Antigens and Innate Immunity

Antigens and Innate Immunity

The immune system performs two vital functions that are critical for the maintenance of homeostasis and survival: (1) inducing an effective and safe response against foreign antigens (infectious and noninfectious) and (2) avoiding a response to components of “self” antigens by enforcing stringent regulatory controls over dangerous self-reactive cells that are capable of mounting devastating immune attacks on “self” tissues. Because the induction of immune responses depends on antigens, this chapter first discusses the nature and characteristics of antigens.


Antigens (or Immunogens) Stimulate Immune Cells to Induce an Immune Response

An antigen, or immunogen, is defined as any substance that is capable of stimulating immune cells (T and B cells) to induce an immune response. Antigens can be broadly divided into two large categories: (1) infectious (microbial) and (2) noninfectious (Figure 54-1). Infectious antigens include components that are derived from bacteria, viruses, protozoa, and helminths. Noninfectious antigens include those derived from “self” (autoantigens), food, plants, dust, or insect and animal venoms, as well as synthetic and cell surface proteins.

An antigen is composed of many molecular units to which an antibody binds. These small units on an antigen are called antigenic epitopes, or antigenic determinants. Thus a single antigen may be composed of many antigenic epitopes. In the strictest sense, antibodies bind to an antigenic epitope of an antigen. Some of these antigenic epitopes are shared among different bacteria (e.g., epitopes on Brucella and Yersinia) or between a bacteria and host cells (e.g., Mycobacterium heat shock proteins and synovial tissue; Mycoplasma and lung tissue). These types of antigenic epitopes are called cross-reactive epitopes.

Figure 54-2 shows the following antigenic structures of bacteria:

• Bacterial cell wall. Cell walls of gram-positive bacteria differ from those of gram-negative bacteria. Gram-positive bacteria are composed of a thick layer of short chains of amino acids or peptides and carbohydrates (peptidoglycans). The cell wall of gram-negative bacteria has a thin layer of peptidoglycan and is largely composed of lipopolysaccharides, which are potent endotoxins.

• Capsule. Certain bacteria produce a protective outer covering called a capsule, which is composed of polysaccharides.

• Pili. These small, hairlike protein structures on some bacteria enable the bacteria to adhere to target host cells and transfer genetic information from one bacterium to another.

• Flagella. Some bacteria possess flagella for mobility. Flagella contain a protein called flagellin, which can be antigenic.

• Nucleic acids. Nucleic acids, such as bacterial deoxyribonucleic acid (DNA), tend to be antigenic because of differences in methylation compared with mammalian DNA. The antibodies against bacterial DNA tend to cross-react with the host’s DNA.

Viruses have nucleic acids (ribonucleic acid [RNA] or DNA), surrounded by a protein coat called a capsid. Some viruses have an envelope, a lipid membrane–like structure covering the capsid. On the envelope are glycoprotein projections that the viruses use to attach to the host target cells. All these components may be antigenic.

External structures of protozoa and helminths tend to be antigenic. Similarly, fungal spores are antigenic. Pollens, glycoproteins of certain foods, the unique biochemical structure of synthetic chemicals, insect saliva, and venoms are all good antigens. It is beyond the scope of this chapter to discuss each of these antigens in detail.

The immune system is exposed to and tolerates “self” antigens found on all of its own tissues. These antigens can be cell surface antigens (e.g., thyroglobulin, myelin peptides) or internal antigens (e.g., cardiolipin, nucleic acids, histones). In certain individuals who are allergic, antigens derived from food (e.g., peanuts, strawberries, fish) or plants (e.g., pollen, spores) induce an immediate and potent immune reaction. Many synthetic chemicals and drugs are minute in size and tend to be adsorbed onto cell surface antigens to create a new antigenic epitope. With ever-increasing synthesis of chemicals (pesticides, agricultural chemicals, drugs, and consumer products, to name a few), it is likely that synthetic chemicals may become an important class of antigens in the future.

The Degree of Immune Response Depends on Several Characteristics of the Antigen

The degree of immune response induced by an antigen is called antigenicity or immunogenicity. Understanding the characteristics of antigens that provoke a strong or weak immune response provides important insight into the body’s ability to combat invading antigens successfully. Furthermore, this understanding is useful in designing a vaccine preparation with potent antigenicity. Characteristics that contribute to potent antigenicity include the following:

• Foreign versus self antigens. Antigens that are considered to be foreign to the host tend to be highly antigenic. For example, if a horse is injected separately with antigens that are derived from a dog or from its own tissues, the horse will mount a strong immune response to the dog antigens, but not to its own (self) tissues.

• Size. The size of an antigen also influences the level of immune response. Large antigens enable better processing by antigen-presenting cells (e.g., macrophages, dendritic cells) and subsequent presentation of antigenic peptides to lymphocytes for induction of an immune response. Examples of large antigens include bacterial and insect toxins, viral capsids, surface proteins on protozoa and helminths, and venoms. At the other extreme, very small antigens (e.g., small synthetic antigens, endogenous hormones, pesticides) tend to be ineffective in provoking an immune response. Very small antigens are inherently incapable of inducing immune responses; however, when bound to a larger protein, they can be potent antigens. Such small compounds are referred to as haptens. A good example of a hapten is a poison ivy–derived chemical, urishiol, which readily combines with many proteins (e.g., skin proteins) to induce a vigorous immune response.

