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Figure 4-3. The time course of elicitation of antibodies upon initial exposure and subsequent exposure. After exposure to an antigen such as antigen A, IgM is usually the first antibody detected during an acute infection, but levels decrease again after about two weeks. It takes five to seven days for selection and proliferation of B cells producing IgG against antigen A to appear in the blood. After a period of time, the levels of IgG also decrease. Subsequent exposure to antigen A again results in production of IgM at about the same levels as after the first exposure, but the levels of antigen A-specific IgG are now much higher. In contrast, exposure to antigen B along with the second exposure to antigen A does not enhance the antigen B-specific IgG levels.
IgD. IgD monomer is initially coexpressed with IgM on the surface of mature B cells as they exit the bone marrow and migrate to peripheral lymphoid tissues. IgD appears to function primarily to signal B cell activation.
IgE. A serum antibody with a function different from that of IgG and IgM is IgE. IgE is a monomer that is normally found in extremely low concentrations in serum (only 0.05% of total Ig concentration), usually as an Fc receptor-bound complex on the surface of mast cells and basophils. If two IgE molecules bound to mast cells are complexed by a polyvalent antigen (i.e., an antigen with multiple antibody-binding sites), it causes clustering of the Fc receptors, which stimulates the mast cell to release granules containing potent proinflammatory chemokines, in particular the vasoactive amines histamine and serotonin, as well as leukotrienes and cytokines such as IL-4 and IL-13 (Figure 4-4). These IgE-induced responses also initiate the strong inflammatory reactions associated with allergies and asthma (Box 4-2).
Figure 4-4. Antibody-mediated mast cell degranulation. Antigen-mediated clustering of IgE bound to Fc receptors on mast cells triggers degranulation and release of allergic mediators, such as histamines, serotonin, vasoactive amines, and other inflammatory cytokines.
Box 4-2.
The Dark Side of Adaptive Immunity: Allergy and Autoimmunity
Hypersensitivity is a set of undesirable, uncomfortable, and sometimes fatal reactions resulting from an overstimulation of inflammatory responses that cause host damage. Allergens that cause hypersensitivity include plant pollens, fungal spores, insect venom, animal dander, house dust mites, some foods, and certain chemicals (e.g., poison ivy, latex, jewelry, detergents, cosmetics). There are five types of hypersensitivity with differing times of onset and immune mediators:
Type I hypersensitivity occurs within minutes and is mediated through antigen binding and clustering of IgE-Fc receptors on mast cells and basophils, which causes release of histamine and vasoactive cytokines (as in Figure 4-4).
Type II hypersensitivity occurs within hours and is mediated through IgG- or IgM-receptor clustering on a target (infected) host cell, which the immune system then perceives as nonself and targets for attack by MAC by complement and/or ADCC by NK cells or macrophages.
Type III hypersensitivity occurs within hours and is mediated by IgG antibody binding to soluble, circulating 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
