The Primary Response
The Secondary Response
Response to Multiple Antigens Administered Simultaneously
Function of Antibodies
Antibodies in the Fetus
Tests for Evaluation of Humoral Immunity
Practice Questions: USMLE & Course Examinations
Humoral (antibody-mediated) immunity is directed primarily against (1) exotoxin-mediated diseases such as tetanus and diphtheria, (2) infections in which virulence is related to polysaccharide capsules (e.g., pneumococci, meningococci, Haemophilus influenzae), and (3) certain viral infections. In this chapter, the kinetics of antibody synthesis (i.e., the primary and secondary responses) are described. The functions of the various immunoglobulins are summarized in this chapter and are described in detail in Chapter 59.
THE PRIMARY RESPONSE
The primary response occurs the first time that antigen is encountered. In the primary response, antibodies are detectable in the serum after a longer lag period than occurs in the secondary response. This concept is medically important because the protection afforded by a vaccine the first time it is given is delayed compared with the protection afforded by a booster shot in which a faster secondary response occurs.
The lag period of the primary response is typically 7 to 10 days but can be longer depending on the nature and dose of the antigen and the route of administration (e.g., parenteral or oral). A small clone of B cells and plasma cells specific for the antigen is formed. The serum antibody concentration continues to rise for several weeks, then declines and may drop to very low levels (Figure 60–1). The first antibodies to appear in the primary response are IgM, followed by IgG or IgA. IgM levels decline earlier than IgG levels.
FIGURE 60–1 Antibody synthesis in the primary and secondary responses. In the primary response, immunoglobulin (Ig) M is the first type of antibody to appear. In the secondary response, IgG appears earlier and shows a more rapid rise and a higher final concentration than in the primary response. If at the time of the second exposure to the antigen (Ag1), a second, non–cross-reacting antigen (Ag2) was injected, a primary response to Ag2 would occur while a secondary response to Ag1 was occurring.
THE SECONDARY RESPONSE
When there is a second encounter with the same antigen or a closely related (or cross-reacting) one, months or years after the primary response, there is a rapid antibody response (the lag period is typically only 3–5 days) to higher levels than the primary response. This is attributed to the persistence of antigen-specific “memory cells” after the first contact. These memory cells proliferate to form a large clone of specific B cells and plasma cells, which mediate the secondary antibody response.
During the secondary response, the amount of IgM produced is similar to that after the first contact with antigen. However, a much larger amount of IgG antibody is produced, and the levels tend to persist much longer than in the primary response.
With each succeeding exposure to the antigen, the antibodies tend to bind antigen more firmly. Antibody binding improves because mutations occur in the DNA that encodes the antigen-binding site, a process called somatic hypermutation. Some mutations result in the insertion of different amino acids in the hypervariable region that result in a better fit and cause the antigen to be bound more strongly. The subset of plasma cells with these improved hypervariable regions are more strongly (and more frequently) selected by antigen and therefore constitute an increasingly larger part of the population of antibody-producing cells. This process is called affinity maturation. One important effect of booster doses of vaccines is to improve antibody binding by enhancing the affinity maturation process.
Affinity maturation occurs in the germinal centers of the follicles in the spleen and lymph nodes. Follicle dendritic cells capture antigen–antibody complexes on their surface via Fc receptors. The complexes interact with an activated B cell bearing the immunoglobulin that best fits the antigen, and it is that B cell that is stimulated to form a clone of many B cells capable of synthesizing the improved antibody.
RESPONSE TO MULTIPLE ANTIGENS ADMINISTERED SIMULTANEOUSLY
When two or more antigens are administered at the same time, the host reacts by producing antibodies to all of them. Competition of antigens for antibody-producing mechanisms occurs experimentally but appears to be of little significance in medicine. Combined immunization is widely used (e.g., the diphtheria, tetanus, and pertussis [DTP] vaccine or the measles, mumps, rubella [MMR] vaccine).
FUNCTION OF ANTIBODIES
The primary function of antibodies is to protect against infectious agents or their products (see Table 59–2). Antibodies provide protection because they can (1) neutralize toxins and viruses and (2) opsonize microorganisms. Opsonization is the process by which antibodies make microorganisms more easily ingested by phagocytic cells. This occurs by either of two reactions: (1) the Fc portion of IgG interacts with its receptors on the phagocyte surface to facilitate ingestion or (2) IgG or IgM activates complement to yield C3b, which interacts with its receptors on the surface of the phagocyte.
Antibodies can be induced actively in the host or acquired passively and are thus immediately available for defense. In medicine, passive immunity is used in the neutralization of the toxins of diphtheria, tetanus, and botulism by antitoxins and in the inhibition of such viruses as rabies and hepatitis A and B viruses early in the incubation period.
ANTIBODIES IN THE FETUS
Antibodies in the fetus are primarily IgG acquired by transfer of maternal IgG across the placenta. Some antibodies can be made by the fetus if infection occurs, such as in congenital syphilis. Newborn infants can make IgG (and other isotypes, such as IgM and IgA) to certain protein antigens. For example, the vaccine against hepatitis B that contains hepatitis B surface antigen is effective when given to newborns. After birth, maternal IgG declines and protection from maternal IgG is lost by 3 to 6 months.
TESTS FOR EVALUATION OF HUMORAL IMMUNITY
Evaluation of humoral immunity consists primarily of measuring the amount of each of the three important immunoglobulins (i.e., IgG, IgM, and IgA) in the patient’s serum. This is usually done by nephelometry. Immunoelectrophoresis can also provide valuable information. These techniques are described in Chapter 64.
1. Regarding the primary and secondary (anamnestic) immune responses, which one of the following is most accurate?
(A) The IgM made in the primary response is made primarily by memory B cells.
(B) The lag phase is shorter in the primary response than in the secondary response.
(C) In the primary response, memory B cells are produced, but memory T cells are not.
(D) The amount of IgG made in the secondary response is greater than the amount made in the primary response.
2. Which one of the following is a function of humoral (antibody-mediated) immunity?
(A) Neutralize bacterial toxins
(B) Activate the alternative pathway of complement
(C) Inhibit the growth of Mycobacterium tuberculosis
(D) Inhibit the growth of virus-infected cells by enhancing the production of perforins
PRACTICE QUESTIONS: USMLE & COURSE EXAMINATIONS
Questions on the topics discussed in this chapter can be found in the Immunology section of PART XIII: USMLE (National Board) Practice Questions starting on page 713. Also see PART XIV: USMLE (National Board) Practice Examination starting on page 731.