• Biochemical structure and complexity. In general, proteins tend to be more antigenic than lipids or carbohydrates. Large size alone is insufficient to provoke a good immune response. For example, many sugars and lipids, even though large in size, are ineffective in inducing an immune response because they consist of simple repeating units (e.g., repeating sugars in starch), which lack complexity. Complex carbohydrates and lipids, on the other hand, as found in many microbes, are strong immunogens. Carbohydrates and lipids, when combined with protein to form glycoproteins and lipoproteins, respectively, have increased complexity and thus are good antigens.

• Stability and degradability. For immune cells to respond, stability of an antigen is an important feature. Flexible antigens, such as flagellin in a bacterium, are poor immunogens. However, when stabilized and rendered less flexible, as done in vaccine preparations, flagellin tends to be a potent immunogen. For an immune response to be initiated, the antigen ingested by phagocytic cells (e.g., macrophages) must be degraded and broken down into small peptides. Lymphocytes (T cells) will only respond to the peptides and not to large, native molecules. Antigens such as steel pins or plastic heart valves, even though large and complex, are inert and not degradable and thus are not good antigens.

Large, complex proteins (or lipoproteins or glycoproteins) that can be degraded and processed therefore tend to be excellent antigens. Other parameters that influence an individual’s ability to respond to antigens include genetics (e.g., major histocompatibility complex genes), endogenous biomolecules that regulate and modulate immune responses (e.g., hormones, neuropeptides), and the level and route of exposure of antigens.

An antibody that is induced in response to an antigen will specifically bind to the antigen. Any minor alteration of the antigen will negatively impact the antibody’s ability to bind to an antigen. Therefore, invading microbes often alter their antigens to prevent the binding of induced antibodies, thus avoiding immune attack.

Body’s Defense Against Invading Antigens

Both Nonimmune and Immune Mechanisms Defend Against Invading Antigens

The body is confronted with literally billions of antigens. Consequently, a unique challenge presented to the immune system is to respond effectively only to foreign antigens while refraining from response to “self” antigens. The induction of immune responses requires energy and protein, and antigens require extensive cellular division (and hence utilization of protein reserves); the body cannot mount immune responses to each of the innumerable antigens it encounters constantly. Instead, the body is well equipped to handle antigens effectively before resorting to a specific immune response.

Initially, most antigens are effectively handled by nonspecific defense mechanisms, such as impervious and formidable physical barriers (e.g., skin and other body surfaces) and antimicrobial body fluids (e.g., lysozymes in tears, saliva, gastric juices). These are considered the first line of defense and are discussed next. Should the antigen survive this “body armor,” phagocytic cells (e.g., neutrophils, macrophages-monocytes) and natural killer (NK, NK-T) cells can effectively eliminate the invading antigens. These cells ingest and destroy a wide range of antigens and thus are non–antigen-specific. These cellular defenses constitute a second line of the body’s defense. The body’s initial defense (physical, chemical, and phagocytic antigen-presenting cells; natural killer cells) constitute the innate immune system. The antigen-presenting cells closely interact with specific T and B cells to induce a specific immune response. Thus, specific immune responses by the “adaptive” immune system tend to be the last line of the body’s defense (see Chapter 55). Collectively, both nonimmune and immune mechanisms effectively counter invading microbes.

A First Line of Defense Includes Physical and Chemical Barriers such as the Skin and Internal Body Fluids

The physical nonimmune defense barriers include external body surfaces such as skin and internal body surfaces such as the gastrointestinal (GI), reproductive, respiratory, and the urogenital tracts. The skin plays a major role in preventing the entry of organisms through a variety of nonimmunological means, including the secretion of sebum from sebaceous glands, which maintains a low pH, and secretion of enzymes that are not conducive for the invading pathogens. Periodic natural desquamation of the skin also results in sloughing off any invading pathogens. Nonpathogenic bacteria also occupy skin surfaces, thereby preventing the adherence of pathogenic organisms to their target cells, which is prerequisite for entry into the body. Any changes in the skin, such as cuts, burns, and dry or very humid skin, will result in the entry of microbes. In addition to the nonimmunological mechanisms, skin is also rich in dendritic cells (Langerhans cells) and γ-δ T cells that contribute to warding off invading pathogens. The natural flushing action of urine and milk assist in elimination of infectious antigens, as evidenced by the infectious conditions that result from stasis of urine or milk.

Many body fluids are inhospitable to invading pathogens. For example, mucus in the mucosal tissues (respiratory, urogenital, and GI tracts), saliva, tears, gastric juices, and urine are rich in enzymes (e.g., lysozymes) and are low in pH. As with the skin, the GI tract is covered with nonpathogenic bacteria, which prevent the adhesion of pathogenic bacteria to their target cells. Furthermore, resident normal bacterial florae in gastric tissues secrete butyric or lactic acids, which not only maintain a low pH in gastric fluids, but also are bacteriostatic to other microbes. Vaginal epithelium is rich in glycogen and promotes the growth of Lactobacillus, which secretes lactic acids. In the respiratory tract the antigen load is decreased by a variety of mechanisms, including the turbulence created when air is inhaled due to the anatomical construction of the lower respiratory tract, which narrows and branches. Microorganisms in inhaled air are carried by this turbulence and are forced onto the walls of the respiratory tract, which are rich in sticky mucus and bactericidal lysozymes. The ciliary action of the respiratory tract also eliminates antigens effectively.

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Jul 18, 2016 | Posted by in PHARMACOLOGY, TOXICOLOGY & THERAPEUTICS | Comments Off on Antigens and Innate Immunity

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