The third line of defense in the human body is adaptive (acquired) immunity, often called the immune response or immunity.¹ Once external barriers have been compromised and inflammation (see Chapter 7) has been activated, the adaptive immune response is called into action. The molecules and cells of the immune response are closely integrated with those of the innate response. Both systems are essential for complete protection against infectious disease: inflammation is relatively rapid, nonspecific, and short-lived, whereas adaptive immunity is slower acting, specific, and very long-lived. Thus, inflammation is the “first responder” that contains the initial injury and slows spread of infection, whereas adaptive immunity slowly augments the initial defenses against infection and provides long-term security against reinfection. The collaborative and beneficial nature of inflammation and adaptive immunity can, on occasion, fail. Chapter 9 discusses these medically relevant aberrations in both inflammation and immunity, including allergies, diseases that involve unwanted immunologic destruction of healthy tissue, and diseases that are caused by a deficiency in the normal immune or inflammatory responses. Chapter 10 presents an overview of infection and Chapter 11 discusses the connection between stress and disease and the interrelatedness of the immune, nervous, and endocrine systems.

General Characteristics of Adaptive Immunity

The immune system of the normal adult is continually challenged by a spectrum of substances that it may recognize as foreign, or “non-self.” These substances, called foreign antigens, are often associated with pathogens such as viruses, bacteria, fungi, or parasites, although they are also found on noninfectious environmental agents such as pollens, foods, and bee venom, and still others are associated with clinically derived drugs, vaccines, transfusions, and transplanted tissues (Table 8-1). Unlike inflammation, which is nonspecifically activated by damage to cells as well as by the action of pathogenic microorganisms, the immune response is primarily designed to afford long-term specific protection (i.e., immunity) against particular invading microorganisms; that is, it has a “memory” function. The products of the adaptive immune response include a type of serum protein—immunoglobulins, or antibodies—and a type of blood cell—lymphocytes (Figure 8-1).

TABLE 8-1

CLINICAL USE OF ANTIGEN OR ANTIBODY

ANTIGEN SOURCE	PROTECTION: COMBAT ACTIVE DISEASE	PROTECTION: VACCINATION	DIAGNOSIS	THERAPY
Infectious agents	Neutralize or destroy pathogenic microorganisms (e.g., antibody response against viral infections)	Induce safe and protective immune response (e.g., recommended childhood vaccines)	Measure circulating antigen from infectious agent or antibody (e.g., diagnosis of hepatitis B infection)	Passive treatment with antibody to treat or prevent infection (e.g., administration of antibody against hepatitis A)
Cancers	Prevent tumor growth or spread (e.g., immune surveillance to prevent early cancers)	Prevent cancer growth or spread (e.g., vaccination with cancer antigens)	Measure circulating antigen (e.g., circulating PSA for diagnosis of prostate cancer)	Immunotherapy (e.g., treatment of cancer with antibodies against cancer antigens)
Environmental substances	Prevent entrance into body (e.g., secretory IgA limits systemic exposure to potential allergens)	No clear example	Measure circulating antigen or antibody (e.g., diagnosis of allergy by measuring circulating IgE)	Immunotherapy (e.g., administration of antigen for desensitization of individuals with severe allergies)
Self-antigens	Immune system tolerance to self-antigens, which may be altered by an infectious agent leading to autoimmune disease (see Chapter 9)	Some cases of vaccination alter tolerance to self-antigens leading to autoimmune disease	Measure circulating antibody against self-antigen for diagnosis of autoimmune disease (see Chapter 9)	No clear example

PSA, Prostate-specific antigen.

Specificity and memory are the primary characteristics that differentiate the immune response from other protective mechanisms. This chapter first discusses the nature of that specificity by defining the various types of antigens that may be seen by the immune system, the ways in which they are recognized by antibodies and lymphocytes, and the specific intercellular recognition molecules that are necessary for effective immune responses. After the recognition molecules are defined, the development of the immune response is discussed. An immune response can be divided into two phases (Figure 8-2). Before birth, humans produce a large population of T lymphocytes (T cells) and B lymphocytes (B cells) that have the capacity to recognize almost any foreign antigen found in the environment. Each individual T or B cell, however, specifically recognizes only one particular antigen, but the sum of the population of lymphocyte specificities may represent millions of foreign antigens. This process is called the generation of clonal diversity and occurs in specialized (primary) lymphoid organs—the thymus for T cells and the bone marrow for B cells. While passing through these tissues, the lymphocytes mature and undergo changes that commit them to becoming either B or T cells. Lymphocytes are released from these organs into the circulation as immature cells that have the capacity to react with antigen (immunocompetent). These cells migrate to other (secondary) lymphoid organs in the body in preparation for exposure to antigen (Figure 8-3).

