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Abstract
One of the key phenomena in the adaptive immune response to infection and immunization is affinity maturation, during which antibody genes are mutated and selected, typically resulting in a substantial increase in binding affinity to the eliciting antigen. Advances in technology on several fronts have made it possible to clone large numbers of heavy-chain light-chain pairs from individual B cells and thereby identify whole sets of clonally related antibodies. These collections could provide the information necessary to reconstruct their own history - the sequence of changes introduced into the lineage during the development of the clone - and to study affinity maturation in detail. But the success of such a program depends entirely on accurately inferring the founding ancestor and the other unobserved intermediates. Given a set of clonally related immunoglobulin V-region genes, the method described here allows one to compute the posterior distribution over their possible ancestors, thereby giving a thorough accounting of the uncertainty inherent in the reconstruction.I demonstrate the application of this method on heavy-chain and light-chain clones, assess the reliability of the inference, and discuss the sources of uncertainty.
Highlights
During the course of an infection, the host’s immune system produces antibody molecules that bind to molecular determinants on the infectious agent, thereby neutralizing the agent and targeting it for removal by additional antimicrobial effectors
The heavy and light chain immunoglobulin (Ig) genes that encode the components of the antibody molecule result initially from the stochastic intrachromosomal rearrangement of gene segments arrayed in libraries of such gene segments[1]
These genes are further modified after the activation of the B cells that possess them through somatic hypermutation targeted to the rearranged Ig genes[2]
Summary
During the course of an infection, the host’s immune system produces antibody molecules that bind to molecular determinants (antigens) on the infectious agent, thereby neutralizing the agent and targeting it for removal by additional antimicrobial effectors. The heavy and light chain immunoglobulin (Ig) genes that encode the components of the antibody molecule result initially from the stochastic intrachromosomal rearrangement of gene segments arrayed in libraries of such gene segments[1]. These genes are further modified after the activation of the B cells that possess them through somatic hypermutation targeted to the rearranged Ig genes[2]. Those B cells whose Ig genes encode molecules with greater affinity for the eliciting antigen gain a proliferative and survival advantage In this way, the overall affinity of the pool of serum antibodies increases, sometimes by two or more orders of magnitude. This affinity maturation[3] is an essential component of the establishment of humoral immunity, the basis for the large majority of successful vaccines[4]
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