Affinity maturation of antibodies
Table 1. Calculated number of generations required to generate the observed mutations after three injections of coupled phOx Response
In a recent article Tim Manser (Immunol. Today 1990, 11, 305308) addressed the issue of the efficiency of the affinity maturation of antibodies. He assumed that the rate of B-cell division is incompatible with the fast accumulation of mutants, because somatic mutation "does not occur throughout the immune response". He goes on to state that "two weeks after immunization, the frequency of mutation assayed by hybridomas (particularly translationally silent mutations not subject to selection) does not differ greatly from that seen in the early secondary response (Ref. 20 and T. Manser, unpublished observations)". I will be interested to see the unpublished observations, but Ref. 20 (of Ref. 1) states quite clearly the contrary: "Our model is based on the quantitative increase in the number of somatic mutations observed between the primary, the secondary and the tertiary response (Even et al., 1985; Berek & Milstein, 1987) "2-3. This is true for both silent and nonsilent mutations (Table 1). It is generally accepted that the number of somatic mutations is higher in secondary than in primary responses. However, not everyone agrees that the increase in somatic mutations is due to the capacity of memory cells to undergo further rounds of somatic mutation after a new antigenic stimulus. For instance, it has been suggested that the data "cannot exclude ... selection and outgrowth over time of rare preexisting mutants through preferential stimulation ''4. There is good evidence that, after a limited number of cell divisions during which hypermutation takes place, the mutational machinery is shut off (reviewed in Ref. 4), possibly due to the end of the antigenic stimulation. In my view, there is also good evidence that re-stimulation of memory B cells leads not only to proliferation of pre-existing mutants, but also to new rounds of hypermutation. This evidence derives from the accumulation of mutants in late primary, secondary and tertiary responses to oxazolone 1. Thus, in the study of the maturation of the response to ox-
Accumulated mutants (in 103 bases)
Number of generations required for mutation rate
Table 1. Calculated number of generations required to generate the observed mutations after three injections of coupled phOx Response
In a recent article Tim Manser (Immunol. Today 1990, 11, 305308) addressed the issue of the efficiency of the affinity maturation of antibodies. He assumed that the rate of B-cell division is incompatible with the fast accumulation of mutants, because somatic mutation "does not occur throughout the immune response". He goes on to state that "two weeks after immunization, the frequency of mutation assayed by hybridomas (particularly translationally silent mutations not subject to selection) does not differ greatly from that seen in the early secondary response (Ref. 20 and T. Manser, unpublished observations)". I will be interested to see the unpublished observations, but Ref. 20 (of Ref. 1) states quite clearly the contrary: "Our model is based on the quantitative increase in the number of somatic mutations observed between the primary, the secondary and the tertiary response (Even et al., 1985; Berek & Milstein, 1987) "2-3. This is true for both silent and nonsilent mutations (Table 1). It is generally accepted that the number of somatic mutations is higher in secondary than in primary responses. However, not everyone agrees that the increase in somatic mutations is due to the capacity of memory cells to undergo further rounds of somatic mutation after a new antigenic stimulus. For instance, it has been suggested that the data "cannot exclude ... selection and outgrowth over time of rare preexisting mutants through preferential stimulation ''4. There is good evidence that, after a limited number of cell divisions during which hypermutation takes place, the mutational machinery is shut off (reviewed in Ref. 4), possibly due to the end of the antigenic stimulation. In my view, there is also good evidence that re-stimulation of memory B cells leads not only to proliferation of pre-existing mutants, but also to new rounds of hypermutation. This evidence derives from the accumulation of mutants in late primary, secondary and tertiary responses to oxazolone 1. Thus, in the study of the maturation of the response to ox-
Accumulated mutants (in 103 bases)
Number of generations required for mutation rate
