scholarly journals Induction of long-lived germinal centers associated with persisting antigen after viral infection.

1996 ◽  
Vol 183 (5) ◽  
pp. 2259-2269 ◽  
Author(s):  
M F Bachmann ◽  
B Odermatt ◽  
H Hengartner ◽  
R M Zinkernagel
Keyword(s):  
T Cell ◽  
B Cells ◽  
Viral Infection ◽  
Neutralizing Antibody ◽  
Germinal Centers ◽  
Memory B Cells ◽  
Specific Memory ◽  
Specific Amplification ◽  
Antibody Levels ◽  
Red Pulp

Vesicular stomatitis virus (VSV) induces an early T cell-independent neutralizing lgM response that is followed by a long-lived, T cell-dependent lgG response. We used the specific amplification factor of several 100x of VSV-virions for immunohistology to analyze the localization of VSV-specific B cells at different time points after immunization. At the peak of the IgM response (day 4), VSV-specific B cells were predominantly present in the red pulp and marginal zone but not in the T area. These B cells were mostly stained in the cytoplasm, characterizing them as antibody secreting cells. By day 6 after immunization, germinal centers (GC) containing surface-stained VSV-specific B cells became detectable and were fully established by day 12. At the same time, large VSV-specific B cell aggregates were present in the red pulp. High numbers of VSV-specific GC associated with persisting antigen were present 1 mo after immunization and later, i.e., considerably longer than has been observed for haptens. Some GC, exhibiting follicular dendritic cells and containing VSV-specific, proliferating B cells were still detectable up to 100 d after immunization. Long-lived GC were also observed after immunization with recombinant VSV-glycoprotein in absence of adjuvants. Thus some anti-virally protective (memory) B cells are cycling and locally proliferate in long-lived GC in association with persisting antigen and therefore seem responsible for long-term maintenance of elevated antibody levels. These observations extend earlier studies with carrier hapten antigens in adjuvant depots or complexed with specific IgG; they are the first to show colocalization of antigen and specific memory B cells and to analyze a protective neutralizing antibody response against an acute viral infection.

scholarly journals COVID-19 convalescents exhibit deficient humoral and T cell responses to variant of concern Spike antigens at 12 month post-infection

2021 ◽  
Author(s):  
Pablo Garcia-Valtanen ◽  
Christopher Martin Hope ◽  
Makutiro Ghislain Masavuli ◽  
Arthur Eng Lip Yeow ◽  
Harikrishnan Balachandran ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Post Infection ◽  
T Cell Responses ◽  
Memory B Cells ◽  
Pseudotyped Virus ◽  
Cell Responses ◽  
Specific Memory ◽  
Cell Functionality

Background The duration and magnitude of SARS-CoV-2 immunity after infection, especially with regard to the emergence of new variants of concern (VoC), remains unclear. Here, immune memory to primary infection and immunity to VoC was assessed in mild-COVID-19 convalescents one year after infection and in the absence of viral re-exposure or COVID-19 vaccination. Methods Serum and PBMC were collected from mild-COVID-19 convalescents at ~6 and 12 months after a COVID-19 positive PCR (n=43) and from healthy SARS-CoV-2-seronegative controls (n=15-40). Serum titers of RBD and Spike-specific Ig were quantified by ELISA. Virus neutralisation was assessed against homologous, pseudotyped virus and homologous and VoC live viruses. Frequencies of Spike and RBD-specific memory B cells were quantified by flow cytometry. Magnitude of memory T cell responses was quantified and phenotyped by activation-induced marker assay, while T cell functionality was assessed by intracellular cytokine staining using peptides specific to homologous Spike virus antigen and four VoC Spike antigens. Findings At 12 months after mild-COVID-19, >90% of convalescents remained seropositive for RBD-IgG and 88.9% had circulating RBD-specific memory B cells. Despite this, only 51.2% convalescents had serum neutralising activity against homologous live-SARS-CoV-2 virus, which decreased to 44.2% when tested against live B.1.1.7, 4.6% against B.1.351, 11.6% against P.1 and 16.2%, against B.1.617.2 VoC. Spike and non-Spike-specific T cells were detected in >50% of convalescents with frequency values higher for Spike antigen (95% CI, 0.29-0.68% in CD4+ and 0.11-0.35% in CD8+ T cells), compared to non-Spike antigens. Despite the high prevalence and maintenance of Spike-specific T cells in Spike 'high-responder' convalescents at 12 months, T cell functionality, measured by cytokine expression after stimulation with Spike epitopes corresponding to VoC was severely affected. Interpretations SARS-CoV-2 immunity is retained in a significant proportion of mild COVID-19 convalescents 12 months post-infection in the absence of re-exposure to the virus. Despite this, changes in the amino acid sequence of the Spike antigen that are present in current VoC result in virus evasion of neutralising antibodies, as well as evasion of functional T cell responses.