The lymphocytes remain dormant until antigen initiates the second phase of the immune response, clonal selection. This process involves a complex interaction among cells. To initiate an effective immune response, most antigens must be “processed” because they cannot react directly with cells of the immune system but must be shown or “presented” to the immune cells in a very specific manner. This is the job of antigen-processing (antigen-presenting) cells, generally referred to as APCs. In general, three groups of cells must cooperate to make an immune response. The APCs interact with subpopulations of T cells that facilitate immune responses (T-helper cells), and immunocompetent B or T cells, resulting in differentiation of B cells into active antibody-producing cells (plasma cells) and T cells into effector cells, such as T-cytotoxic cells. The last portion of this chapter discusses how these products (antibody and T cells) protect against infection, including how they interact with components of the inflammatory process.

Humoral and Cell-Mediated Immunity

The immune response has two arms: antibody and T cells, both of which protect against infection.² Antibody circulates in the blood and binds to antigens on infectious agents. This interaction can result in direct inactivation of the microorganism or activation of a variety of inflammatory mediators (e.g., complement, phagocytes) that will destroy the pathogen. Antibody is primarily responsible for protection against many bacteria and viruses. This arm of the immune response is termed humoral immunity.

T cells also undergo differentiation during an immune response and develop into several subpopulations of cells that react directly with antigen on the surface of infectious agents. Some develop into T cells that can stimulate the activities of other leukocytes via cell-to-cell contact or through the secretion of cytokines. Others develop into T-cytotoxic cells (Tc cells) that attack and kill targets directly. Targets for Tc cells include cells infected by a variety of viruses, as well as cells that have become cancerous. This arm of the immune response is termed cellular immunity. As discussed in this chapter, the humoral and cellular immune responses are interdependent at many levels. In the end, the success of an acquired immune response depends on the functions of both the humoral and the cellular responses, as well as the appropriate interactions between them. Additionally, both arms produce specialized subpopulations of memory cells that are long-lived and capable of “remembering” the antigen and responding more rapidly and efficiently on subsequent exposure to the same antigen. On reexposure, memory cells do not require much further differentiation and will therefore rapidly become new plasma cells or effector T cells.

Active vs. Passive Immunity

Adaptive immunity can be either active or passive, depending on whether the antibodies or T cells are produced by the individual in response to antigen or are administered directly. Active acquired immunity (active immunity) is produced by an individual either after natural exposure to an antigen or after immunization, whereas passive acquired immunity (passive immunity) does not involve the host’s immune response at all. Rather, passive immunity occurs when preformed antibodies or T lymphocytes are transferred from a donor to the recipient. This can occur naturally, as in the passage of maternal antibodies across the placenta to the fetus, or artificially, as in a clinic using immunotherapy for a specific disease. Unvaccinated individuals who are exposed to particular infectious agents (e.g., hepatitis A virus, rabies virus) often will be given immunoglobulins that are prepared from individuals who already have antibodies against that particular pathogen. Whereas active acquired immunity is long-lived, passive immunity is only temporary because the donor’s antibodies or T cells are eventually destroyed.

Recognition and Response

The foundation of any successful immune response is the specific recognition of antigen by antibody or receptors on the surface of B or T cells, followed by a set of complex intercellular communications among a variety of antigen-presenting cells and lymphocytes. To fully understand the immune response, it is necessary to initially understand the basis for that recognition. Many of the molecules discussed in this chapter are part of a nomenclature that uses the prefix “CD” followed by a number (e.g., CD1 or CD2) (Table 8-2). The definition of the CD (cluster of differentiation) format has changed over time. It was originally used to describe proteins found on the surface of lymphocytes. Currently, CD is the accepted format for labeling a very large family of proteins found on the surface of many cells. Many have alternative names, which may be used in this chapter. The list of identified molecules is constantly increasing (the number of molecules with a CD designation is probably in excess of 250). In a similar fashion, the list of known cytokines is continually growing, with more than 100 having been identified so far. A large number of CD molecules and cytokines contribute to the acquired immune response. We have attempted to focus on a small number of highly important examples to illustrate the immensely complicated, but highly effective, interactions that take place to produce a protective immune response.

