peripheral b cells
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2022 ◽  
pp. annrheumdis-2021-221558
Author(s):  
Michael Bonelli ◽  
Daniel Mrak ◽  
Selma Tobudic ◽  
Daniela Sieghart ◽  
Maximilian Koblischke ◽  
...  

ObjectivesSARS‐CoV‐2-induced COVID-19 has led to exponentially rising mortality, particularly in immunosuppressed patients, who inadequately respond to conventional COVID-19 vaccination.MethodsIn this blinded randomised clinical trial, we compare the efficacy and safety of an additional booster vaccination with a vector versus mRNA vaccine in non-seroconverted patients. We assigned 60 patients under rituximab treatment, who did not seroconvert after their primary mRNA vaccination with either BNT162b2 (Pfizer–BioNTech) or mRNA-1273 (Moderna), to receive a third dose, either using the same mRNA or the vector vaccine ChAdOx1 nCoV-19 (Oxford–AstraZeneca). Patients were stratified according to the presence of peripheral B cells. The primary efficacy endpoint was the difference in the SARS-CoV-2 antibody seroconversion rate between vector (heterologous) and mRNA (homologous) vaccinated patients by week 4. Key secondary endpoints included the overall seroconversion and cellular immune response; safety was assessed at week 1 and week 4.ResultsSeroconversion rates at week 4 were comparable between vector (6/27 patients, 22%) and mRNA (9/28, 32%) vaccines (p=0.6). Overall, 27% of patients seroconverted; specific T cell responses were observed in 20/20 (100%) vector versus 13/16 (81%) mRNA vaccinated patients. Newly induced humoral and/or cellular responses occurred in 9/11 (82%) patients. 3/37 (8%) of patients without and 12/18 (67%) of the patients with detectable peripheral B cells seroconverted. No serious adverse events, related to immunisation, were observed.ConclusionsThis enhanced humoral and/or cellular immune response supports an additional booster vaccination in non-seroconverted patients irrespective of a heterologous or homologous vaccination regimen.


Blood ◽  
2021 ◽  
Author(s):  
Reem Dowery ◽  
David Benhamou ◽  
Eli Benchetrit ◽  
Ofer Harel ◽  
Alex Nevelsky ◽  
...  

Loss of B lymphocyte regeneration in the bone marrow (BM) is an immunological hallmark of advanced age, which impairs the replenishment of peripheral B-cell subsets and results in impaired humoral responses, thereby contributing to immune system dysfunction associated with aging. A better understanding of the mechanism behind this loss may suggest ways to restore immune competence and promote healthy aging. In the present work, we uncover an immune-endocrine regulatory circuit that mediates cross-talk between peripheral B-cells and progenitors in the BM, to balance B-lymphopoiesis in both human and mouse aging. We found that tumor necrosis factor alpha (TNFα), which is highly produced by peripheral B-cells in aging, stimulates the production of insulin-like growth factor-binding protein 1 (IGFBP-1), which binds and sequesters insulin-like growth factor 1 (IGF1) in the circulation, thereby restraining its activity in promoting B-lymphopoiesis in the BM. Upon B-cell depletion in aged humans and mice, circulatory TNFα decreases, resulting in increased IGF1 and reactivation of B-lymphopoiesis. Perturbation of this circuit by administration of IGF1 to old mice or anti-TNFa antibodies to human patients restored B-lymphopoiesis in the BM. Hence, we suggest that in both human and mouse aging, peripheral B-cells utilize the TNFα/IGFBP-1/IGF1 axis to repress B-lymphopoiesis.


2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lina Ma ◽  
Xinxin Tao ◽  
Xiaoyan He ◽  
Peng Wang ◽  
Long Ma ◽  
...  

AbstractThe number of central and peripheral B cells and their responsiveness are decreased in aged mice. The diversity of mice central and peripheral B cell repertoires with increasing age has not been elucidated. In this study, we demonstrated that there were significant differences in the usage of some V, D, and J genes in the BCR H-CDR3 repertoire of bone marrow B cells, spleen B cells and spleen memory B cells in 3-, 12-, and 20-month-old mice. In the productive, pseudogene, and out-of-frame sequences, bone marrow B cells had significant differences in 5′J trimming with age; peripheral spleen B cells and memory B cells had significant differences in N1 insertion, N2 insertion, P5’D insertion, and 5’D trimming with age. The BCR H-CDR3 repertoire diversity of mice bone marrow B cells, spleen B cells and spleen memory B cells decreased with increasing age. The proportion of overlap in bone marrow and spleen B cells, but not spleen memory B cells, of mice at different ages was lower at 3 months than at 12 and 20 months. This study is the first to report the homogeneity and heterogeneity of the CDR3 repertoire of central and peripheral B cells change as mice age, to further investigation of the decline and response of B cell immunity in young/middle/old-aged mice.


2020 ◽  
Author(s):  
Lina Ma ◽  
Xinsheng Yao ◽  
Tao Xinxin ◽  
He Xiaoyan ◽  
Wang Peng ◽  
...  

Abstract The number of central and peripheral B cells and their responsiveness are decreased in aged mice. The diversity of mouse central and peripheral B cell repertoires with increasing age has not been elucidated. In this study, we demonstrated that there were significant differences in the usage of some V, D, and J genes in the BCR H-CDR3 repertoire of bone marrow B cells, spleen B cells and spleen memory B cells in 3-, 12-, and 20-month-old mice. In the productive, pseudogene, and out-of-frame sequences, bone marrow B cells had significant differences in 5′J trimming with age; peripheral spleen B cells and memory B cells had significant differences in N1 insertion, N2 insertion, P5'D insertion, and 5'D trimming with age. The BCR H-CDR3 repertoire diversity of mouse bone marrow B cells, spleen B cells and spleen memory B cells decreased with increasing age. The proportion of overlap in bone marrow and spleen B cells, but not spleen memory B cells, of mice at different ages was lower at 3 months than at 12 and 20 months. This study is the first to report the homogeneity and heterogeneity of the CDR3 repertoire of central and peripheral B cells change as mice age, to further investigation of the decline and response of B cell immunity in young/middle/old-aged mice.


