scholarly journals Somatic Mutations During an Immune Response inXenopusTadpoles

1995 ◽  
Vol 4 (3) ◽  
pp. 227-234 ◽  
Author(s):  
Melanie Wilson ◽  
Anne Marcuz ◽  
Louis Du Pasquier
Keyword(s):  
Immune Response ◽  
Somatic Mutations ◽  
Somatic Hypermutation ◽  
Point Mutations ◽  
Base Point ◽  
High Ratio ◽  
Cell Repertoire ◽  
Cdna Sequences ◽  
B Cell Repertoire ◽  
Reduced Rate

The tadpole B-cell repertoire is less diverse than that of the adult frog; their antibodies are of lower affinity and are less heterogenous. In order to determine whether this difference is due to a lack of or a reduced rate of somatic hypermutation, we analyzed and compared cDNA sequences utilizing VH1 elements with germline counterparts in isogenic LG7 tadpoles during an immune response. Indeed, tadpole VH1 sequences contained somatic mutations. There were zeo to 5 mutations per sequence, all single base-point mutations, with the high ratio of GC to AT base-pair alterations similar to that observed in adult frogs.

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

eLife ◽  
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.

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

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.

Bim establishes the B-cell repertoire from early to late in the immune response

2020 ◽  
Author(s):  
Akiko Sugimoto-Ishige ◽  
Michishige Harada ◽  
Miho Tanaka ◽  
Tommy Terooatea ◽  
Yu Adachi ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Late Response ◽  
Cell Repertoire ◽  
High Affinity ◽  
B Cell Repertoire

Abstract In T cell-dependent antibody responses, some of the activated B cells differentiate along extrafollicular pathways into low-affinity memory and plasma cells, whereas others are involved in subsequent germinal center (GC) formation in follicular pathways, in which somatic hypermutation and affinity maturation occur. The present study demonstrated that Bim, a proapoptotic BH3-only member of the Bcl-2 family, contributes to the establishment of the B-cell repertoire from early to late stages of immune responses to T cell-dependent antigens. Extrafollicular plasma cells grew in the spleen during the early immune response, but their numbers rapidly declined with the appearance of GC-derived progeny in wild-type mice. By contrast, conditional Bim deficiency in B cells resulted in expansion of extrafollicular IgG1+ antibody-forming cells (AFCs) and this expansion was sustained during the late response, which hampered the formation of GC-derived high-affinity plasma cells in the spleen. Approximately 10% of AFCs in mutant mice contained mutated VH genes; thus, Bim deficiency appears not to impede the selection of high-affinity AFC precursor cells. These results suggest that Bim contributes to the replacement of low-affinity antibody by high-affinity antibody as the immune response progresses.

scholarly journals Immune response to a thymus-dependent form of B512 dextran requires the presence of Lyb-5+ lymphocytes.

1983 ◽  
Vol 157 (2) ◽  
pp. 657-666 ◽  
Author(s):  
K E Stein ◽  
D A Zopf ◽  
C B Miller ◽  
B M Johnson ◽  
P K Mongini ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Keyhole Limpet Hemocyanin ◽  
Antibody Responses ◽  
Cell Repertoire ◽  
Specific Antibodies ◽  
Adult Mice ◽  
B Cell Repertoire ◽  
Direct Demonstration ◽  
Dependent Form

Studies of the ontogeny of the immune response to B512 dextran (Dex) show that antibody responses equal to those of adult mice are not attained until 12 wk of age. We have examined the anti-Dex response after immunization with a thymus-dependent antigen isomaltohexaosyl-keyhole limpet hemocyanin (IM6-KLH) and have shown that the development of the cross-reacting anti-Dex response parallels the development of Lyb-5+ B cells. Adult levels of anti-Dex antibody after immunization with IM6-KLH are achieved in mice between 3 and 12 wk of age, a time when Lyb-5+ cells have reached adult levels. Neonatal mice, immunized at 1 d or 1 wk after birth, failed to produce a significant amount of anti-Dex antibodies, although they did produce IM6-specific antibodies after immunization with IM6-KLH. Data, which support the conclusion from these experiments that Lyb-5+ cells are required for an anti-polysaccharide response even when the immunizing antigen is thymus-dependent, include the failure of IM6-KLH to stimulate a normal anti-Dex response in mice with the xid defect and the direct demonstration in normal adult mice that elimination of Lyb-5+ cells from spleens of mice primed with IM6-KLH abolishes the ability of these cells to transfer an anti-Dex response. The data imply that the expressed B cell repertoire in adult animals is skewed such that the vast majority of B cells capable of responding to polysaccharide determinants are in the Lyb-5+ subset.

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

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.

scholarly journals Inferring processes underlying B-cell repertoire diversity

2015 ◽  
Vol 370 (1676) ◽  
pp. 20140243 ◽  
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.

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

2017 ◽  
Vol 214 (7) ◽  
pp. 1991-2003 ◽  
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.

scholarly journals Broad sarbecovirus neutralizing antibodies define a key site of vulnerability on the SARS-CoV-2 spike protein

2020 ◽  
Author(s):  
Anna Z. Wec ◽  
Daniel Wrapp ◽  
Andrew S. Herbert ◽  
Daniel Maurer ◽  
Denise Haslwanter ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Rational Design ◽  
Somatic Hypermutation ◽  
Protein A ◽  
Neutralizing Antibody ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Cell Repertoire ◽  
Human Coronavirus ◽  
B Cell Repertoire

Broadly protective vaccines against known and pre-emergent coronaviruses are urgently needed. Critical to their development is a deeper understanding of cross-neutralizing antibody responses induced by natural human coronavirus (HCoV) infections. Here, we mined the memory B cell repertoire of a convalescent SARS donor and identified 200 SARS-CoV-2 binding antibodies that target multiple conserved sites on the spike (S) protein. A large proportion of the antibodies display high levels of somatic hypermutation and cross-react with circulating HCoVs, suggesting recall of pre-existing memory B cells (MBCs) elicited by prior HCoV infections. Several antibodies potently cross-neutralize SARS-CoV, SARS-CoV-2, and the bat SARS-like virus WIV1 by blocking receptor attachment and inducing S1 shedding. These antibodies represent promising candidates for therapeutic intervention and reveal a new target for the rational design of pan-sarbecovirus vaccines.

scholarly journals Inferring processes underlying B-cell repertoire diversity.

2015 ◽  
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, 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.

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

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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