TABLE 8-2

SELECT CD MOLECULES AND THEIR FUNCTIONS

CD MOLECULES	PRIMARY LOCATION	FUNCTIONS
CD1	APCs	Presents lipid antigens
CD2	All T cells, NK cells	T-cell marker; adhesion molecule that binds to CD58 (LFA-3) and provides a co-stimulatory signal
CD3	All T cells	Associated with TCR and provides intracellular signaling
CD4	Th cells	Binds to MHC class II as co-receptor with the TCR
CD8	Tc cells	Binds to MHC class I as co-receptor with the TCR
CD19	B cells	Complexes with CD21 to form a co-receptor for B cells
CD20	B cells	Major regulator of B-cell function
CD21	B cells	Receptor for complement that complexes with CD19 to form a co-receptor for B cells
CD25	Activated T cells	α-Chain of IL-2 receptor
CD28	T cells	Adhesion molecule that binds to CD80 to provide co-stimulatory signal for Tc cells
CD40	B cells, macrophages	Adhesion molecule that binds to CD154 to provide co-stimulatory signal for B cells
CD45	All lymphocytes	Has multiple types; augments antigen signal
CD58 (LFA-3)	Most cells	Adhesion molecule that binds to CD2 to provide a co-stimulatory signal
CD80 (B7-1)	APCs	Adhesion molecule that binds to CD28 to provide a co-stimulatory signal
CD154 (CD40L)	Th2 cells	Adhesion molecule that binds to CD40 to provide a co-stimulatory signal

APCs, Antigen-presenting cells; IL, interleukin; MHC, major histocompatibility complex; NK, natural killer; Tc, cytotoxic cell; TCR, T-cell receptor; Th, helper T cell.

Antigens and Immunogens

An antigen is a molecule that can react with antibodies or antigen receptors on B and T cells. Most, but not all, antigens are also immunogens. An antigen that is immunogenic will induce an immune response resulting in the production of antibodies or functional T cells. Although the terms antigen and immunogen commonly are used as synonyms, there are some differences between the two, so a substance may be antigenic yet not be immunogenic.

To function as an antigen, at least a portion of a molecule’s chemical structure must be recognized by and bound to an antibody and/or to specific receptors on a lymphocyte. The precise portion of the antigen that is configured for recognition and binding is called its antigenic determinant, or epitope. The matching portion on the antibody or the lymphocyte receptor is sometimes referred to as the antigen-binding site, or paratope. The size of an antigenic determinant is relatively small, perhaps just a few amino acids or carbohydrate residues on the surface of a large molecule (Figure 8-4). Therefore, macromolecules (e.g., proteins, polysaccharides, nucleic acids) usually contain multiple and diverse antigenic determinants, and the immune response against the macromolecule will usually consist of a mixture of specific antibodies against several of these determinants.

Certain criteria influence the degree to which an antigen is immunogenic. These include: (1) being foreign to the host, (2) being appropriate in size, (3) having an adequate chemical complexity, and (4) being present in a sufficient quantity.

Foremost among the criteria for immunogenicity is the antigen’s foreignness. A self-antigen that fulfills all these criteria except foreignness does not normally elicit an immune response. Thus most individuals are tolerant to their own antigens. The immune system has an exquisite ability to distinguish self (self-antigens) from non-self (foreign antigens). Tolerance, once thought to be a state of nonresponsiveness in which the immune system passively allowed self-antigens to persist, is now known to have a variety of mechanisms. In some cases, a state of central tolerance exists, in which lymphocytes with receptors against self-antigens have been eliminated. In other cases, tolerance is peripheral tolerance and part of the adaptive immune response. Rather than merely tolerating some self-antigens, the immune system actively prevents their recognition by lymphocytes and antibodies. The response to self-antigens may be actively regulated by specialized T lymphocytes called T-regulatory (Treg) cells (see Figure 8-2). Some pathogens have a survival advantage by their capacity to mimic self-antigens and avoid inducing an immune response.

Molecular size also contributes to an antigen’s immunogenicity. In general, large molecules (those bigger than 10,000 daltons), such as proteins, polysaccharides, and nucleic acids, are most immunogenic. Low-molecular-weight molecules, such as amino acids, monosaccharides, fatty acids, and the purine and pyrimidine bases, tend to be unable to induce an immune response. Many small molecules can function as haptens: antigens that are too small to be immunogens by themselves but become immunogenic in combination with larger molecules that function as carriers for the hapten. For example, the antigens of penicillin and poison ivy are haptens, but they initiate allergic responses only after binding to large-molecular-weight proteins in the allergic individual’s blood or skin. Antigens that induce an allergic response are also called allergens.

