scholarly journals Germinal center activity and B cell maturation promote protective antibody responses against Plasmodium pre-erythrocytic infection

2021 ◽  
Author(s):  
Ganesh Ram R. Visweswaran ◽  
Kamalakannan Vijayan ◽  
Ramyavardhanee Chandrasekaran ◽  
Olesya Trakhimets ◽  
Samantha L. Whiteside ◽  
...  

AbstractBlocking Plasmodium, the causative agent of malaria, at the asymptomatic pre-erythrocytic stage would abrogate disease pathology and prevent transmission. Rodent-infectious species of Plasmodium such as P. yoelii (Py) serve as key tools to study vaccine efficacy and disease biology in immune-competent experimental animals. Here we evaluated the differences in vaccine-elicited humoral immunity in two widely used, and vastly diverged, inbred mouse strains, BALB/cJ and C57BL/6J, and identified immunological factors associated with protection. We vaccinated with Py circumsporozoite protein (CSP), the major surface antigen on the sporozoite, and evaluated protective efficacy after mosquito bite challenge. Vaccination achieved 60% sterile protection and otherwise delayed blood stage patency in BALB/cJ mice, whereas; all C57BL/6J mice were infected similar to controls. Interestingly, protection was mediated by antibodies, and could be passively transferred from immunized BALB/cJ mice into naïve C57BL/6J. Dissection of the underlying immunological features of protection revealed early deficits in antibody titers and polyclonal avidity in C57BL/6J mice. Additionally, PyCSP-vaccination in BALB/cJ induced a significantly higher proportion of antigen-specific B-cells and class-switched memory B-cell (MBCs) populations than in C57BL/6J mice. Strikingly, C57BL/6J mice also had markedly fewer germinal center experienced, CSP-specific class-switched MBCs compared to BALB/cJ mice. Analysis of the IgG γ chain repertoires by next generation sequencing in PyCSP-specific memory B-cell repertoires also revealed higher somatic hypermutation rates in BALB/cJ mice than in C57BL/6J mice. These findings indicate that BALB/cJ mice achieved higher levels of B cell maturation in response to vaccination with PyCSP, which likely enabled the development of protective antibody responses. Overall, our study indicates that germinal center activity and B cell maturation are key processes in the development of vaccine-elicited protective antibodies against CSP.

JCI Insight ◽  
2020 ◽  
Vol 5 (10) ◽  
Author(s):  
Hannah G. Kelly ◽  
Hyon-Xhi Tan ◽  
Jennifer A. Juno ◽  
Robyn Esterbauer ◽  
Yi Ju ◽  
...  

2021 ◽  
Vol 12 ◽  
Author(s):  
Lynda Mottram ◽  
Anna Lundgren ◽  
Ann-Mari Svennerholm ◽  
Susannah Leach

Vaccines against enteric diseases could improve global health. Despite this, only a few oral vaccines are currently available for human use. One way to facilitate such vaccine development could be to identify a practical and relatively low cost biomarker assay to assess oral vaccine induced primary and memory IgA immune responses in humans. Such an IgA biomarker assay could complement antigen-specific immune response measurements, enabling more oral vaccine candidates to be tested, whilst also reducing the work and costs associated with early oral vaccine development. With this in mind, we take a holistic systems biology approach to compare the transcriptional signatures of peripheral blood mononuclear cells isolated from volunteers, who following two oral priming doses with the oral cholera vaccine Dukoral®, had either strong or no vaccine specific IgA responses. Using this bioinformatical method, we identify TNFRSF17, a gene encoding the B cell maturation antigen (BCMA), as a candidate biomarker of oral vaccine induced IgA immune responses. We then assess the ability of BCMA to reflect oral vaccine induced primary and memory IgA responses using an ELISA BCMA assay on a larger number of samples collected in clinical trials with Dukoral® and the oral enterotoxigenic Escherichia coli vaccine candidate ETVAX. We find significant correlations between levels of BCMA and vaccine antigen-specific IgA in antibodies in lymphocyte secretion (ALS) specimens, as well as with proportions of circulating plasmablasts detected by flow cytometry. Importantly, our results suggest that levels of BCMA detected early after primary mucosal vaccination may be a biomarker for induction of long-lived vaccine specific memory B cell responses, which are otherwise difficult to measure in clinical vaccine trials. In addition, we find that ALS-BCMA responses in individuals vaccinated with ETVAX plus the adjuvant double mutant heat-labile toxin (dmLT) are significantly higher than in subjects given ETVAX only. We therefore propose that as ALS-BCMA responses may reflect the total vaccine induced IgA responses to oral vaccination, this BCMA ELISA assay could also be used to estimate the total adjuvant effect on vaccine induced-antibody responses, independently of antigen specificity, further supporting the usefulness of the assay.


