scholarly journals The BioNTech / Pfizer vaccine BNT162b2 induces class-switched SARS-CoV-2-specific plasma cells and potential memory B cells as well as IgG and IgA serum and IgG saliva antibodies upon the first immunization

2021 ◽  
Author(s):  
Anne S. Lixenfeld ◽  
Inga Künsting ◽  
Emily L. Martin ◽  
Vera von Kopylow ◽  
Selina Lehrian ◽  
...  
Keyword(s):  
B Cells ◽  
Respiratory Tract ◽  
Development Process ◽  
Plasma Cells ◽  
Memory B Cells ◽  
The Body ◽  
Cd4 T Cell ◽  
First Line ◽  
Underlying Mechanisms

AbstractTo treat the SARS-CoV-2 virus, that enters the body through the respiratory tract, different vaccines in particular against the SARS-CoV-2 spike (S)-protein have been developed or are in the development process. For the BioNTech / Pfizer mRNA vaccine BNT162b2, which is injected twice, protection against COVID-19 has been described for the first weeks after the second vaccination. The underlying mechanisms of defense and the long-term effectiveness of this vaccine against COVID-19 are currently under investigation.In addition to the induction of systemic antibodies (Abs), Ab responses in the respiratory tract would help to form a first line of defense against SARS-CoV-2. Furthermore, protection depends on Fab-part-dependent neutralizing capacities, however, Fc-part-mediated effector mechanisms might also be important. Long-term defense would be based on the induction of long-lived antibody-producing plasma cells (PCs) and memory B cells.Here, we established different assays to analyze anti-SARS-CoV-2-S IgG and IgA Abs in blood serum and saliva as well as SARS-CoV-2-S1-reactive IgG and IgA PCs and potential memory B cells in the blood of individuals upon their first immunization with BNT162b2.We show that the vaccine induces in particular anti-SARS-CoV-2-S IgG1 and IgG3 as well as IgA1 and in some individuals also IgG2 and IgA2 serum Abs. In the saliva, we found no anti-SARS-CoV-2-S IgA, but instead IgG Abs. Furthermore, we found SARS-CoV-2-S reactive IgG+ blood PCs and potential memory B cells as well as SARS-CoV-2-S reactive IgA+ PCs and/or potential memory B cells in some individuals.Our data suggest that the vaccine induces a promising CD4+ T cell-dependent systemic IgG1 and IgG3 Ab response with IgG+ PCs and potential memory B cells. In addition to the systemic IgG response, the systemic IgA and saliva IgG response might help to improve a first line of defense in the respiratory tract against SARS-CoV-2 and its mutants.

Comparable Long-Term Persistence of Anti-FVIII Antibodies in Hemophilic E17 Mice on Different Genetic Backgrounds Despite Significant Differences in the Amplitude of the Immune Responses.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 1027-1027
Author(s):  
Natalie Bauer ◽  
Christina Hausl ◽  
Rafi U. Ahmad ◽  
Bernhard Baumgartner ◽  
Hans Peter Schwarz ◽  
...  
Keyword(s):  
Immune Response ◽  
B Cells ◽  
Genetic Background ◽  
Neutralizing Antibodies ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Mouse Strains ◽  
Igg Antibodies ◽  
Specific Memory

Abstract About 30% of patients with severe hemophilia A develop neutralizing antibodies against FVIII (FVIII inhibitors) following replacement therapy. The type of FVIII gene mutation as well as other predisposing genetic factors contribute to the inhibitor phenotype. Based on these findings, we asked if the genetic background modulates the long-term persistence of anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells in the E17 murine hemophilia model. Furthermore, we asked if the recently described inhibition of memory-B-cell re-stimulation by high doses of FVIII is influenced by the genetic background of the murine model. E17 mice on two different genetic backgrounds (C57Bl/6J and Balb/c) were treated with four doses of 200 ng human FVIII at weekly intervals. Anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells were followed up to 12 months after the last dose of FVIII. Antibody titers and subclasses of antibodies (IgM, IgG1, IgG2a, IgG2b, IgG3) were measured by ELISA. Antibody secreting plasma cells in spleen and bone marrow were detected by ELISPOT as described (Hausl et al., Thromb Haemost 2002). The re-stimulation of FVIII-specific memory B cells was studied as described recently (Hausl et al., Blood 2005). Anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells were first detectable in E17 Balb/c mice. IgM antibodies in the circulation and IgM secreting plasma cells in the spleen were observed after the first dose of FVIII, IgG antibodies and IgG secreting plasma cells after the second dose. No anti-FVIII antibodies after the first dose of FVIII were observed in E17 C57BL/6J mice but both IgM and IgG antibodies as well as IgM and IgG producing plasma cells were detectable after the second dose of FVIII. The antibody response involved all IgG subclasses in both mouse strains. However, IgG1 was dominant in E17 Balb/c mice whereas IgG2a was dominant in E17 C57BL/6J mice. When the in vitro restimulation of FVIII-specific memory B cells was examined, similar patterns were observed for both mouse strains. Low concentrations of FVIII between 10 and 100 ng/ml FVIII restimulated memory B cells and induced their differentiation into antibody secreting plasma cells whereas high concentrations of FVIII between 1,000 and 20,000 ng/ml FVIII inhibited memory-B-cell-restimulation. These results indicate that the dose-dependent effect of FVIII on the restimulation of FVIII-specific memory B cells does not depend on the genetic background. The major difference between both hemophilic mouse strains was the amplitude of the anti-FVIII immune response. Peak titers of anti-FVIII antibodies and peak concentrations of anti-FVIII antibody secreting plasma cells in spleen and bone marrow were significantly higher in E17 C57BL/6J mice than in E17 Balb/c mice. Whether or not higher ELISA titers correlate with higher Bethesda titers of neutralizing antibodies is currently being investigated. Despite the substantial differences in the amplitude of the immune response, anti-FVIII antibodies and anti-FVIII antibody secreting plasma cells persisted for the whole observation period of 12 months after the last dose of FVIII in both mouse strains. We conclude that the amplitude of the anti-FVIII immune response in hemophilic mice is significantly different between E17 C57BL/6J and E17 Balb/c mice. However, the persistence of the immune response is comparable.