Chemical complexity affects immunogenicity. The best immunogens contain a diversity of chemically different components. For instance, a large synthetic protein consisting only of alanine amino acids would not be very immunogenic, despite its size and foreignness. However, if other amino acids, such as tyrosine, tryptophan, or phenylalanine, were inserted into the structure, the degree of immunogenicity would increase greatly.

Finally, antigens that are present in extremely small or large quantities may be unable to elicit an immune response and therefore by definition are also nonimmunogenic. In many cases, high or low extremes of antigen quantities may induce a state of tolerance rather than immunity.

Even if an antigen fulfills all these criteria, the quality and intensity of the immune response may still be affected by a variety of additional factors. For example, the route and vehicle of antigenic entry or administration are critical to the immunogenicity of some antigens. This has important clinical implications. The most common routes for clinical administration of antigen, such as vaccines, are intravenous, intraperitoneal, subcutaneous, intranasal, and oral. Each route preferentially stimulates a different set of lymphocyte-containing (lymphoid) tissues and therefore results in the induction of different types of cell-mediated or humoral immune responses. For some vaccines, the route may affect the protectiveness of the immune response so that the individual is protected if immunized by one route, but may remain susceptible to infection if administered through a different route. Immunogenicity of an antigen also may be altered by being delivered along with substances that stimulate the immune response; these substances are known as adjuvants. Finally, the genetic makeup of a host can play a critical role in the immune system’s ability to respond to many antigens; some individuals appear to be unable to respond to immunization with a particular antigen, whereas they respond well to other antigens. For instance, a small percentage of the population fails to produce a measurable immune response to the most common vaccines, despite multiple injections. Many other factors can modulate the immune response. These include the individual’s age, nutritional status, genetic background, and reproductive status, as well as exposure to traumatic injury, concurrent disease, or the use of immunosuppressive medications.

Molecules That Recognize Antigen

Antigen is directly recognized by three molecules: circulating antibody and antigen receptors on the surface of B lymphocytes (B-cell receptor, or BCR) and T lymphocytes (T-cell receptor, or TCR) (Figure 8-5).

Antibody

An antibody, or immunoglobulin, is a serum glycoprotein produced by plasma cells in response to a challenge by an immunogen. The term immunoglobulin is used to denote all molecules that are known to have specificity for antigen, whereas the term antibody is generally used to denote one particular set of immunoglobulins with specificity against a known antigen. There are five molecular classes of immunoglobulins (IgG, IgA, IgM, IgE, and IgD) that are characterized by antigenic, structural, and functional differences (Figure 8-6). Within two of the immunoglobulin classes are several distinct subclasses including four subclasses of IgG and two subclasses of IgA.

Classes

IgG is the most abundant class of immunoglobulins; they constitute 80% to 85% of those circulating in the body and account for most of the protective activity against infections (Tables 8-3 and 8-4). As a result of selective transport across the placenta, maternal IgG is also the major class of antibody found in blood of the fetus and newborn. Four subclasses of IgG have been described: IgG1, IgG2, IgG3, and IgG4.

TABLE 8-3

PHYSICOCHEMICAL PROPERTIES OF IMMUNOGLOBULINS

CLASS	SUBCLASS	HEAVY CHAIN	MOLECULAR WEIGHT (DALTONS)	ADULT SERUM LEVELS (mg/dl)
IgG	IgG1	(γ1)	146,000	800-900
	IgG2	(γ2)	146,000	280-300
	IgG3	(γ3)	165,000	90-100
	IgG4	(γ4)	146,000	50
IgM	IgM	(μ)	970,000	120-150
IgA	IgA1	(α1)	160,000	280-300
	IgA2	(α2)		50
	sIgA	(α1, α2)	385,000	5
IgD	IgD	(δ)	184,000	3
IgE	IgE	(ε)	190,000	0.03

Ig, Immunoglobulin; s, secretory.

