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Tag words: immunity, pathogen, immunology, immune system, immunological system, immune response, adaptive immunity, acquired immunity, active immunity, passive immunity, antigen, antigen presentation, antibody, antibodies, lymphokine, complement, opsonization, antibody-mediated immunity, AMI, cell mediated immunity, CMI, IgG, IgA, IgM, IgE, B cells, T cells, NK cells, IL-1, IL-2, IL-4.

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Immune Defense against Bacterial Pathogens: Adaptive or Acquired Immunity (page 5)

(This chapter has 6 pages)

© Kenneth Todar, PhD

Antibody-mediated Immunity

Antibodies are proteins produced by lymphocytes that can specifically bind a wide variety of protein and polysaccharide antigens and elicit a response that is significant in antimicrobial defense. In conjunction with the complement system, antibodies are the mediators of humoral (circulating) immunity, and their presence on mucosal surfaces provides resistance to many infectious agents. Antibodies are essential for the prevention and/or cure of many types of bacterial and viral infections.

As mediators of immunity, it was discovered at the turn of the century that antibodies were contained within the serum fraction of blood. It was demonstrated in 1939 that antibodies were specifically located in the gamma fraction of electrophoresed serum, thus the term gamma globulin was coined for serum containing antibodies. Antibodies themselves, were called immunoglobulins.

The Classes of Antibodies

There are a number of types of antibodies or immunoglobulins that react stereochemically and specifically with an antigen that induced their formation. Each of these classes of immunoglobulins (abbreviated Ig) is produced by a specific clone of plasma cells. Five immunoglobulin classes are defined on the basis of their heavy chain composition, named IgG, IgM, IgA, IgE, and IgD. IgG and IgA are further divided into subclasses.

The classes of immunoglobulins have different physical and chemical characteristics and they exhibit unique biological properties. Their synthesis occurs at different stages and rates during an immunological response and/or during the course of an infection. Their importance and functions in host resistance (immunity) are different.

IgG. Immunoglobulin G is the predominant Ig in the serum; it makes up about 80% of the total antibody found in an animal at any given time, being 75% of the total serum antibody. It can diffuse out of the blood stream into the extravascular spaces and it is the most common Ig found there. Its concentration in tissue fluids is increased during inflammation. It is particularly effective at the neutralization of bacterial exotoxins and viruses. It also has opsonizing ability and complement-fixing ability. IgG crosses the placental barrier, and thereby provides passive immunity to the fetus and infant for the first six months of life.

IgG is the model for our understanding the structure and function of antibody molecules, so examination of its biochemical properties is appropriate before discussion of the other types of immunoglobulins.

Figure 5. Model of an Immunoglobulin: the Structure of IgG (see discussion below)

IgG is a protein with a molecular weight of about 150,000 daltons. The protein consists of two identical heavy (H) chains (each with a mw of about 50kDa) and two identical light (L) chains (mw about 25kDa). Each L chain is connected to a H chain and the two H-chains are connected to one another by disulfide bridges. The molecule is drawn to look like a Y. The stem of the Y is called the Fc region and it consists mainly of two halves of the identical H chains. Each of the "arms" of the Y contains one complete L-chain and half of one of the H-chains. The Y stem stands on the carboxy termini of the H chains; the tips of the arms contain the amino termini of the H and L-chains. Each arm is sometimes referred to as the Fab region of the molecule. The Fab region is the antigen binding fragment of the antibody molecule. A specific region of the antigen (called the antigenic determinant) will react stereochemically with the antigen-binding region at the amino terminus of each Fab. Hence, the IgG molecule, which has two antigen binding fragments [(Fab)2] is said to be divalent: it can bind to two Ag molecules. The polypeptide composition of the Fc region of all IgG1 antibody molecules is relatively constant regardless of antibody specificity; however, the Fab regions always differ in their exact amino acid sequences depending upon their antigenic specificity. Even though the antigen does not react with the Fc region of the IgG molecule, this should not be taken to mean that the Fc region has no importance or biological activity. On the contrary, specific amino acid regions of the Fc portion of the molecule are recognized by receptors on phagocytes and certain other cells, and the Fc domain contains a peptide region that will bind to and activate complement, which is often required for the manifestation of AMI.

