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Introduction
ANTIBODY REPERTOIRES AND PATHOGEN RECOGNITION: THE ROLE OF GERMLINE DIVERSITY AND SOMATIC HYPERMUTATION.
Mihaela Oprea
Introduction
Rationale
Brief introduction to the immune system
Innate versus adaptive immunity
The development of an immune response
Self-nonself discrimination
The anticipatory capacity of the immune system
Structural components of the immune receptors
How much can germline diversity do?
Shape space coverage with distance-dependent matching
Model
Lower bound on the evolved fitness
Upper bound on the evolved fitness
The fitness of evolved libraries
The strategy of evolved libraries
Shape space coverage with other matching rules
Lower bound on the fitness
The fitness and structure of evolved libraries
Implications for random antibody libraries
Somatic hypermutation targets the antigen-binding regions of antibody genes
Calculating the predicted replacement mutability of a sequence
All human immunoglobulin
V
-region sequences have higher average replacement mutability of CDR nucleotides than of FR nucleotides
Statistical analysis on the level of individual sequences
Contribution of nucleotide composition, codon composition and codon usage bias to the predicted FR and CDR replacement mutability of human
V
H
sequences
Are human
V
-region sequences optimized for somatic hypermutation?
Similar mutability pattern in
V
genes from other species
Higher predicted replacement mutability of T cell receptor CDRs than T cell receptor FRs
Non-immunoglobulin genes would have low mutability under somatic hypermutation
In non-immunoglobulin genes, predicted mutability is correlated with A/T content
A significant proportion of non-immunoglobulin genes also have codon bias consistent with low mutability under somatic hypermutation
Mutants must be generated and selected in a step-wise fashion during the germinal center reaction
Affinity maturation during the germinal center reaction
One-pass selection model of the germinal center reaction
Basic model
Amplification of high affinity cells in the memory population is a logarithmic function of their selection coefficient
Implications for affinity maturation in the germinal centers
Mutation rate estimation
Cell division, cell cycle times
Computational model of a growing culture of cells
Mean number of mutants in a culture of size
N
Continuum approximation of the Luria-Delbrück distribution
Cell-cycle correction to the continuum Luria-Delbrück distribution for 2-phase models of the cell cycle
Inference procedures.
Constructing confidence intervals for the mean mutation rate in cultures of cells that have a gamma-distributed cell cycle time
Estimating mutation rates in real cultures
Bacterial growth
Emergence of high affinity mutants in the germinal centers
Conclusions
Summary of results
Germline diversity does not contribute to the direct recognition of pathogens
Immunoglobulin genes evolved plasticity for somatic hypermutation
The efficiency of affinity maturation can only be explained by multiple rounds of mutation-selection-expansion of lymphocytes
Improved methods for mutation rate estimation
Future work
In lieu of closing
Non-immunoglobulin genes
Bibliography
About this document ...
Mihaela Oprea
1999-04-11
