Structural Diversity of B-Cell Receptor Repertoires along the B-cell Differentiation Axis in Humans and Mice

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 paratopes of more than 180 million human and mouse B-cell receptor (BCR) repertoire sequences. These structurally annotated paratopes 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 paratope 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 paratope structure usage. Our results establish the paratope 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.

Maturation of the Human Immunoglobulin Heavy Chain Repertoire With Age

“…The SAAB+ pipeline was employed to annotate IgH repertoires with structural information ( 19 ). Briefly, IgH repertoires were numbered with the IMGT scheme ( 20 ) and filtered for structural viability using “ANARCI parsing” ( 21 ) as per the first steps of the ABOSS algorithm ( 22 ).…”

“…Only CDR-H3 sequences with loop lengths between 5 and 16 were investigated. The expected average RMSD of CDR-H3 template prediction for the human IgH repertoire data is 2.8 Å, with an expected coverage of 48% ( 19 ). PDB templates within a 0.6 Å RMSD radius were clustered together ( 19 ), reducing 2,943 PDB templates to 1,169 CDR-H3 PDB clusters.…”

Maturation of the human B-cell receptor repertoire with age

“…Only CDR-H3 sequences with loop lengths between 5 and 16 were investigated. The expected average RMSD of CDR-H3 template prediction for the human BCR repertoire data is 2.8 Å, with an expected coverage of 48% (19). PDB templates within a 0.6 Å RMSD radius were clustered together (19), reducing 2'943 PDB templates to 1'169 CDR-H3 PDB clusters.…”

“…The SAAB+ pipeline was employed to annotate BCR repertoires with structural information (19). Briefly, BCR repertoires were numbered with the IMGT scheme (20) and filtered for structural viability using 'ANARCI parsing' (21) as per the first steps of the ABOSS algorithm (22).…”

Methods for sequence and structural analysis of B and T cell receptor repertoires

“…We note here that, since B cells can undergo affinity-driven maturation, such receptors need not derive from a similar common clone. Recently, the SAAB + tool was developed to characterize structural properties of CDRs from differentiated B cells [70] . It is likely that more tools trained to identify “convergence” of functionally related antibodies will appear in the future as more sequence data from donors with shared BCR epitopes become available.…”