Affinity Maturation Is the Result of Repeated Mutation and Selection

The average affinity of the antibodies produced during the course of the humoral response increases remarkably during the process of affinity maturation, an effect first noticed by H. N. Eisen and G. W. Siskind when they immunized rabbits

VISUALIZING CONCEPTS

Plasma Exiting B-CeU cell popuhticm

VISUALIZING CONCEPTS

Affinity Maturation

Plasma Exiting B-CeU cell popuhticm

Tingible-body macrophage

Centroblast (activated B cell)

Germinal center

Tingible-body macrophage

Centroblast (activated B cell)

Germinal center

Entering B-cell population Affinity = Kaj

Entering B-cell population Affinity = Kaj

FIGURE 11-17

Overview of cellular events within germinal centers. Antigen-stimulated B cells migrate into germinal centers, where they reduce expression of surface Ig and undergo rapid cell division and mutation of rearranged immunoglobulin V region genes within the dark zone. Subsequently, division stops and the B cells migrate to the light zone and increase their expression of surface Ig. At this stage they are called centrocytes. Within the light zone centrocytes must interact with follicular dendritic cells and T helper cells to survive. Follicular dendritic cells bind antigen-antibody complexes along their long extensions and the centro cytes must compete with each other to bind antigen. B cells bearing high-affinity membrane immunoglobulin (antibodies shown in blue) are most likely to compete successfully. Those that fail this antigen-mediated selection (antibodies shown in black) die by apoptosis. B cells that pass antigen selection and receive a second survival signal from TH cells differentiate into either memory B cells or antibody-secreting plasma cells. The encounter with TH cells may also induce class switching. A major outcome of the germinal center is to generate higher affinity B cells (Ka2) from B cells of lower affinity ( Ka1).

Frequency Somatic Hypermutation

0 200 400 600 800 1000 1200 1400 1600 1800 2000 Nucleotides

Promoter L

C region

FIGURE 11-18

The frequency of somatic hypermutation decreases with the distance from the rearranged V(D)J gene. Experimental measurement of the mutation frequency shows that few if any mutations are seen upstream of the promoter of the rearranged gene. Mutations do not extend into the portion of the gene encoding the constant region becaue there are no mutations at positions more than about 1.5 kb 3' of the rearranged gene. [Adapted from P. Gearhart, in Fundamental Immunology, 3rd ed, 1993, p. 877.]

with the hapten-carrier complex DNP-BGG. The affinity of the serum anti-DNP antibodies produced in response to the antigen was then measured at 2,5, and 8 weeks after immunization. The average affinity of the anti-DNP antibodies increased about 140-fold from 2 weeks to 8 weeks. Subsequent work has shown that affinity maturation is mainly the result of somatic hypermutation.

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