scholarly journals Functional capacities of human IgM memory B cells in early inflammatory responses and secondary germinal center reactions

2015 ◽  
Vol 112 (6) ◽  
pp. E546-E555 ◽  
Author(s):  
Marc Seifert ◽  
Martina Przekopowitz ◽  
Sarah Taudien ◽  
Anna Lollies ◽  
Viola Ronge ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocytes ◽  
Germinal Center ◽  
B Cell Lymphoma ◽  
Memory B Cells ◽  
Immune Memory ◽  
Special Role ◽  
Memory B Cell ◽  
Functional Capacities

The generation and functions of human peripheral blood (PB) IgM+IgD+CD27+ B lymphocytes with somatically mutated IgV genes are controversially discussed. We determined their differential gene expression to naive B cells and to IgM-only and IgG+ memory B cells. This analysis revealed a high similarity of IgM+(IgD+)CD27+ and IgG+ memory B cells but also pointed at distinct functional capacities of both subsets. In vitro analyses revealed a tendency of activated IgM+IgD+CD27+ B cells to migrate to B-cell follicles and undergo germinal center (GC) B-cell differentiation, whereas activated IgG+ memory B cells preferentially showed a plasma cell (PC) fate. This observation was supported by reverse regulation of B-cell lymphoma 6 and PR domain containing 1 and differential BTB and CNC homology 1, basic leucine zipper transcription factor 2 expression. Moreover, IgM+IgD+CD27+ B lymphocytes preferentially responded to neutrophil-derived cytokines. Costimulation with catecholamines, carcinoembryonic antigen cell adhesion molecule 8 (CEACAM8), and IFN-γ caused differentiation of IgM+IgD+CD27+ B cells into PCs, induced class switching to IgG2, and was reproducible in cocultures with neutrophils. In conclusion, this study substantiates memory B-cell characteristics of human IgM+IgD+CD27+ B cells in that they share typical memory B-cell transcription patterns with IgG+ post-GC B cells and show a faster and more vigorous restimulation potential, a hallmark of immune memory. Moreover, this work reveals a functional plasticity of human IgM memory B cells by showing their propensity to undergo secondary GC reactions upon reactivation, but also by their special role in early inflammation via interaction with immunomodulatory neutrophils.

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 Human memory B cells originate from three distinct germinal center-dependent and -independent maturation pathways

Blood ◽  
2011 ◽  
Vol 118 (8) ◽  
pp. 2150-2158 ◽  
Author(s):  
Magdalena A. Berkowska ◽  
Gertjan J. A. Driessen ◽  
Vasilis Bikos ◽  
Christina Grosserichter-Wagener ◽  
Kostas Stamatopoulos ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Somatic Hypermutation ◽  
Phenotypic Diversity ◽  
Human Memory ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Effector Cells ◽  
B Cell Subsets

Abstract Multiple distinct memory B-cell subsets have been identified in humans, but it remains unclear how their phenotypic diversity corresponds to the type of responses from which they originate. Especially, the contribution of germinal center-independent responses in humans remains controversial. We defined 6 memory B-cell subsets based on their antigen-experienced phenotype and differential expression of CD27 and IgH isotypes. Molecular characterization of their replication history, Ig somatic hypermutation, and class-switch profiles demonstrated their origin from 3 different pathways. CD27−IgG+ and CD27+IgM+ B cells are derived from primary germinal center reactions, and CD27+IgA+ and CD27+IgG+ B cells are from consecutive germinal center responses (pathway 1). In contrast, natural effector and CD27−IgA+ memory B cells have limited proliferation and are also present in CD40L-deficient patients, reflecting a germinal center-independent origin. Natural effector cells at least in part originate from systemic responses in the splenic marginal zone (pathway 2). CD27−IgA+ cells share low replication history and dominant Igλ and IgA2 use with gut lamina propria IgA+ B cells, suggesting their common origin from local germinal center-independent responses (pathway 3). Our findings shed light on human germinal center-dependent and -independent B-cell memory formation and provide new opportunities to study these processes in immunologic diseases.

