Y. Wang et al., Antigen persistence is required for somatic mutation and affinity maturation of immunoglobulin, EUR J IMMUN, 30(8), 2000, pp. 2226-2234
Whether germinal centers (GC) with follicular dendritic cell (FDC) clusters
are the essential sites for affinity maturation of immunoglobulin is still
controversial. To re-evaluate the role of GC/FDC in affinity maturation an
d somatic mutation in a defined antigen system, lymphotoxin-alpha(-/-) and
TNF receptor I-/- mice, lacking GC/FDC, were immunized with (4-hydroxy-3-ni
trophenyl) acetyl-sheep RBC (NP-SRBC). In contrast to soluble hapten-carrie
r systems, NP-SRBC allows us to compare affinity maturation in the presence
or absence of adjuvant. These mice showed a dramatically impaired ability
to generate high-affinity IgG to NP, but retained the ability to produce lo
w-affinity anti-NP IgG when NP-SRBC was used in the absence of adjuvant. In
contrast to wild-type mice, somatic mutation of the expressed IgG heavy ch
ain gene was rarely detected in these GC/FDC-deficient mice. This suggests
that GC/FDC are essential for affinity maturation. Trapping antigen-specifi
c B cells inside the T cell zone of TNFRI-/- mice may prolong the interacti
on between T and B cells, which allows class switching but no further affin
ity maturation of IgG. Interestingly, GC/FDC-deficient mice could be induce
d to generate high-affinity, somatically mutated IgG antibodies by immuniza
tion with the same amount of NP-SRBC antigen emulsified in incomplete Freun
d's adjuvant or repeated immunization with the antigen alone. Thus, these d
ata support a model in which prolonged availability of antigen is required
for somatic mutation and affinity maturation, and FDC or adjuvants facilita
te such processes by slowly releasing antigens.