Systems Analysis Reveals High Genetic and Antigen-Driven Predetermination of Antibody Repertoires throughout B Cell Development

Abstract

Antibody repertoire diversity and plasticity is crucial for broad protective immunity. Repertoires change in size and diversity across multiple B cell developmental stages and in response to antigen exposure. However, we still lack fundamental quantitative understanding of the extent to which repertoire diversity is predetermined. Therefore, we implemented a systems immunology framework for quantifying repertoire predetermination on three distinct levels: (1) B cell development (pre-B cell, naive B cell, plasma cell), (2) antigen exposure (three structurally different proteins), and (3) four antibody repertoire components (V-gene usage, clonal expansion, clonal diversity, repertoire size) extracted from antibody repertoire sequencing data (400 million reads). Across all three levels, we detected a dynamic balance of high genetic (e.g., >90% for V-gene usage and clonal expansion in naive B cells) and antigen-driven (e.g., 40% for clonal diversity in plasma cells) predetermination and stochastic variation. Our study has implications for the prediction and manipulation of humoral immunity.

A compact vocabulary of paratope-epitope interactions enables predictability of antibody-antigen binding

“…Recent reports have, however, provided preliminary evidence for the potential predictability of antibody-antigen interaction: (i) The antibody repertoire field has now established that antibody sequence diversity underlies predictable rules (Elhanati et al, 2015;Greiff et al, 2017bGreiff et al, , 2017a. (ii) The presence of transferable "specificity units" between distinct antibody molecules was recently suggested by showing that tightly binding functional antibodies may be conceived by designing and improving seemingly unrelated paratopes (Nimrod et al, 2018).…”

A comparison of unamplified and massively multiplexed PCR amplification for murine antibody repertoire sequencing

“…Additionally, it is important to consider that all repertoire sequencing is merely a snapshot of a constantly shifting image . We will also never be able to fully capture the full diversity of the B‐cell immunoglobulin repertoire, which is estimated to range from 10 6 ‐10 7 possible unique rearrangements and mutations to as much as 10 13 . The failure of the KSU data set to detect rare clones compared to the amplified data sets is likely due to this; but even the amplified data sets only sampled a fraction of the total repertoire.…”

“…25 We will also never be able to fully capture the full diversity of the B-cell immunoglobulin repertoire, which is estimated to range from 10 6 -10 7 possible unique rearrangements and mutations 25,39 to as much as 10 13 . 15 The failure of the KSU data set to detect rare clones compared to the amplified data sets is likely due to this; but even the amplified data sets only sampled a fraction of the total repertoire. Therefore, one must decide how "deep" is adequate for the question being addressed.…”

“…These data sets are created using massively multiplexed PCR reactions that are subsequently sequenced on the Illumina platform. Multiplex amplification strategies have been used to explore the T-cell 10,11 and B-cell repertoires, [12][13][14][15] and biases, omissions. 10,11,[16][17][18] and PCR artifacts have been detected in the data sets.…”

The Bayesian optimist's guide to adaptive immune receptor repertoire analysis

“…For example, vaccination of human twins gives rather different results, 111 whereas there is significant evidence of genetic predetermination for vaccination in mouse. 112 Indeed, it has recently been proposed that this represents a fundamental difference between the immune systems of these two species. 113 One can also consider various bulk properties of the memory BCR repertoire, and consider the difference between the naive repertoire and the mature repertoire.…”