Immunology (Lippincott Illustrated Reviews Series) 2nd Edition

Chapter 2: Antigens and Receptors

I. OVERVIEW

Immune responses are initiated by the interaction between a ligand and a receptor protein on the cell’s surface of a soluble receptor. These interactions trigger the activation of leukocytes or white blood cells. The complementary shapes of the ligand and its receptor are critical. The effectiveness of interaction often increases with the affinity or strength of interaction between ligand and receptor (Fig. 2.1). Receptors may be displayed on cell surfaces (e.g., cell-surface receptors) or may be soluble molecules (e.g., secreted products of leukocytes). Ligands may be expressed by cells as cell-surface molecules (e.g., on microbes) or as soluble molecules (e.g., the secreted products of cells).

Several factors influence the binding of a ligand to a cell-surface receptor: The shape and charge affect binding affinity, the collective affinities where multiple receptors may be involved (avidity), the intra-cellular signals that are triggered, and the presence of other receptors that may also influence the action in question. The context in which cells receive signals can influence whether they respond to those signals (Fig. 2.2). Cells must often correlate information from multiple activated receptors, some providing positive signals and others providing negative signals, to determine what action they will ultimately take. Ligands recognized by cells of both the innate and adaptive immune systems are collectively known as antigens. The smallest individually identifiable part of an antigen that is bound by a receptor is known as an epitope.

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Figure 2.1

Receptor–ligand interactions. Receptors bind molecules or ligands that may be either soluble or bound to membranes. If the binding is sufficient, the receptor is able to provide a signal to the cell.

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Figure 2.2

Receptor–ligand context influences outcome. A cell integrates messages coming from multiple receptors to determine what action it ultimately takes.

The innate immune system employs a limited set of receptors to recognize epitopes expressed by a wide range of microorganisms. The adaptive immune system, on the other hand, generates a vast number of epitope-specific lymphocyte receptors that are expressed only by bone marrow–derived lymphocytes (B lymphocytes or B cells) and thymus-derived lymphocytes (T lymphocytes or T cells). Different receptors on B cells and T cells precisely recognize molecular features of epitopes as an important initial step in generating an immune response. As with receptors in general, both the molecular nature of the antigen and how it interacts with leukocyte receptors greatly influence the immune response that will be generated through the binding of these highly specialized receptors.

II. ANTIGENS

Classically, an antigen is defined as an organism, a molecule, or part of a molecule that is recognized by the immune system. Antigens may be simple or complex, protein, carbohydrate, or synthetic in origin. Often, the term is associated primarily with those molecules recognized by the extremely diverse receptors found on T and B lymphocytes. We will follow this usage and reserve the terms “antigen” and “epitope” for the substances that are recognized and bound by these somatically generated B- and T-cell receptors. It must be noted, however, that molecules designated as antigens in this context may also be bound by other types of receptors on other cells.

A. Epitopes: The basic recognition unit

Antigen receptors recognize discrete regions of molecules called antigenic determinants or epitopes, the smallest part of an antigen that is “seen” by somatically generated B- and T-cell receptors (Fig. 2.3). Different lymphocytes, each with a unique set of receptors, may recognize different epitopes on the same antigen. Some receptors (e.g., those of B cells) can recognize their specific epitopes whether they are part of free-soluble molecules, surface-bound molecules, or even degraded (proteolytic) fragments of antigens. Other receptors (e.g., T-cell receptors) can bind only to epitopes that are on small fragments affixed to specialized host cell surface molecules that display them to the T cells. Depending on the nature of the immune responses they trigger, antigens/epitopes are divided into three broad functional types: immunogens, haptens, and tolerogens.

B. Immunogens

Immunogens contain epitopes that both induce an immune response and are the targets of that response (Table 2.1). The magnitude of the immune response by the innate system is the same, no matter how many times it encounters the same immunogen. In contrast, re-exposure of the adaptive immune system to the same immunogen usually increases the intensity of the epitope-specific immune response. Although epitopes on antigens may bind to soluble or cell-surface receptors, not all antigens are immunogens. Unfortunately, the terms “antigen” and “immunogen” are often used interchangeably. In this text, we use the term “immunogen” to mean a substance or antigen that evokes a specific, positive immune response and the term “antigen” to mean a molecule or cell recognized by the immune system. Some nonimmunogenic molecules (e.g., haptens) can be bound to an immunogen. In this context, the immunogen is referred to as a carrier.

