In situ studies of the primary immune response to (4-hydroxy-3-nitrophenyl)acetyl. III. The kinetics of V region mutation and selection in germinal center B cells.
Abstract
In the murine spleen, germinal centers are the anatomic sites for antigen-driven hypermutation
and selection of immunoglobulin (Ig) genes. To detail the kinetics of Ig mutation
and selection, 178 VDJ sequences from 16 antigen-induced germinal centers were analyzed.
Although germinal centers appeared by day 4, mutation was not observed in germinal
center B cells until day 8 postimmunization; thereafter, point mutations favoring
asymmetrical transversions accumulated until day 14. During this period, strong phenotypic
selection on the mutant B lymphocytes was inferred from progressively biased distributions
of mutations within the Ig variable region, the loss of crippling mutations, decreased
relative clonal diversity, and increasingly restricted use of canonical gene segments.
The period of most intense selection on germinal center B cell populations preceded
significant levels of mutation and may represent a physiologically determined restriction
on B cells permitted to enter the memory pathway. Noncanonical Ig genes recovered
from germinal centers were mostly unmutated although they probably came from antigen-reactive
cells. Together, these observations demonstrate that the germinal center microenvironment
is rich and temporally complex but may not be constitutive for somatic hypermutation.
Type
Journal articleSubject
AnimalsB-Lymphocytes
Base Sequence
DNA, Single-Stranded
Female
Genes, Immunoglobulin
Immunoglobulin Heavy Chains
Immunoglobulin Variable Region
Kinetics
Mice
Mice, Inbred C57BL
Molecular Sequence Data
Mutation
Nitrophenols
Phenotype
Phenylacetates
Polymerase Chain Reaction
Spleen
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https://hdl.handle.net/10161/11486Collections
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Show full item recordScholars@Duke
Garnett H. Kelsoe
James B. Duke Distinguished Professor of Immunology
1. Lymphocyte development and antigen-driven diversification of immunoglobulin and
T cell antigen receptor genes. 2. The germinal center reaction and mechanisms for
clonal selection and self - tolerance. The origins of autoimmunity. 3. Interaction
of innate- and adaptive immunity and the role of inflammation in lymphoid organogenesis.
4. The role of secondary V(D)J gene rearrangment in lymphocyte development and malignancies.
5. Mathematical modeling of immune responses,

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