Abstract
Generating a diverse B cell immunoglobulin repertoire is essential for protection against infection. The repertoire in humans can now be comprehensively measured by high-throughput sequencing. Using hepatitis B vaccination as a model, we determined how the total immunoglobulin sequence repertoire changes following antigen exposure in humans, and compared this to sequences from vaccine-specific sorted cells. Clonal sequence expansions were seen 7days after vaccination, which correlated with vaccine-specific plasma cell numbers. These expansions caused an increase in mutation, and a decrease in diversity and complementarity-determining region 3 sequence length in the repertoire. We also saw an increase in sequence convergence between participants 14 and 21days after vaccination, coinciding with an increase of vaccine-specific memory cells. These features allowed development of a model for in silico enrichment of vaccine-specific sequences from the total repertoire. Identifying antigen-specific sequences from total repertoire data could aid our understanding B cell driven immunity, and be used for disease diagnostics and vaccine evaluation.
Highlights
The human B cell immunoglobulin repertoire has the theoretical potential to include up to 1011 unique variants (Glanville et al, 2009); such diversity is key to confer immunity against the variety of antigens that may be encountered during a lifetime
Using hepatitis B (HepB) booster vaccination as a model system, we applied indepth sequence analysis of the immunoglobulin heavy chain repertoire from circulating B cells to thoroughly characterize how the B cell repertoire responds to secondary antigen encounter
These changes were characterized by a decrease in diversity, an increase in mutation, and a decrease in CDR3 sequence length — features that appear to be generally characteristic of more activated B cells (Galson et al, 2015), and can be related to the appearance of vaccine-induced plasma cells (PCs) in the peripheral blood at this time
Summary
The human B cell immunoglobulin repertoire has the theoretical potential to include up to 1011 unique variants (Glanville et al, 2009); such diversity is key to confer immunity against the variety of antigens that may be encountered during a lifetime. Decreases in cost of next-generation sequencing make it feasible to use this technology to characterize the immunoglobulin heavy chain repertoire in large numbers of samples. This approach has already yielded clinical applications in the monitoring of minimal disease residue in B cell lymphoma patients (Boyd et al, 2009), and the rapid identification of monoclonal antibody sequences (Reddy et al, 2010), and has shown promise for increasing understanding of autoimmune conditions (Palanichamy et al, 2014) and in disease diagnostics (Parameswaran et al, 2013)
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