Deep sequencing and human antibody repertoire analysis

Antibodies are created and refined by somatic evolution in B cell populations, which endows the human immune system with the ability to recognize and eliminate diverse pathogens. However, the evolutionary processes that sculpt antibody repertoires remain poorly understood. Here, using an unbiased repertoire-scale approach, we show that the population genetic signatures of evolution are evident in human B cell lineages and reveal how antibodies evolve somatically. We measured the dynamics and genetic diversity of B cell responses in five adults longitudinally before and after influenza vaccination using high-throughput antibody repertoire sequencing. We identified vaccine-responsive B cell lineages that carry signatures of selective sweeps driven by positive selection, and discovered that they often display evidence for selective sweeps favoring multiple subclones. We also found persistent B cell lineages that exhibit stable population dynamics and carry signatures of neutral drift. By exploiting the relationship between B cell fitness and antibody binding affinity, we demonstrate the potential for using phylogenetic approaches to identify antibodies with high binding affinity. This quantitative characterization reveals that antibody repertoires are shaped by an unexpectedly broad spectrum of evolutionary processes and shows how signatures of evolutionary history can be harnessed for antibody discovery and engineering.

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Age-associated changes in the circulating human antibody repertoire are upregulated in autoimmunity

Immunity & Ageing ◽

10.1186/s12979-020-00193-x ◽

2020 ◽

Vol 17 (1) ◽

Author(s):

Aaron Arvey ◽

Michael Rowe ◽

Joseph Barten Legutki ◽

Gang An ◽

Anantha Gollapudi ◽

...

Keyword(s):

Autoimmune Disease ◽

Regression Model ◽

Serum Antibody ◽

Antibody Repertoire ◽

Human Antibody ◽

Humoral Immune ◽

Peptide Microarrays ◽

Highly Correlated ◽

Circulating Antibody

Abstract Background The immune system undergoes a myriad of changes with age. While it is known that antibody-secreting plasma and long-lived memory B cells change with age, it remains unclear how the binding profile of the circulating antibody repertoire is impacted. Results To understand humoral immunity changes with respect to age, we characterized serum antibody binding to high density peptide microarrays in a diverse cohort of 1675 donors. We discovered thousands of peptides that bind antibodies in age-dependent fashion, many of which contain di-serine motifs. Peptide binding profiles were aggregated into an “immune age” by a machine learning regression model that was highly correlated with chronological age. Applying this regression model to previously-unobserved donors, we found that a donor’s predicted immune age is longitudinally consistent over years, suggesting it could be a robust long-term biomarker of humoral immune ageing. Finally, we assayed serum from donors with autoimmune disease and found a significant association between “accelerated immune ageing” and autoimmune disease activity. Conclusions The circulating antibody repertoire has increased binding to thousands of di-serine peptide containing peptides in older donors, which can be represented as an immune age. Increased immune age is associated with autoimmune disease, acute inflammatory disease severity, and may be a broadly relevant biomarker of immune function in health, disease, and therapeutic intervention.

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Understanding the human antibody repertoire

mAbs ◽

10.1080/19420862.2020.1729683 ◽

2020 ◽

Vol 12 (1) ◽

pp. 1729683 ◽

Cited By ~ 8

Author(s):

Anthony R Rees

Keyword(s):

Antibody Repertoire ◽

Human Antibody

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Human antibody repertoire frequently includes antibodies to a bacterial biofilm associated protein

PLoS ONE ◽

10.1371/journal.pone.0219256 ◽

2019 ◽

Vol 14 (7) ◽

pp. e0219256 ◽

Cited By ~ 2

Author(s):

Stefan Ryser ◽

Edgar Tenorio ◽

Angeles Estellés ◽

Lawrence M. Kauvar

Keyword(s):

Bacterial Biofilm ◽

Antibody Repertoire ◽

Human Antibody

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Bovine antibodies with ultra long H3 Complementarity Determining Regions

Acta Crystallographica Section A Foundations and Advances ◽

10.1107/s2053273314097447 ◽

2014 ◽

Vol 70 (a1) ◽

pp. C255-C255

Author(s):

Robyn Stanfield ◽

Vaughn Smider ◽

Ian Wilson

Keyword(s):

Disulfide Bonds ◽

The Other ◽

Sequence Length ◽

Antibody Repertoire ◽

Human Antibody ◽

Structural Homology ◽

Disulfide Bonding ◽

Cysteine Rich Protein ◽

Complementarity Determining Regions ◽

Bovine Antibody

About 10% of the bovine antibody repertoire exhibit extremely long H3 complementarity determining regions (CDRs). These H3 CDRs are usually described as `loops' in the more familiar mouse and human antibody Fab structures, but the ultra long bovine H3 CDRs are actually small, cysteine-rich protein domains that vary in size from 44 to 64 amino acids. We have recently determined the structures for two bovine antibody Fab fragments, and will describe these, as well as compare them with two other previously determined bovine Fab structures (Wang et al., Cell, 2013). One new Fab has a relatively short H3 CDR region of 44 residues, with just one disulfide bond, while the other boasts one of the longest H3 CDRs, with 63 residues and four disulfide bonds. These H3 CDRs fold to form apparently rigid `stem' regions, that present the disulfide bonded `knob' domain far above the five other Fab CDR loops. Despite extreme diversity in sequence, length and disulfide bonding patterns, the CDRs share structural homology, both in their long stems and in the more variable knob regions.

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