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

Erin M Mitsunaga,Michael P Snyder

doi:10.1074/mcp.ra119.001633

Abstract

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.

Highlights

Human antibody response studies are largely restricted to periods of high immune activity
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
Prior studies centered on analyzing the human B cell repertoire have often focused on either a specific immunological challenge [2, 3, 4] or the B cell subset-specificity of complementarity-determining region 3s (CDR3s), the hypervariable region of the antibody protein responsible for determining antigen-binding specificity [5]; these regions are formed by random combinations of the variable (V), diversity (D), and joining (J) gene segments [6, 7, 8]

Summary

Introduction

Human antibody response studies are largely restricted to periods of high immune activity (e.g. vaccination). Whereas experiments designed to analyze B cell subset-specific CDR31 properties avoid this issue, the sampling resolution was usually restricted to a single blood draw from participating individuals, resulting in a static perspective on an otherwise dynamic system Studies that combine both multi-time point sampling of an immune challenge event on sorted B cell subsets are becoming more common [9, 10, 11, 12], but understanding the B cell repertoire of healthy individuals over time [13] and through infection is quite rare.

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Results

Conclusion