C. Haptens

Haptens are small, normally nonimmunogenic, molecules, usually of nonbiologic origin, that behave like synthetic epitopes. Haptens are antigens and can bind to immune receptors but cannot by themselves induce a specific immune response and hence are not immunogenic. However, when a hapten is chemically bound to an immunogen (also called a carrier), immune responses may be generated against both the hapten and the epitopes on the immunogen (see Table 2.1).

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Figure 2.3

Epitopes and antigens: degrees of complexity. Complex antigens may contain large numbers of different epitopes.

D. Tolerogens

During development of the immune repertoire (the sum of all of the epitopes for which a given individual has generated immunologic receptors), tolerance to self molecules and cells develops first. Therefore, a lack of immune response to self antigens exists in the normal, healthy state. Nonself antigens are subsequently recognized as foreign. Tolerance can also develop later in life, for example, to antigens that are administered orally.Tolerogens induce adaptive immune unresponsiveness. However, unlike immunogens, exposure to a tolerogen results in a diminished response rather than an enhanced one.

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E. Immunogenicity

Although there are no firm rules for predicting whether a substance is an immunogen prior to exposure to the immune system, there are several guidelines:

• Size: Proteins greater than 10 kDa are usually more immunogenic.

• Complexity: Complex proteins with numerous, diverse epitopes are more likely to induce an immune response than are simple peptides that contain only one or a few epitopes.

• Conformation and accessibility: Epitopes must be “seen by” and be accessible to the immune system.

• Chemical properties: A protein immunogen has to be enzymatically cleavable by phagocytes. For example, L-amino acid-containing polypeptides are generally good immunogens, whereas D-amino acid-containing polypeptides are poor immunogens because proteolytic enzymes are able to cleave only the L-forms of amino acids. Many carbohydrates, steroids, and lipids tend to be poor immunogens. Amino acids and haptens are, by themselves, not immunogenic (Fig. 2.4).

III. RECEPTORS

The immune system depends on receptors, and the ligands that are bound by them, for its function. The engagement of receptors provides the initiating event that can lead to a wide variety of activities, depending on the particular receptor and ligand, and on the type of cell or molecules that the receptor is associated with. Some receptors are designed to bind molecules that then generate signals between cells. Others sample the environment to detect the presence of intruders. Yet others examine their neighbors to be sure that they belong to self and do not present a threat.

A. Preformed receptors

The initial defense to an infectious agent comes from elements of the innate immune system that contain preformed receptors that allow a quick response. This response confers some protection whereas the adaptive immune system prepares to respond.

1. Pattern recognition receptors: Receptors of the innate immune system recognize broad structural motifs (similarities in design) that are generally not present within the host but are instead found on microbes. These receptors, pattern recognition receptors (PRRs), are present in soluble forms (e.g., complement proteins, which compose a particular kind of immune defense system discussed later in this chapter) or on host cell surfaces. They recognize pathogen-associated molecular patterns (PAMPs), which include combinations of sugars, some proteins, lipids, and nucleic acids broadly associated with microbes (Fig. 2.5). PRR binding to PAMPs triggers various forms of inflammation intended to destroy the pathogens.

2. Toll-like receptors: In humans, PRRs also include toll-like receptors (TLRs) that are present on various host cells (Table 2.2). When triggered by binding to a PAMP on an infectious organism, TLRs mediate the generation of defensive responses that include transcriptional activation, synthesis, and secretion of cytokines (immune chemicals secreted by immune cells) to promote inflammation, and the attraction of macrophages, neutrophils, natural killer (NK) cells, and dendritic cells to the site of infection.

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Figure 2.4

Factors governing immunogenicity. In general, the greater the size and complexity of the antigen, the greater the variety of possible epitopes and the greater the immunogenicity.

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Figure 2.5

Pattern recognition receptors (PRRs). Pattern recognition receptors detect and bind pathogen-associated molecular patterns (PAMPs).