scholarly journals Case Report: Persistent Hypogammaglobulinemia More Than 10 Years After Rituximab Given Post-HSCT

2021 ◽  
Vol 12 ◽  
Author(s):  
Fanny Luterbacher ◽  
Fanette Bernard ◽  
Frédéric Baleydier ◽  
Emmanuelle Ranza ◽  
Peter Jandus ◽  
...  
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Virus Reactivation ◽  
Normal Numbers ◽  
Cell Stage ◽  
Hematopoietic Stem ◽  
Barr Virus ◽  
Anti Cd20

Rituximab (RTX) is an anti-CD20 monoclonal antibody that targets B cells—from the immature pre-B-cell stage in the bone marrow to mature circulating B cells—while preserving stem cells and plasma cells. It is used to treat autoimmune diseases, hematological malignancies, or complications after hematopoietic stem cell transplantation (HSCT). Its safety profile is acceptable; however, a subset of patients can develop persistent hypogammaglobulinemia and associated severe complications, especially in pediatric populations. We report the unrelated cases of two young men aged 17 and 22, presenting with persistent hypogammaglobulinemia more than 7 and 10 years after treatment with RTX, respectively, and administered after HSCT for hemolytic anemia and Epstein–Barr virus reactivation, respectively. Both patients’ immunological workups showed low levels of total immunoglobulin, vaccine antibodies, and class switched-memory B cells but an increase in naive B cells, which can also be observed in primary immunodeficiencies such as those making up common variable immunodeficiency. Whole exome sequencing for one of the patients failed to detect a pathogenic variant causing a Mendelian immunological disorder. Annual assessments involving interruption of immunoglobulin replacement therapy each summer failed to demonstrate the recovery of endogenous immunoglobulin production or normal numbers of class switched-memory B cells 7 and 10 years after the patients’ respective treatments with RTX. Although the factors that may lead to prolonged hypogammaglobulinemia after rituximab treatment (if necessary) remain unclear, a comprehensive immunological workup before treatment and long-term follow-up are mandatory to assess long-term complications, especially in children.

Effects Of Bendamustine Plus Rituximab On The Distribution Of Normal Peripheral Blood Leucocyte Populations In Advanced-Stage Chronic Lymphocytic Leukemia (CLL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5289-5289 ◽  
Author(s):  
Georgiana Grigore ◽  
Martin Perez-Andres ◽  
Susana Barrena ◽  
Rosa Ana Rivas ◽  
Marcos González ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Lymphocytic Leukemia ◽  
Cd4 T Cell ◽  
Advanced Stage ◽  
Time Point

