Maintenance of Long Term γ-Herpesvirus B Cell Latency Is Dependent on CD40-Mediated Development of Memory B Cells

The mechanisms that regulate B cell memory and the rapid recall response to antigen remain poorly defined. This study focuses on the rapid expression of B cell memory upon antigen recall in vivo, and the replenishment of quiescent B cell memory that follows. Based on expression of CD138 and B220, we reveal a unique and major subtype of antigen-specific memory B cells (B220−CD138−) that are distinct from antibody-secreting B cells (B220+/−CD138+) and B220+CD138− memory B cells. These nonsecreting somatically mutated B220− memory responders rapidly dominate the splenic response and comprise >95% of antigen-specific memory B cells that migrate to the bone marrow. By day 42 after recall, the predominant quiescent memory B cell population in the spleen (75–85%) and the bone marrow (>95%) expresses the B220− phenotype. Upon adoptive transfer, B220− memory B cells proliferate to a lesser degree but produce greater amounts of antibody than their B220+ counterparts. The pattern of cellular differentiation after transfer indicates that B220− memory B cells act as stable self-replenishing intermediates that arise from B220+ memory B cells and produce antibody-secreting cells on rechallenge with antigen. Cell surface phenotype and Ig isotype expression divide the B220− compartment into two main subsets with distinct patterns of integrin and coreceptor expression. Thus, we identify new cellular components of B cell memory and propose a model for long-term protective immunity that is regulated by a complex balance of committed memory B cells with subspecialized immune function.

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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

Clinical and Vaccine Immunology ◽

10.1128/cvi.00270-13 ◽

2013 ◽

Vol 20 (9) ◽

pp. 1388-1395 ◽

Cited By ~ 39

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.

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BAFFR controls early memory B cell responses but is dispensable for germinal center function

Journal of Experimental Medicine ◽

10.1084/jem.20191167 ◽

2020 ◽

Vol 218 (2) ◽

Cited By ~ 1

Author(s):

Angelica W.Y. Lau ◽

Vivian M. Turner ◽

Katherine Bourne ◽

Jana R. Hermes ◽

Tyani D. Chan ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Memory B Cells ◽

Term Survival ◽

Cell Responses ◽

Tnf Superfamily ◽

Surface Receptor ◽

Early Memory

The TNF superfamily ligand BAFF maintains the survival of naive B cells by signaling through its surface receptor, BAFFR. Activated B cells maintain expression of BAFFR after they differentiate into germinal center (GC) or memory B cells (MBCs). However, the functions of BAFFR in these antigen-experienced B cell populations remain unclear. Here, we show that B cell–intrinsic BAFFR does not play a significant role in the survival or function of GC B cells or in the generation of the somatically mutated MBCs derived from them. Instead, BAFF/BAFFR signaling was required to generate the unmutated, GC-independent MBCs that differentiate directly from activated B cell blasts early in the response. Furthermore, amplification of BAFFR signaling in responding B cells did not affect GCs or the generation of GC-derived MBCs but greatly expanded the GC-independent MBC response. Although BAFF/BAFFR signaling specifically controlled the formation of the GC-independent MBC response, both types of MBCs required input from this pathway for optimal long-term survival.

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Value of Autoantibody Expression During Long-Term Follow-Up in Paediatric ALL Patients After Allogeneic Haematopoietic Stem Cell Transplantation

Frontiers in Pediatrics ◽

10.3389/fped.2021.788360 ◽

2021 ◽

Vol 9 ◽

Author(s):

Anita Lawitschka ◽

Leila Ronceray ◽

Dorothea Bauer ◽

Michael Rittenschober ◽

Natalia Zubarovskaya ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Nk Cells ◽