3. Killer activation receptors: NK cells are part of the lymphocyte lineage that do not express the extremely variable types of antigen-specific receptors found on B cells and T cells. Nevertheless, they do bear receptors that are able to detect alterations in host cells that have been infected by pathogens, particularly viruses. Killer activation receptors (KARs) on NK cells allow them to recognize the presence of stress-related molecules (called MICA and MICB molecules in humans) expressed by host cells that are unhealthy or abnormal for various reasons, including being infected. Binding of MICA or MICB molecules by the NK cell’s KARs induces the NK cell to attach and destroy the targeted (e.g., infected) host cell (Fig. 2.6). This process, and its important role in innate immunity, is discussed in greater detail in Chapter 4.

4. Killer inhibition receptors: Another set of receptors, the killer inhibition receptors (KIRs), is used by NK cells to monitor major histocompatibility complex (MHC) class I molecules normally displayed on the cell surfaces of all nucleated cells in the body (see Fig. 2.6). By scrutinizing MHC class I molecules, NK cells determine the normality of host cells. Many processes, including some cancers and some types of viral infection, decrease the number of MHC class I molecules displayed on the surface of the affected cell. Once bound to a target cell via its KARs, the NK cells use their KIRs to assess the expression of MHC class I molecules on that cell. If NK cells determine that the level is subnormal, they proceed to kill the target cell. If they determine that normal levels are present, the killing process is terminated and the target cell is released unharmed.

5. Complement receptors: The complement system is a complex set of soluble molecules that generate various reactions that attract immune cells to the site of infection and lead to destruction of microbes. Some of these activities are accomplished by the binding of certain complement components or their fragments to microbial surfaces and “tagging” that microbe for destruction by other elements of the immune system. Cell-surface bound complement receptors on phagocytic cells and B cells recognize these bound complement fragments and facilitate the binding, ingestion, and internal degradation of the tagged microbes (Fig. 2.7).

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Figure 2.6

Killer-cell activation receptors (KARs) and killer-cell inhibition receptors (KIRs).

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6. Fc receptors: Immunoglobulins (including those epitope-binding immunoglobulins termed antibodies) are classified as IgA (immunoglobulin A), IgD, IgE, IgG, and IgM based on their structure. Although the structural and functional details of immunoglobulins are discussed in detail in Chapters 8 and 9, the important point for our purposes here is that epitope binding by IgA, IgG, or IgM antibodies triggers a conformational change in the “tail” or Fc portion of the antibody. Fc receptors (FcRs) are expressed on the surfaces of phagocytic cells (see Fig. 2.8). Phagocytic cells recognize and bind epitope-engaged antibodies (recognizable by the altered conformation of the Fc region), which leads to the phagocytosis of the epitope-antibody-FcR complex. Antibodies that have not bound one or more epitopes do not bind to FcRs, and in this way, an antibody that has not bound to an epitope remains in circulation. The Fc receptor that binds IgE is the exception, which binds IgE molecules that have not yet encountered their epitopes; intracellular signaling does not occur until the IgE antibody binds the appropriate antigen.

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Figure 2.7

Complement receptors. Binding by complement receptors on phagocytic cells facilitates binding, ingestion, and destruction of microbes.

B. Somatically generated receptors

The preformed receptors of the innate immune system (e.g., PRRs, TLRs, and complement) are encoded in the germline and passed on intact from one generation to the next. In contrast, the specialized receptors of B cells and T cells of the adaptive immune system are regenerated anew in the lymphocytes of each individual through random somatic chromosomal rearrangements and mutations. The result is a vast array of receptors specific for precise molecular details found in unique epitopes that may be encountered in the future.

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Figure 2.8

Fc receptors. Like complement receptors, Fc receptors permit phagocytes to identify and ingest microbes and molecules that antibodies have previously “tagged” for destruction. The receptor for IgE is an exception, however, it binds free IgE and no cellular signaling occurs prior to the binding of antigen to the IgE.

1. B-cell receptors: B-cell receptors (BCRs) are cell-surface bound monomeric immunoglobulin (see Chapter 8) associated with disulfide-linked heterodimers called Igα and Igβ (Fig. 2.9). When a BCR binds an epitope, the specialized cytoplasmic tails of Igα and Igβ initiate an intracellular signaling cascade that may lead to B-cell activation. In addition, some activated B cells terminally differentiate into plasma cells, which secrete immunoglobulins that have the same epitope-binding specificity as their BCR. The structure and function of immunoglobulins are described in greater detail in Chapters 8 and 9.