Understanding the structure and properties of IgG is useful to discussion of its function in host defense. Since the IgG molecule is divalent, it can cross-link Ag molecules, which may lead to precipitation or agglutination of antigens; if IgG is bound to Ag on a microbial cell surface, its Fc region may provide an extrinsic ligand which will be recognized by specific receptors on phagocytes. Such microbial cells or viruses coated with IgG molecules are said to be opsonized for phagocytosis. Opsonized pathogens are taken up and destroyed much more readily by phagocytes than their non-opsonized counterparts. IgG, as well as IgM and IgA, will neutralize the activity of toxins, including bacterial exotoxins. Furthermore, cross-linked IgG molecules on the surface of a cell can bind and activate complement from the serum and set off a cascade of reactions that can lead to destruction of the cell. It is because of its relatively small size and its persistence in the serum of a mother that IgG is shared with the fetus in utero, such that an infant is born with the full complement of mother's IgG antibodies.

IgM is the first immunoglobulin to be synthesized by infants and the first to appear in the blood stream during the course of an infection. Mainly, it is confined to the bloodstream giving the host protection against blood-borne pathogens. IgM makes up about 10% of the total serum immunoglobulins. IgM is arranged to resemble a pentamer of five immunoglobulin molecules (mw = 900kDa) tethered together at by their Fc domains (Figure 6). In addition to covalent linkages between the monomeric subunits, the pentamer is stabilized by a 15kDa polypeptide called the J chain. IgM, therefore, has a theoretical "valence" of 10 (i.e., it has exposed 10 Fab domains). Probably, the most important role of IgM is its ability to function early in the immune responses against blood-borne pathogens. As might be expected, IgM is very efficient at agglutinating particulate antigens. Also, IgM binds complement strongly and such IgM antibodies bound to a microbial surface act as opsonins, rendering the microbe more susceptible to phagocytosis. In the presence of complement and IgM whole microbial cells may be killed and lysed. IgM also appears on the surfaces of mature B cells as a transmembranous monomer where it functions as an antigen receptor, capable of activating B cells when bound to antigen.

Figure 6. Schematic representation of the various Classes of Immunoglobulins

IgA exists as a 160kDa monomer in serum and as a 400kDa dimer in secretions. As in the case of IgM, polymerization (dimerization) is via a J-chain (Figure 6). There are two subclasses based on different heavy chains, IgA1 and IgA2. IgA1 is produced in bone marrow and makes up most of the serum IgA. Both IgA1 and IgA2 are synthesized in GALT (gut associated lymphoid tissues) to be secreted onto the mucosal surfaces. Since IgA may be synthesized locally and secreted in the seromucous secretions of the body, it is sometimes referred to as secretory antibody or sIgA. Quantitatively, IgA is synthesized in amounts greater than IgG, but it has a short half life in serum (6 days), and it is lost in secretory products. The concentration of IgA in serum is about 15% of the total antibody. Secretion of dimeric IgA is mediated by a 100kDa glycoprotein called the secretory component. It is the addition of the secretory component to the IgA molecules that accounts for their ability to exit the body to mucosal surfaces via the exocrine glands. IgM can be transported similarly but makes up a small proportion of secretory antibodies.

Secretory IgA is the predominant immunoglobulin present in gastrointestinal fluids, nasal secretions, saliva, tears and other mucous secretions of the body. IgA antibodies are important in resistance to infection of the mucosal surfaces of the body, particularly the respiratory, intestinal and urogenital tracts. IgA acts as a protective coating for the mucous surfaces against microbial adherence or initial colonization. IgA can also neutralize toxin activity on mucosal surfaces. Fc receptors for IgA-coated microbes are found on monocytes and neutrophils in the lower respiratory tract, suggesting that IgA may have a role (in the lung, at least) in opsonization of pathogens. IgA does not activate complement, however.

