Bacterial Pathogenesis. Brenda A. Wilson
antigens and forming a large immune complex that deposits at certain sites, such as joints, and causes local inflammation at those sites.
Type IV hypersensitivity is a delayed response that takes one to two days to manifest and is caused by CD4+ Th1-memory-cell-mediated inflammatory responses to antigens or allergens.
Type V hypersensitivity (autoimmunity) is an IgG- or IgM-mediated immune response (similar to Type II) that is caused by antibodies binding to host cell antigens, which the immune system then perceives as nonself. This type of response sometimes occurs through molecular mimicry, in which a foreign antigen (such as a bacterium or bacterial product) shares structural features (epitopes) with certain host molecules, such that infection or exposure to the foreign antigen elicits antibodies against the common epitopes and thereby generates antibodies also against the host. Certain infections with superantigen-producing bacteria and viruses elicit strong nonspecific T cell or B cell activation and massive inflammatory responses that can also lead to autoimmunity.
Many of the symptoms of infections caused by metazoal parasites (such as helminths, also known as parasitic worms) are traceable to elevated levels of IgE during infection. The release of mast cell granules in the vicinity of the intestinal wall may provoke an allergic response in the host that leads to ejection of the metazoal parasites from the intestinal or pulmonary mucosal sites. An interesting fact to ponder is that the human body evolved over millions of years to respond to worm infestations, with IgE functioning as part of that response. However, in recent times, particularly in developed countries, worms have been almost entirely eliminated from the human intestinal landscape. As such, in these more developed areas where metazoal infections are relatively uncommon, IgE is actually most often associated with noninfectious diseases such as allergies or asthma.
The most serious complication of the massive release of mast cell granules is anaphylaxis, which can rapidly kill a person. Is the rise in allergies and asthma seen in developed countries due to an immunological imbalance caused by elimination of a former enemy, thereby leaving the worm-oriented part of the specific and nonspecific defenses with nothing to do except cause trouble? Rest assured that this is not the start of a “bring back the worms” initiative, but it is interesting to contemplate the potential negative consequences of an abrupt change (in evolutionary terms) in our exposure to invaders that have been with us since we first appeared as a species.
Secretory Antibodies: Antibodies That Protect Mucosal Surfaces
IgA. In its monomeric form, IgA represents about 10 to 15% of the total serum antibody content. The role of IgA in blood and tissue is to aid in the clearance of antigen-antibody immune complexes from the blood. Because IgA monomer is a poor opsonin and activator, IgA in blood binds to the Fc receptor on immune effector cells, stimulating inflammatory responses and causing ADCC. By far the most important form of IgA, however, is the dimeric secretory IgA (sIgA), the dominant antibody in mucosal secretions of the gastrointestinal, urogenital, and respiratory tracts, including tears, salivary glands, sweat, bile, colostrum, and milk.
Dimeric sIgA consists of two IgA antibody monomers joined end-to-end through disulfide bonds to a J-chain peptide and to another tightly bound peptide, called the secretory piece (Figure 4-1), acquired during transport out into the mucin layer (more on this later). The main role of sIgA is to attach to incoming microbes or toxic microbial components and trap them in the mucus layer, thus preventing them from reaching the epithelial surface. Because sIgA is also secreted into mother’s milk, sIgA, like IgG, serves as an important protection against infection for infants who have not yet developed their own set of immune responses.
IgA is heavily glycosylated in the hinge region, which protects it from proteolysis. The secretory piece also helps protect the protease-sensitive sites in the H-chain from cleavage by bacterial and host proteases. Humans have two subtypes of IgA, IgA1 and IgA2. An interesting evolutionary development is the production of an IgA1-specific protease by a number of pathogenic bacteria (e.g., Neisseria gonorrhoeae), which is thought to have provided a selective pressure that resulted in human development of another gene encoding IgA2 that lacks the sites recognized by the IgA1 protease.
Pathogen and Toxin Neutralization by Antibodies
Just as sIgA antibodies are able to bind to microbes and prevent mucosal binding and entry into the host epithelium, both IgG and IgM antibodies bind to the surfaces of invading bacteria and viruses and prevent them from attaching to and entering target host cells (neutralization of the pathogen) (see Table 4-1). Antibodies are able to act as neutralizing agents because they are bulky molecules that can block interaction between microbial surface proteins and the receptors they recognize on host cells. Antibodies can also neutralize toxic proteins produced and secreted by bacteria by binding to the toxins and preventing them from binding to host cell surface receptors, thereby blocking their toxic effects (toxin neutralization). In addition, antibodies can directly neutralize the catalytic activities of secreted bacterial enzymes such as proteases, nucleases, or glycosidases that normally work to degrade host extracellular molecules and allow the pathogen to disseminate throughout the body.
An example of protective antibody neutralization of a bacterial toxin is the antibody response to Corynebacterium diphtheriae, the cause of diphtheria, a serious toxin-mediated disease of children. Corynebacteria often live innocuously in the upper respiratory tract, but when they become infected with a corynebacteriophage encoding the diphtheria toxin gene, they are then able to produce and secrete the diphtheria toxin, which enters cells lining the respiratory tract and bloodstream. Diphtheria toxin is one of the most potent bacterial toxins known and can kill many types of human cells. The action of the toxin in the throat is evident from a grayish or whitish “pseudo-membrane” patch that consists of dead epithelial cells and mucus. In some cases, this membrane can grow to the point at which it causes asphyxiation. If the toxin makes it through the bloodstream to the heart, it can cause death due to heart failure. The most effective protective response to infection by toxin-producing C. diphtheriae, which is also the response elicited by the antidiphtheria vaccine, is the production of antibodies that bind to diphtheria toxin and prevent it from binding to and killing human cells (neutralization of the toxin).
Affinity and Avidity
A characteristic of antibody binding to antigens, which is of critical importance in assessing the effectiveness of the antibody, is the avidity of the antigen-binding site for the epitope it binds. Avidity is a combination of affinity (the strength of the binding interaction between an antigen-binding site and an epitope) and valence (the number of antigen-binding sites available for binding epitopes on an antigen). A single epitope can elicit a mixture of antibodies that vary considerably in affinity. This variation may arise because the body cannot know in advance what epitopes it will encounter, so it produces a variety of antibodies with differing antigen-binding sites, some of which will have a high affinity for a particular antigen. In fact, as the antibody response to an epitope develops, the B cells producing antibodies with the highest affinity will proliferate the most, and eventually those high-affinity antibodies will predominate.
High affinity is important, but it is not sufficient to ensure that an antibody bound to an epitope will retain its hold on the epitope. Because the binding between antigen-binding sites and epitopes is noncovalent, the interaction is reversible. Thus, there is an off-rate, as well as an on-rate, associated with antibody binding to an epitope. The importance of valence is that an antibody with a higher valence will be significantly less likely to detach from the antigen to which it is bound. If two antigen-binding sites of an antibody monomer bind to two adjacent epitopes on an antigen, the probability that both of them will detach at the same time is much lower than the probability that a single antigen-binding site will detach from its epitope. Thus, higher valence can improve the apparent strength of binding of an antibody to an epitope by orders of magnitude.
The differences in affinity and avidity between the first responders IgM/IgA and the adaptive IgG antibodies become important when one considers the roles that these different antibodies play in the immune response. Antibodies, such as IgM and sIgA, that appear early and have lower affinity and less specificity for the invading microbe need to have