TABLE 8-4

BIOLOGIC PROPERTIES OF IMMUNOGLOBULINS

SUBCLASS	COMPLEMENT ACTIVATION		BINDING TO FC RECEPTORS ON				PLACENTAL TRANSFER	PRESENCE IN SECRETIONS	INDUCTION OF AGGLUTINATION
	CLASSICAL	ALTERNATIVE	MACROPHAGES	PMNs	MAST CELLS	PLATELETS
IgG1	++	−	+	+	−	+	+++	±	+
IgG2	+	−	−	−	−	+	+	±	+
IgG3	+++	−	+	+	−	+	+++	±	+
IgG4	−	−	−	±	+	+	++	±
IgM	++++	−	−	−	−	−	−	+	+++
IgA1	−	+	−	±	−	−	−	+	−
IgA2	−	+	−	±	−	−	−	+	−
sIgA	−	−	−	−	−	−	−	++++	−
IgD	−	±	−	−	−	−	−	−	−
IgE	−	±	?	−	+++	−	−	+	−

Fc, Crystalline fragment; Ig, immunoglobulin; PMN, polymorphonuclear neutrophil; sIgA, secretory immunoglobulin A; −, lack of activity; +, relative degree of activity.

IgA can be divided into two subclasses, IgA1 and IgA2. IgA1 molecules are found predominantly in the blood, whereas IgA2 is the predominant class of antibody found in normal body secretions. The IgA molecules found in bodily secretions are dimers anchored together through a J chain and “secretory piece.” This secretory piece is attached to the IgAs inside mucosal epithelial cells and may function to protect these immunoglobulins against degradation by enzymes also found in the secretions.

IgM is the largest of the immunoglobulins and usually exists as a pentamer that is stabilized by a J (joining) chain. It is the first antibody produced during the initial, or primary, response to antigen. IgM is synthesized early in neonatal life, and its synthesis may be increased as a response to infection in utero.

Information on the role of IgD is limited. This class of immunoglobulins is found in very low concentrations in the blood, where they do not appear to have a known function. IgD is located primarily on the surface of developing B lymphocytes, where they function as one type of B-cell antigen receptor.

IgE is the least concentrated of any of the immunoglobulin classes in the circulation. It appears to have very specialized functions as a mediator of many common allergic responses (see Chapter 9) and in the defense against parasitic infections.

Molecular Structure

Structural analysis of immunoglobulins began with Porter’s early studies on the effects of the enzyme papain on IgG.³ The nomenclature of antibody structure originated from that work. Limited digestion with the enzyme papain cleaved IgG into three fragments, two of which were identical. The two identical fragments were found to retain the ability to bind antigen, and each was termed an antigen-binding fragment (Fab).⁴ The third fragment crystallized when separated from the Fab portions and was termed the crystalline fragment (Fc) (see Figure 8-5).

What Porter learned about the structure of IgG still applies not only to this class of immunoglobulins but also to each of the other classes. The Fab portions of an immunoglobulin contain the recognition sites (receptors) for antigenic determinants and confer the molecule’s specificity toward a particular antigen. The Fc portion is responsible for most of the biologic functions of antibodies, including activation of the complement cascade and opsonization by binding to Fc receptors on the surface of the cells of the innate immune system.

The basic structure of the antibody molecule consists of four polypeptide chains—two identical light (L) chains and two identical heavy (H) chains (see Figure 8-5). Within the same molecule, the two heavy chains are identical and the two light chains are identical. The class of antibody is determined by which heavy chain is used: gamma (IgG), mu (IgM), alpha (IgA), epsilon (IgE), or delta (IgD). The light chains of an antibody molecule are of either the kappa (κ) or the lambda (λ) type. The light and heavy chains are held together by two major forces: noncovalent bonds and disulfide linkages. A set of disulfide linkages between the heavy chains occurs in the hinge region and in some instances lends a degree of molecular flexibility at that site so that the Fab regions can move.

Light and heavy chains are further subdivided into constant (C) and variable (V) regions. The constant regions have relatively stable amino acid sequences within a particular immunoglobulin class or subclass. Thus the amino acid sequence of the constant region of one IgG1 should be almost identical with the sequence of the same region of another IgG1, even if they react with different antigens. Conversely, among different antibodies, the sequences of the variable regions are characterized by a large number of amino acid differences. Therefore, two IgG1 molecules against different antigens may have many differences in the amino acid sequence of their variable regions. The variable region can be further subdivided because most of the region’s variability in amino acid sequence is localized in three areas of the variable region. These three areas were once called hypervariable regions, but are now called complementary-determining regions (CDRs). The four regions separating the CDRs have relatively stable amino acid sequences and are called framework regions (FRs).

