scholarly journals Hyperproliferation of B Cells Specific for a Weakly Immunogenic PorA in a Meningococcal Vaccine Model

2008 ◽  
Vol 15 (10) ◽  
pp. 1598-1605 ◽  
Author(s):  
Thomas A. Luijkx ◽  
Jacqueline A. M. van Gaans-van den Brink ◽  
Harry H. van Dijken ◽  
Germie P. J. M. van den Dobbelsteen ◽  
Cécile A. C. M. van Els
Keyword(s):  
B Cells ◽  
B Cell ◽  
Bactericidal Activity ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Vaccine Antigen ◽  
Cell Subpopulation ◽  
Cell Subpopulations ◽  
Group B

ABSTRACT Highly homologous meningococcal porin A (PorA) proteins induce protective humoral immunity against Neisseria meningitidis group B infection but with large and consistent differences in the levels of serum bactericidal activity achieved. We investigated whether a poor PorA-specific serological outcome is associated with a limited size of the specific B-cell subpopulation involved. The numbers of PorA-specific splenic plasma cells, bone marrow (BM) plasma cells, and splenic memory B cells were compared between mice that received priming and boosting with the weakly immunogenic PorA (P1.7-2,4) protein and those that received priming and boosting with the highly immunogenic PorA (P1.5-1,2-2) protein. Immunoglobulin G (IgG) titers (except at day 42), bactericidal activity, and the avidity of IgG produced against P1.7-2,4 were significantly lower at all time points after priming and boosting than against P1.5-1,2-2. These differences, however, were not associated with a lack of P1.7-2,4-specific plasma cells. Instead, priming with both of the PorAs resulted in the initial expansion of comparable numbers of splenic and BM plasma cells. Moreover, P1.7-2,4-specific BM plasma cells, but not P1.5-1,2-2-specific plasma cells, expanded significantly further after boosting. Likewise, after a relative delay during the priming phase, the splenic P1.7-2,4-specific memory B cells largely outnumbered those specific for P1.5-1,2-2, upon boosting. These trends were observed with different vaccine formulations of the porins. Our results show for the first time that B-cell subpopulations involved in a successfully maturated antibody response against a clinically relevant vaccine antigen are maintained at smaller population sizes than those associated with poor affinity maturation. This bears consequences for the interpretation of immunological memory data in clinical vaccine trials.

scholarly journals Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires

2022 ◽  
Author(s):  
Artem I. Mikelov ◽  
Evgeniia I. Alekseeva ◽  
Ekaterina A. Komech ◽  
Dmitriy B. Staroverov ◽  
Maria A. Turchaninova ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Inflammatory Diseases ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Immune Memory ◽  
Memory B Cell ◽  
Antibody Secreting Cells

B-cell mediated immune memory holds both plasticity and conservatism to respond to new challenges and repeated infections. Here, we analyze the dynamics of immunoglobulin heavy chain (IGH) repertoires of memory B cells, plasmablasts and plasma cells sampled several times during one year from peripheral blood of volunteers without severe inflammatory diseases. We reveal a high degree of clonal persistence in individual memory B-cell subsets with inter-individual convergence in memory and antibody-secreting cells (ASCs). Clonotypes in ASCs demonstrate clonal relatedness to memory B cells and are transient in peripheral blood. Two clusters of expanded clonal lineages displayed different prevalence of memory B cells, isotypes, and persistence. Phylogenetic analysis revealed signs of reactivation of persisting memory B cell-enriched clonal lineages, accompanied by new rounds of affinity maturation during proliferation to ASCs. Negative selection contributes to both, persisting and reactivated lineages, saving functionality and specificity of BCRs to protect from the current and future pathogens.

scholarly journals Positive Selection in the Light Zone of Germinal Centers

2021 ◽  
Vol 12 ◽  
Author(s):  
Rinako Nakagawa ◽  
Dinis Pedro Calado
Keyword(s):  
B Cells ◽  
Positive Selection ◽  
B Cell ◽  
Plasma Cells ◽  
Selection Process ◽  
Germinal Centers ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Cell Fates ◽  
High Affinity

