The fundamental principles of antibody repertoire architecture revealed by large-scale network analysis

ABSTRACT The antibody repertoire is a vast and diverse collection of B-cell receptors and antibodies that confer protection against a plethora of pathogens. The architecture of the antibody repertoire, defined by the network similarity landscape of its sequences, is unknown. Here, we established a novel high-performance computing platform to construct large-scale networks from high-throughput sequencing data (>100’000 unique antibodies), in order to uncover the architecture of antibody repertoires. We identified three fundamental principles of antibody repertoire architecture across B-cell development: reproducibility, robustness and redundancy. Reproducibility of network structure explains clonal expansion and selection. Robustness ensures a functional immune response even under extensive loss of clones (50%). Redundancy in mutational pathways suggests that there is a pre-programmed evolvability in antibody repertoires. Our analysis provides guidelines for a quantitative network analysis of antibody repertoires, which can be applied to other facets of adaptive immunity (e.g., T cell receptors), and may direct the construction of synthetic repertoires for biomedical applications.