BAFF enhances chemotaxis of primary human B cells: a particular synergy between BAFF and CXCL13 on memory B cells

Blood ◽  
2008 ◽  
Vol 111 (5) ◽  
pp. 2744-2754 ◽  
Author(s):  
Gamal Badr ◽  
Gwenoline Borhis ◽  
Eric A. Lefevre ◽  
Nada Chaoul ◽  
Frederique Deshayes ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Stromal Cells ◽  
B Lymphocyte ◽  
Memory B Cells ◽  
Follicular Dendritic Cells ◽  
Human B Cells ◽  
Lymphocyte Survival ◽  
B Cell Homeostasis ◽  
Cell Chemotaxis

B-cell–activating factor of the TNF family, (BAFF), and a proliferation-inducing ligand (APRIL) regulate B-lymphocyte survival and activation. We report that BAFF, but not APRIL, increased the chemotactic response of primary human B cells to CCL21, CXCL12, and CXCL13. The BAFF-induced increase in B-cell chemotaxis was totally abolished by blockade of BAFF-R and was strongly dependent on the activation of PI3K/AKT, NF-κB, and p38MAPK pathways. BAFF had similar effects on the chemotaxis of naive and memory B cells in response to CCL21 but increased more strongly that of memory B cells to CXCL13 than that of naive B cells. Our findings indicate a previously unreported role for the BAFF/BAFF-R pair in mature B-cell chemotaxis. The synergy between CXCL13 and BAFF produced by stromal cells and follicular dendritic cells may have important implications for B-cell homeostasis, the development of normal B-cell areas, and for the formation of germinal center–like follicles that may be observed in various autoimmune diseases.

scholarly journals Absence of surface IgD does not impair naive B cell homeostasis and memory B cell formation in humans

2018 ◽  
Author(s):  
J. Nechvatalova ◽  
S.J.W. Bartol ◽  
Z. Chovancova ◽  
L. Boon ◽  
M. Vlkova ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Genetic Defect ◽  
Memory B Cells ◽  
Cell Homeostasis ◽  
Human B Cells ◽  
B Cell Homeostasis

One Sentence SummaryHuman B cells with a genetic defect in IGHD develop normally in vivo, and do not have a competitive disadvantage to IgD-expressing B cells for developing into memory B cells.AbstractSurface immunoglobulin D (IgD) is co-expressed with IgM on naive mature B cells. Still, the role of surface IgD remains enigmatic even 50 years after its initial discovery. We here examined the in vivo role of surface IgD in human B-cell homeostasis and antibody responses in four individuals with heterozygous nonsense mutations in IGHD. All IGHD heterozygous individuals had normal numbers of B cells and serum immunoglobulins, and did not show signs of immunodeficiency or immune dysregulation. IgD+ and IgD– naive mature B cells were present in equal numbers and showed similar immunophenotypes, except for decreased expression of CD79b in the IgD– subset. Furthermore, both IgD+ and IgD– naive mature B cells had normal replication histories, similar capacities to differentiate into plasma cells upon in vitro stimulation, and Ig switched memory B cells showed similar levels of somatic hypermutations. Thus human B cells lacking IgD expression develop normally and generate immunological memory in vivo, suggesting that surface IgD might function more restricted in regulating of B-cell activation to specific antigenic structures.

scholarly journals Comparative In Vitro Immune Stimulation Analysis of Primary Human B Cells and B Cell Lines

2016 ◽  
Vol 2016 ◽  
pp. 1-9 ◽  
Author(s):  
Kristien Van Belle ◽  
Jean Herman ◽  
Louis Boon ◽  
Mark Waer ◽  
Ben Sprangers ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Lines ◽  
Cell Activation ◽  
B Lymphocyte ◽  
Cell Model ◽  
Lymphocyte Activation ◽  
Screening Assay ◽  
Human B Cells

B cell specific immunomodulatory drugs still remain an unmet medical need. Utilisation of validated simplified in vitro models would allow readily obtaining new insights in the complexity of B cell regulation. For this purpose we investigated which human B lymphocyte stimulation assays may be ideally suited to investigate new B lymphocyte immunosuppressants. Primary polyclonal human B cells underwent in vitro stimulation and their proliferation, production of immunoglobulins (Igs) and of cytokines, and expression of cell surface molecules were analysed using various stimuli. ODN2006, a toll-like receptor 9 (TLR9) agonist, was the most potent general B cell stimulus. Subsequently, we investigated on which human B cell lines ODN2006 evoked the broadest immunostimulatory effects. The Namalwa cell line proved to be the most responsive upon TLR9 stimulation and hence may serve as a relevant, homogeneous, and stable B cell model in an in vitro phenotypic assay for the discovery of new targets and inhibitors of the B cell activation processes. As for the read-out for such screening assay, it is proposed that the expression of activation and costimulatory surface markers reliably reflects B lymphocyte activation.

scholarly journals Concurrent engagement of CD40 and the antigen receptor protects naive and memory human B cells from APO-1/Fas-mediated apoptosis.

