Immunology. Richard Coico
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4 D. C5a is an anaphylatoxin, which induces degranulation of mast cells, resulting in the release of histamine, causing vasodilation and contraction of smooth muscles. C5a is also chemotactic, attracting leukocytes to the area of its release where an antigen is reacting with antibodies and activates the complement system; this is a part of the inflammatory response to an infection. C5b deposits on membranes and initiates the formation of the terminal membrane attack complex. Neither C5a nor C5b promotes the attachment of lymphocytes to macrophages.
5 D. The alternative pathway of complement activation connects with the classical pathway at the activation of C3. Thus, it does not require C1, C4, or C2. Properdin is essential for the activation through the alternative pathway, since it stabilizes the complex formed between C3b and activated serum factor B, C3bBb, which acts as a C3 convertase, and activates C3. During activation of the alternative pathway both C3a and C5a are generated; both are anaphylatoxins and cause degranulation of mast cells. Factor H is a key regulator of the alternative pathway.
6 A. DAF is a cell surface regulator of complement activation that destabilizes the C3 convertases of the alternate and classical pathways (C3bBb and C4b2a, respectively). Like other regulators of complement activation—including CR1, factor H, and C4bBP—these proteins accelerate decay (dissociation) of the C3 convertase, releasing the component with enzymatic activity (Bb or C2a) from the component bound to the cell membrane (C3b or C4b).
7 E. Each of these pathogens and particles of microbial origin can initiate the alternative pathway of complement activation. Teichoic acid from the cell walls of Gram‐positive organisms, as well as parasites such as trypanosomes, can also activate complement via this pathway.
5 IMMUNOGENS AND ANTIGENS
INTRODUCTION
Immune responses arise as a result of exposure to foreign stimuli. The compound that evokes the response is referred to either as antigen or immunogen. The distinction between these terms is functional. An antigen is any agent capable of binding specifically to components of the immune system, such as the B‐cell receptor (BCR) on B lymphocytes and soluble antibodies. By contrast, an immunogen is any agent capable of inducing an immune response and is therefore immunogenic. The distinction between the terms is necessary because there are many compounds that are incapable of inducing an immune response, yet they are capable of binding with components of the immune system that have been induced specifically against them. Thus all immunogens are antigens, but not all antigens are immunogens.
This difference becomes obvious in the case of low molecular weight compounds, a group of substances that includes many antibiotics and drugs. By themselves, these compounds are incapable of inducing an immune response but when they are coupled with much larger entities, such as proteins, the resultant conjugate induces an immune response that is directed against various parts of the conjugate, including the low molecular weight compound. When manipulated in this manner, the low molecular weight compound is referred to as a hapten (from the Greek hapten, which means “to grasp”); the high molecular weight compound to which the hapten is conjugated is referred to as a carrier. Thus a hapten is a compound that, by itself, is incapable of inducing an immune response but against which an immune response can be induced by immunization with the hapten conjugated to a carrier.
Immune responses have been demonstrated against all the known biochemical families of compounds, including carbohydrates, lipids, proteins, and nucleic acids. Similarly, immune responses to drugs, antibiotics, food additives, cosmetics, and small synthetic peptides can also be induced, but only when these are coupled to a carrier. In this chapter, we discuss the major attributes of compounds that render them antigenic and immunogenic.
REQUIREMENTS FOR IMMUNOGENICITY
A substance must possess the following characteristics to be immunogenic: (1) foreignness; (2) high molecular weight; (3) chemical complexity; and, in most cases, (4) degradability and interaction with host major histocompatibility complex (MHC) molecules.
Foreignness
Animals normally do not respond immunologically to self. Thus, for example, if a rabbit is injected with its own serum albumin, it will not mount an immune response; it recognizes the albumin as self. By contrast, if rabbit serum albumin is injected into a guinea pig, the guinea pig recognizes the rabbit serum albumin as foreign and mounts an immune response against it. To prove that the rabbit, which did not respond to its own albumin, is immunologically competent, it can be injected with guinea pig albumin. The competent rabbit will mount an immune response to guinea pig serum albumin because it recognizes the substance as foreign.
Thus, the first requirement for a compound to be immunogenic is foreignness. The more foreign the substance, the more immunogenic it is. In general, compounds that are part of self are not immunogenic to that individual. However, there are exceptional cases in which an individual mounts an immune response against his or her own tissues. This condition is termed autoimmunity (see Chapter 12).
High Molecular Weight
The second feature that determines whether a compound is immunogenic is its molecular weight. In general, small compounds that have a molecular weight of less than 1000 Da (e.g., penicillin, progesterone, aspirin) are not immunogenic; those of molecular weights between 1000 and 6000 Da (e.g., insulin, adrenocorticotropic hormone [ACTH]) may or may not be immunogenic; and those of molecular weights greater than 6000 Da (e.g., albumin, tetanus toxin) are generally immunogenic. In short, relatively small substances have decreased immunogenicity whereas large substances have increased immunogenicity.
Chemical Complexity
The third characteristic necessary for a compound to be immunogenic is a certain degree of physicochemical complexity. Thus, for example, simple molecules such as homopolymers of amino acids (e.g., a polymer of lysine with a molecular weight of 30,000 Da) are seldom good immunogens. Similarly, a homopolymer of poly‐γ‐D‐glutamic acid (the capsular material of Bacillus anthracis) with a molecular weight of 50,000 Da is not immunogenic. The absence of immunogenicity is because these compounds, although of high molecular weight, are not sufficiently chemically complex. However, if the complexity is increased by attaching various moieties (such as dinitrophenol or other low molecular weight compounds), which by themselves are not immunogenic, to the ε amino group of polylysine, the entire macromolecule becomes immunogenic. The resulting immune response is directed not only against the coupled low molecular weight compounds but also against the high molecular weight homopolymer. In general, an increase in the chemical complexity of a compound is accompanied by an increase in its immunogenicity. Thus copolymers of several amino acids, such as polyglutamic, alanine, and lysine (poly‐GAT), tend to be highly immunogenic.
Because many immunogens are proteins, it is important to understand the structural features of these molecules. Each of the four levels of protein structure contributes to the molecule’s immunogenicity. The acquired immune response recognizes many structural features and chemical properties of compounds. For example, antibodies can recognize various structural features of a protein, such as its primary structure (the amino acid sequence), secondary structures (the structure of the backbone of the polypeptide chain, such as an α‐helix or β‐pleated sheet), and tertiary structures (formed by the three‐dimensional configuration of the protein, which is conferred by the folding of the polypeptide chain and held by disulfide bridges, hydrogen bonds, hydrophobic interactions, etc.) (