Antigen Binding

The combined amino acid sequences of the variable regions of both the heavy (V_H) and light (V_L) chains determine the conformation of the antigen-binding site and therefore the antigenic specificity of the immunoglobulin molecule. Most proteins will naturally fold and take on secondary or tertiary structures. As the immunoglobulin molecules fold, the FRs control the accuracy of folding in the variable region, and the CDRs in both variable regions are moved into proximity, resulting in an antigen-binding site formed by the three CDRs of the heavy chain and the three CDRs of the light chain. The chemical nature of the particular amino acids in those sites, as well as the topography of the site, determines the specificity toward a particular antigen. The antigen that will bind most strongly must have complementary chemistry and topography with the binding site formed by the antibody. The antigen fits into this binding site with the specificity of a key into a lock and is held there by noncovalent chemical interactions (Figure 8-7). In some cases the substitution of a single critical amino acid in a CDR may have a significant effect on the shape of the binding site and thus the specificity of the antibody molecule.

Because the heavy and light chains are identical within the same antibody molecule, the two binding sites are also identical and have specificity for the same antigen. The number of functional binding sites is called the antibody’s valence. Most antibody classes (i.e., IgG, IgE, IgD, and circulating IgA) have a valence of 2, but secretory IgA has a valence of 4. IgM, being a pentamer, has a theoretical valence of 10, but can simultaneously use only about five binding sites because a large antigen binding to one site blocks antigen binding to another site.

B-Cell Receptor Complex

The B-cell receptor (BCR) complex is located on the surface of B lymphocytes (see Figure 8-5). Its role is to recognize antigen, but unlike circulating antibody, the receptor must communicate that information to the cell’s nucleus. Therefore, the BCR complex consists of antigen-recognition molecules and accessory molecules involved in intracellular signaling (Igα and Igβ). BCRs on the surface of immunocompetent B cells are membrane-associated IgM (mIgM) and IgD (mIgD) immunoglobulins that are produced from the same genes that are used by plasma cells to produce soluble antibodies. As a BCR, however, mIgM is a monomer rather than the pentamer primarily found in the blood.

The BCR signaling complex consists of two Igα and Igβ heterodimers that are closely associated with the BCR and contain tyrosine kinase signaling activity. The antibody portion of the BCR complex is responsible for recognition and binding to an antigen, but by itself cannot provide the intracellular signals required to activate the B cell and complete its maturation and the production of antibodies. That message is conveyed by the Igα and Igβ heterodimers.

T-Cell Receptor Complex

T lymphocytes use a similar but distinct array of proteins in their recognition and response to antigens. The T-cell receptor (TCR) complex is composed of an antibody-like transmembrane protein (TCR) and a group of accessory proteins (collectively referred to as CD3) that are involved in intracellular signaling (see Figure 8-5). Similar to activation of the B lymphocyte, the TCR is responsible for recognition and binding to the antigen, whereas the accessory proteins are responsible for the intracellular signaling necessary for activation and differentiation of the T cell. Each of the individual components of the TCR complex is important, and several severe defects in the T-cell immune response have been related to mutations in individual components of the complex (see Chapter 9).

Molecules That Present Antigen

For an effective immune response, most antigens must be processed within cells and expressed on the surface of those cells in a very specific manner. Some types of antigen are managed only by highly specialized cells: antigen-presenting cells, or APCs. Other types of antigens can be processed and presented by almost any type of cell. Several sets of cell surface molecules have the responsibility for appropriately presenting antigen. These molecules are described below.

Major Histocompatibility Complex

An essential set of recognition molecules are members of the major histocompatibility complex (MHC). Most antibody and cellular immune responses are dependent on antigen presentation by APCs. Additionally, the role of T-cytotoxic cells in killing virally infected cells depends on presentation of the viral antigen on the infected cell’s surface. Antigen presentation is the primary role of molecules of the MHC.

MHC molecules are glycoproteins found on the surface of all human cells except red blood cells. They are divided into two general classes, class I and class II, based on their molecular structure, distribution among cell populations, and function in antigen presentation. MHC class I molecules are heterodimers composed of a large α-chain along with a smaller chain called β2-microglobulin. MHC class II molecules are also heterodimers with both α- and β-chains. The general properties of each of the MHC classes are summarized in Figure 8-8.

Molecules of the two MHC classes are encoded from different genetic loci that are located as a large complex of genes on the short arm of human chromosome 6 (see Figure 8-8). The MHC also contains other genes that control the quality and quantity of an immune response, which are commonly referred to as class III MHC genes. The primary MHC class I genes consist of three closely linked loci on this chromosome labeled A, B, and C. The primary MHC class II genes are located within the D region, which actually consists of three separate and independent loci: DR, DP, and DQ.