Germinal centers (GCs) are essential sites for the production of high-affinity antibody secreting plasma cells (PCs) and memory-B cells (MBCs), which form the framework of vaccination. Affinity maturation and permissive selection in GCs are key for the production of PCs and MBCs, respectively. For these purposes, GCs positively select “fit” cells in the light zone of the GC and instructs them for one of three known B cell fates: PCs, MBCs and persistent GC-B cells as dark zone entrants. In this review, we provide an overview of the positive selection process and discuss its mechanisms and how B cell fates are instructed.

scholarly journals Genome-Wide Histone Acetylation Profiling in Chronic Lymphocytic Leukemia Reveals a Distinctive Signature in Stereotyped Subset #8

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1241-1241
Author(s):  
Maria Tsagiopoulou ◽  
Vicente Chapaprieta ◽  
Nuria Russiñol ◽  
Fotis Psomopoulos ◽  
Nikos Papakonstantinou ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Research Funding ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Memory B Cells ◽  
Site Analysis ◽  
Total Variability ◽  
Cell Subpopulations ◽  
Chromatin Acetylation

In CLL, subsets of patients carrying stereotyped B cell receptors (BcR) share similar biological and clinical features independently of IGHV gene somatic hypermutation status. Although the chromatin landscape of CLL as a whole has been recently characterized, it remains largely unexplored in stereotyped cases. Here, we analyzed the active chromatin regulatory landscape of 3 major CLL stereotyped subsets associated with clinical aggressiveness. We performed chromatin-immunoprecipitation followed by sequencing (ChIP-Seq) with an antibody for the H3K27ac histone mark in sorted CLL cells from 19 cases, including clinically aggressive subsets #1 (clan I genes/IGKV(D)1-39, IG-unmutated CLL (U-CLL)(n=3)], #2 [IGHV3-21/IGLV3-21, IG-mutated CLL (M-CLL)(n=3)] and #8 [IGHV4-39/IGKV1(D)-39, U-CLL(n=3)] which we compared to non-stereotyped CLL cases [5 M-CLL|5 U-CLL]. In addition, a series of 15 normal B cell samples from different stages of B-cell differentiation were analyzed [naive B cells from peripheral blood (n=3), tonsillar naive B cells (n=3), germinal centre (GC) B cells (n=3), memory B cells (n=3), tonsillar plasma cells (n=3)]. Initial unsupervised principal component analysis (PCA) disclosed a distinct chromatin acetylation pattern in CLL, regardless of stereotypy status, versus normal B cells. CLL as a whole was found to be closer to naive and memory B cells rather than GC B cells and plasma cells. Detailed analysis of individual principal components (PC) revealed that PC4, which accounts for 5% of the total variability, segregated subset #8 cases and GC B cells from other CLLs and normal B cell subpopulations. Although PC4 accounts for only a small part of the total variability (5%), this suggests that subset #8 cases may share some chromatin features with proliferating GC B cells, in line with the fact that subset #8 BcR are IgG-switched. We also investigated whether stereotyped CLLs have different chromatin acetylation features compared to non-stereotyped CLLs matched by IGHV somatic hypermutation status and identified 878 Differential Regions (DR) in subset #8 vs. U-CLL, 84 DR in subset #1 vs. U-CLL and 66 DR in #2 compared vs. M-CLL. As subset #8 cases seemed to have the most distinct profile, we further characterized the detected regions. The 435 and 443 regions gaining and losing activation, respectively, mostly targeted promoters (29.5%) and regulatory elements located in introns (31%) and distal intergenic regions (21.8%). Hierarchical clustering based on the 878 DRs enabled the clear discrimination of subset #8 cases from U-CLL and normal B cells; however, it is worth noting that for several of these 878 DRs the acetylation patterns were shared between subset #8 and normal B cell subpopulations rather than subset #8 and U-CLL. Of note, 11/435 regions gaining activity on subset #8 were found within the gene encoding for the EBF1 transcription factor (TF); additional regions were associated with genes significant to CLL pathogenesis, e.g. TCF4 and E2F1. Moreover, 3 DRs losing activity in subset #8 were located within the CTLA4 gene and 2 DRs within the IL21R gene, which we have recently reported as hypermethylated and not expressed in subset #8. Next, we performed TF binding site analysis by MEME/AME suit, separately for regions gaining or losing activity, and identified significant enrichment (adj-p<0.001) on TFs such as AP-1, FOX, GATA, IRF. The regions losing activity in subset #8 showed a higher number of enriched TFs versus those gaining activity (165 vs 93 TFs), particularly displaying enrichment for many HOX family members . However, a cluster of TFs with enrichment on TF binding site analysis, such as FOXO1, FOXP1, MEF2D, PRDM1, RUNX1, RXRA, STAT6, were also located within the 878 DRs discriminating subset #8 from either U-CLL or normal B cell subpopulations. Taken together, subset #8 cases have a distinct chromatin acetylation signature which includes both loss and gain of active elements, shared features with proliferating GC B cells, and specific changes in chromatin activity of several genes and TFs relevant to B cell/CLL biology. These findings further underscore the concept that BcR stereotypy defines subsets of patients with consistent biological profile, while they may also be relevant to the particular clinical behavior of subset #8, known to be associated with the highest risk of Richter's transformation amongst all CLL. Disclosures Stamatopoulos: Abbvie: Honoraria, Research Funding; Janssen: Honoraria, Research Funding.