1996 ◽  
Vol 183 (4) ◽  
pp. 1377-1388 ◽  
Author(s):  
C Lagresle ◽  
P Mondière ◽  
C Bella ◽  
P H Krammer ◽  
T Defrance
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Survival ◽  
Antigen Receptor ◽  
Cell Types ◽  
Memory B Cells ◽  
Apoptotic Pathway ◽  
Cell Responses ◽  
Human B Cells ◽  
B Cell Survival

Naive and memory B cells were isolated from human tonsils and examined for expression of APO-1/Fas and for their sensitivity to the APO-1-dependent apoptosis. APO-1 was found to be constitutively expressed on memory but not on naive B cells. The susceptibility of both cell types to the APO-1 apoptotic pathway was acquired upon CD40 triggering and was correlated with increased expression of the APO-1 receptor. Both naive and memory B cells were protected from the APO-1-mediated death signal after dual ligation of the Ag receptor adn CD40. Our findings suggest that the APO-1 pathway controls the specificity of B cell responses to T-dependent Ags and that occupancy of the Ag receptor dictates the outcome of APO-1-ligation on B cell survival.

scholarly journals B-cell populations discriminate between pediatric- and adult-onset multiple sclerosis

2016 ◽  
Vol 4 (1) ◽  
pp. e309 ◽  
Author(s):  
Alexander Schwarz ◽  
Bettina Balint ◽  
Mirjam Korporal-Kuhnke ◽  
Sven Jarius ◽  
Kathrin von Engelhardt ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Plasma Cells ◽  
Cross Sectional Study ◽  
Memory B Cells ◽  
Immunoglobulin M ◽  
Adult Onset ◽  
Cross Sectional

Objective:To comparatively assess the B-cell composition in blood and CSF of patients with pediatric-onset multiple sclerosis (pedMS) and adult-onset multiple sclerosis (adMS).Methods:In this cross-sectional study, we obtained blood and CSF samples from 25 patients with pedMS (8–18 years) and 40 patients with adMS (23–65 years) and blood specimens from 66 controls (1–55 years). By using multicolor flow cytometry, we identified naive, transitional, isotype class-switched memory, nonswitched memory, and double-negative memory B-cell subsets as well as plasmablasts (PB) and terminally differentiated plasma cells (PC). Flow cytometric data were compared to concentrations of B-cell-specific cytokines in serum and CSF as determined by ELISA.Results:Frequencies of circulating naive B-cells decreased with higher age in controls but not in patients with multiple sclerosis (MS). B-cell patterns in CSF differed between pedMS and adMS with an acute relapse: in pedMS-derived CSF samples, high frequencies of nonswitched memory B cells and PB were present, whereas class-switched memory B cells and PC dominated in the CSF of patients with adMS. In pedMS, PB were also elevated in the periphery. Accumulation of PB in the CSF correlated with high intrathecal CXCL-13 levels and augmented intrathecal synthesis of immunoglobulin G and immunoglobulin M.Conclusions:We demonstrate distinct changes in intrathecal B-cell homeostasis in patients with pedMS during active disease, which differ from those in adults by an expansion of plasmablasts in blood and CSF and similarly occur in prototypic autoantibody-driven autoimmune disorders. This emphasizes the particular importance of activated B-lymphocyte subsets for disease progression in the earliest clinical stages of MS.

scholarly journals Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells

2013 ◽  
Vol 210 (12) ◽  
pp. 2739-2753 ◽  
Author(s):  
Elissa K. Deenick ◽  
Danielle T. Avery ◽  
Anna Chan ◽  
Lucinda J. Berglund ◽  
Megan L. Ives ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Function ◽  
Memory B Cells ◽  
B Cell Differentiation ◽  
Loss Of Function ◽  
Human B Cells ◽  
Human B Cell

Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell–dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10– and IL-21–mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21–induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.

Assessing B Lymphocyte Clonal Diversity, Expansion, and Convergent Evolution By High-Throughput Sequencing Of Rearranged IGH Segments From Naïve and Memory Repertoires

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1045-1045
Author(s):  
William S DeWitt ◽  
Paul Lindau ◽  
Ryan O Emerson ◽  
Anna Sherwood ◽  
David Williamson ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Convergent Evolution ◽  
High Throughput Sequencing ◽  
B Lymphocyte ◽  
Somatic Hypermutation ◽  
Memory B Cells ◽  
Antigen Specificity ◽  
Employment Equity ◽  
Equity Ownership