A Broad Spectrum of Functional HIV-Specific Memory B Cells in the Blood of Infected Individuals With High CD4+ T-Cell Counts

2011 ◽  
Vol 57 (3) ◽  
pp. e56-e58 ◽  
Author(s):  
Kevin Kunz ◽  
Sven Reiche ◽  
Yamen Dwai ◽  
Christiane Cordes ◽  
Ivanka Krznaric ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Broad Spectrum ◽  
Memory B Cells ◽  
Cd4 T Cell ◽  
Cell Counts ◽  
Specific Memory

scholarly journals Highly-specific memory B cells generation after the 2nd dose of BNT162b2 vaccine compensate for the decline of serum antibodies and absence of mucosal IgA

2021 ◽  
Author(s):  
Eva Piano Mortari ◽  
Cristina Russo ◽  
Maria Rosaria Vinci ◽  
Sara Terreri ◽  
Ane Fernandez Salinas ◽  
...  
Keyword(s):  
B Cells ◽  
Specific Antibody ◽  
Herd Immunity ◽  
Vaccine Dose ◽  
Memory B Cells ◽  
Immune Protection ◽  
Serum Antibodies ◽  
Specific Memory ◽  
Antibody Levels ◽  
Insufficient Number

Specific memory B cells and antibodies are reliable read-out of vaccine efficacy. We analyzed these biomarkers after one and two doses of BNT162b2 vaccine. The second dose significantly increases the level of highly-specific memory B cells and antibodies. Two months after the second dose, specific antibody levels decline, but highly specific memory B cells continue to increase thus predicting a sustained protection from COVID-19. We show that although mucosal IgA is not induced by the vaccination, memory B cells migrate in response to inflammation and secrete IgA at mucosal sites. We show that first vaccine dose may lead to an insufficient number of highly specific memory B cells and low concentration of serum antibodies thus leaving vaccinees without the immune robustness needed to ensure viral elimination and herd immunity. We also clarify that the reduction of serum antibodies does not diminish the force and duration of the immune protection induced by vaccination. The vaccine does not induce sterile immunity. Infection after vaccination may be caused by the lack of local preventive immunity because of the absence of mucosal IgA.

Memory B Cells Protect from CMV Infection in the Absence of T Cells.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 619-619 ◽  
Author(s):  
Thomas H. Winkler ◽  
Florian Weisel ◽  
Karin Klenovsek ◽  
Michael Mach
Keyword(s):  
Bone Marrow ◽  
Immune Response ◽  
T Cell ◽  
B Cells ◽  
Memory B Cells ◽  
Primary Immune Response ◽  
Immunodeficient Mice ◽  
Virus Dissemination ◽  
Specific Memory ◽  
T Cell Help