scholarly journals CD4+T Cells Promote Antibody Production but Not Sustained Affinity Maturation during Borrelia burgdorferi Infection

2014 ◽  
Vol 83 (1) ◽  
pp. 48-56 ◽  
Author(s):  
Rebecca A. Elsner ◽  
Christine J. Hastey ◽  
Nicole Baumgarth
Keyword(s):  
T Cells ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Antibody Responses ◽  
Content Type ◽  
High Affinity

CD4 T cells are crucial for enhancing B cell-mediated immunity, supporting the induction of high-affinity, class-switched antibody responses, long-lived plasma cells, and memory B cells. Previous studies showed that the immune response toBorrelia burgdorferiappears to lack robust T-dependent B cell responses, as neither long-lived plasma cells nor memory B cells form for months after infection, and nonswitched IgM antibodies are produced continuously during this chronic disease. These data prompted us to evaluate the induction and functionality ofB. burgdorferiinfection-induced CD4 TFHcells. We report that CD4 T cells were effectively primed and TFHcells induced afterB. burgdorferiinfection. These CD4 T cells contributed to the control ofB. burgdorferiburden and supported the induction ofB. burgdorferi-specific IgG responses. However, while affinity maturation of antibodies against a prototypic T-dependentB. burgdorferiprotein, Arthritis-related protein (Arp), were initiated, these increases were reversed later, coinciding with the previously observed involution of germinal centers. The cessation of affinity maturation was not due to the appearance of inhibitory or exhausted CD4 T cells or a strong induction of regulatory T cells.In vitroT-B cocultures demonstrated that T cells isolated fromB. burgdorferi-infected but notB. burgdorferi-immunized mice supported the rapid differentiation of B cells into antibody-secreting plasma cells rather than continued proliferation, mirroring the induction of rapid short-lived instead of long-lived T-dependent antibody responsesin vivo. The data further suggest thatB. burgdorferiinfection drives the humoral response away from protective, high-affinity, and long-lived antibody responses and toward the rapid induction of strongly induced, short-lived antibodies of limited efficacy.

scholarly journals Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kristian Assing ◽  
Christian Nielsen ◽  
Marianne Jakobsen ◽  
Charlotte B. Andersen ◽  
Kristin Skogstrand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Formation ◽  
Memory B Cells ◽  
Memory B Cell

Abstract Background Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. Case presentation We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001. Conclusions To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

scholarly journals IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses

2010 ◽  
Vol 207 (2) ◽  
pp. 353-363 ◽  
Author(s):  
Michelle A. Linterman ◽  
Laura Beaton ◽  
Di Yu ◽  
Roybel R. Ramiscal ◽  
Monika Srivastava ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Formation ◽  
Affinity Maturation ◽  
Tfh Cells ◽  
Follicular Helper ◽  
Early Memory ◽  
Bone Marrow Chimeras ◽  
Follicular Response

During T cell–dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell–intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell–autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1+ GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.

