Characteristics of Antigens and Immunogens
Earlier we encountered the concept of an antigen, which can now be more fully defined as any molecule or fragment of a molecule that has the potential to trigger a specific immune response by lymphocytes. This property is known as antigenicity. For a substance to be antigenic, it must meet several criteria related to foreignness, size, shape, and accessibility that are dis cussed next. A related set of more specific terms are immunogen and immunogenicity. An immunogen is a type of antigen that actually does induce a specific immune response when introduced into the body.
The difference between these terms is subtle and addresses the fact that some antigens may not fit all of the actual conditions to stimulate an immune reaction, whereas immunogens do. One example involves the small polysaccharides from the capsule of the bacterium Haemophilus influenzae, one cause of meningitis. These molecules are foreign and antigenic, but they are too small to trigger a lymphocyte response: They are anti genic but not immunogenic. To produce a vaccine from this type of antigen, it must be altered so that the immune system can more readily recognize and react to it (see the discussion of hap tens later in this section). In most of the succeeding discussions on immune responsiveness, we will use the more general term antigen because it encompasses all possibilities of eliciting immune reactions.
One important characteristic of an antigen is that the immune cells react to it as nonself or as foreign, meaning that it is not a “normal” constituent of the body. Whole microbes or their parts, cells, or substances that arise from other humans, animals, plants, and various molecules all possess this quality of foreign ness and thus are potentially antigenic to the immune system of an individual (figure 1). Molecules of complex composition such as proteins and protein- containing compounds prove to be more immunogenic than repetitious polymers composed of a single type of unit. Most materials that serve as antigens fall into these categories: ● proteins and large polypeptides (enzymes, cell surface receptors, hormones, exotoxins);
● molecules that contain two or more different macromolecules bound together. Examples of these include:
● lipoproteins (combinations of lipids and proteins) and lipopolysaccharides (combinations of lipids and carbohydrates). These substances originate from the cell membranes or cell walls of microbes.
●nucleoproteins (DNA complexed to proteins); unbound DNA is too regular and repetitive in structure to be antigenic;
● polysaccharides (certain bacterial capsules) and glycolipids (mycolic acid of M. tuberculosis).
Fig1. Characteristics of antigens. (a) Whole cells of plants, animals, bacteria, or fungi, along with viruses, are easily recognized immunogens. (b) Proteins are nearly always good immunogens, and these complex molecules have many epitopes. (c) The repetitive nature of large molecules like starch (left) and DNA (right) generally makes them poor immunogens despite their size. Small, simple molecules (like the individual glucose monomers of which starch is composed) are particularly bad immunogens. (a): Image Source/Alamy Stock Photo; (b): ibreakstock/Shutterstock; (c1): McGraw Hill; (c2): Comstock/Getty Images
Effects of Molecular Shape and Size on Antigenicity
To initiate an immune response, a substance must also be large enough to “catch the attention” of the surveillance cells. Molecules with a molecular weight (MW) of less than 1,000 are seldom complete antigens, and those between 1,000 MW and 10,000 MW are weakly so. Complex macromolecules of at least 100,000 MW are the most immunogenic, a category also dominated by large proteins. Note that large size alone is not sufficient for antigenicity. Glycogen, a polymer of glucose with a highly repetitious structure, has a MW over 100,000 and is not normally antigenic, whereas insulin, a protein with a MW of 6,000, can be antigenic.
A lymphocyte’s capacity to discriminate differences in molecular shape is so fine that it recognizes and responds to only a portion of the antigen molecule. This molecular fragment, called the epitope or antigenic determinant, provides the primary signal that the molecule is foreign (figure 1b). The shape of this determinant fits like a key to the receptor “lock” of the lymphocyte, which then recognizes and responds to it. Certain amino acids accessible at the surface of proteins or carbohydrate side chains protruding from a protein receptor are typical examples. Many foreign cells and molecules are very complex antigenically, with numerous determinants, each of which will elicit a separate and different lymphocyte response. Examples include bacterial cell wall, membrane, flagellar, capsular, and toxin antigens; and viruses, which express various surface and core antigens.
Small foreign molecules that are too small by themselves to elicit an immune response are called haptens. However, if a hapten is linked to a larger carrier molecule, the combination develops immunogenicity (figure 2). The carrier group contributes to the size of the complex and enhances the orientation of the antigen, while the hapten serves as the epitope. Haptens include such molecules as vaccine antigens, drugs, metals, and a variety of chemicals. Many haptens develop immunogenicity in the body by combining with large carrier molecules such as serum proteins.
Fig2. The hapten-carrier phenomenon. (a) Haptens are antigens that are too small to be discovered by an animal’s immune system and do not elicit a response. (b) When a hapten binds to a large molecule, the hapten serves as an epitope and stimulates a response and an antibody that is specific for it.
Functional Categories
of Antigens Because each human being is genetically and biochemically unique (except for identical twins), the proteins and other molecules of one person can be antigenic to another. Alloantigens are cell sur face markers and molecules that occur in some members of the same species but not in others. Alloantigens are the basis for an individual’s blood group and major histocompatibility profile, and they are responsible for incompatibilities that can occur in blood transfusion or organ grafting.
Some bacterial proteins, called superantigens, are potent stimuli for T cells. Notable examples of these types of antigens are toxic shock toxin and enterotoxin of Staphylococcus. Reactions with superantigens may cause the massive release of cytokines, leading to cell death.
Antigens that evoke allergic reactions, called allergens.
On occasion, even a normal part of self can take on the character of an antigen. During lymphocyte differentiation, immune tolerance to self tissue occurs, but a few anatomical sites can contain sequestered (hidden) molecules that escape this assessment. Such molecules, called autoantigens, can occur in tissues (of the eye and thyroid gland, for example) that are walled off early in embryonic development before the surveillance system is in complete working order. Because tolerance to these substances has not yet been established, they can subsequently be mistaken as foreign; this mechanism appears to account for some types of autoimmune diseases such as rheumatoid arthritis.
With a working knowledge of some factors in the development of immune specificity, we can now continue our coverage of the immune response as outlined in figure 3.
Fig3. Overview of the origins and events of adaptive immune responses.