The class I and class II MHC loci are the most genetically diverse (polymorphic) of any human genetic loci. Within the human population, the number of possible different alleles (i.e., forms of the gene) expressed by each locus is astounding: 649 at the A locus, 1029 at the B locus, 350 at the C locus, 643 at the DR locus (α and β), 125 at the DQ locus (α and β), and 154 at the DP locus (α and β). These numbers are based on the polymorphism of observed DNA sequences and may not reflect differences in function. Clearly, not every allele is expressed in the same individual. Humans have two copies of each MHC locus (one inherited from each parent) that are codominant so that molecules encoded by each parent’s genes are expressed on the cell surface. Within an individual, each locus will be expressing only one allele. For instance, each person will have only two different A proteins (one from each parent). However, with the tremendous number of possible alleles that can be expressed, it is likely that any two unrelated individuals will have different sets of MHC molecules on their cell surfaces so that each of us is distinct.

Transplantation

The diversity of MHC molecules becomes clinically relevant during organ transplantation. Cells in transplanted tissue or organs from one individual will have a different set of MHC surface antigens than those of the recipient; therefore, the recipient can mount an immune response against the foreign MHC antigens, resulting in rejection of the transplanted tissue. As a result of studies of transplantation, the human MHC molecules are also referred to as human leukocyte antigens (HLAs), and the different MHC genetic loci are commonly called HLA-A, HLA-B, HLA-C, HLA-DR, HLA-DQ, and HLA-DP. To minimize the chance of tissue rejection, the donor and recipient are often tissue typed beforehand to identify differences in HLA antigens. The more similar two individuals are in their HLA tissue type, the more likely a transplant from one to the other will be successful.

Although a large number of alleles exist at the molecular level, the diversity is considerably less at the antigenic level: there are approximately 67 different HLA-A antigens, 149 HLA-B antigens, and 39 HLA-C antigens. Because of the large number of different alleles, it is highly unlikely that a perfect “match” can be found in the general population between a potential donor and the recipient.

The specific combination of alleles at the six major HLA loci on one chromosome (A, B, C, DR, DQ, and DP) is termed a haplotype. Each individual has two HLA haplotypes, one from the paternal chromosome 6 and another from the maternal chromosome. Because the different HLA loci within the MHC are in such close proximity to one another, haplotypes are not usually disrupted by recombination and are thus inherited intact. Each parent passes on one HLA haplotype to each of his or her offspring, meaning that children usually share one haplotype with each parent (Figure 8-9). Odds dictate that children will share one haplotype with half of their siblings and either no haplotypes or both haplotypes with a quarter of their siblings. Thus the chance of finding a match among siblings is much higher (25%) than that from the general population.

It should be noted, however, that although HLA alleles are the primary contributor to rejection of a transplant, a number of other antigens also have a role in determining tissue compatibility. Some of these are encoded on other chromosomes and are inherited independently of HLA antigens. This means that although two people have the same HLA makeup, a graft or transplant still may be rejected because of differences between other antigens. It is preferable to obtain a graft or transplant from a closely related individual, such as a sibling, because the chance of sharing both the same HLA antigens and other undetermined antigenic differences encoded outside the MHC is much greater.

CD1

Another set of antigen-presenting molecules are members of the CD1 group. CD1 molecules have very low genetic polymorphism, a structure similar to MHC class I, and are found primarily on APCs and cells in the thymus. Unlike MHC molecules that present proteins, the CD1 molecules appear to specialize in presenting lipid antigens contained in lipoproteins, glycolipids, and other molecules. These antigens are commonly important factors in infections with bacteria of the Mycobacterium spp. (e.g., Mycobacterium tuberculosis that causes tuberculosis and Mycobacterium leprae that causes leprosy), which have a very large amount of lipid in their cell membranes.

Molecules That Hold Cells Together

The efficient development of an immune response requires several antigen-independent interactions between cells. The interactions between specific cellular receptors and their ligands result in intracellular signaling events that are independent of the TCR or BCR complexes but are necessary complements to the antigen-specific signal. Several of these molecules are listed in Box 8-1.