1985 ◽  
Vol 161 (4) ◽  
pp. 816-831 ◽  
Author(s):  
S Raychaudhuri ◽  
M P Cancro

The cellular mechanism and genetic restriction of neonatally induced HA-specific suppressor T (Ts) cells have been examined. The in vivo effect of these Ts cells on antibody production, primary B cell proliferation, B cell surface marker changes, and helper T (Th) cell priming during primary responses to HA have been determined. The results indicate that, although antigen-induced B cell proliferative responses and surface marker changes occur in the presence of Ts cells, differentiation to Ig secretion, and long-lived memory B cell production are prevented. Further, antigen-specific Th cell priming is completely ablated by Ts cells, suggesting that Ts act by preventing the delivery of Th signals required for both the later stages of primary B cell maturation, and the formation of memory B cell populations. Finally, in vivo cell mixing experiments using congenic mice indicate that this Ts-Th interaction is restricted by loci on mouse chromosome 12.


2010 ◽  
Vol 11 (7) ◽  
pp. 523-530 ◽  
Author(s):  
H Artac ◽  
I Reisli ◽  
R Kara ◽  
I Pico-Knijnenburg ◽  
S Adin-Çinar ◽  
...  

2021 ◽  
Author(s):  
Haley L. Dugan ◽  
Christopher Stamper ◽  
Lei Li ◽  
Siriruk Changrob ◽  
Nicholas Asby ◽  
...  

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0127527 ◽  
Author(s):  
Xinxin Ci ◽  
Masayuki Kuraoka ◽  
Hongxia Wang ◽  
Zachary Carico ◽  
Kristen Hopper ◽  
...  

1977 ◽  
Vol 145 (1) ◽  
pp. 10-20 ◽  
Author(s):  
B Huber ◽  
R K Gershon ◽  
H Cantor

CBA/N mice have an X-linked B-cell maturation defect which is reflected in part in an absence or dysfunction of a subclass of mature B cells. We have immunized the defective male offspring of the mating (CBA/N female X BALB/c male) with BALB/c spleen cells. The resulting antiserum (alphaLyb3) selectively reacts with a component on the surface of a portion of B cells from a panel of H-2 different mouse strains. Binding of alphaLyb3 serum to this B-cell subclass results in substantial (10- to 20-fold) enhancement of the antibody response to low doses of SRBC. Both binding and enhancing activity are removed by absorption with B cells from B6 and BALB/c, but not CBA/N mice. Absorption of the serum with bone marrow cells, T cells, or thymocytes from Lyb3+ strains does not remove activity. Since the enhanced plaque-forming cell (PFC) responses are specific for the immunizing antigen, and since no PFC response is produced by injection of the antiserum alone, this enhancement probably reflects a second signal produced by specific interaction between antibody and the surface Lyb3 component. Moreover, this signal can partially replace the requirement for T cells in the production of antibody to a "thymus-dependent" antigen. These findings (taken in conjunction with the previously described immune defects in CBA/N mice and other studies of B-cell maturation) suggest to us that Lyb3 is a cell surface component expressed selectively on a mature B-cell subclass. This component is important in B-cell triggering by antigen and fails to develop in CBA/N mice, due to a dysfunction of a regulatory gene on the CBA/N X chromosome.


2021 ◽  
Vol 6 (56) ◽  
pp. eabe6291 ◽  
Author(s):  
Hamish W. King ◽  
Nara Orban ◽  
John C. Riches ◽  
Andrew J. Clear ◽  
Gary Warnes ◽  
...  

Protective humoral memory forms in secondary lymphoid organs where B cells undergo affinity maturation and differentiation into memory or plasma cells. Here, we provide a comprehensive roadmap of human B cell maturation with single-cell transcriptomics matched with bulk and single-cell antibody repertoires to define gene expression, antibody repertoires, and clonal sharing of B cell states at single-cell resolution, including memory B cell heterogeneity that reflects diverse functional and signaling states. We reconstruct gene expression dynamics during B cell activation to reveal a pre–germinal center state primed to undergo class switch recombination and dissect how antibody class–dependent gene expression in germinal center and memory B cells is linked with a distinct transcriptional wiring with potential to influence their fate and function. Our analyses reveal the dynamic cellular states that shape human B cell–mediated immunity and highlight how antibody isotype may play a role during their antibody-based selection.


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