Abstract
During maturing antibody responses the increase in affinity for target antigens is achieved by genetic diversification of antibody genes followed by selection for improved binding. The effect this process has on the specificity of antibody for variants of the antigen is not well-defined, despite the potential role of antibody diversification in generating enhanced protection against pathogen escape mutants, or novel specificities after vaccination. To investigate this, a library of single amino-acid substitution epitope variants has been screened with serum obtained at different time-points after immunization of mice with the HIV gp41 peptide epitope ELDKWA. The serum IgG response is shown to mature and increase affinity for ELDKWA, and the titre and affinity of IgG against most epitope variants tested increases. Furthermore there is a bias towards high affinity serum IgG binding to variant epitopes with conservative substitutions, although underlying this trend there is also significant binding to many epitopes with non-conservative substitutions. Thus, maturation of the antibody response to a single epitope results in a broadening of the high-affinity response toward variant epitopes. This implies that many pathogen epitope escape variants that could manifest as single amino-acid substitutions would not emerge by escaping immune surveillance.
Highlights
The relationship between serum antibody affinity and specificity is poorly understood
To investigate how specificity changes during an antibody response serum IgG was screened at different times after immunisation with the HIV gp41 epitope ELDKWA [15], against a library of ELDKWA variants
ELDKWA was chosen as the antigen because it is short and so should not contain multiple independent epitopes, it is well characterised, derived from a real protein and the epitope is maintained in a linear peptide [15,16]
Summary
The relationship between serum antibody affinity and specificity is poorly understood. As an antibody response progresses the number of Vregions or CDR3s used against some antigens may reduce [2,3] against others numbers may increase [4], and while at a coarse level the repertoire may become more restricted, somatic hypermutation in germinal centers diversifies V-genes to such an extent that at the sequence level many cells have different receptors [2,3,5,6,7] These different antibodies would each have slightly different antigen binding regions that may have specificity beyond that for the immunizing epitope [8,9] and there is evidence that somatic mutation can change antibody specificity altogether [10,11]. Generation of frank self-reactivity can lead to rapid apoptosis in germinal centres [12,13,14], and so defines an extreme limit of the diversification of specificity, the overall scope of reactivity produced during antibody maturation is currently little understood
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