Haematopoietic Stem Cell Transplantation ◽

Memory B Cells ◽

Haematopoietic Stem Cell ◽

Long Term Follow Up ◽

Autoantibody Profiles

Objectives: Chronic graft-versus-host disease (cGvHD) following haematopoietic stem cell transplantation (HSCT) shares many similarities with de novo autoimmune disorders, being associated with the presence of autoantibodies. However, data on the implication of autoantibodies in paediatric HSCT recipients are scarce. In this single-centre study of paediatric patients with acute lymphoblastic leukaemia (ALL) surviving longer than 3 months, our objectives were to evaluate autoantibody expression and investigate the correlation with cGvHD and immune reconstitution using serially monitored parameters.Methods: We investigated circulating autoantibodies together with cellular and humoral parameters [including major T- and B-cell subsets, natural killer (NK) cells, and immunoglobulin levels] in 440 samples from 74 patients (median age 10.9 years, range 2.7–22.2 years) serially during long-term follow-up of median 8 years (range 0.4–19.3 years). Evaluations comprised of patient and transplant characteristics, precisely reviewed details of National Institute of Health (NIH)-defined cGvHD, and outcome data such as relapse, overall survival (OS) and mortality. Analysis of these clinical parameters was performed to identify possible associations.Results: Autoantibodies were detected in 65% (48/74) of patients. Anti-nuclear antibodies were the most common, occurring in 75% (36/48) of patients with autoantibodies. When comparing demographic data and transplant characteristics, there were no significant differences between patients with and without autoantibody expression; 5-year OS was excellent, at 96.4 and 95.8%, respectively. Neither the expression of autoantibodies nor the occurrence of cGvHD correlated with significantly worse OS or relapse rate. Furthermore, there was no significant association between autoantibody profiles and the incidence, overall severity or organ involvement of cGvHD. Patients with autoantibodies showed significantly better immune reconstitution, with overall higher numbers of T cells, B cells, and serum immunoglobulins. In autoantibody-positive patients with cGvHD, autoantibody production positively correlated with the expansion of CD56+ NK cells (236.1 vs. 165.6 × 103 cells/mL, respectively; p = 0.023) and with signs of B-cell perturbation, such as higher CD21low B cells (23.8 vs. 11.8 × 103 cells/mL, respectively; p = 0.044) and a higher ratio of CD21low B cells/CD27+ memory B cells (1.7 vs. 0.4, respectively; p = 0.006) in comparison to autoantibody-positive patients without cGvHD. Furthermore, when assessing the correlation between autoantibody positivity and the activity of cGvHD at time of analysis, indicators of aberrant B-cell homeostasis were substantiated by a lower proportion of CD27+ memory B cells (9.1 vs. 14.9%, respectively; p = 0.028), a higher ratio of class-switched CD27+IgD−/CD27+ memory B cells (3.5 vs. 5.1%, respectively; p = 0.013), significantly elevated numbers of CD21low B cells (36.8 vs. 11.8 × 103 cells/mL, respectively; p = 0.013) and a higher ratio of CD21lowB cells/CD27+ memory B cells (2.4 vs. 0.4, respectively; p = 0.034) in the active vs. the no cGvHD group. We then assessed the potential role of autoantibody expression in the context of elevated CD19+CD21low B cells (cutoff >7%), a well-known marker of cGvHD. Surprisingly we found a significant higher proportion of those cases where elevated CD21low B cells correlated with active cGvHD in samples from the autoantibody-negative group vs. the antibody-positive group (82 vs. 47%, respectively; p = 0.0053).When comparing immune parameters of the large proportion of survivors (89%) with the small proportion of non-survivors (11%), data revealed normalisation within the B-cell compartment of survivors: there were increased numbers of CD27+ memory B cells (54.9 vs. 30.6 × 103 cells/mL, respectively; p = 0.05), class-switched CD27+IgD− B cells (21.2 vs. 5.0 × 103 cells/mL, respectively; p < 0.0001), and immunoglobulin G4 (40.9 vs. 19.4 mg/dL, respectively; p < 0.0001). Overall mortality was significantly associated with an elevated proportion of CD21low B cells (13.4 vs. 8.8%, respectively; p = 0.039) and CD56+ NK cells (238.8 vs. 314.1 × 103 cells/mL, respectively; p = 0.019). In multivariate analysis, better OS was significantly associated with lower numbers of CD56+ NK cells [hazard ratio (HR) 0.98, p = 0.041] and higher numbers of CD27+ memory B cells [(HR) 1.62, p = 0.014].Conclusion: Our data shows that autoantibody profiles are not suitable biomarkers for diagnosing cGvHD in children or for predicting cGvHD severity, disease course and outcome. We identified a number of indicators of aberrant immune homeostasis associated with active cGvHD in paediatric ALL patients after HSCT. These findings confirm published results and suggest that candidate B cell subpopulations may serve as a surrogate measure for characterisation of cGvHD in paediatric HSCT for malignant diseases, and warrants confirmation in larger, multicentre studies.

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The presence of circulating antibody secreting cells and long-lived memory B cell responses to reticulocyte binding protein 1a in Plasmodium vivax patients

Malaria Journal ◽

10.1186/s12936-021-04015-3 ◽

2021 ◽

Vol 20 (1) ◽

Author(s):

Piyawan Kochayoo ◽

Pattarawan Sanguansuttikul ◽

Pongsakorn Thawornpan ◽

Kittikorn Wangriatisak ◽

John H. Adams ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Memory B Cells ◽

Antibody Responses ◽

Blood Stage ◽

Memory B Cell ◽

Cell Responses ◽

Antibody Titers ◽

B Cell Responses

Abstract Background Development of an effective vaccine against blood-stage malaria requires the induction of long-term immune responses. Plasmodium vivax Reticulocyte Binding Protein 1a (PvRBP1a) is a blood-stage parasite antigen which is associated with invasion of red blood cells and induces antibody responses. Thus, PvRBP1a is considered as a target for design of a blood-stage vaccine against vivax malaria. Methods Both cross-sectional and cohort studies were used to explore the development and persistence of long-lived antibody and memory B cell responses to PvRBP1a in individuals who lived in an area of low malaria endemicity. Antibody titers and frequency of memory B cells specific to PvRBP1a were measured during infection and following recovery for up to 12 months. Results IgG antibody responses against PvRBP1a were prevalent during acute vivax malaria, predominantly IgG1 subclass responses. High responders to PvRBP1a had persistent antibody responses for at least 12-month post-infection. Further analysis of high responder found a direct relation between antibody titers and frequency of activated and atypical memory B cells. Furthermore, circulating antibody secreting cells and memory B cells specific to PvRBP1a were generated during infection. The PvRBP1a-specific memory B cells were maintained for up to 3-year post-infection, indicating the ability of PvRBP1a to induce long-term humoral immunity. Conclusion The study revealed an ability of PvRBP1a protein to induce the generation and maintenance of antibody and memory B cell responses. Therefore, PvRBP1a could be considered as a vaccine candidate against the blood-stage of P. vivax.

