Inferring processes underlying B-cell repertoire diversity.

We quantify the VDJ recombination and somatic hypermutation processes in human B-cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, due to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

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Inferring processes underlying B-cell repertoire diversity

Philosophical Transactions of the Royal Society B Biological Sciences ◽

10.1098/rstb.2014.0243 ◽

2015 ◽

Vol 370 (1676) ◽

pp. 20140243 ◽

Cited By ~ 94

Author(s):

Yuval Elhanati ◽

Zachary Sethna ◽

Quentin Marcou ◽

Curtis G. Callan ◽

Thierry Mora ◽

...

Keyword(s):

B Cell ◽

Somatic Hypermutation ◽

Cell Receptor ◽

Statistical Properties ◽

Cell Repertoire ◽

Vdj Recombination ◽

Site Model ◽

Human B Cells ◽

B Cell Repertoire ◽

Repertoire Diversity

We quantify the VDJ recombination and somatic hypermutation processes in human B cells using probabilistic inference methods on high-throughput DNA sequence repertoires of human B-cell receptor heavy chains. Our analysis captures the statistical properties of the naive repertoire, first after its initial generation via VDJ recombination and then after selection for functionality. We also infer statistical properties of the somatic hypermutation machinery (exclusive of subsequent effects of selection). Our main results are the following: the B-cell repertoire is substantially more diverse than T-cell repertoires, owing to longer junctional insertions; sequences that pass initial selection are distinguished by having a higher probability of being generated in a VDJ recombination event; somatic hypermutations have a non-uniform distribution along the V gene that is well explained by an independent site model for the sequence context around the hypermutation site.

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The pre-B-cell receptor: selector of fitting immunoglobulin heavy chains for the B-cell repertoire

Nature Reviews Immunology ◽

10.1038/nri1649 ◽

2005 ◽

Vol 5 (7) ◽

pp. 578-584 ◽

Cited By ~ 129

Author(s):

Fritz Melchers

Keyword(s):

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Cell Repertoire ◽

Heavy Chains ◽

B Cell Repertoire

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Different B cell subpopulations show distinct patterns in their IgH repertoire metrics

eLife ◽

10.7554/elife.73111 ◽

2021 ◽

Vol 10 ◽

Author(s):

Marie Ghraichy ◽

Valentin von Niederhäusern ◽

Aleksandr Kovaltsuk ◽

Jacob D Galson ◽

Charlotte M Deane ◽

...

Keyword(s):

B Cell ◽

In Silico ◽

Plasma Cells ◽

Somatic Hypermutation ◽

Bioinformatic Analysis ◽

Cell Repertoire ◽

Humoral Immune ◽

B Cell Repertoire ◽

Cell Subpopulations ◽

The Individual

Several human B-cell subpopulations are recognized in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. Using advanced bioinformatic analysis and machine learning, we show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.

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A multi-objective based clustering for identifying clonally-related sequences from high-throughput B cell repertoire data

10.1101/2021.10.01.462736 ◽

2021 ◽

Author(s):

Nika Abdollahi ◽

Anne Langlois De Septenville ◽

Hugues Ripoche ◽

Frederic Davi ◽

Juliana Silva Bernardes

Keyword(s):

B Cell ◽

High Throughput ◽

High Throughput Sequencing ◽

Somatic Hypermutation ◽

Clustering Algorithms ◽

Objective Functions ◽

Cell Repertoire ◽

Multi Objective ◽

B Cell Repertoire ◽

Attractive Option

The adaptive B cell response is driven by the expansion, somatic hypermutation, and selection of B cell clones. A high number of clones in a B cell population indicates a highly diverse repertoire, while clonal size distribution and sequence diversity within clones can be related to antigen's selective pressure. Identifying clones is fundamental to many repertoire studies, including repertoire comparisons, clonal tracking and statistical analysis. Several methods have been developed to group sequences from high-throughput B cell repertoire data. Current methods use clustering algorithms to group clonally-related sequences based on their similarities or distances. Such approaches create groups by optimizing a single objective that typically minimizes intra-clonal distances. However, optimizing several objective functions can be advantageous and boost the algorithm convergence rate. Here we propose a new method based on multi-objective clustering. Our approach requires V(D)J annotations to obtain the initial clones and iteratively applies two objective functions that optimize cohesion and separation within clones simultaneously. We show that under simulations with varied mutation rates, our method greatly improves clonal grouping as compared to other tools. When applied to experimental repertoires generated from high-throughput sequencing, its clustering results are comparable to the most performing tools. The method based on multi-objective clustering can accurately identify clone members, has fewer parameter settings and presents the lowest running time among existing tools. All these features constitute an attractive option for repertoire analysis, particularly in the clinical context to unravel the mechanisms involved in the development and evolution of B cell malignancies.