Abstract Infections with cytomegalovirus are still a major clinical problem in immunosuppressed patients e.g. after bone marrow or stem cell transplantation. To prevent clinical overt disease resulting from disseminated virus infection, immunoprophylaxis and/or -therapy are considered a major goal. The humoral immune response contributes to immune protection against CMV by providing neutralizing antibodies. However, in the early phase after transplantation a primary immune response is not possible. Humoral anti-CMV immune effector functions can only be provided by memory B cells. The activation requirements for resting memory B cells are unclear. Using non-infectious hCMV particles in mice we have recently shown that activation of virus-specific memory B cells to secrete IgG is independent of cognate or bystander T cell help. To analyze whether transfer of memory B cells into immunodeficient mice can protect from lethal infection we switched to an infectious animal model using mCMV. When memory B cells from mCMV-infected mice were adoptively transferred into RAG-1−/− mice, a strong IgG anti-mCMV titer developed within 4–6 days after infection with mCMV. Virus dissemination and subsequent disease was inhibited. A 100–1000 fold decrease of virus titers and a 1.000–10.000 fold decrease of viral DNA load in spleen and lung was observed in mice that received mCMV specific memory B cells. Even in an established mCMV infection virus dissemination and subsequent disease could be prevented by means of adoptive memory B cell transfer. In further experiments we also used a virus mutant that cannot be controlled by NK cells in C57Bl/6 mice. Even in this experimental system we could demonstrate that adoptive transfer of memory B cells in the absence CD4 and CD8 cells is sufficient to protect from viral dissemination and rapid lethality. Our results show that memory B cells can mediate protection against mCMV in the absence of cognate or bystander T cell help. Similar regimens might be a therapeutic option for CMV reactivation after bone marrow transplantation in patients.

T cell–independent restimulation of FVIII-specific murine memory B cells is facilitated by dendritic cells together with toll-like receptor 7 agonist

Blood ◽  
2011 ◽  
Vol 118 (11) ◽  
pp. 3154-3162 ◽  
Author(s):  
Aniko G. Pordes ◽  
Christina K. Baumgartner ◽  
Peter Allacher ◽  
Rafi U. Ahmad ◽  
Markus Weiller ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
T Cell ◽  
B Cells ◽  
Memory B Cells ◽  
Toll Like Receptor ◽  
Tlr7 Agonist ◽  
Specific Memory ◽  
Coxsackie B Viruses ◽  
T Cell Help ◽  
Antibody Subclass

Abstract Memory B cells are involved in long-term maintenance of antibody-dependent immunologic disorders. Therefore, it is essential to understand how the restimulation of FVIII-specific memory B cells in hemophilia A with FVIII inhibitors is regulated. We asked whether concurrent activation of the innate immune system by an agonist for toll-like receptor (TLR) 7 is able to facilitate the differentiation of FVIII-specific memory B cells in the absence of T-cell help. TLR7 recognizes single-stranded RNA as contained in RNA viruses such as influenza, Sendai, and Coxsackie B viruses. Our results indicate that highly purified murine memory B cells do not differentiate into FVIII-specific antibody-secreting cells in the presence of FVIII and the TLR7 agonist when cultured in the absence of CD4+ T cells. However, CD11c+ dendritic cells facilitate the T cell–independent differentiation of FVIII-specific memory B cells but only in the presence of FVIII and the TLR7 agonist. In contrast to T cell–dependent restimulation, the antibody response after T cell–independent restimulation of FVIII-specific memory B cells is skewed toward IgG2a, an antibody subclass that is efficient in activating the complement system and in inducing Fc-receptor–mediated effector functions, both are required for effective immune responses against pathogens.

scholarly journals Regulation of IgG memory responses by helper and suppressor T cells activated by the type 2 antigen, polyvinylpyrrolidone.

