Deep Characterization of the Human Antibody Response to Natural Infection Using Longitudinal Immune Repertoire Sequencing

Human antibody response studies are largely restricted to periods of high immune activity (e.g. vaccination). To comprehensively understand the healthy B cell immune repertoire and how this changes over time and through natural infection, we conducted immune repertoire RNA sequencing on flow cytometry-sorted B cell subsets to profile a single individual's antibodies over 11 months through two periods of natural viral infection. We found that 1) a baseline of healthy variable (V) gene usage in antibodies exists and is stable over time, but antibodies in memory cells consistently have a different usage profile relative to earlier B cell stages; 2) a single complementarity-determining region 3 (CDR3) is potentially generated from more than one VJ gene combination; and 3) IgG and IgA antibody transcripts are found at low levels in early human B cell development, suggesting that class switching may occur earlier than previously realized. These findings provide insight into immune repertoire stability, response to natural infections, and human B cell development.