scholarly journals Trade-offs in antibody repertoires to complex antigens

2015 ◽  
Vol 370 (1676) ◽  
pp. 20140245 ◽  
Author(s):  
Lauren M. Childs ◽  
Edward B. Baskerville ◽  
Sarah Cobey
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Distant Interactions ◽  
Trade Offs ◽  
Cell Clones ◽  
Evolutionary Advantage ◽  
Mechanistic Basis ◽  
Selection Of

Pathogens vary in their antigenic complexity. While some pathogens such as measles present a few relatively invariant targets to the immune system, others such as malaria display considerable antigenic diversity. How the immune response copes in the presence of multiple antigens, and whether a trade-off exists between the breadth and efficacy of antibody (Ab)-mediated immune responses, are unsolved problems. We present a theoretical model of affinity maturation of B-cell receptors (BCRs) during a primary infection and examine how variation in the number of accessible antigenic sites alters the Ab repertoire. Naive B cells with randomly generated receptor sequences initiate the germinal centre (GC) reaction. The binding affinity of a BCR to an antigen is quantified via a genotype–phenotype map, based on a random energy landscape, that combines local and distant interactions between residues. In the presence of numerous antigens or epitopes, B-cell clones with different specificities compete for stimulation during rounds of mutation within GCs. We find that the availability of many epitopes reduces the affinity and relative breadth of the Ab repertoire. Despite the stochasticity of somatic hypermutation, patterns of immunodominance are strongly shaped by chance selection of naive B cells with specificities for particular epitopes. Our model provides a mechanistic basis for the diversity of Ab repertoires and the evolutionary advantage of antigenically complex pathogens.

scholarly journals Enforced Expression of Bcl-2 Selectively Perturbs Negative Selection of Dual Reactive Antibodies

2001 ◽  
Vol 8 (3-4) ◽  
pp. 223-234 ◽  
Author(s):  
Evangelia Notidis ◽  
Shailaja Hande ◽  
Tim Manser
Keyword(s):  
B Cells ◽  
B Cell ◽  
Negative Selection ◽  
Somatic Hypermutation ◽  
Serum Antibody ◽  
Affinity Maturation ◽  
Peripheral Tolerance ◽  
Cell Compartment ◽  
Memory B Cell ◽  
Selection Of

We investigated the role of apoptosis in the development of B cell memory by analyzing the (p-azophenylarsonate) Ars response in a line of A strain mice in which expression of human Bcl-2 was enforced in the B cell compartment. Previous studies of the Ars immune response in these A. Bcl-2 mice, demonstrated that a large percentage of the antibodies expressed by the Ars induced memory B cell compartment had accumulated point mutations via somatic hypermutation that increased their affinity for both Ars and the autoantigen DNA (“dual reactive” antibodies). This was in sharp contrast to normal A strain mice which displayed no dual reactive B cells in their Ars induced memory B cell compartment. These data suggested that interference with apoptotic pathways regulated by Bcl-2 allows developing memory B cells that have acquired autoreactivity to bypass a peripheral tolerance checkpoint. Further studies of these mice, reported here, demonstrate that enforced expression of Bcl-2 does not alter serum antibody affinity maturation nor positive selection of B cells expressing somatically mutated antibody with an increased affinity for Ars. Moreover, the somatic hypermutation process was unaffected in A. Bcl-2 mice. Thus, enforced expression of Bcl-2 in A. Bcl-2 mice appears to selectively alter a negative selection process that operates during memory B cell differentiation.

scholarly journals Germinal center reutilization by newly activated B cells

2009 ◽  
Vol 206 (13) ◽  
pp. 2907-2914 ◽  
Author(s):  
Tanja A. Schwickert ◽  
Boris Alabyev ◽  
Tim Manser ◽  
Michel C. Nussenzweig
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Anatomical Structures ◽  
Class Switch ◽  
Cell Clones ◽  
T Cell Help ◽  
Activated B Cells

Germinal centers (GCs) are specialized structures in which B lymphocytes undergo clonal expansion, class switch recombination, somatic hypermutation, and affinity maturation. Although these structures were previously thought to contain a limited number of isolated B cell clones, recent in vivo imaging studies revealed that they are in fact dynamic and appear to be open to their environment. We demonstrate that B cells can colonize heterologous GCs. Invasion of primary GCs after subsequent immunization is most efficient when T cell help is shared by the two immune responses; however, it also occurs when the immune responses are entirely unrelated. We conclude that GCs are dynamic anatomical structures that can be reutilized by newly activated B cells during immune responses.