Abstract Introduction Management of B-cell chronic lymphocytic leukemia (CLL) is currently undergoing profound changes. Accordingly, new treatment options with an expected less toxicity than standard regimens are been explored. Recent results show that chemoimmunotherapy may improve the life expectancy of CLLpatients and has proven to be more efficient than chemotherapy alone in depleting malignant cells. Despite its efficacy, little is known about its precise immunomodulatory effects. Aim To evaluate the effects of chemoimmunotherapy with bendamustine plusrituximab (BR) on the distribution of normal residual leucocyte populations in peripheral blood (PB) from advanced-stage CLL patients, with special emphasis on maturation-associated B-cell subsets (immature, naïve, memory IgM/IgG/IgA and plasma cells). Material and Methods Distribution of PB neoplastic cells and residual normal immune cell subpopulations were analyzed in 72 CLL patients with advanced disease (Binet B/C), before therapy (M0) and after 1 course of BR (M1). The same analysis was repeated 3 months after completing treatment (M3) in 31/72 patients. PB leucocyte cell subsets were identified at each time-point by 8-color flow cytometry with monoclonal antibody reagents against CD3, CD4, CD5, CD8, TCRgd, CD19, CD20, CD27, CD38, CD45, CD56, sIgM, sIgA, sIgG, sIgLambda and sIgKappa. Results After the first BR course, absolute counts of all PB myeloid subsets were significantly decreased as compared to time M0, including neutrophils (2,744±1,830 vs 4,764±2,906 cells/uL, p<0.001), eosinophils (132±185 vs 215±245 cells/uL; p<0.001), basophils (37±28 vs 59±47 cells/uL, p<0.001), monocytes (334±280 vs 504±424 cells/uL, p=0.001) and dendritic cells (DCs, 41±40 vs 89±168 cells/uL, p=0.02), as well as NK cells (120±147 vs 550±599 cells/uL, p<0.001). At M3, all these populations remained decreased when compared to M0, but at similar levels to M1 (except for the absolute number of DCs, found to be increased vs. M1 -74±46 vs 41±40 cells/uL, p=0.008- and closer to M0). In turn, total T cells were reduced in M1 as compared to M0 values (818±655 vs 3,905±2,375 cells/uL, p<0.001), due to decreased numbers of CD4+ (424±376 vs 1,573±1,204 cells/uL, p<0.001), CD8+ (342±330 vs 1,334±1,218 cells/uL, p<0.001) and TCRgd (21±28 vs 141±289 cells/uL, p=0.001) T cells, leading to an increased CD4/CD8 ratio (1.8±1.3 vs 1.4±0.8, p=0.004). Also, decreased levels of CD4 (222±156 cells/uL), CD8 (501±544 cells/uL) and TCRgd (21±40 cells/uL) T cells were observed at time M3 vs. baseline values. No changes (p>0.05) were observed for CD8 and TCRgd for M3 vs. M1, while CD4+ T-cell numbers were significantly reduced (p=0.006), resulting in an inverted CD4/CD8 ratio (0.9±1.0 vs. 1.8±1.3, p=0.005) at the M3 time-point. As regards B cells, the absolute count of both neoplastic and normal B lymphocytes were significantly decreased at time M1 vs. M0 (3,363±9,353 vs 53,521±56,602 CLL cells/uL and 2±6 vs 58±107 normal B-cells/uL, p=0.006 and p<0.001, respectively). Within the normal residual B-cell compartment, we found significantly decreased numbers of immature (0.07±0.22 vs 6.55±21.64 cells/uL, p=0.01) and memory (1.3±14.7 vs 35.1±43.6 cells/uL, p<0.001) B cells -including sIgM (0.5±2.3 vs 14.5±24.8 cells/uL, p<0.001), sIgG (0.2±1.0 vs 11.5±17.2 cells/uL; p<0.001) and sIgA (0.6±3.1 vs 9.5±12.5 cells/uL, p<0.001) memory B cells-. At time M3, decreased (p<0.01) naïve (0.46±2.58 cells/uL) and memory B-cells (1.34±6.75 cells/uL), including IgM (0.46±2.58 cells/uL), IgG (0.34±1.69 cells/uL) and IgA (0.09±0.31 cells/uL), but not immature cells (2.28±8.84 cells/uL, p=0.9), were observed as compared to time M0. Differences did not reach statistical significance when comparing M3 vs. M1. The number of circulating plasma cells did not significantly vary during treatment. Conclusions All PB leucocyte subsets are affected by BR treatment in advanced-stage CLL. Interestingly, at time M3 the CD4+ T-cell subset continues to be decreased, while the other T-cell compartments seem to remain stable. Also, normal B cells are affected by BR treatment, and the depletion induced after one course therapy is maintained even three months after finishing BR therapy, except for immature B cells, that seem to be the first to recover in PB. Further studies will offer a more accurate insight into the biology of cell recovery during and after BR therapy in CLL patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Secondary Immunization Generates Clonally Related Antigen-Specific Plasma Cells and Memory B Cells

2010 ◽  
Vol 185 (5) ◽  
pp. 3103-3110 ◽  
Author(s):  
Daniela Frölich ◽  
Claudia Giesecke ◽  
Henrik E. Mei ◽  
Karin Reiter ◽  
Capucine Daridon ◽  
...  
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Memory B Cells

scholarly journals Reduced peripheral blood regulatory B cell levels are not associated with the Expanded Disability Status Scale score in multiple sclerosis

