B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.

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THU0293 B-cell responses to type I interferon define disease activity in SLE and can be measured by cell surface tetherin (CD317)

10.1136/annrheumdis-2017-eular.6002 ◽

2017 ◽

Author(s):

YM El-Sherbiny ◽

MY Md Yusof ◽

A Psarras ◽

E Hensor ◽

R Tooze ◽

...

Keyword(s):

Cell Surface ◽

Disease Activity ◽

B Cell ◽

Type I Interferon ◽

Type I ◽

Cell Responses ◽

B Cell Responses

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Type 1 interferon supports B cell responses to polysaccharide antigens but is not required for MPL/TDCM adjuvant effects on innate B cells

10.1101/2021.10.30.466603 ◽

2021 ◽

Author(s):

Ariel Spurrier ◽

Jamie Jennings-Gee ◽

Karen Haas

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Lipid A ◽

Type I ◽

Type I Ifn ◽

Cell Responses ◽

Monophosphoryl Lipid A ◽

B Cell Responses ◽

Adjuvant Effects

We previously described monophosphoryl lipid A (MPL) and synthetic cord factor, trehalose-6,6-dicorynomycolate (TDCM) significantly increases antibody (Ab) responses to T cell independent type 2 antigens (TI-2 Ags) in a manner dependent on B cell-intrinsic TLR4 expression as well as MyD88 and TRIF adapter proteins. Given the requirement for TRIF in optimal MPL/TDCM adjuvant effects and the capacity of MPL to drive type I IFN production, we aimed to investigate the extent to which adjuvant effects on TI-2 Ab responses depend on type I IFN receptor (IFNAR) signaling. We found IFNAR-/- mice had impaired early TI-2 Ag-induced B cell activation and expansion and that B cell-intrinsic type I IFN signaling on B cells was essential for normal antibody responses to TI-2 Ags, including haptenated Ficoll and the pneumococcal vaccine, Pneumovax23. However, MPL/TDCM significantly increased TI-2 IgM and IgG responses in IFNAR-/- mice. MPL/TDCM enhanced TI-2 Ab production primarily by activating innate B cells (B-1b and splenic CD23- B cells) as opposed to CD23+ enriched follicular B cells. In summary, our study highlights an important role for type I IFN in supporting early B cell responses to TI-2 Ags through B cell-expressed IFNAR, but nonetheless demonstrates an MPL/TDCM adjuvant significantly increases TI-2 Ab responses independently of type I IFN signaling and does so by predominantly supporting increased polysaccharide-specific Ab production by innate B cell populations.

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Peripheral tolerance checkpoints imposed by ubiquitous antigen expression limit antigen-specific B-cell responses under strongly immunogenic conditions

10.1101/2020.03.10.985127 ◽

2020 ◽

Author(s):

Jeremy F. Brooks ◽

Peter R. Murphy ◽

James E.M. Barber ◽

James W. Wells ◽

Raymond J. Steptoe

Keyword(s):

B Cells ◽

B Cell ◽

Plasma Cells ◽

Affinity Maturation ◽

Peripheral Tolerance ◽

Cell Detection ◽

Autoantibody Production ◽

Cell Responses ◽

Counter Selection ◽

B Cell Responses

AbstractA series of layered peripheral checkpoints maintain self-reactive B cells in an unresponsive state. Autoantibody production occurs when these checkpoints are breached, however, when and how this occurs is largely unknown. In particular, how self-reactive B cells are restrained during bystander inflammation in otherwise healthy individuals is poorly understood. A weakness has been the unavailability of methods capable of dissecting physiologically-relevant B-cell responses, without the use of an engineered B-cell receptor. Resolving this will provide insights that decipher how this process goes awry during autoimmunity or could be exploited for therapy. Here we use a strong adjuvant to provide bystander innate and adaptive signals that promote B-cell responsiveness, in conjunction with newly developed B cell detection tools to study in detail the ways that peripheral tolerance mechanisms limit the expansion and function of self-reactive B cells activated under these conditions. We show that although autoreactive B cells are recruited into the germinal centre, their development does not proceed, possibly through rapid counter-selection. Consequently, differentiation of plasma cells is blunted, and autoantibody responses are transient and devoid of affinity maturation. We propose this approach and these tools can be more widely applied to track antigen-specific B cell responses to more disease relevant antigens, without the need for BCR transgenic mice, in settings where tolerance pathways are compromised or have been genetically manipulated to drive stronger insights into the biology underlying B cell-mediated autoimmunity.