scholarly journals Mechanisms behind Functional Avidity Maturation in T Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Marina Rode von Essen ◽  
Martin Kongsbak ◽  
Carsten Geisler
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Cell Receptor ◽  
Affinity Maturation ◽  
Functional Avidity ◽  
Cell Clones ◽  
Genes Encoding ◽  
Avidity Maturation

During an immune response antigen-primed B-cells increase their antigen responsiveness by affinity maturation mediated by somatic hypermutation of the genes encoding the antigen-specific B-cell receptor (BCR) and by selection of higher-affinity B cell clones. Unlike the BCR, the T-cell receptor (TCR) cannot undergo affinity maturation. Nevertheless, antigen-primed T cells significantly increase their antigen responsiveness compared to antigen-inexperienced (naïve) T cells in a process called functional avidity maturation. This paper covers studies that describe differences in T-cell antigen responsiveness during T-cell differentiation along with examples of the mechanisms behind functional avidity maturation in T cells.

EBV Transformation of Tonsil Germinal Centre B Cells Carrying Functionally Inactivated IgV Gene.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3248-3248
Author(s):  
Sridhar Chaganti ◽  
Noelia Begue Pastor ◽  
Mark T. Drayson ◽  
Andy I. Bell ◽  
Alan B. Rickinson
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
B Cell Lymphoma ◽  
Affinity Maturation ◽  
Germinal Centre ◽  
Chain Gene ◽  
Lymphoid Tissues ◽  
Memory B Cell

Abstract Somatic hypermutation of immunoglobulin (Ig) gene sequences in the germinal centres of lymphoid tissues is necessary for affinity maturation of B cell responses to antigen challenge. This process generates a few clones with improved affinity that are selected into B cell memory and many clones with other non favourable Ig mutations, including some cells with functionally inactivated Ig gene that normally die by apoptosis. It is postulated that infection with Epstein-Barr virus (EBV), a B lymphotropic agent linked to several types of B cell lymphoma, can rescue germinal centre cells with unfavourable mutations. This creates a pool of infected cells at greater risk of developing into lymphomas. In the present work, CD38+ germinal centre B cells were separated from tonsil by negative selection for IgD and CD39. Peripheral blood naïve and memory B cell subpopulations were FACS sorted as IgD+, CD27− and IgD−, CD27+ fractions respectively. These cells were infected with EBV (B95.8 strain) in vitro and seeded at limiting dilutions onto fibroblast feeders. EBV transformed lymphoblastoid cell lines (LCLs) from such cultures were analysed for surface Ig phenotype. Naïve B cell transformants were consistently IgM+, IgD+. Memory B cell transformants were IgM+ in some cases but more frequently IgG+ or IgA+. Germinal centre transformants showed the same spectrum of surface Ig phenotypes as memory cell transformants but in addition we identified six germinal centre derived LCLs which were consistently surface Ig negative. Sequencing from these lines confirmed that in at least three cases EBV had rescued cells with functionally inactivated Ig heavy chain gene.

scholarly journals WASp Is Crucial for the Unique Architecture of the Immunological Synapse in Germinal Center B-Cells

2021 ◽  
Vol 9 ◽  
Author(s):  
Yanan Li ◽  
Anshuman Bhanja ◽  
Arpita Upadhyaya ◽  
Xiaodong Zhao ◽  
Wenxia Song
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lipid Bilayers ◽  
Germinal Center ◽  
Actin Polymerization ◽  
Immunological Synapse ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Membrane Protrusions ◽  
Germinal Center B Cells

B-cells undergo somatic hypermutation and affinity maturation in germinal centers. Somatic hypermutated germinal center B-cells (GCBs) compete to engage with and capture antigens on follicular dendritic cells. Recent studies show that when encountering membrane antigens, GCBs generate actin-rich pod-like structures with B-cell receptor (BCR) microclusters to facilitate affinity discrimination. While deficiencies in actin regulators, including the Wiskott-Aldrich syndrome protein (WASp), cause B-cell affinity maturation defects, the mechanism by which actin regulates BCR signaling in GBCs is not fully understood. Using WASp knockout (WKO) mice that express Lifeact-GFP and live-cell total internal reflection fluorescence imaging, this study examined the role of WASp-mediated branched actin polymerization in the GCB immunological synapse. After rapid spreading on antigen-coated planar lipid bilayers, GCBs formed microclusters of phosphorylated BCRs and proximal signaling molecules at the center and the outer edge of the contact zone. The centralized signaling clusters localized at actin-rich GCB membrane protrusions. WKO reduced the centralized micro-signaling clusters by decreasing the number and stability of F-actin foci supporting GCB membrane protrusions. The actin structures that support the spreading membrane also appeared less frequently and regularly in WKO than in WT GCBs, which led to reductions in both the level and rate of GCB spreading and antigen gathering. Our results reveal essential roles for WASp in the generation and maintenance of unique structures for GCB immunological synapses.