2. T-cell receptors: Structurally similar to immunoglobulin molecules, T-cell receptors (TCRs) are heterodimers, consisting of either an αβ or a γδ chain pair (an αβ receptor is shown in Figure 2.10;γδ receptors have similar structures). TCRs are always membrane bound and recognize antigen combined with MHC molecules. They are associated with the cluster of differentiation 3 or CD3 complex of transmembrane surface molecules. The CD3 complex functions much like the Igα and Igβ of BCRs in that it links the TCR with intracellular signaling molecules. An additional accessory molecule (CD4 or CD8) is also present to serve as a type of coreceptor for the TCR. The structure and function of the T-cell receptors are described in greater detail in Chapters 8 and 9.

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Figure 2.9

Immunoglobulins serve as B-cell receptors (BCRs). B cells bear receptors that are composed of two identical large (heavy) chains and two identical smaller (light) chains. Molecules such as Igα and Igβ are associated with BCRs and help provide a signal to the cell when the BCR binds an epitope.

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Figure 2.10

αβ T-cell receptors (TCRs). T cells bear receptors that are composed of two chains, either an αβ combination (shown) or a γδ combination. The CD3 complex is associated with the TCR and facilitates cell signaling (see Chapter 10).

Chapter Summary

• Antigens contain one or more epitopes or antigenic determinants, the basic units recognized by immune receptors.

• Antigens may be classified as immunogens if they stimulate an immune response, as haptens if they induce an immune response only when coupled to an immunogenic carrier molecule, or as tolerogens if they cause cells of the immune system to become selectively unresponsive to reexposure to these same molecules.

• Preformed receptors on cells of the innate immune system allow a rapid host response to a pathogen. The adaptive immune system uses somatically generated receptors.

• Pattern recognition receptors (PRRs) bind pathogen-associated molecular patterns (PAMPs), which are combinations of sugars, proteins, lipids, and nucleic acids on pathogens, resulting in inflammation with the goal of destroying the pathogen.

• Toll-like receptors (TLRs) mediate cytokine production to promote inflammation and trafficking of immune cells to the site.

• Natural killer (NK) cells use killer activated receptors (KARs) to identify abnormal host cells and killer inhibitor receptors (KIRs) to inhibit their destruction when not appropriate.

• Complement receptors (CRs) are displayed on phagocytic cells and B cells that allow for recognition of microbes and immune complexes.

• Fc receptors (FcRs) bind epitope-antibody complexes and stimulate phagocytosis.

• Monomeric immunoglobulins serve as epitope-specific B-cell receptors (BCRs); B cells on maturation differentiate into plasma cells that secrete immunoglobin with specificity identical to that of the membrane-bound BCR.

• T-cell receptors (TCRs) exist solely in membrane-bound forms and recognize epitopes bound by major histocompatibility complex (MHC) molecules.

Study Questions

2.1. Dansyl (5-dimethylaminonaphthalene-1-sulfonyl) is a synthetic molecule that binds to receptors on certain B cells but does not stimulate them to produce dansyl-specific antibodies unless it is first conjugated to a larger, immunogenic molecule such as bovine serum albumin. These findings indicate that dansyl is a(n)

A. adjuvant.

B. carrier.

C. hapten.

D. immunogen.

E. tolerogen.

The answer is C. Dansyl is a hapten in that it meets three criteria: It is a synthetic molecule; by itself, it does not stimulate an immune response; and when it is coupled to an immunogenic molecule, an immune response is stimulated toward both dansyl and the immunogen. An adjuvant increases the intensity of an immune response. A carrier molecule is also an immunogen. An immunogen is a substance that stimulates an immune response. A tolerogen causes unresponsiveness.

2.2. Which of the following is most likely to induce 
the greatest adaptive immune response in a 
25-year-old man?

A. 250,000-Da plasma protein from the same 25-year-old human male

B. 150,000-Da toxin produced by bacteria

C. 500-Da plasma protein from a chimpanzee

D. 400-Da cholesterol molecule from an unrelated human female

E. 200-Da carbohydrate molecule common to all species

The answer is B. Bacterial toxins are often very immunogenic. An individual should normally not make adaptive immune responses against her or his own plasma proteins. A 500-Da plasma protein from a chimpanzee is small enough to “fall under the radar” of the adaptive immune system, most likely because it lacks sufficient numbers of epitopes. A cholesterol molecule is most likely not immunogenic irrespective of size. Immune responses in normal individuals will not be directed against carbohydrates that their tissues or fluids express.