A reservoir of rituximab-resistant splenic memory B cells contributes to relapses after B-cell depletion therapy

2019 ◽  
Author(s):  
Etienne Crickx ◽  
Pascal Chappert ◽  
Sandra Weller ◽  
Aurélien Sokal ◽  
Imane Azzaoui ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Complete Response ◽  
Memory B Cells ◽  
Chain Gene ◽  
Gene Repertoire ◽  
Heavy Chain Gene ◽  
Immunoglobulin Heavy Chain Gene ◽  
Pathogenic Antibodies

AbstractImmune thrombocytopenia (ITP) is an autoimmune disease mediated by pathogenic antibodies directed against platelet antigens, including GPIIbIIIa. Taking advantage of spleen samples obtained from ITP patients, we characterized by multiples approaches the onset of disease relapses occurring after an initial complete response to rituximab. Analysis of splenic B cell immunoglobulin heavy chain gene repertoire at bulk level and from single anti-GPIIbIIIa B cells revealed that germinal centers were fueled by B cells originating from the ongoing lymphopoiesis, but also by rituximab-resistant memory B cells, both giving rise to anti-GPIIbIIIa plasma cells. We identified a population of splenic memory B cells that resisted rituximab through acquisition of a unique phenotype and contributed to relapses, providing a new target in B cell mediated autoimmune diseases.

scholarly journals Differential T- and B-Cell Responses to Pertussis in Acellular Vaccine-Primed versus Whole-Cell Vaccine-Primed Children 2 Years after Preschool Acellular Booster Vaccination

2013 ◽  
Vol 20 (9) ◽  
pp. 1388-1395 ◽  
Author(s):  
Rose-Minke Schure ◽  
Lotte H. Hendrikx ◽  
Lia G. H. de Rond ◽  
Kemal Öztürk ◽  
Elisabeth A. M. Sanders ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Booster Vaccination ◽  
Memory B Cells ◽  
Vaccine Antigen ◽  
Whole Cell ◽  
Cell Responses

ABSTRACTThis study investigated long-term cellular and humoral immunity against pertussis after booster vaccination of 4-year-old children who had been vaccinated at 2, 3, 4, and 11 months of age with either whole-cell pertussis (wP) or acellular pertussis (aP) vaccine. Immune responses were evaluated until 2 years after the preschool booster aP vaccination. In a cross-sectional study (registered trial no. ISRCTN65428640), blood samples were taken from wP- and aP-primed children prebooster and 1 month and 2 years postbooster. Pertussis vaccine antigen-specific IgG levels, antibody avidities, and IgG subclasses, as well as T-cell cytokine levels, were measured by fluorescent bead-based multiplex immunoassays. The numbers of pertussis-specific memory B cells and gamma interferon (IFN-γ)-producing T cells were quantified by enzyme-linked immunosorbent spot assays. Even 2 years after booster vaccination, memory B cells were still present and higher levels of pertussis-specific antibodies than prebooster were found in aP-primed children and, to a lesser degree, also in wP-primed children. The antibodies consisted mainly of the IgG1 subclass but also showed an increased IgG4 portion, primarily in the aP-primed children. The antibody avidity indices for pertussis toxin and pertactin in aP-primed children were already high prebooster and remained stable at 2 years, whereas those in wP-primed children increased. All measured prebooster T-cell responses in aP-primed children were already high and remained at similar levels or even decreased during the 2 years after booster vaccination, whereas those in wP-primed children increased. Since the Dutch wP vaccine has been replaced by aP vaccines, the induction of B-cell and T-cell memory immune responses has been enhanced, but antibody levels still wane after five aP vaccinations. Based on these long-term immune responses, the Dutch pertussis vaccination schedule can be optimized, and we discuss here several options.

scholarly journals Multiscale Modeling of Germinal Center Recapitulates the Temporal Transition From Memory B Cells to Plasma Cells Differentiation as Regulated by Antigen Affinity-Based Tfh Cell Help