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 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 Very Low Affinity B Cells Form Germinal Centers, Become Memory B Cells, and Participate in Secondary Immune Responses When Higher Affinity Competition Is Reduced

2002 ◽  
Vol 195 (9) ◽  
pp. 1215-1221 ◽  
Author(s):  
Joseph M. Dal Porto ◽  
Ann M. Haberman ◽  
Garnett Kelsoe ◽  
Mark J. Shlomchik
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
B Lymphocytes ◽  
Germinal Center ◽  
Germinal Centers ◽  
Association Constants ◽  
Memory B Cells ◽  
B Cell Antigen Receptor ◽  
The Relationship

To understand the relationship between the affinity of the B cell antigen receptor (BCR) and the immune response to antigen, two lines of immunoglobulin H chain transgenic (Tg) mice were created. H50Gμa and T1(V23)μa mice express μ H chain transgenes that associate with the λ1 L chains to bind the (4-hydroxy-3-nitrophenyl)acetyl hapten with association constants (Kas) of only 1.2 × 105 M−1 and 3 × 104 M−1, respectively. Both lines mounted substantial antibody-forming cell (AFC) and germinal center (GC) responses. H50Gμa Tg mice also generated memory B cells. T1(V23)μa B cells formed AFC and GCs, but were largely replaced in late GCs by antigen-specific cells that express endogenous BCRs. Thus, B lymphocytes carrying BCRs with affinities previously thought to be irrelevant in specific immune responses are in fact capable of complete T cell–dependent immune responses when relieved of substantial competition from other B cells. The failure to observe such B cells normally in late primary responses and in memory B cell populations is the result of competition, rather than an intrinsic inability of low affinity B cells.

scholarly journals Follicular Lymphoma-Like B-Cells in Healthy Individuals: A Novel Intermediate Step in Early Lymphomagenesis.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 821-821 ◽  
Author(s):  
Sandrine Roulland ◽  
Jean-marc Navarro ◽  
Pierre Grenot ◽  
Michele Milili ◽  
Julie Agopian ◽  
...  
Keyword(s):  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Memory B Cells ◽  
Intermediate Step ◽  
Low Grade ◽  
Healthy Individuals ◽  
Memory B Cell ◽  
B Cell Subsets

Abstract Follicular lymphoma (FL) is one of the most common B-cell lymphoma, and remains virtually incurable despite its relatively indolent nature. T(14;18)(q32;q21), the genetic hallmark and early initiating event of FL pathogenesis, is also present at low frequency (10−5–10−7) in blood from healthy individuals (HI), indicating that t(14;18) and the ensuing BCL2 overexpression is necessary but not sufficient for malignant transformation. It has long been assumed that in HI, t(14;18) is carried by circulating quiescent naïve B-cells, where its oncogenic potential would be restrained. Yet, several reports, including long-term persistence and immunomodulation of t(14;18)+ cells in lymphoma-free individuals, led us to question this model and investigate the status of circulating t(14;18)+ cells in HI. We first determined if t(14;18)+ cells are naïve B-cells by assessing class-switch recombination (CSR) on the translocated allele. Using 2 long-range PCR assays designed to amplify unswitched BCL2/Sμ and switched BCL2/Sg regions, DNA samples from 6 HI with t(14;18) were tested. Contrary to previous assumptions, our data clearly show that most peripheral t(14;18)+ cells already underwent CSR (n=5/6) and therefore that most t(14;18)+ cells are not naïve B-cells. Are they then memory B cells? Naïve and memory B cell subsets from 9 HI were isolated by cell sorting according to IgD and CD27 markers, and the rate of t(14;18) analyzed in each subset relatively to that of the total B cells. Strikingly, while the level of naïve t(14;18)+ cells remained at baseline for all individuals, memory B-cells tightly accounted for the wide modulation of t(14;18) frequencies observed between individuals. In addition, sequence analysis of t(14;18) clones revealed that this wide modulation was not due to the accumulation of clonally unrelated t(14;18) naïve B-cells, but rather to the clonal expansion of t(14;18)-bearing memory B-cells. To further define the t(14;18)+ cells, we next examined the repartition of the translocation in the IgD−/CD27+ and IgD+/CD27+ memory B-cell subsets. Unexpectedly, we found that the IgD+/CD27+ subset contained significantly higher rates of translocation than the IgD−/CD27+, both in terms of prevalence and frequency. Thus, while CSR is found in the majority of translocated alleles (~75%), most t(14;18)+ memory B cells have not switched their productive allele (~70%) and express an IgM/D. Most importantly, although atypical among physiological peripheral B-cells, this “allelic paradox” is a specific hallmark of FL, and suggests the presence of the same selective pressure in favor of sIgM expression on a B-cell population that is at the same time permanently driven to switch. In line with B-cell hyperplasia in BCL2 transgenic mice slowly progressing to low grade lymphoma, it is likely that “FL-like” cells in HI are rescued by BCL2 from apoptosis, and “frozen” at a differentiation stage in which constitutive AID expression drives continuous somatic hypermutation and CSR activity, two mechanisms conferring a high propensity for genomic instability. Altogether, our findings identify a novel intermediate step in early lymphomagenesis, and strongly impact both on the current understanding of disease progression from potent pre-malignant niches, and on the proper handling of t(14;18) frequency in blood as a potential early biomarker for lymphoma.