2020 ◽  
Vol 11 ◽  
Author(s):  
Shumin Yuan ◽  
Yuqing Liu ◽  
Brian Till ◽  
Yongping Song ◽  
Zibing Wang

Author(s):  
Marta Ferreira-Gomes ◽  
Andrey Kruglov ◽  
Pawel Durek ◽  
Frederik Heinrich ◽  
Caroline Tizian ◽  
...  

Here we have analyzed the dynamics of the adaptive immune response triggered by SARS-CoV-2 in severely affected COVID-19 patients, as reflected by activated B cells egressing into the blood, at the single cell level. Early on, before seroconversion in response to SARS-CoV-2 spike protein, activated peripheral B cells displayed a type 1 interferon-induced gene expression signature. After seroconversion, activated B cells lost this signature, expressed IL-21- and TGF-β-induced gene expression signatures, and mostly IgG1 and IgA1. In the sustained immune reaction of the COVID-19 patients, until day 59, activated peripheral B cells shifted to expression of IgA2, reflecting instruction by TGF-β. Despite the continued generation of activated B cells, those cells were not found in the lungs of deceased COVID-19 patients, nor did the IgA2 bind to dominant antigens of SARS-CoV-2. In severe COVID-19, SARS-CoV-2 thus triggers a chronic immune reaction distracted from itself and instructed by TGF-β.


2020 ◽  
Author(s):  
Lina Ma ◽  
Xinsheng Yao

Abstract The number of central and peripheral B cells and their responsiveness are decreased in agedmice. The diversity of mouse central and peripheral B cell repertoires with increasing age has notbeen elucidated. In this study, we demonstrated that there were significant differences in theusage of some V, D, and J genes in the BCR H-CDR3 repertoire of bone marrow B cells, spleen Bcells and spleen memory B cells in 3-, 12-, and 20-month-old mice. In the productive, pseudogene,and out-of-frame sequences, bone marrow B cells had significant differences in 5′J trimmingwith age; peripheral spleen B cells and memory B cells had significant differences in N1 insertion,N2 insertion, P5'D insertion, and 5'D trimming with age. The BCR H-CDR3 repertoire diversityof mouse bone marrow B cells, spleen B cells and spleen memory B cells decreased withincreasing age. The proportion of overlap in bone marrow and spleen B cells, but not spleenmemory B cells, of mice at different ages was lower at 3 months than at 12 and 20 months.Thisstudy is the first to report the homogeneity and heterogeneity of the CDR3 repertoire of centraland peripheral B cells change as mice age , to further investigation of the decline and response ofB cell immunity in young/middle/old-aged mice.


2019 ◽  
Vol 16 (1) ◽  
Author(s):  
Jan W. Traub ◽  
Hannah L. Pellkofer ◽  
Katja Grondey ◽  
Ira Seeger ◽  
Christoph Rowold ◽  
...  

Abstract Background In the past, multiple sclerosis (MS) medications have been primarily designed to modulate T cell properties. Based on the emerging concept that B cells are equally important for the propagation of MS, we compared the effect of four commonly used, primarily T cell-targeting MS medications on B cells. Methods Using flow cytometry, we analyzed peripheral blood mononuclear cells (PBMC) of untreated (n = 19) and dimethyl fumarate (DMF; n = 21)-, fingolimod (FTY; n = 17)-, glatiramer acetate (GA; n = 18)-, and natalizumab (NAT; n = 20)-treated MS patients, focusing on B cell maturation, differentiation, and cytokine production. Results While GA exerted minor effects on the investigated B cell properties, DMF and FTY robustly inhibited pro-inflammatory B cell function. In contrast, NAT treatment enhanced B cell differentiation, activation, and pro-inflammatory cytokine production when compared to both intraindividual samples collected before NAT treatment initiation as well as untreated MS controls. Our mechanistic in vitro studies confirm this observation. Conclusion Our data indicate that common MS medications have differential, in part opposing effects on B cells. The observed activation of peripheral B cells upon NAT treatment may be instructive to interpret its unfavorable effect in certain B cell-mediated inflammatory conditions and to elucidate the immunological basis of MS relapses after NAT withdrawal. Trial registration Protocols were approved by the ethical review committee of the University Medical Center Göttingen (#3/4/14).


2019 ◽  
Vol 116 (33) ◽  
pp. 16519-16528 ◽  
Author(s):  
Aurélia Faure ◽  
Mitch Hayes ◽  
Bill Sugden

Primary effusion lymphomas (PELs) are causally associated with Kaposi’s sarcoma-associated herpesvirus (KSHV) and 86% of PELs are coinfected with Epstein–Barr virus (EBV). Understanding how PELs develop has been impaired by the difficulty of infecting B cells with KSHV in vitro, and the inability of KSHV to transform them. We show that EBV supports an optimal coinfection of 2.5% of peripheral B cells by KSHV. This coinfection requires 1 or more transforming genes of EBV but not entry into KSHV’s lytic cycle. We demonstrate that dually infected B cells are stably transformed in vitro and show that while both viruses can be maintained, different cells exhibit distinct, transformed properties. Transformed cells that grow to predominate in a culture express increased levels of most KSHV genes and differentially express a subset of cellular genes, as do bona fide PEL cells. These dually infected peripheral B cells are thus both stably transformed and allow in vitro molecular dissection of early steps in the progression to lymphomagenesis.


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