Insights into the Structural Basis of Antibody Affinity Maturation from Next-Generation Sequencing

Abstract

Affinity maturation is the process whereby the immune system generates antibodies of higher affinities during a response to antigen. It is unique in being the only evolutionary mechanism known to operate on a molecule in an organism’s own body. Deciphering the structural mechanisms through which somatic mutations in antibody genes increase affinity is critical to understanding the evolution of immune repertoires. Next-generation sequencing (NGS) has allowed the reconstruction of antibody clonal lineages in response to viral pathogens, such as HIV-1, which was not possible in earlier studies of affinity maturation. Crystal structures of antibodies from these lineages bound to their target antigens have revealed, at the atomic level, how antibodies evolve to penetrate the glycan shield of envelope glycoproteins, and how viruses in turn evolve to escape neutralization. Collectively, structural studies of affinity maturation have shown that increased antibody affinity can arise from any one or any combination of multiple diverse mechanisms, including improved shape complementarity at the interface with antigen, increased buried surface area upon complex formation, additional interfacial polar or hydrophobic interactions, and preorganization or rigidification of the antigen-binding site.

Regulation of IgE by T follicular helper cells

“…Somatic hypermutation is a process that enables these B cells to mutate their BCRs through the induction of the enzyme activation‐induced cytidine deaminase (AID). Typically, the higher the rate of mutation in a BCR, the higher the affinity it develops for a given antigen …”

“…Affinity maturation is the process by which B cell clones that begin with low-affinity antibodies for a given antigen ultimately generate antibodies with up to a 5000-fold increase in affinity during the course of an immune response. 38 The process of affinity maturation typically takes place in organized structures within secondary lymphoid organs called germinal centers (GCs), where antigen-experienced B cells mutate their BCRs and compete to capture and present antigens to T cells. B cells with higher-affinity BCRs have an advantage over lower-affinity B cells because they can efficiently acquire antigens from follicular dendritic cells in the GC that act as antigen depots.…”

“…Typically, the higher the rate of mutation in a BCR, the higher the affinity it develops for a given antigen. 38 Much of the evidence for the GC selection-based models for affinity maturation comes from studying IgG. 6,39 Whether the GC-dependent selection model holds true for IgE has been an area of active investigation during the past decade.…”

Immunoglobulin gene analysis as a tool for investigating human immune responses

“…We have produced some structures for antibodies that are polyreactive, showing that their long CDR‐H3 loops appear to project out of the antigen binding site, but the longer the CDR‐H3 then the more likely the antibody would have a flexible conformation and this work is still in its preliminary stages 160. Others have usefully employed modeling techniques to investigate the maturation of anti‐HIV and anti‐influenza antibodies 161. The pipeline for our modeling to date involves making multiple models initially and picking the best one before performing multiple simulations of conformation, using tCONCORD to give an ensemble that can be analyzed 160.…”

“…160 Others have usefully employed modeling techniques to investigate the maturation of anti-HIV and anti-influenza antibodies. 161 The pipeline for our modeling to date involves making multiple models initially and picking the best one before performing multiple simulations of conformation, using tCONCORD to give an ensemble that can be analyzed. 160 Although this rigorous treatment gives us confidence in the predicted structures, it is computationally quite expensive and difficult to apply in high throughput.…”