Abstract
Most current analysis tools for antibody next-generation sequencing data work with primary sequence descriptors, leaving accompanying structural information unharnessed. We have used novel rapid methods to structurally characterize the complementary-determining regions (CDRs) of more than 180 million human and mouse B-cell receptor (BCR) repertoire sequences. These structurally annotated CDRs provide unprecedented insights into both the structural predetermination and dynamics of the adaptive immune response. We show that B-cell types can be distinguished based solely on these structural properties. Antigen-unexperienced BCR repertoires use the highest number and diversity of CDR structures and these patterns of naïve repertoire paratope usage are highly conserved across subjects. In contrast, more differentiated B-cells are more personalized in terms of CDR structure usage. Our results establish the CDR structure differences in BCR repertoires and have applications for many fields including immunodiagnostics, phage display library generation, and "humanness" assessment of BCR repertoires from transgenic animals. The software tool for structural annotation of BCR repertoires, SAAB+, is available at https://github.com/oxpig/saab_plus.
Highlights
B-cells are essential components of the adaptive immune system in jawed vertebrates
Each individual has a huge B-cell receptors (BCR) repertoire, where each individual BCR has a specific binding site composed of the complementary-determining regions (CDRs) capable of recognising a specific antigen
Drug discovery and immunodiagnostics inspired by the adaptive immune system rely on our ability to accurately interrogate the structural diversity of the binding sites of the BCR repertoire
Summary
B-cells are essential components of the adaptive immune system in jawed vertebrates They play a key role in recognizing foreign molecules (antigens) via membrane-bound B-cell receptors (BCR), and antibodies (secreted BCRs). Somatic hypermutation (SHM) recursively introduces changes to the variable (Fv) domain of naïve BCR repertoires. These occur primarily in the antibody binding interface (paratope, which consists mostly of CDR residues)[3], leading to structural changes. Those B-cells whose paratopes are epitopecomplementary are clonally expanded, and further diversified and selected to enhance antigen binding properties. There are five main heavy constant regions (isotypes), each with a unique profile of effector functions and antigen binding avidity
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