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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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Longitudinal Analysis Reveals Distinct Antibody and Memory B Cell Responses in SARS-CoV2 Naïve and Recovered Individuals Following mRNA Vaccination

10.1101/2021.03.03.21252872 ◽

2021 ◽

Author(s):

Rishi R. Goel ◽

Sokratis A. Apostolidis ◽

Mark M. Painter ◽

Divij Mathew ◽

Ajinkya Pattekar ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Memory B Cells ◽

Antibody Responses ◽

Short Term ◽

Memory B Cell ◽

Cell Responses ◽

Specific Memory ◽

B Cell Responses ◽

Antibody Levels

ABSTRACTNovel mRNA vaccines for SARS-CoV2 have been authorized for emergency use and are currently being administered to millions of individuals worldwide. Despite their efficacy in clinical trials, there is limited data on vaccine-induced immune responses in individuals with a prior SARS-CoV2 infection compared to SARS-CoV2 naïve subjects. Moreover, how mRNA vaccines impact the development of antibodies as well as memory B cells in COVID-19 experienced versus COVID-19 naïve subjects remains poorly understood. In this study, we evaluated antibody responses and antigen-specific memory B cell responses over time in 33 SARS-CoV2 naïve and 11 SARS-CoV2 recovered subjects. mRNA vaccination induced significant antibody and memory B cell responses against full-length SARS-CoV2 spike protein and the spike receptor binding domain (RBD). SARS-CoV2 naïve individuals benefitted from both doses of mRNA vaccine with additional increases in antibodies and memory B cells following booster immunization. In contrast, SARS-CoV2 recovered individuals had a significant immune response after the first dose with no increase in circulating antibodies or antigen-specific memory B cells after the second dose. Moreover, the magnitude of the memory B cell response induced by vaccination was lower in older individuals, revealing an age-dependence to mRNA vaccine-induced B cell memory. Side effects also tended to associate with post-boost antibody levels, but not with post-boost memory B cells, suggesting that side effect severity may be a surrogate of short-term antibody responses. The frequency of pre-vaccine antigen-specific memory B cells in SARS-CoV2 recovered individuals strongly correlated with post-vaccine antibody levels, supporting a key role for memory B cells in humoral recall responses to SARS-CoV2. This observation may have relevance for future booster vaccines and for responses to viral variants that partially escape pre-existing antibodies and require new humoral responses to be generated from memory B cells. Finally, post-boost antibody levels were not correlated with post-boost memory responses in SARS-CoV2 naïve individuals, indicating that short-term antibody levels and memory B cells are complementary immunological endpoints that should be examined in tandem when evaluating vaccine response. Together, our data provide evidence of both serological response and immunological memory following mRNA vaccination that is distinct based on prior SARS-CoV2 exposure. These findings may inform vaccine distribution in a resource-limited setting.Abstract Figure

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Plasmacytoid Dendritic Cells and Type I Interferon Promote Extrafollicular B Cell Responses to Extracellular Self-DNA

Immunity ◽

10.1016/j.immuni.2020.04.015 ◽

2020 ◽

Vol 52 (6) ◽

pp. 1022-1038.e7 ◽

Cited By ~ 3

Author(s):

Chetna Soni ◽

Oriana A. Perez ◽

William N. Voss ◽

Joseph N. Pucella ◽

Lee Serpas ◽

...

Keyword(s):

Dendritic Cells ◽

B Cell ◽

Type I Interferon ◽

Plasmacytoid Dendritic Cells ◽

Type I ◽

Cell Responses ◽

B Cell Responses

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Targeting Vaccine-Induced Extrafollicular Pathway of B Cell Differentiation Improves Rabies Postexposure Prophylaxis

Journal of Virology ◽

10.1128/jvi.02435-16 ◽

2017 ◽

Vol 91 (8) ◽

Cited By ~ 6

Author(s):

Shannon L. Haley ◽

Evgeni P. Tzvetkov ◽

Samantha Meuwissen ◽

Joseph R. Plummer ◽

James P. McGettigan

Keyword(s):