2021 ◽  
Vol 11 ◽  
Author(s):  
Elena Merino Tejero ◽  
Danial Lashgari ◽  
Rodrigo García-Valiente ◽  
Xuefeng Gao ◽  
Fabien Crauste ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Asymmetric Division ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Germinal Center Reaction

Germinal centers play a key role in the adaptive immune system since they are able to produce memory B cells and plasma cells that produce high affinity antibodies for an effective immune protection. The mechanisms underlying cell-fate decisions are not well understood but asymmetric division of antigen, B-cell receptor affinity, interactions between B-cells and T follicular helper cells (triggering CD40 signaling), and regulatory interactions of transcription factors have all been proposed to play a role. In addition, a temporal switch from memory B-cell to plasma cell differentiation during the germinal center reaction has been shown. To investigate if antigen affinity-based Tfh cell help recapitulates the temporal switch we implemented a multiscale model that integrates cellular interactions with a core gene regulatory network comprising BCL6, IRF4, and BLIMP1. Using this model we show that affinity-based CD40 signaling in combination with asymmetric division of B-cells result in switch from memory B-cell to plasma cell generation during the course of the germinal center reaction. We also show that cell fate division is unlikely to be (solely) based on asymmetric division of Ag but that BLIMP1 is a more important factor. Altogether, our model enables to test the influence of molecular modulations of the CD40 signaling pathway on the production of germinal center output cells.

scholarly journals The effect of pneumococcal immunization on total and antigen-specific B cells in patients with severe chronic kidney disease

2019 ◽  
Vol 20 (1) ◽  
Author(s):  
Gabrielle Nicole Gaultier ◽  
William McCready ◽  
Marina Ulanova
Keyword(s):  
Chronic Kidney Disease ◽  
B Cells ◽  
Kidney Disease ◽  
B Cell ◽  
Pneumococcal Infection ◽  
Fold Increase ◽  
Memory B Cells ◽  
Noticeable Effect ◽  
Post Immunization ◽  
Cell Subpopulations

Abstract Background While the 23-valent pneumococcal polysaccharide vaccine (PPV23) is routinely used in Canada and some other countries to prevent pneumococcal infection in adults with chronic kidney disease (CKD), patients develop a suboptimal antibody response to PPV23 due to their immune dysfunction. The 13-valent pneumococcal conjugate vaccine (PCV13) has superior immunogenicity in some categories of immunocompromised adults; however, its effect on the immune response in CKD patients has only been addressed by two recent studies with conflicting results. The effect of PPV23 or PCV13 on B cells in these patients has not been previously studied. We studied the absolute numbers and proportions of B cells and subpopulations in two groups of adult patients with severe CKD pre- and 7 days post-immunization with PCV13: pneumococcal vaccine naïve and previously immunized with PPV23 (over one year ago). Results PPV23 immunized patients had significantly lower proportions and absolute numbers of class switched memory (CD19 + CD27 + IgM-), as well as lower absolute numbers of IgM memory (CD19 + CD27 + IgM+) and class switched B cells (CD19 + CD27-IgM-) compared to PPV23 naïve patients. Following PCV13 immunization, the differences in absolute numbers of B-cell subpopulations between groups remained significant. The PPV23 immunized group had higher proportions of CD5- B cells along with lower proportions and absolute numbers of CD5+ B cells compared to PPV23 naïve patients both pre- and post-immunization with PCV13. However, previous PPV23 immunization did not have a noticeable effect on the numbers of total IgG or serotype 6B and 14 specific antibody-secreting cells detected 7 days post-immunization with PCV13. Nevertheless, fold increase in anti-serotype 14 IgG concentrations 28 days post-PCV13 was greater in PPV23 naïve than in previously immunized patients. Conclusions The results suggest that immunization with PPV23 may result in long-term changes in B-cell subpopulations such as increased prevalence of CD5- B cells and decreased prevalence of class switched memory B cells in the peripheral blood. Because previous immunization with PPV23 in patients with CKD is associated with a significant decrease in the total class switched memory B cells in response to subsequent immunization with PCV13, this may reduce PCV13 immunogenicity in the setting of PPV23 followed by PCV13. Trial registration Registered February 24, 2015 at ClinicalTrials.gov (NCT 02370069).

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