BOX 8-1   IMPORTANT ADHESION MOLECULE PAIRINGS

Th-cell CD4	⇔	MHC class II on APC
Tc-cell CD8	⇔	MHC class I on APC
Tc-cell CD2	⇔	CD58 (LFA-3) on APC
Tc-cell CD28	⇔	CD80 (B7-1) on APC
Tc-cell LFA-1	⇔	ICAM-1 on APC
Th-cell CD40L (CD154)	⇔	CD40 on B cell
Th-cell CD40L (CD154)	⇔	CD40 on APC

APC, Antigen-presenting cell; ICAM, intercellular adhesion molecule; LFA, lymphocyte function associated antigen; MHC, major histocompatibility complex; Tc, cytotoxic cell; Th, helper T cell.

Cytokines and Their Receptors

As discussed in Chapter 7, cytokines are low-molecular-weight proteins, or glycoproteins, that function as chemical signals between cells. A large number of cytokines are secreted by APCs and lymphocytes and provide both positive and negative regulation of the immune response. The effects of particular cytokines depend on binding to specific cellular receptors, which are linked to intracellular signaling pathways. The lymphocyte may respond in many ways. One of the most common responses is an increase in the production of proteins, many of which are other cytokines or cytokine receptors. Many cytokines also cause a lymphocyte to proliferate and differentiate. The participation of cytokines is essential to the development of an adequate immune response, and in general, the precise combination of cytokines influences the ultimate response of a given cell. Specific deficiencies in the immune response that result from genetic mutations that lead to defective cytokine production or defective cytokine receptors are discussed in Chapter 9. Table 8-5 provides information about key cytokines and receptors that are known to influence the immune response.

TABLE 8-5

KEY CYTOKINES AND RECEPTORS THAT INFLUENCE THE IMMUNE RESPONSE

CYTOKINE	PRIMARY SOURCE	PRIMARY FUNCTION
Interleukin (IL)
IL-1	APCs	Stimulates T cells to proliferation and differentiation; induces acute-phase proteins in inflammatory response; endogenous pyrogen
IL-2	Th1 cells, NK cells	Stimulates proliferation and differentiation of T cells and NK cells
IL-4	Th2 cells, mast cells	Induces B-cell proliferation and differentiation; up-regulates MHC class II expression; induces class-switch to IgE
IL-5	Th2 cells, mast cells	Induces eosinophil proliferation and differentiation; induces B-cell proliferation and differentiation
IL-6	Th2 cells, APCs	Induces B-cell proliferation and differentiation into plasma cells; induces acute-phase proteins in inflammatory response
IL-7	Thymic epithelial cells, bone marrow stromal cells	Major cytokine for induction of B- and T-cell proliferation and differentiation in central lymphoid organs
IL-8	Macrophages	Chemotactic factor for neutrophils
IL-10	Th cells, B cells	Inhibits cytokine production; activator of B cells
IL-12	B cells, APCs	Induces NK-cell proliferation; increases production of IFN-γ
IL-13	Th2 cells	IL-4–like properties; decreases inflammatory responses
IL-17	Th17 cells	Increases inflammation; increased influx of neutrophils and macrophages; increased epithelial cell chemokine production
IL-22	Th17 cells	Increases inflammation; increased epithelial cell production of antimicrobial peptides
Interferon (IFN)
IFN-α, IFN-β	Macrophages, some virally infected cells	Antiviral; increases expression of MHC class I; activates NK cells
IFN-γ	Th1 cells, NK cells, Tc cells	Increases expression of MHC class II; activates macrophages and NK cells
Tumor Necrosis Factor (TNF)
TNF-α (cachectin)	Macrophages	IL-1–like properties; induces cellular proliferation
TNF-β (lymphotoxin)	Tc cells	Kills some cells; increases phagocytosis by macrophages and neutrophils
Transforming Growth Factor (TGF)
TGF-β	Lymphocytes, macrophages, fibroblasts	Chemotactic for macrophages; increases macrophage IL-1 production; stimulates wound healing

CYTOKINE RECEPTORS	LIGAND	ADDITIONAL INFORMATION
Class I receptor dimers (α- and β-chains)	IL-3, IL-5, IL-6, IL-11, IL-12, IL-13	IL-3 and IL-5 share a common α-chain; IL-6 and IL-11 share a common β-chain
Trimers (α-, β-, and γ-chains)	IL-2, IL-4, IL-7, IL-9, IL-15	All share a common γ-chain
Class II receptors	IFN-α, -β, and -γ	Two chains
TNF receptors	TNF-α, TNF-β, CD40, Fas	Single chain
Immunoglobulin-like receptors	IL-1	Single chain with immunoglobulin-like characteristics

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