B Cells ◽

B Cell ◽

Cell Activation ◽

Antibody Responses ◽

B Cell Differentiation ◽

B Cell Activation ◽

Postexposure Prophylaxis ◽

Effective Prevention ◽

Cell Responses ◽

B Cell Responses

ABSTRACT Vaccine-induced B cells differentiate along two pathways. The follicular pathway gives rise to germinal centers (GCs) that can take weeks to fully develop. The extrafollicular pathway gives rise to short-lived plasma cells (PCs) that can rapidly secrete protective antibodies within days of vaccination. Rabies virus (RABV) postexposure prophylaxis (PEP) requires rapid vaccine-induced humoral immunity for protection. Therefore, we hypothesized that targeting extrafollicular B cell responses for activation would improve the speed and magnitude of RABV PEP. To test this hypothesis, we constructed, recovered, and characterized a recombinant RABV-based vaccine expressing murine B cell activating factor (BAFF) (rRABV-mBAFF). BAFF is an ideal molecule to improve early pathways of B cell activation, as it links innate and adaptive immunity, promoting potent B cell responses. Indeed, rRABV-mBAFF induced a faster, higher antibody response in mice and enhanced survivorship in PEP settings compared to rRABV. Interestingly, rRABV-mBAFF and rRABV induced equivalent numbers of GC B cells, suggesting that rRABV-mBAFF augmented the extrafollicular B cell pathway. To confirm that rRABV-mBAFF modulated the extrafollicular pathway, we used a signaling lymphocytic activation molecule (SLAM)-associated protein (SAP)-deficient mouse model. In response to antigen, SAP-deficient mice form extrafollicular B cell responses but do not generate GCs. rRABV-mBAFF induced similar anti-RABV antibody responses in SAP-deficient and wild-type mice, demonstrating that BAFF modulated immunity through the extrafollicular and not the GC B cell pathway. Collectively, strategies that manipulate pathways of B cell activation may facilitate the development of a single-dose RABV vaccine that replaces current complicated and costly RABV PEP. IMPORTANCE Effective RABV PEP is currently resource- and cost-prohibitive in regions of the world where RABV is most prevalent. In order to diminish the requirements for rabies immunoglobulin (RIG) and multiple vaccinations for effective prevention of clinical rabies, a more rapidly protective vaccine is needed. This work presents a successful approach to rapidly generate antibody-secreting PCs in response to vaccination by targeting the extrafollicular B cell pathway. We demonstrate that the improved early antibody responses induced by rRABV-mBAFF confer improved protection against RABV in a PEP model. Significantly, activation of the early extrafollicular B cell pathway, such as that demonstrated here, could improve the efficacy of vaccines targeting other pathogens against which rapid protection would decrease morbidity and mortality.

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mTOR Promotes Antiviral Humoral Immunity by Differentially Regulating CD4 Helper T Cell and B Cell Responses

Journal of Virology ◽

10.1128/jvi.01653-16 ◽

2016 ◽

Vol 91 (4) ◽

Cited By ~ 13

Author(s):

Lilin Ye ◽

Junghwa Lee ◽

Lifan Xu ◽

Ata-Ur-Rasheed Mohammed ◽

Weiyan Li ◽

...

Keyword(s):

T Cell ◽

B Cells ◽

B Cell ◽

Humoral Immunity ◽

Specific Inhibitor ◽

Antibody Responses ◽

Cd4 T Cell ◽

Rapamycin Treatment ◽

Cell Responses ◽

B Cell Responses

ABSTRACT mTOR has important roles in regulation of both innate and adaptive immunity, but whether and how mTOR modulates humoral immune responses have yet to be fully understood. To address this issue, we examined the effects of rapamycin, a specific inhibitor of mTOR, on B cell and CD4 T cell responses during acute infection with lymphocytic choriomeningitis virus. Rapamycin treatment resulted in suppression of virus-specific B cell responses by inhibiting proliferation of germinal center (GC) B cells. In contrast, the number of memory CD4 T cells was increased in rapamycin-treated mice. However, the drug treatment caused a striking bias of CD4 T cell differentiation into Th1 cells and substantially impaired formation of follicular helper T (Tfh) cells, which are essential for humoral immunity. Further experiments in which mTOR signaling was modulated by RNA interference (RNAi) revealed that B cells were the primary target cells of rapamycin for the impaired humoral immunity and that reduced Tfh formation in rapamycin-treated mice was due to lower GC B cell responses that are essential for Tfh generation. Additionally, we found that rapamycin had minimal effects on B cell responses activated by lipopolysaccharide (LPS), which stimulates B cells in an antigen-independent manner, suggesting that rapamycin specifically inhibits B cell responses induced by B cell receptor stimulation with antigen. Together, these findings demonstrate that mTOR signals play an essential role in antigen-specific humoral immune responses by differentially regulating B cell and CD4 T cell responses during acute viral infection and that rapamycin treatment alters the interplay of immune cell subsets involved in antiviral humoral immunity. IMPORTANCE mTOR is a serine/threonine kinase involved in a variety of cellular activities. Although its specific inhibitor, rapamycin, is currently used as an immunosuppressive drug in transplant patients, it has been reported that rapamycin can also stimulate pathogen-specific cellular immunity in certain circumstances. However, whether and how mTOR regulates humoral immunity are not well understood. Here we found that rapamycin treatment predominantly inhibited GC B cell responses during viral infection and that this led to biased helper CD4 T cell differentiation as well as impaired antibody responses. These findings suggest that inhibition of B cell responses by rapamycin may play an important role in regulation of allograft-specific antibody responses to prevent organ rejection in transplant recipients. Our results also show that consideration of antibody responses is required in cases where rapamycin is used to stimulate vaccine-induced immunity.

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