scholarly journals Understanding the human antibody repertoire

mAbs ◽  
2020 ◽  
Vol 12 (1) ◽  
pp. 1729683 ◽  
Author(s):  
Anthony R Rees
Keyword(s):  
Antibody Repertoire ◽  
Human Antibody

scholarly journals Signatures of selection in the human antibody repertoire: Selective sweeps, competing subclones, and neutral drift

2019 ◽  
Vol 116 (4) ◽  
pp. 1261-1266 ◽  
Author(s):  
Felix Horns ◽  
Christopher Vollmers ◽  
Cornelia L. Dekker ◽  
Stephen R. Quake
Keyword(s):  
B Cell ◽  
Binding Affinity ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Selective Sweeps ◽  
Human Immune System ◽  
Evolutionary Processes ◽  
Neutral Drift ◽  
Cell Lineages ◽  
Antibody Repertoires

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.

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

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.

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

PLoS ONE ◽  
2019 ◽  
Vol 14 (7) ◽  
pp. e0219256 ◽  
Author(s):  
Stefan Ryser ◽  
Edgar Tenorio ◽  
Angeles Estellés ◽  
Lawrence M. Kauvar
Keyword(s):  
Bacterial Biofilm ◽  
Antibody Repertoire ◽  
Human Antibody

scholarly journals Bovine antibodies with ultra long H3 Complementarity Determining Regions

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.

scholarly journals Mechanisms That Shape Human Antibody Repertoire Development in Mice Transgenic for Human Ig H and L Chain Loci

2017 ◽  
Vol 198 (10) ◽  
pp. 3963-3977 ◽  
Author(s):  
Nancy S. Longo ◽  
Tobias Rogosch ◽  
Michael Zemlin ◽  
Moncef Zouali ◽  
Peter E. Lipsky
Keyword(s):  
Antibody Repertoire ◽  
Human Antibody ◽  
Repertoire Development

scholarly journals Regulatory Approved Monoclonal Antibodies Contain Framework Mutations Predicted From Human Antibody Repertoires

2021 ◽  
Vol 12 ◽  
Author(s):  
Brian M. Petersen ◽  
Sophia A. Ulmer ◽  
Emily R. Rhodes ◽  
Matias F. Gutierrez-Gonzalez ◽  
Brandon J. Dekosky ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
High Frequency ◽  
In Silico ◽  
Sequence Data ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Therapeutic Antibodies ◽  
T Cell Epitopes ◽  
Antibody Repertoires ◽  
Dynamics Simulations

Monoclonal antibodies (mAbs) are an important class of therapeutics used to treat cancer, inflammation, and infectious diseases. Identifying highly developable mAb sequences in silico could greatly reduce the time and cost required for therapeutic mAb development. Here, we present position-specific scoring matrices (PSSMs) for antibody framework mutations developed using baseline human antibody repertoire sequences. Our analysis shows that human antibody repertoire-based PSSMs are consistent across individuals and demonstrate high correlations between related germlines. We show that mutations in existing therapeutic antibodies can be accurately predicted solely from baseline human antibody sequence data. We find that mAbs developed using humanized mice had more human-like FR mutations than mAbs originally developed by hybridoma technology. A quantitative assessment of entire framework regions of therapeutic antibodies revealed that there may be potential for improving the properties of existing therapeutic antibodies by incorporating additional mutations of high frequency in baseline human antibody repertoires. In addition, high frequency mutations in baseline human antibody repertoires were predicted in silico to reduce immunogenicity in therapeutic mAbs due to the removal of T cell epitopes. Several therapeutic mAbs were identified to have common, universally high-scoring framework mutations, and molecular dynamics simulations revealed the mechanistic basis for the evolutionary selection of these mutations. Our results suggest that baseline human antibody repertoires may be useful as predictive tools to guide mAb development in the future.

scholarly journals Immunological fingerprint of 4CMenB recombinant antigens via protein microarray reveals key immunosignatures correlating with bactericidal activity

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
E. Bartolini ◽  
E. Borgogni ◽  
M. Bruttini ◽  
A. Muzzi ◽  
M. Giuliani ◽  
...  
Keyword(s):  
Immune Response ◽  
Epitope Mapping ◽  
Ad Hoc ◽  
Protein Microarray ◽  
Age Groups ◽  
Antibody Repertoire ◽  
Human Antibody ◽  
Adolescents And Adults ◽  
High Flexibility ◽  
Multicomponent Vaccine

Abstract Serogroup B meningococcus (MenB) is a leading cause of meningitis and sepsis across the world and vaccination is the most effective way to protect against this disease. 4CMenB is a multi-component vaccine against MenB, which is now licensed for use in subjects >2 months of age in several countries. In this study, we describe the development and use of an ad hoc protein microarray to study the immune response induced by the three major 4CMenB antigenic components (fHbp, NHBA and NadA) in individual sera from vaccinated infants, adolescents and adults. The resulting 4CMenB protein antigen fingerprinting allowed the identification of specific human antibody repertoire correlating with the bactericidal response elicited in each subject. This work represents an example of epitope mapping of the immune response induced by a multicomponent vaccine in different age groups with the identification of protective signatures. It shows the high flexibility of this microarray based methodology in terms of high-throughput information and minimal volume of biological samples needed.

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