Characteristics Of Antibodies

By a genetically determined mechanism, immunocompetent humans are able to produce antibodies specifically directed against almost all the antigens with which they might come into contact throughout their lifetimes and which the body recognizes as foreign. Antigens may be part of the physical structure of the pathogen, or they may be a chemical produced and released by the pathogen, such as an exotoxin. One pathogen may contain or produce many different antigens that the host will recognize as foreign, so that infection with one agent may cause a number of different antibodies to be produced. In addition, some antigenic determinants of a pathogen may not be available for recognition by the host until the pathogen has undergone a physical change. For example, until a pathogenic bacterium has been digested by a human polymorphonuclear leukocyte, certain antigens deep within the cell wall are not detected by the host immune system. Once the bacterium is broken down, these new antigens are revealed and antibodies can be produced against them. For this reason, a patient may produce different antibodies at different times during the course of a single disease. The immune response to an antigen also matures with continued exposure, and the antibodies produced against it become more specific and more avid (able to bind more tightly).

Antibodies function' by (1) attaching to the surface of pathogens and making the pathogens more amenable to ingestion by phagocytic cells (opsonizing antibodies); (2) binding to and blocking surface receptors for host cells (neutralizing antibodies); or

(3) attaching to the surface of pathogens and contributing to their destruction by the lytic action of complement (complement-fixing antibodies). Although routine diagnostic serologic methods are usually used to measure only two antibody classes, IgM and IgG, there are five different classes of antibodies, immunoglobulin G (IgG), immunoglobulin M (IgM), immunoglobulin A (IgA), immunoglobulin D (IgD), and immunoglobulin E (IgE). IgA is the predominant class of antibody in saliva, tears, and intestinal secretions. The role of IgD in infection is unknown, and IgE rises during infections by several parasites.

The basic structure of an antibody molecule comprises two mirror images, each composed of two identical protein chains (Figure 10-1). At the terminal ends are the antigen-binding sites, which specifically attach to the antigen against which the antibody was produced. Depending on the specificity of the antibody, antigens of some similarity, but not total identity, to the inducing antigen may also be bound; this is called a cross reaction. The complement-binding site is found in the center of the molecule in a structure that is similar for all antibodies of the same class. IgM is produced as a first response to many antigens, although the levels remain high only transiently. Thus, presence of IgM usually indicates recent or active exposure to antigen or infection. On the other hand, IgG antibody may persist long after infection has run its course. The IgM antibody type (Figure 10-2) consists of five identical proteins, with the basic antibody structures linked together at the bases, leaving 10 antigen-binding sites available. The second antibody class, IgG, consists of one basic antibody molecule with two binding sites (see Figure 10-1). The differences in the size and conformation between these two classes of immunoglobulins result in differences in activities and functions.

Features of the Humoral Immune Response Useful in Diagnostic Testing

Immunocompetent humans produce both IgM and IgG antibodies in response to most pathogens. In most cases, IgM is produced by a patient only after the first interaction with a given pathogen and is no longer detectable within a relatively short period afterward. For serologic diagnostic purposes, one important difference between IgG and IgM is that IgM cannot cross the placenta of pregnant women. Therefore, any IgM detected in the serum of a newborn baby must have been produced by the baby itself. The larger number of binding sites on IgM molecules can help to clear the offending pathogen more quickly, even though each individual antigen-binding site may not be the most efficient for attaching the antigen. Over time, the cells that were producing IgM switch to producing IgG.

IgG is often more specific for the antigen (more avid). The IgG has only two antigen-binding sites, but it can also bind complement. When IgG has bound to an antigen, the base of the molecule may be left projecting out in the environment. Structures on the IgG's base attract and bind the cell membranes of phagocytes, increasing the chances of engulfment and destruction of the pathogen by the host cells. A second encounter with the same pathogen usually induces only an IgG response. Because the B lymphocytes retain memory of this pathogen, they can respond more quickly and with larger numbers of antibodies than at the initial interaction. This enhanced response is called the anamnestic response. Because the B-cell memory is not perfect, occasional clones of memory cells will be stimulated by an antigen that is similar but not identical

First stimulus Second stimulus

Figure 10-3 Relative humoral response to antigen stimulation over time.

First stimulus Second stimulus

Figure 10-3 Relative humoral response to antigen stimulation over time.

to the original antigen; thus the anamnestic response -May be polyclonal and nonspecific For example, reinfection with cytomegalovirus may stimulate memory B cells to produce antibody against Epstein-Barr virus (another herpes family virus), which they encountered previously, in addition to andbody against cytomegalovirus. The relative humoral responses over time are diagrammed in Figure 10-3.

Interpretation of Serologic Tests

A central dogma of serology is the concept of rise in titer. Ehe titer of andbody is the reciprocal of the highest dilution of the padent's serum in which the andbody is still detectable. Patients with large amounts of antibody have high titers, because antibody is still detectable at very high dilutions of serum. Serum for antibody levels should be drawn during the acute phase of the disease (when it is first discovered or suspected) and again during convalescence (usually at least 2 weeks later). These specimens are called acute and convalescent sera. For some infections, such as legionnaires' disease and hepatitis, titers may not rise until months after the acute infection, or they may never rise.

Patients with intact humoral immunity develop increasing amounts of antibody to a disease-causing pathogen over several weeks. If it is the patient's first encounter with the pathogen and the specimen has been obtained early enough, no or very low titers of antibody will be detected at the onset of disease. In the case of a second encounter, the patient's serum will usually contain measurable antibody during the initial phase of the disease and the level of the antibody will quickly increase, because of the anamnestic response. For most pathogens, an increase in the patient's titer of two doubling dilutions (e.g., from a positive result at 1:8 to a positive result at 1:32) is considered to be diagnostic of current infection. This is called a fourfold rise in titer.

Accurate results used for diagnosis of many infections are achieved only when acute and conva lescent sera are tested concurrently in the same test system, because variables inherent in the procedures and laboratory error can easily result in differences of one doubling (or twofold) dilution in the results obtained from even the same sample tested at the same time. Unfortunately, a certain proportion of infected patients may never show a rise in titer, necessitating the use of other diagnostic measures. Because the delay inherent in testing paired acute and convalescent sera results in diagnostic information that arrives too late to influence initial therapy, increasing numbers of early (IgM) serologic testing assays are being commercially evaluated. Moreover, it is sometimes more realistic to see a fourfold fall in titer between acute and convalescent sera when they are tested concurrentiy in the same system because sera may be collected late in the course of an infection in many cases when antibodies have already begun to decrease.

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