scholarly journals Distinct clonal evolution of B-cells in HIV controllers with neutralizing antibody breadth

eLife ◽  
2021 ◽  
Vol 10 ◽  
Author(s):  
Deniz Cizmeci ◽  
Giuseppe Lofano ◽  
Evan Rossignol ◽  
Anne-Sophie Dugast ◽  
Dongkyoon Kim ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Somatic Hypermutation ◽  
Clonal Evolution ◽  
Neutralizing Antibody ◽  
Affinity Maturation ◽  
Gene Repertoire ◽  
Immunoglobulin Gene ◽  
Hiv Controllers ◽  
Hiv 1

A minor subset of individuals infected with HIV-1 develop antibody neutralization breadth during the natural course of the infection, often linked to chronic, high-level viremia. Despite significant efforts, vaccination strategies have been unable to induce similar neutralization breadth and the mechanisms underlying neutralizing antibody induction remain largely elusive. Broadly neutralizing antibody responses can also be found in individuals who control HIV to low and even undetectable plasma levels in the absence of antiretroviral therapy, suggesting that high antigen exposure is not a strict requirement for neutralization breadth. We therefore performed an analysis of paired heavy and light chain B-cell receptor (BCR) repertoires in 12,591 HIV-1 envelope-specific single memory B-cells to determine alterations in the BCR immunoglobulin gene repertoire and B-cell clonal expansions that associate with neutralizing antibody breadth in 22 HIV controllers. We found that the frequency of genomic mutations in IGHV and IGLV was directly correlated with serum neutralization breadth. The repertoire of the most mutated antibodies was dominated by a small number of large clones with evolutionary signatures suggesting that these clones had reached peak affinity maturation. These data demonstrate that even in the setting of low plasma HIV antigenemia, similar to what a vaccine can potentially achieve, BCR selection for extended somatic hypermutation and clonal evolution can occur in some individuals suggesting that host-specific factors might be involved that could be targeted with future vaccine strategies.

scholarly journals Local BLyS production by T follicular cells mediates retention of high affinity B cells during affinity maturation

2013 ◽  
Vol 211 (1) ◽  
pp. 45-56 ◽  
Author(s):  
Radhika Goenka ◽  
Andrew H. Matthews ◽  
Bochao Zhang ◽  
Patrick J. O’Neill ◽  
Jean L. Scholz ◽  
...  
Keyword(s):  
B Cells ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Affinity Maturation ◽  
Local Source ◽  
High Affinity ◽  
Cell Clones ◽  
B Lymphocyte Stimulator ◽  
Efficient Selection

We have assessed the role of B lymphocyte stimulator (BLyS) and its receptors in the germinal center (GC) reaction and affinity maturation. Despite ample BLyS retention on B cells in follicular (FO) regions, the GC microenvironment lacks substantial BLyS. This reflects IL-21–mediated down-regulation of the BLyS receptor TACI (transmembrane activator and calcium modulator and cyclophilin ligand interactor) on GC B cells, thus limiting their capacity for BLyS binding and retention. Within the GC, FO helper T cells (TFH cells) provide a local source of BLyS. Whereas T cell–derived BLyS is dispensable for normal GC cellularity and somatic hypermutation, it is required for the efficient selection of high affinity GC B cell clones. These findings suggest that during affinity maturation, high affinity clones rely on TFH-derived BLyS for their persistence.

The immunoglobulin heavy-chain locus hs3b and hs4 3′ enhancers are dispensable for VDJ assembly and somatic hypermutation

Blood ◽  
2003 ◽  
Vol 102 (4) ◽  
pp. 1421-1427 ◽  
Author(s):  
Caroline Le Morvan ◽  
Eric Pinaud ◽  
Catherine Decourt ◽  
Armelle Cuvillier ◽  
Michel Cogné
Keyword(s):  
B Cells ◽  
B Cell ◽  
Heavy Chain ◽  
Somatic Hypermutation ◽  
Class Switch Recombination ◽  
Immunoglobulin Heavy Chain ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Class Switch ◽  
Endogenous Locus