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Identification of Antigen-Specific B-Cell Receptor Sequences from the Total B-Cell Repertoire

Critical Reviews in Immunology ◽

10.1615/critrevimmunol.2016016462 ◽

2015 ◽

Vol 35 (6) ◽

pp. 463-478 ◽

Cited By ~ 10

Author(s):

Jacob D. Galson ◽

Dominic F. Kelly ◽

Johannes Truck

Keyword(s):

B Cell ◽

Cell Receptor ◽

B Cell Receptor ◽

Cell Repertoire ◽

B Cell Repertoire

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Self-reactive VH4-34–expressing IgG B cells recognize commensal bacteria

Journal of Experimental Medicine ◽

10.1084/jem.20160201 ◽

2017 ◽

Vol 214 (7) ◽

pp. 1991-2003 ◽

Cited By ~ 37

Author(s):

Jean-Nicolas Schickel ◽

Salomé Glauzy ◽

Yen-Shing Ng ◽

Nicolas Chamberlain ◽

Christopher Massad ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Healthy Donor ◽

Somatic Hypermutation ◽

Gene Segment ◽

Commensal Bacteria ◽

Healthy Individuals ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Variable Heavy

The germline immunoglobulin (Ig) variable heavy chain 4–34 (VH4-34) gene segment encodes in humans intrinsically self-reactive antibodies that recognize I/i carbohydrates expressed by erythrocytes with a specific motif in their framework region 1 (FWR1). VH4-34–expressing clones are common in the naive B cell repertoire but are rarely found in IgG memory B cells from healthy individuals. In contrast, CD27+IgG+ B cells from patients genetically deficient for IRAK4 or MYD88, which mediate the function of Toll-like receptors (TLRs) except TLR3, contained VH4-34–expressing clones and showed decreased somatic hypermutation frequencies. In addition, VH4-34–encoded IgGs from IRAK4- and MYD88-deficient patients often displayed an unmutated FWR1 motif, revealing that these antibodies still recognize I/i antigens, whereas their healthy donor counterparts harbored FWR1 mutations abolishing self-reactivity. However, this paradoxical self-reactivity correlated with these VH4-34–encoded IgG clones binding commensal bacteria antigens. Hence, B cells expressing germline-encoded self-reactive VH4-34 antibodies may represent an innate-like B cell population specialized in the containment of commensal bacteria when gut barriers are breached.

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Functional characterization and lineage analysis of broadly neutralizing human antibodies against dengue virus identified by single B cell transcriptomics

10.1101/790642 ◽

2019 ◽

Author(s):

Natasha D. Durham ◽

Aditi Agrawal ◽

Eric Waltari ◽

Derek Croote ◽

Fabio Zanini ◽

...

Keyword(s):

Dengue Virus ◽

B Cell ◽

Neutralizing Antibodies ◽

Somatic Hypermutation ◽

Functional Characterization ◽

Vaccine Design ◽

Protein Domain ◽

Cell Repertoire ◽

B Cell Repertoire ◽

Domain I

AbstractEliciting broadly neutralizing antibodies (bNAbs) against the four dengue virus serotypes (DENV1-4) that are spreading into new territories is an important goal of vaccine design. To delineate bNAb targets, we characterized 28 monoclonal antibodies belonging to expanded and hypermutated clonal families identified by transcriptomic analysis of single plasmablasts from DENV-infected individuals. Among these, we identified two somatically related bNAbs that potently neutralized DENV1-4. Mutagenesis studies revealed that the major recognition determinants of these bNAbs are in E protein domain I, distinct from the only known class of human bNAbs against flaviviruses with a well-defined epitope. B cell repertoire analysis from acute-phase peripheral blood suggested a memory origin and divergent somatic hypermutation pathways for these bNAbs, and a limited number of mutations was sufficient for neutralizing activity. Our study suggests multiple B cell evolutionary pathways leading to DENV bNAbs targeting a novel epitope that can be exploited for vaccine design.

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Different B cell subpopulations show distinct patterns in their IgH repertoire metrics

10.1101/2021.09.01.458522 ◽

2021 ◽

Author(s):

Marie Ghraichy ◽

Valentin von Niederhäusern ◽

Aleksandr Kovaltsuk ◽

Jacob Daniel Galson ◽

Charlotte M Deane ◽

...

Keyword(s):

B Cell ◽

In Silico ◽

Plasma Cells ◽

Somatic Hypermutation ◽

Bioinformatic Analysis ◽

Cell Repertoire ◽

Humoral Immune ◽

B Cell Repertoire ◽

Cell Subpopulations ◽

The Individual

Background: Several human B-cell subpopulations are recognized in the peripheral blood, which play distinct roles in the humoral immune response. These cells undergo developmental and maturational changes involving VDJ recombination, somatic hypermutation and class switch recombination, altogether shaping their immunoglobulin heavy chain (IgH) repertoire. Methods: Here, we sequenced the IgH repertoire of naïve, marginal zone, switched and plasma cells from 10 healthy adults along with matched unsorted and in silico separated CD19+ bulk B cells. We used advanced bioinformatic analysis and machine learning to thoroughly examine and compare these repertoires. Results: We show that sorted B cell subpopulations are characterised by distinct repertoire characteristics on both the individual sequence and the repertoire level. Sorted subpopulations shared similar repertoire characteristics with their corresponding in silico separated subsets. Furthermore, certain IgH repertoire characteristics correlated with the position of the constant region on the IgH locus. Conclusion: Overall, this study provides unprecedented insight over mechanisms of B cell repertoire control in peripherally circulating B cell subpopulations.

Download Full-text