1985 ◽  
Vol 161 (6) ◽  
pp. 1357-1367 ◽  
Author(s):  
H Braley-Mullen
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Suppressor Cells ◽  
Memory B Cells ◽  
High Dose ◽  
Suppressor T Cells ◽  
Specific Memory ◽  
Specific Igg

T cells from CAF1 mice immunized with various amounts of the type 2 antigen polyvinylpyrrolidone (PVP) were assessed for their ability to provide help to PVP-specific memory B cells for the production of IgG. Low doses (0.0025 micrograms) of PVP consistently activated helper T cells (Th), which were required for the production of IgG by primed B cells. In contrast, T cells from mice primed with higher amounts (0.25 or 25 micrograms) of PVP did not provide significant help to the same B cells for IgG production. Moreover, when mixed with B cells and low-dose PVP-primed Th, T cells from mice primed with 0.25 or 25 micrograms PVP suppressed PVP-specific IgG, but not IgM antibody responses. The suppressor cells induced by higher amounts of PVP were eliminated either by injecting cyclophosphamide (CY) before priming with PVP, or by treating the primed T cells with anti-Lyt-2.2 and C before transfer. Pretreatment of suppressor T cell (Ts) donors with CY or removal of Lyt-2+ T cells not only eliminated Ts activity, but also unmasked significant Th activity in the T cells from high-dose PVP-primed mice. Thus, both low and high amounts of PVP can activate Th, although high amounts of PVP also induce Ts, the activity of which predominates in a normal unfractionated T cell population. The amount of PVP (0.0025 micrograms) that induces dominant help for IgG memory responses was only marginally immunogenic for induction of primary PVP-specific IgM responses, while 0.25 and 25 micrograms PVP, which induce dominant suppression for IgG memory responses, are optimally immunogenic for primary IgM responses. These results are discussed in the context of the inability of most type 2 antigens to elicit primary IgG responses or to prime memory B cells for production of IgG, responses which are dependent on the function of antigen-specific Th.

A strategy for selective, CD4+ T cell-independent activation of virus-specific memory B cells for limiting dilution analysis

2006 ◽  
Vol 313 (1-2) ◽  
pp. 110-118 ◽  
Author(s):  
Xiaofeng Li ◽  
Daisy J. Vanitha ◽  
Hye Mee Joo ◽  
Yuxia He ◽  
Barry T. Rouse ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Memory B Cells ◽  
Cd4 T Cell ◽  
Limiting Dilution Analysis ◽  
Specific Memory ◽  
Limiting Dilution

scholarly journals SARS-CoV-2 Vaccine Induced Atypical Immune Responses in Antibody Defects: Everybody Does their Best

2021 ◽  
Author(s):  
Ane Fernandez Salinas ◽  
Eva Piano Mortari ◽  
Sara Terreri ◽  
Concetta Quintarelli ◽  
Federica Pulvirenti ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
Vaccine Dose ◽  
Memory B Cells ◽  
Cell Responses ◽  
Specific Memory ◽  
Immune Deficiencies ◽  
Iga Antibody ◽  
Specific Igg

Abstract Background Data on immune responses to SARS-CoV-2 in patients with Primary Antibody Deficiencies (PAD) are limited to infected patients and to heterogeneous cohorts after immunization. Methods Forty-one patients with Common Variable Immune Deficiencies (CVID), six patients with X-linked Agammaglobulinemia (XLA), and 28 healthy age-matched controls (HD) were analyzed for anti-Spike and anti-receptor binding domain (RBD) antibody production, generation of Spike-specific memory B-cells, and Spike-specific T-cells before vaccination and one week after the second dose of BNT162b2 vaccine. Results The vaccine induced Spike-specific IgG and IgA antibody responses in all HD and in 20% of SARS-CoV-2 naive CVID patients. Anti-Spike IgG were detectable before vaccination in 4 out 7 CVID previously infected with SARS-CoV-2 and were boosted in six out of seven patients by the subsequent immunization raising higher levels than patients naïve to infection. While HD generated Spike-specific memory B-cells, and RBD-specific B-cells, CVID generated Spike-specific atypical B-cells, while RBD-specific B-cells were undetectable in all patients, indicating the incapability to generate this new specificity. Specific T-cell responses were evident in all HD and defective in 30% of CVID. All but one patient with XLA responded by specific T-cell only. Conclusion In PAD patients, early atypical immune responses after BNT162b2 immunization occurred, possibly by extra-follicular or incomplete germinal center reactions. If these responses to vaccination might result in a partial protection from infection or reinfection is now unknown. Our data suggests that SARS-CoV-2 infection more effectively primes the immune response than the immunization alone, possibly suggesting the need for a third vaccine dose for patients not previously infected.