Abstract The more distal enhancers of the immunoglobulin heavy-chain 3′ regulatory region, hs3b and hs4, were recently demonstrated as master control elements of germline transcription and class switch recombination to most immunoglobulin constant genes. In addition, they were shown to enhance the accumulation of somatic mutations on linked transgenes. Since somatic hypermutation and class switch recombination are tightly linked processes, their common dependency on the endogenous locus 3′ enhancers could be an attractive hypothesis. VDJ structure and somatic hypermutation were analyzed in B cells from mice carrying either a heterozygous or a homozygous deletion of these enhancers. We find that hs3b and hs4 are dispensable both for VDJ assembly and for the occurrence of mutations at a physiologic frequency in the endogenous locus. In addition, we show that cells functionally expressing the immunoglobulin M (IgM) class B-cell receptor encoded by an hs3b/hs4-deficient locus were fully able to enter germinal centers, undergo affinity maturation, and yield specific antibody responses in homozygous mutant mice, where IgG1 antibodies compensated for the defect in other IgG isotypes. By contrast, analysis of Peyer patches from heterozygous animals showed that peanut agglutinin (PNAhigh) B cells functionally expressing the hs3b/hs4-deficient allele were dramatically outclassed by B cells expressing the wild-type locus and normally switching to IgA. This study thus also highlights the role of germinal centers in the competition between B cells for affinity maturation and suggests that membrane IgA may promote recruitment in an activated B-cell compartment, or proliferation of activated B cells, more efficiently than IgM in Peyer patches.

scholarly journals Altered Germinal-Center Metabolism in B Cells in Autoimmunity

Metabolites ◽  
2022 ◽  
Vol 12 (1) ◽  
pp. 40
Author(s):  
Ashton K. Shiraz ◽  
Eric J. Panther ◽  
Christopher M. Reilly
Keyword(s):  
B Cells ◽  
B Cell ◽  
Lupus Erythematosus ◽  
Germinal Center ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Cell Metabolism ◽  
Affinity Maturation ◽  
B Cell Differentiation ◽  
Contributing Factors

B lymphocytes play an important role in the pathophysiology of many autoimmune disorders by producing autoantibodies, secreting cytokines, and presenting antigens. B cells undergo extreme physiological changes as they develop and differentiate. Aberrant function in tolerogenic checkpoints and the metabolic state of B cells might be the contributing factors to the dysfunctionality of autoimmune B cells. Understanding B-cell metabolism in autoimmunity is important as it can give rise to new treatments. Recent investigations have revealed that alterations in metabolism occur in the activation of B cells. Several reports have suggested that germinal center (GC) B cells of individuals with systemic lupus erythematosus (SLE) have altered metabolic function. GCs are unique microenvironments in which the delicate and complex process of B-cell affinity maturation occurs through somatic hypermutation (SHM) and class switching recombination (CSR) and where Bcl6 tightly regulates B-cell differentiation into memory B-cells or plasma cells. GC B cells rely heavily on glucose, fatty acids, and oxidative phosphorylation (OXPHOS) for their energy requirements. However, the complicated association between GC B cells and their metabolism is still not clearly understood. Here, we review several studies of B-cell metabolism, highlighting the significant transformations that occur in GC progression, and suggest possible approaches that may be investigated to more precisely target aberrant B-cell metabolism in SLE.

scholarly journals Uhrf1 regulates germinal center B cell expansion and affinity maturation to control viral infection

2018 ◽  
Vol 215 (5) ◽  
pp. 1437-1448 ◽  
Author(s):  
Chao Chen ◽  
Sulan Zhai ◽  
Le Zhang ◽  
Jingjing Chen ◽  
Xuehui Long ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Ring Finger ◽  
Affinity Maturation ◽  
Virus Clearance ◽  
Germinal Center B Cell ◽  
Pathogen Clearance

The production of high-affinity antibody is essential for pathogen clearance. Antibody affinity is increased through germinal center (GC) affinity maturation, which relies on BCR somatic hypermutation (SHM) followed by antigen-based selection. GC B cell proliferation is essentially involved in these processes; it provides enough templates for SHM and also serves as a critical mechanism of positive selection. In this study, we show that expression of epigenetic regulator ubiquitin-like with PHD and RING finger domains 1 (Uhrf1) was markedly up-regulated by c-Myc–AP4 in GC B cells, and it was required for GC response. Uhrf1 regulates cell proliferation–associated genes including cdkn1a, slfn1, and slfn2 by DNA methylation, and its deficiency inhibited the GC B cell cycle at G1-S phase. Subsequently, GC B cell SHM and affinity maturation were impaired, and Uhrf1 GC B knockout mice were unable to control chronic virus infection. Collectively, our data suggest that Uhrf1 regulates GC B cell proliferation and affinity maturation, and its expression in GC B cells is required for virus clearance.

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