Secretory IgA is also transferred in milk, via the colostrum, from a nursing mother to an infant. This provides passive immunity to many pathogens, especially those that enter by way of the GI tract. The transfer of IgA via the milk lasts about six months in the mother, during which time the nursing infant is protected from many infectious agents. Under these circumstances, the infectious agent might multiply to a limited extent, which stimulates the infant's own immune response without causing significant disease. Thus, as in the case with transplacental IgG, the infant acquires active immunity while undergoing protection by passive immunity.

IgE  is a 190kDa immunoglobulin that accounts for merely 0.002% of the total serum immunoglobulins. It is produced especially by plasma cells below the respiratory and intestinal epithelia. The majority of IgE is bound to tissue cells, especially mast cells. If an infectious agent succeeds in penetrating the IgA barrier, it comes up against the next line of defense, the MALT (mucosa-associated lymphoid tissues) system which is manned by IgE. IgE is bound very firmly to specific Fc receptors on the surface of mast cells. Contact with Ag leads to release of mediators of inflammation from the mast cells, which effectively recruits various agents of the immune responses including complement, chemotactic factors for phagocytes, T-cells, etc. Although a well-known manifestation of this reaction is a type of immediate hypersensitivity reaction called atopic allergy (e.g. hives, asthma, hay fever, etc.). However, the MALT responses are an important defense mechanism because they amplify the local inflammatory response that facilitates rejection of a pathogen.

IgD is a 175kDa molecule that resembles IgG in its monomeric form. IgD antibodies are found for the most part on the surfaces of B lymphocytes. The same cells may also carry IgM antibody. It is thought that IgD and IgM function as mutually-interacting antigen receptors for control of B-cell activation and suppression. Hence, IgD may have an immunoregulatory function. Recall that only specific subclones of B-cells respond to a specific Ag upon stimulation. The B-cell bears a specific receptor (in the form of IgD) for the Ag that it specifically recognizes. It stands to reason that the basis of this specificity is mediated by a molecule with immunoglobulin characteristics. The T-cell receptor (TCR) is also a molecule with immunoglobulin-like characteristics.

Functions of Antibodies in Host Defense

The functions of  antibodies, and hence the AMI response, in host defense against pathogenic microbes is summarized below.

Opsonization Antibodies enhance phagocytic engulfment of microbial antigens. IgG and IgM Abs have a combining site for the Ag and a site for cytophilic association with phagocytes. Bacteria and viral particles are ingested with increased efficiency.

Steric hindrance Antibodies combine with the surfaces of microorganisms and may block or prevent their attachment to susceptible cells or mucosal surfaces. Ab against a viral component can block attachment of the virus to susceptible host cells and thereby reduce infectivity. Secretory IgA can block attachment of pathogens to mucosal surfaces.

Toxin Neutralization Toxin-neutralizing antibodies (antitoxins) react with a soluble bacterial toxin and block the interaction of the toxin with its specific target cell or substrate in the host.

Agglutination and Precipitation Antibodies combine with the surfaces of microorganisms or soluble antigens and cause them to agglutinate or precipitate. This reduces the number of separate infectious units and makes them more readily phagocytosed because the clump of particles is larger in size. Also, floccules or aggregates of neutralized toxin may be removed by phagocytes.

Activation of Complement Antibodies combined with the surface antigens of microbes activate the complement cascade which has four principal effects related to host defense:

1. induction of the inflammatory response

2. attraction of phagocytes to the site of immunological encounter

3. opsonization of cells which increases efficiency of phagocytosis

4. lysis of certain bacteria or viruses

Antibody-dependent cell cytotoxicity (ADCC): IgG can enable certain cells (Natural Killer or NK cells) to recognize and kill opsonized target cells. Certain other types of cells including monocytes and neutrophils also act this way. NK cells attach to opsonized target cells by means of an IgG Fc receptor and kill by an extracellular mechanism after attachment. ADCC will be discussed as part of cell-mediated immunity.

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Kenneth Todar has taught microbiology to undergraduate students at The University of Texas, University of Alaska and University of Wisconsin since 1969.

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