How B-Cell Receptor Repertoire Sequencing Can Be Enriched with Structural Antibody Data

Aleksandr Kovaltsuk, Konrad Krawczyk, Jacob D. Galson, Dominic F. Kelly, Charlotte M. Deane, Johannes Trück
2017 Frontiers in Immunology  
Next-generation sequencing of immunoglobulin gene repertoires (Ig-seq) allows the investigation of large-scale antibody dynamics at a sequence level. However, structural information, a crucial descriptor of antibody binding capability, is not collected in Ig-seq protocols. Developing systematic relationships between the antibody sequence information gathered from Ig-seq and low-throughput techniques such as X-ray crystallography could radically improve our understanding of antibodies. The
more » ... g of Ig-seq datasets to known antibody structures can indicate structurally, and perhaps functionally, uncharted areas. Furthermore, contrasting naïve and antigenically challenged datasets using structural antibody descriptors should provide insights into antibody maturation. As the number of antibody structures steadily increases and more and more Ig-seq datasets become available, the opportunities that arise from combining the two types of information increase as well. Here, we review how these data types enrich one another and show potential for advancing our knowledge of the immune system and improving antibody engineering. iNTRODUCTiON Antibodies are proteins produced by the B cells of jawed vertebrates. Their primary function is to recognize structural sequence motifs (epitopes) within molecules (antigens) usually related to pathogens, which may lead to direct neutralization of those pathogens or their toxins. Further functions of antibodies are activation of the complement system or tagging of antigens for elimination by other immune pathways. Antibodies have the capacity for binding an extraordinary variety of epitopes as a result of their sequence diversity, which is estimated at 10 13 unique molecules in the human antibody repertoire (1). An antibody is a large complex molecule (~150 kDa). It can be divided into two parts, the crystallizable fragment (Fc) and the antigen binding fragment (Fab). The Fab fragment is further split into constant and variable regions. There are five possible main Fc portions in humans, and which one is used on a particular antibody is governed by the process of class switching (2). The variable region (Fv) is composed of two domains called the heavy (VH) and light (VL) chains. Within each B cell, the antibody Fv domains are built by somatic recombination between V(D)J segments (3, 4). Upon antigen recognition, somatic hypermutation introduces further diversification into the naïve Fv domains (5). Within each of the VL and VH chains lie three hypervariable loops, the complementarity determining regions (CDRs), which are the most Frontiers in Immunology | www.frontiersin.org
doi:10.3389/fimmu.2017.01753 pmid:29276518 pmcid:PMC5727015 fatcat:w5zqlbyvkvejbesfrybp23caem