scholarly journals The memory B cell response to influenza vaccination is impaired in older persons

2021 ◽  
Author(s):  
Edward J Carr ◽  
Adam K Wheatley ◽  
Danika L Hill ◽  
Michelle A Linterman
Keyword(s):  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Response ◽  
Older Persons ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Age Related ◽  
Single Cell Rna Sequencing ◽  
B Cell Response

AbstractInfluenza imparts an age-related increase in mortality and morbidity. The most effective countermeasure is vaccination; however, vaccines offer modest protection in older adults. To investigate how ageing impacts the memory B cell response we tracked haemagglutinin specific B cells by indexed flow sorting and single cell RNA sequencing in twenty healthy adults administered the trivalent influenza vaccine. We found age-related skewing in the memory B cell compartment six weeks after vaccination, with younger adults developing haemagglutinin specific memory B cells with an FCRL5+ “atypical” phenotype, showing evidence of somatic hypermutation and positive selection, which happened to a lesser extent in older persons. We confirmed the germinal center ancestry of these FCRL5+ “atypical” memory B cells using scRNASeq from fine needle aspirates of influenza responding human lymph nodes and paired blood samples. Together, this study shows that the aged human germinal center reaction and memory B cell response following vaccination is defective.SummaryImmune responses to vaccination wane with age. Using single cell RNA sequencing of influenza vaccine specific B cells, this study delineates changes in B cell memory generation, antibody mutation and their subsequent selection in older persons.

scholarly journals Exit from germinal center to become quiescent memory B cells depends on metabolic reprograming and provision of a survival signal

2020 ◽  
Vol 218 (1) ◽  
Author(s):  
Takeshi Inoue ◽  
Ryo Shinnakasu ◽  
Chie Kawai ◽  
Wataru Ise ◽  
Eiryo Kawakami ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Fate ◽  
Germinal Center ◽  
Small Population ◽  
Memory B Cells ◽  
Memory B Cell ◽  
Survival Signal ◽  
Survival And Development ◽  
T Cell Help

A still unanswered question is what drives the small fraction of activated germinal center (GC) B cells to become long-lived quiescent memory B cells. We found here that a small population of GC-derived CD38intBcl6hi/intEfnb1+ cells with lower mTORC1 activity favored the memory B cell fate. Constitutively high mTORC1 activity led to defects in formation of the CD38intBcl6hi/intEfnb1+ cells; conversely, decreasing mTORC1 activity resulted in relative enrichment of this memory-prone population over the recycling-prone one. Furthermore, the CD38intBcl6hi/intEfnb1+ cells had higher levels of Bcl2 and surface BCR that, in turn, contributed to their survival and development. We also found that downregulation of Bcl6 resulted in increased expression of both Bcl2 and BCR. Given the positive correlation between the strength of T cell help and mTORC1 activity, our data suggest a model in which weak help from T cells together with provision of an increased survival signal are key for GC B cells to adopt a memory B cell fate.

scholarly journals Homologous and Variant-Specific Memory B-Cell and Antibody Responses after SARS-CoV-2 mRNA Vaccination

