Specificity and Overlap in Gene Segment-defined Antibody Repertoires

Abstract

Background: To date several studies have sought to catalog the full suite of antibodies that humans naturally produce against single antigens or other specificities (repertoire). Here we analyze the properties of all sequenced repertoires in order to better understand the specificity of antibody responses. Specifically, we ask whether the large-scale sequencing of antibody repertoires might provide a diagnostic tool for detecting antigen exposure. We do this by examining the overlap in V({H-}), D(-), and J({H-}) segment usage among sequenced repertoires. Results: We find that repertoire overlap in V({H-}), D(-), and J({H-}) segment use is least for V(_H) segments and greatest for J(_H) segments, consistent with there being more V(_H) than J(_H) segments in the human genome. We find that for any two antigens chosen at random, chances are 90 percent that their repertoires' V(_H) segments will overlap by less than half, and 98 percent that their VDJ(_H) combinations will overlap by ≤10 percent. We ran computer simulations to test whether enrichment for specific VDJ(_H) combinations could be detected in "antigen-exposed" populations, and found that enrichment is detectable with moderate-to-high sensitivity and high specificity, even when some VDJ(_H) combinations are not represented at all in some test sets. Conclusion: Thus, as large-scale sequencing becomes cost-effective for clinical testing, we suggest that sequencing an individual's expressed antibody repertoire has the potential to become a useful diagnostic modality.