Antigens

Since the function of the adaptive immune system is to defend the body against invading microorganisms, it is essential that these organisms be recognized as soon as they invade the body. The body must be able to recognize that these are foreign (and dangerous) if they are to stimulate an immune response. The innate immune system recognizes only a limited number of PAMPs—those that are characteristic of major groups of pathogens. The adaptive immune system, in contrast, can recognize and respond to almost all the foreign macromolecules present in an invading microorganism. These foreign macromolecules are called antigens.

Bacteria are single-celled prokaryotic organisms consisting of a cytoplasm containing the essential elements of cell structure surrounded by a lipid-rich cytoplasmic membrane (Figure 9-1). Outside the cytoplasmic membrane is a thick, carbohydrate-rich cell wall. The major components of the bacterial surface thus include the cell wall and its associated protein structures, the capsule, the pili, and the flagella. The cell wall of Gram-positive organisms is largely composed of peptidoglycan (chains of alternating N-acetyl glucosamine and N-acetyl muramic acid cross-linked by short peptide side chains) (see Figure 2-2). Gram-positive cell walls also contain lipoteichoic acids that are involved in the transport of ions across the cell wall. The cell wall in Gram-negative organisms, in contrast, consists of a thin layer of peptidoglycan covered by an outer membrane consisting of a lipopolysaccharide. Most of the antigenicity of Gram-negative bacteria is associated with the lipopolysaccharide. This consists of an oligosaccharide attached to a lipid (lipid A) and to a series of repeating trisaccharides. The structure of these trisaccharides determines the antigenicity of the organism. Many bacteria are classified according to this antigenic structure. For example, the genus Salmonella contains a major species, Salmonella enterica, that is classified into more than 2300 serovars based on antigenicity. These polysaccharide antigens are called O antigens. The outer cell wall lipopolysaccharides of Gram-negative bacteria bind to toll-like receptors (TLRs) and other pattern-recognition receptors and induce the production of inflammatory cytokines when an animal is infected. These cytokines cause a fever and sickness, so bacterial lipopolysaccharides are also called endotoxins.

Bacterial capsules consist mainly of polysaccharides that are usually good antigens. The capsules protect bacteria against phagocytosis and intracellular destruction, whereas anticapsular antibodies can overcome the effects of the capsule and protect an infected animal. Capsular antigens are collectively called K antigens.

Pili and fimbriae are short projections that cover the surfaces of some Gram-negative bacteria; they are classified as F or K antigens. Pili bind bacteria together and play a role in bacterial conjugation and movement. Fimbriae bind bacteria to cell surfaces. Antibodies to fimbrial proteins may be protective since they can prevent bacteria from sticking to body surfaces. Bacterial flagella are long filaments used for bacterial movement. They consist of a single protein called flagellin. Flagellar antigens are collectively called H antigens.

Other significant bacterial antigens include the porins, the heat-shock proteins, and the exotoxins. The porins are proteins that form pores on the surface of Gram-negative organisms. Heat-shock proteins are generated in large amounts in stressed bacteria. The exotoxins are toxic proteins secreted by bacteria or released into the surrounding environment when they die. Exotoxins are highly immunogenic proteins and stimulate the production of antibodies called antitoxins. Many exotoxins, when treated with a mild protein-denaturing agent such as formaldehyde, lose their toxicity but retain their antigenicity. Toxins modified in this way are called toxoids. Toxoids may be used as vaccines to prevent disease caused by toxigenic bacteria such as Clostridium tetani. Bacterial nucleic acids rich in unmethylated CpG sequences serve both as effective antigens for the adaptive immune system and as potent stimulators of innate immunity acting through TLRs.

Viral Antigens

Viruses are very small organisms that can grow only inside living cells. They are thus “obligate,” intracellular parasites. Viruses usually have a relatively simple structure consisting of a nucleic acid core surrounded by a protein layer (Figure 9-2). This protein layer is termed the capsid, and it consists of multiple subunits called capsomeres. Capsid proteins are good antigens, highly capable of stimulating antibody formation. Some viruses may also be surrounded by an envelope containing lipoproteins and glycoproteins. A complete viral particle is called a virion. When a virus infects an animal, the virion proteins are processed and trigger adaptive immune responses. Viruses, however, are not always found free in the circulation but live within cells, where they are protected from the unwelcome attentions of antibodies. Indeed, viral nucleic acid can be integrated into a cell’s genome. In this situation, the viral genes code for new proteins, some of which are expressed on the surface of infected cells. These proteins, although they are synthesized inside an animal’s own cells, can still bind to antigen receptors and provoke adaptive immunity. These newly synthesized foreign proteins are called endogenous antigens to distinguish them from the foreign antigens that enter from the outside and are called exogenous antigens.

Nonmicrobial Antigens

Invading microorganisms are not the only source of foreign material entering the body. Food contains many foreign molecules that under some circumstances may trigger immune responses and cause an allergic reaction. Likewise, inhaled dusts can contain antigenic particles such as pollen grains, and these may enter the body through the respiratory system. Foreign molecules may be injected directly into the body through a snake or mosquito bite, or by a veterinarian. Furthermore, foreign proteins may be injected into animals for experimental purposes. Organ grafts are an effective way of administering a large amount of foreign material to an animal.