scholarly journals IL-21 in Conjunction with Anti-CD40 and IL-4 Constitutes a Potent Polyclonal B Cell Stimulator for Monitoring Antigen-Specific Memory B Cells

Cells ◽  
2020 ◽  
Vol 9 (2) ◽  
pp. 433
Author(s):  
Fridolin Franke ◽  
Greg A. Kirchenbaum ◽  
Stefanie Kuerten ◽  
Paul V. Lehmann
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Immune Monitoring ◽  
Memory B Cells ◽  
B Cell Activation ◽  
Cell Stimulation ◽  
Additional Advantage ◽  
Specific Memory

Detection of antigen-specific memory B cells for immune monitoring requires their activation, and is commonly accomplished through stimulation with the TLR7/8 agonist R848 and IL-2. To this end, we evaluated whether addition of IL-21 would further enhance this TLR-driven stimulation approach; which it did not. More importantly, as most antigen-specific B cell responses are T cell-driven, we sought to devise a polyclonal B cell stimulation protocol that closely mimics T cell help. Herein, we report that the combination of agonistic anti-CD40, IL-4 and IL-21 affords polyclonal B cell stimulation that was comparable to R848 and IL-2 for detection of influenza-specific memory B cells. An additional advantage of anti-CD40, IL-4 and IL-21 stimulation is the selective activation of IgM+ memory B cells, as well as the elicitation of IgE+ ASC, which the former fails to do. Thereby, we introduce a protocol that mimics physiological B cell activation through helper T cells, including induction of all Ig classes, for immune monitoring of antigen-specific B cell memory.

scholarly journals Activation of Virus-specific Memory B Cells in the Absence of T Cell Help

2004 ◽  
Vol 199 (4) ◽  
pp. 593-602 ◽  
Author(s):  
Barbara J. Hebeis ◽  
Karin Klenovsek ◽  
Peter Rohwer ◽  
Uwe Ritter ◽  
Andrea Schneider ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cd4 T Cells ◽  
Plasma Cells ◽  
Human Herpesvirus ◽  
Memory B Cells ◽  
Specific Memory ◽  
T Cell Help

Humoral immunity is maintained by long-lived plasma cells, constitutively secreting antibodies, and nonsecreting resting memory B cells that are rapidly reactivated upon antigen encounter. The activation requirements for resting memory B cells, particularly the role of T helper cells, are unclear. To analyze the activation of memory B cells, mice were immunized with human cytomegalovirus, a complex human herpesvirus, and tick-born encephalitis virus, and a simple flavivirus. B cell populations devoid of Ig-secreting plasma cells were adoptively transferred into T and B cell–deficient RAG-1−/− mice. Antigenic stimulation 4–6 d after transfer of B cells resulted in rapid IgG production. The response was long lasting and strictly antigen specific, excluding polyclonal B cell activation. CD4+ T cells were not involved since (a) further depletion of CD4+ T cells in the recipient mice did not alter the antibody response and (b) recipient mice contained no detectable CD4+ T cells 90 d posttransfer. Memory B cells could not be activated by a soluble viral protein without T cell help. Transfer of memory B cells into immunocompetent animals indicated that presence of helper T cells did not enhance the memory B cell response. Therefore, our results indicate that activation of virus-specific memory B cells to secrete IgG is independent of cognate or bystander T cell help.

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