2018 ◽  
Vol 46 (9) ◽  
pp. 3970-3978 ◽  
Author(s):  
Shujun Guo ◽  
Qingqing Chen ◽  
Xiaoli Liang ◽  
Mimi Mu ◽  
Jing He ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Serum Levels ◽  
Memory B Cells ◽  
Healthy Controls ◽  
Expanded Disability Status Scale ◽  
Disability Status ◽  
Edss Score

Objective To investigate levels of regulatory B (Breg) cells, plasma cells, and memory B cells in the peripheral blood, and interleukin (IL)-10 in the serum of multiple sclerosis (MS) patients, and to determine the correlation between Breg cell levels and the Expanded Disability Status Scale (EDSS) score. Methods Levels of Breg cells, plasma cells, and memory B cells in the peripheral blood of 12 MS patients were measured using flow cytometry. IL-10 serum levels were measured by enzyme-linked immunosorbent assay. The correlation between Breg cell levels and MS EDSS score was measured using Pearson’s correlation coefficient. Results Compared with healthy controls, MS patients had decreased levels of CD19+CD24hiCD38hi Breg cells in their peripheral blood and reduced serum levels of IL-10; however, the ratios of CD19+CD27hiCD38hi plasma cells and CD19+CD27+CD24hi memory B cells to total B cells did not differ significantly between healthy controls and MS patients. CD19+CD24hiCD38hi Breg cell levels in the peripheral blood of MS patients were not significantly correlated with MS EDSS score. Conclusion Peripheral blood CD19+CD24hiCD38hi Breg cell levels and serum IL-10 levels were reduced in MS patients compared with controls, but Breg cell levels were not correlated with MS EDSS score.

scholarly journals Memory B cells, but not long-lived plasma cells, possess antigen specificities for viral escape mutants

2011 ◽  
Vol 208 (13) ◽  
pp. 2599-2606 ◽  
Author(s):  
Whitney E. Purtha ◽  
Thomas F. Tedder ◽  
Syd Johnson ◽  
Deepta Bhattacharya ◽  
Michael S. Diamond
Keyword(s):  
B Cells ◽  
Plasma Cells ◽  
Large Fraction ◽  
West Nile Virus Infection ◽  
Immune Serum ◽  
Memory B Cells ◽  
Viral Escape ◽  
Variant Virus ◽  
Escape Mutants

Memory B cells (MBCs) and long-lived plasma cells (LLPCs) persist after clearance of infection, yet the specific and nonredundant role MBCs play in subsequent protection is unclear. After resolution of West Nile virus infection in mice, we demonstrate that LLPCs were specific for a single dominant neutralizing epitope, such that immune serum poorly inhibited a variant virus that encoded a mutation at this critical epitope. In contrast, a large fraction of MBC produced antibody that recognized both wild-type (WT) and mutant viral epitopes. Accordingly, antibody produced by the polyclonal pool of MBC neutralized WT and variant viruses equivalently. Remarkably, we also identified MBC clones that recognized the mutant epitope better than the WT protein, despite never having been exposed to the variant virus. The ability of MBCs to respond to variant viruses in vivo was confirmed by experiments in which MBCs were adoptively transferred or depleted before secondary challenge. Our data demonstrate that class-switched MBC can respond to variants of the original pathogen that escape neutralization of antibody produced by LLPC without a requirement for accumulating additional somatic mutations.

scholarly journals T-independent antigen induces humoral memory through germinal centers

2022 ◽  
Vol 219 (3) ◽  
Author(s):  
Xin Liu ◽  
Yongshan Zhao ◽  
Hai Qi
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Plasma Cells ◽  
Underlying Mechanism ◽  
Memory B Cells ◽  
Antigen B ◽  
Per Se ◽  
Humoral Responses ◽  
Human And Mouse

T-dependent humoral responses generate long-lived memory B cells and plasma cells (PCs) predominantly through germinal center (GC) reaction. In human and mouse, memory B cells and long-lived PCs are also generated during immune responses to T-independent antigen, including bacterial polysaccharides, although the underlying mechanism for such T-independent humoral memory is not clear. While T-independent antigen can induce GCs, they are transient and thought to be nonproductive. Unexpectedly, by genetic fate-mapping, we find that these GCs actually output memory B cells and PCs. Using a conditional BCL6 deletion approach, we show memory B cells and PCs fail to last when T-independent GCs are precluded, suggesting that the GC experience per se is important for programming longevity of T-independent memory B cells and PCs. Consistent with the fact that infants cannot mount long-lived humoral memory to T-independent antigen, B cells from young animals intrinsically fail to form T-independent GCs. Our results suggest that T-independent GCs support humoral memory, and GC induction may be key to effective vaccines with T-independent antigen.

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