Abstract
The role of Activation-Induced Cytidine Deaminase (AID) in somatic hypermutation and polyclonal antibody affinity maturation has not been shown for polyclonal responses in humans. We investigated whether AID induction in human B cells following H1N1pdm09 vaccination correlated with in-vivo antibody affinity maturation against hemagglutinin domains in plasma of young and elderly individuals. AID was measured by qPCR in B cells from individuals of different ages immunized with the H1N1pdm09 influenza vaccine. Polyclonal antibody affinity in human plasma for the HA1 and HA2 domains of the H1N1pdm09 hemagglutinin was measured by antibody-antigen complex dissociation rates using real time kinetics in Surface Plasmon Resonance. Results show an age-related decrease in AID induction in B cells following H1N1pdm09 vaccination. Levels of AID mRNA before vaccination and fold-increase of AID mRNA expression after H1N1pdm09 vaccination directly correlated with increase in polyclonal antibody affinity to the HA1 globular domain (but not to the conserved HA2 stalk). In the younger population, significant affinity maturation to the HA1 globular domain was observed, which associated with initial levels of AID and fold-increase in AID after vaccination. In some older individuals (>65 yr), higher affinity to the HA1 domain was observed before vaccination and H1N1pdm09 vaccination resulted in minimal change in antibody affinity, which correlated with low AID induction in this age group. These findings demonstrate for the first time a strong correlation between AID induction and in-vivo antibody affinity maturation in humans. The ability to generate high affinity antibodies could have significant impact on the elucidation of age-specific antibody responses following vaccination and eventual clinical efficacy and disease outcome.
Highlights
Antibody affinity maturation is a key aspect of an effective immune response to vaccines likely to provide a significant protection against human pathogens
The discovery of ActivationInduced Cytidine Deaminase (AID) has led to the elucidation of key molecular mechanisms involved in class switch recombination (CSR) and somatic hypermutation (SHM), which occur in B cells as they mature in germinal centers of lymph nodes and spleen in response to antigenic stimulation and T cell signals [1,2]
A positive correlation was observed between fold increase in Activation-Induced Cytidine Deaminase (AID) induction (t28/t0) and the fold increase in hemagglutination inhibition (HI) titers (Table S1), confirming our previous results showing that the in vitro AID mRNA increase in vaccine-stimulated B cells positively correlated with the influenza vaccine-specific HI titers [6,7]
Summary
Antibody affinity maturation is a key aspect of an effective immune response to vaccines likely to provide a significant protection against human pathogens. In two studies on age effects on influenza vaccination, we have shown that levels of AID in vaccinestimulated B cells and serum antibody responses are positively correlated in humans [6,7]. This correlation suggested that a defect in AID induction in PBMC derived B cells (measured in vitro) correlated with the observed decrease in the number of switched memory B cells and a reduced number of IgG plasmablasts after vaccination in vivo [6,7]. While association between CSR and AID has been suggested before, no information to date is available for the direct involvement of AID and SHM and/or antibody affinity maturation in humans
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