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γ-Herpesvirus Latency Is Preferentially Maintained in Splenic Germinal Center and Memory B Cells

Journal of Experimental Medicine ◽

10.1084/jem.20020890 ◽

2002 ◽

Vol 196 (10) ◽

pp. 1363-1372 ◽

Cited By ~ 125

Author(s):

Emilio Flaño ◽

In-Jeong Kim ◽

David L. Woodland ◽

Marcia A. Blackman

Keyword(s):

B Cells ◽

B Cell ◽

Germinal Center ◽

Viral Gene Expression ◽

Memory B Cells ◽

Viral Gene ◽

Long Latency ◽

Cell Life ◽

Unique System

The γ-herpesviruses are oncogenic B cell lymphotrophic viruses that establish life-long latency in the host. Murine γ-herpesvirus 68 (MHV-68) infection of mice represents a unique system for analyzing γ-herpesvirus latency in splenic B cells at different stages of infection. After intranasal infection with MHV-68 we analyzed the establishment of latency 14 days after infection, and the maintenance of latency 3 months after infection in different purified subpopulations of B cells in the spleen. The data show that MHV-68 latency is mainly established in germinal center B cells and that long-term latency is preferentially maintained in two different subsets of isotype-switched B cells, germinal center and memory B cells. Cell cycle analysis indicates that MHV-68 is located in both cycling and resting isotype-switched B cells. Analysis of viral gene expression showed that both lytic and latent viral transcripts were differentially expressed in germinal center and memory B cells during long-term latency. Together, these observations suggested that γ-herpesviruses exploit the B cell life cycle in the spleen.

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Human Memory B Cells TargetingStaphylococcus aureusExotoxins Are Prevalent with Skin and Soft Tissue Infection

mBio ◽

10.1128/mbio.02125-17 ◽

2018 ◽

Vol 9 (2) ◽

Cited By ~ 6

Author(s):

Adam J. Pelzek ◽

Bo Shopsin ◽

Emily E. Radke ◽

Kayan Tam ◽

Beatrix M. Ueberheide ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Acute Phase ◽

Serum Antibody ◽

Cross Reactivity ◽

Memory B Cells ◽

Host Defenses ◽

Cell Memory ◽

B Cell Memory

ABSTRACTStaphylococcus aureusis a Gram-positive opportunistic pathogen that causes superficial and invasive infections in the hospital and community. High mortality from infection emphasizes the need for improved methods for prevention and treatment. AlthoughS. aureuspossesses an arsenal of virulence factors that contribute to evasion of host defenses, few studies have examined long-term humoral and B-cell responses. Adults with acute-phase skin and soft tissue infections were recruited; blood samples were obtained; andS. aureusisolates, including methicillin-resistant strains, were subjected to genomic sequence analysis. In comparisons of acute-phase sera with convalescent-phase sera, a minority (37.5%) of patients displayed 2-fold or greater increases in antibody titers against three or moreS. aureusantigens, whereas nearly half exhibited no changes, despite the presence of toxin genes in most infecting strains. Moreover, enhanced antibody responses waned over time, which could reflect a defect in B-cell memory or long-lived plasma cells. However, memory B cells reactive with a range ofS. aureusantigens were prevalent at both acute-phase and convalescent-phase time points. While some memory B cells exhibited toxin-specific binding, those cross-reactive with structurally related leucocidin subunits were dominant across patients, suggesting the targeting of conserved epitopes. Memory B-cell reactivity correlated with serum antibody levels for selectedS. aureusexotoxins, suggesting a relationship between the cellular and humoral compartments. Overall, although there was no global defect in the representation of anti-S. aureusmemory B cells, there was evidence of restrictions in the range of epitopes recognized, which may suggest potential therapeutic approaches for augmenting host defenses.IMPORTANCEThe contribution of B-cell memory and long-term antibody responses to host defenses againstS. aureusexotoxins remains poorly understood. Our studies confirmed that infection did not commonly lead to enhanced long-term humoral responses. Whereas circulating memory B cells againstS. aureussecreted exotoxins were prevalent, they were dominated by cross-reactivity with structurally related leucocidin subunits, consistent with recognition of conserved epitopes. These findings also provide the first evidence of a relationship between the reactivity of antistaphylococcal circulating memory B cells and serum antibody levels. In general, infection was not associated with a global defect in B-cell memory forS. aureussecreted factors, and responses were highly dominated by cross-reactivity to structurally related exotoxins, which arguably may alone be suboptimal in providing host defenses. Our studies illuminate aspects of theS. aureus-host relationship that may better inform strategies for the development of an effective protective vaccine.

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