobulins, and it is a large molecule consisting of fi ve basic units held together by a J chain. The major role IgM plays is the intravascular neutralization of organisms, especially viruses. The reason for this important physiological role is that it contains fi ve complement-binding sites, resulting in excellent complement activation. This activation permits the segment removal of antigen–antibody complement complexes via complement receptors on phagocytic cells or complement-mediated lysis of the organism. However, in contrast to the IgG molecule, it has relatively low affi nity binding to the antigen in question. Second, because of its size, it does not usually penetrate into tissues. In contrast, IgG is a smaller molecule that penetrates easily into tissues. There are four major classes of IgG: IgG1 and IgG3 activate complement effi ciently and clear most protein antigens, including the removal of microorganisms by phagocytic cells. 

In contrast, IgG2 and IgG4 react mostly with carbohydrate antigens and are relatively poor opsonins. This is the only molecule that crosses the placenta to provide immune protection to the neonate.

Basic Components of the Immune System

It is generally believed that the immune system evolved as the host’s defense against infectious agents, and it is well known that patients with deficiencies in the immune system generally succumb to these infectious diseases

An immune response may be conveniently divided into two parts:

(1) a specifi c response to a given antigen and

(2) a more nonspecifi c augmentation to that response.

An important feature of the specific response is that there is a quicker response to the antigen during a second exposure to that antigen. It is the memory of the initial response that provides the booster effect. For convenience, the specific immune response may be divided into two parts:

(1) the humoral response and

(2) the cellular response to a given antigen. As we shall see, however, both responses are mediated through the lymphocyte. Humoral responses are antibodies produced in response to a given antigen, and these antibodies are proteins, have similar structures, and can be divided into various classes of immunoglobulins. Cellular responses are established by cells and can only be transferred by cells.

Up to the 1940s the general dogma held that only antibodies were involved in the immune response. Dr. Merrill Chase, who began his experiments in a laboratory devoted primarily to the humoral response, clearly showed in a series of elegant experiments that immunity was not just humoral but that a cellular response by the lymphocytes could also produce immunity. Some of the best examples of the power of cellular immunity may be found in the many experiments in which transfer of cells can induce autoimmune disease in animals and humans as well as rejection of an organ graft in both animals and humans by cells.

 The separation of human and cellular immunity was further advanced by the study of immuno      deficient humans and animals. For example, thymectomized or congenitally athymic animals as well as humans cannot carry out graft rejection, yet they are capable of producing some antibody responses. The reverse is also true. Children (and animals) who have an immune defi cit in the humoral response do not make antibodies but can reject grafts and appear to handle viral, fungal, and some bacterial infections quite well. An extraordinary fi nding by Good and colleagues in studying the cloacal lymphoid organ in chickens revealed that, with removal of the bursa Fabricius, these animals lost their ability to produce antibodies and yet retained the ability to reject grafts.

Out of these and many other contributions, a clearer picture of the division of efforts by lymphocytes begins to emerge. Since cellular immune responses require an intact thymus, cellular immune responses are mediated through the T lymphocytes (thymus), while antibody-producing cells, which are dependent on the bone marrow (the bursa equivalent), are known as B (bursa) cells.

Several types of molecules play a vital role in the immune response, and we will deal with each in detail. Antigens, both foreign and self, are substances that may or may not provoke an immune response. Both T cells and B cells have receptors that recognize these antigens. In the case of B cells, antibodies on the surface are a major source (but not the only one) of antigen recognition, and once activated, they differentiate into plasma cells that produce large quantities of antibodies that are secreted into blood and body fluids to block the harmful effects of the antigen.

T cells have similar receptors known as T-cell receptors (TCR), and in the context of the major histocompatibility complex (MHC) molecules provide a means of self-recognition and T-lymphocyte effector functions. Often these effector functions are carried out by messages transmitted between these cells. These soluble messengers are called interleukins or cytokines.