2.3. During an early part of its development, the binding of a lymphocyte’s antigen receptor to its specific epitope may result in the inactivation or death of that cell. Under these circumstances, the epitope in question would be described as a(n)

A. adjuvant.

B. carrier.

C. hapten.

D. immunogen.

E. tolerogen.

The answer is E. A tolerogen is a molecule that selectively causes unresponsiveness by the adaptive immune system. In contrast, an adjuvant serves to increase immunogenicity. A carrier and an immunogen induce adaptive immune responses. A hapten cannot induce an immune response unless it is chemically bound to an immunogen.

2.4. Natural killer (NK) cells lyse Epstein–Barr virus-infected B cells with deficient MHC I expression. The NK receptors that initiate the lytic activity are

A. complement receptors.

B. Fc receptors.

C. killer activation receptors.

D. killer inhibition receptors.

E. monomeric immunoglobulin receptors.

The answer is C. Natural killer (NK) cells scrutinize nucleated cells using killer activation receptors (KARs) that detect stress molecules (MICA and MICB) expressed on cells in response to intracellular infection. Epstein–Barr virus infection causes cells to display stress molecules and at the same time, decrease their expression of MHC class I molecules. Engagement of KAR triggers the lytic activity by the NK cells. Killing of the target cells will proceed unless killer inhibition receptors (recognizing MHC class I molecules on the targets cells) are appropriately engaged. If KIR are not engaged at a sufficient level, the KAR-initiated lysis proceeds. Complement receptors bind activated fragments of complement that occur in the extracellular environment. Fc receptors bind antibodies that engage extracellular environment antigens. NK cells do not express immunoglobulins.

2.5. Antibody mediated recruitment of macrophages occurs through action of

A. complement receptors.

B. Fc receptors.

C. killer activation receptors.

D. pattern recognition receptors.

E. toll-like receptors.

The answer is B. Binding to an epitope causes a conformation change in the Fc portion of the antibody molecule. Fc receptors (FcRs) recognize and bind to the conformationally altered antibody molecule, and this engagement of epitope-bound antibody by FcRs stimulates phagocytosis of cells and molecules “tagged” by antibodies for destruction. Complement receptors bind and facilitate the phagocytosis of cells and molecules tagged by complement components or fragments. Killer activation receptors, pattern recognition receptors, and toll-like receptors do not recognize antigen–antibody complexes.

2.6. A 7-year-old girl has a history of peanut allergy with symptoms that include generalized itching and hives after eating peanuts. Her symptoms became more severe with subsequent accidental exposures to peanuts. For this child, a peanut is most likely a(n)

A. adjuvant.

B. hapten.

C. immunogen.

D. innate immune system antigen.

E. tolerogen.

The answer is C. Repeated exposure to peanuts intensifies the immune reaction, indicating that the child most likely has developed an adaptive immune response to a peanut protein. A tolerogen would serve to diminish the immune response on repeated exposure. It is unlikely that an adjuvant is present that would intensify her allergic response to peanuts. Peanuts by themselves induced this response, but a hapten will not induce an immune response. The fact that the immune response intensifies on repeated exposure effectively rules out an innate immune response.

2.7. Epitope binding before Fc receptor engagement is not required for

A. carrier molecules.

B. hapten-carrier conjugates.

C. haptens.

D. IgE.

E. IgG.

The answer is D. Fc receptors only engage the “tail” or Fc portion of immunoglobulin (Ig) molecules. Only IgE is bound to the appropriate Fc receptor prior to epitope binding. Fc receptor binding is not required for haptens, carriers, or their conjugates.

2.8. Cells of the immune system are triggered by the binding of surface receptors. In general, the action taken is determined by

A. a single receptor per cell.

B. a single type of receptor found on all cells.

C. the integration of signals generated by multiple receptors on single cells.

D. multiple receptors that bind soluble ligands only.

E. nonspecific receptors capable of binding a wide array of ligands.

The answer is C. Cells bear many types of receptors, each capable of specifically binding a different ligand. The signals generated by the binding of various combinations of receptors on the surface of a given cell are integrated by that cell and used to determine the action to be taken.