2021 ◽  
Author(s):  
Iana H. Haralambieva ◽  
Jonathon M. Monroe ◽  
Diane E. Grill ◽  
Inna G Ovsyannikova ◽  
Gregory A. Poland ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Humoral Immunity ◽  
Vaccine Dose ◽  
Neutralizing Antibody ◽  
Memory B Cells ◽  
Immune Memory ◽  
Antibody Activity ◽  
Convenience Sample ◽  
Memory B Cell

Abstract. Importance. A better understanding of the immune memory and functional humoral immunity directed at the emerging Variants of Concern (VoC) strains after SARS-CoV-2 vaccination is essential for predicting the longevity of heterotypic protection. Objective. The aim of our study was to characterize functional humoral immunity (including memory B cell response) after COVID-19 mRNA vaccination and to determine/compare the reactivity of COVID-19 vaccine-induced memory B cells to the emerging SARS-CoV-2 Variants of Concern (VoC). Design, setting, participants and interventions. We designed an exploratory longitudinal observational (convenience sample-based) study at Mayo Clinic, Rochester, MN that enrolled and followed naive subjects and recovered COVID-19 subjects from Olmsted County, MN and surrounding areas after COVID-19 vaccination in January-June 2021. The study enrolled 17 relatively healthy subjects, 59% females and 94% White/Non-Hispanic or Latino with median age at enrollment 41 years. The subjects received either the BNT162b2 (Pfizer/BioNtech) or mRNA-1273 (Moderna) vaccine (n=3) and provided a blood sample at baseline, at;3 weeks after their first vaccine dose/before the second dose, and at;2 weeks after the receipt of their second vaccine dose. Main outcomes and measures. Spike-specific humoral and memory B cells responses were assessed over time after vaccination against the original Wuhan-Hu-1/vaccine and against emerging VoC strains/antigens. Results. We observed a robust neutralizing antibody response after COVID-19 mRNA vaccination, but a reduction in the functional antibody activity to several of the emerging SARS-CoV-2 VoC. Consistent with this, we also found differences in the number of isotype-switched/IgG+ MBCs responding to homologous and variant receptor-binding domain/RBDs after vaccination. We found a reduction of MBCs reactive to RBDs of Beta, Gamma and Delta SARS-CoV-2 VoC strains. Conclusion and relevance. In this exploratory study in subjects following receipt of COVID-19 mRNA vaccine, we found differences in antibody titers observed for VoCs after vaccination that are accompanied with, and can partially be explained by, decreased MBC reactivity against the VoCs. This can further attenuate the generated recall humoral immune response upon exposure to these variants.

scholarly journals Molecular footprints of a germinal center derivation of human IgM+(IgD+)CD27+ B cells and the dynamics of memory B cell generation

2009 ◽  
Vol 206 (12) ◽  
pp. 2659-2669 ◽  
Author(s):  
Marc Seifert ◽  
Ralf Küppers
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Germinal Center ◽  
Cell Clone ◽  
Human Peripheral Blood ◽  
Large Population ◽  
Memory B Cells ◽  
Cell Repertoire ◽  
Memory B Cell

The origin of IgM+CD27+ B lymphocytes with mutated IgV genes, which account for ∼20% of human peripheral blood (PB) B cells, is controversially discussed. A generation in a primary diversification pathway, in T cell–independent immune responses, or in T cell–dependent germinal center (GC) reactions has been proposed. We show here that IgM+IgD+CD27+ and IgM+IgD−/lowCD27+ B cell subsets carry, like class-switched memory B cells, mutations in the Bcl6 gene as a genetic trait of a GC experience. Moreover, the identification of PB IgM+IgD+CD27+ B cells clonally related to GC-derived IgG+ memory B cells with shared and distinct IgV gene mutations demonstrates the GC origin also of the former subset. These findings provide genetic evidence for a GC derivation of somatically mutated IgM+ B cells and indicate that adult humans harbor a large population of IgM+IgD+ post-GC memory B cells. Furthermore, the analysis revealed that a highly diverse and often very large population of memory B cells is generated from a given GC B cell clone, and that (preferentially IgM) memory B cells are generated already early in the GC reaction. This provides novel insights into the dynamics of GC reactions and the generation of a memory B cell repertoire.

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