Abstract Diversity in B lymphocyte antigen specificity, necessary for effective adaptive immunity, arises from structural diversity of the B cell receptor generated by random somatic rearrangement of the immunoglobin heavy (IgH) and light chain loci during lymphocyte development. Antigen-experienced (memory) B cells are stimulated to proliferate upon successful binding of antigen, whereas the extent to which unexperienced (naïve) cells proliferate, if it all, is unclear. During memory clonal expansion, daughter cells undergo somatic hypermutation, which introduces random single nucleotide variants to the rearranged gene segments, selectively optimizing antigen affinity. Among memory B cells that express identical receptor proteins, the extent to which the cells are identical by descent, or rather have convergently evolved from different naïve clones to the same specificity, is also unknown. We performed high-throughput sequencing of rearranged IgH gene segments for B cells sorted into memory (CD19+, CD27+) and naïve (CD19+, CD27-,IgM+, IgD+) samples (∼5 million cells each) from each of three adults. Each sample was split among 188 libraries for multiplex PCR amplification of IgH sequences at ∼10x coverage, allowing us to estimate clonal abundance by measuring the number of libraries occupied by each sequence. Using a maximum entropy inverse model, all three memory samples evince three distinct subpopulations, corresponding to memory cell types of differing abundance. Data from naïve samples suggest extreme diversity with more than 98% of clones occupying one library (i.e., almost surely present in only one cell in the starting material). A measure-theoretic upper bound on mean clone abundance in the naive repertoire was computed based on Monte Carlo simulation, indicating that naïve B cells typically undergo little, if any, expansion. Additionally, somatic hypermutation in the memory samples was investigated to detect convergent evolution of distinct naïve B cell clones toward common amino acid sequence (hence common antigen specificity) in the memory B cell compartment. Disclosures: DeWitt: Adaptive Biotechnologies: Employment, Equity Ownership. Emerson:Adaptive Biotechnologies: Employment, Equity Ownership. Sherwood:Adaptive Biotechnologies: Employment, Equity Ownership. Williamson:Adaptive Biotechnologies: Employment, Equity Ownership. Rieder:Adaptive Biotechnologies: Employment, Equity Ownership. Chung:Adaptive Biotechnologies: Employment, Equity Ownership. Carlson:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties. Robins:Adaptive Biotechnologies: Consultancy, Equity Ownership, Patents & Royalties.

scholarly journals Follicular dendritic cells inhibit human B-lymphocyte proliferation

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1284-1288 ◽  
Author(s):  
AS Freedman ◽  
JM Munro ◽  
K Rhynhart ◽  
P Schow ◽  
J Daley ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Inhibitory Effect ◽  
Germinal Centers ◽  
Follicular Dendritic Cells ◽  
Neoplastic Processes ◽  
Follicular Dendritic

Abstract In germinal centers, B lymphocytes are intimately associated with follicular dendritic cells (FDCs). It has been hypothesized that FDCs are involved in the regulation of B-cell growth and differentiation through cell-cell interactions. In this study, highly enriched preparations of FDCs were isolated by cell sorting using the FDC restricted monoclonal antibody DRC-1. When irradiated FDCs were cultured with mitogen stimulated B cells, B cell 3H-TdR uptake was inhibited by up to 80%. This inhibitory effect was not seen when paraformaldehyde fixed FDCs were added to B-cell cultures, suggesting that the FDCs needed to be metabolically active. Moreover, supernatants from cultured FDCs were similarly able to inhibit B-cell proliferation. These results demonstrate that FDCs may downregulate the clonal expansion of B cells that occurs within lymphoid follicles as part of the normal physiologic immune response. Potentially, the loss of the inhibitory role of FDCs in vivo may be of importance in certain infectious and neoplastic processes in which germinal centers are affected.

scholarly journals Regulation of B cell homeostasis and activation by the tumor suppressor gene CYLD

2007 ◽  
Vol 204 (11) ◽  
pp. 2615-2627 ◽  
Author(s):  
Nadine Hövelmeyer ◽  
F. Thomas Wunderlich ◽  
Ramin Massoumi ◽  
Charlotte G. Jakobsen ◽  
Jian Song ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Splice Variants ◽  
Cell Receptor ◽  
Full Length ◽  
Nuclear Accumulation ◽  
Cell Homeostasis ◽  
B Cell Homeostasis

B cell homeostasis is regulated by multiple signaling processes, including nuclear factor-κB (NF-κB), BAFF-, and B cell receptor signaling. Conditional disruption of genes involved in these pathways has shed light on the mechanisms governing signaling from the cell surface to the nucleus. We describe a novel mouse strain that expresses solely and excessively a naturally occurring splice variant of CYLD (CYLDex7/8 mice), which is a deubiquitinating enzyme that is integral to NF-κB signaling. This shorter CYLD protein lacks the TRAF2 and NEMO binding sites present in full-length CYLD. A dramatic expansion of mature B lymphocyte populations in all peripheral lymphoid organs occurs in this strain. The B lymphocytes themselves exhibit prolonged survival and manifest a variety of signaling disarrangements that do not occur in mice with a complete deletion of CYLD. Although both the full-length and the mutant CYLD are able to interact with Bcl-3, a predominant nuclear accumulation of Bcl-3 occurs in the CYLD mutant B cells. More dramatic, however, is the accumulation of the NF-κB proteins p100 and RelB in CYLDex7/8 B cells, which, presumably in combination with nuclear Bcl-3, results in increased levels of Bcl-2 expression. These findings suggest that CYLD can both positively and negatively regulate signal transduction and homeostasis of B cells in vivo, depending on the expression of CYLD splice variants.

scholarly journals Follicular dendritic cells inhibit human B-lymphocyte proliferation

Blood ◽  
1992 ◽  
Vol 80 (5) ◽  
pp. 1284-1288 ◽  
Author(s):  
AS Freedman ◽  
JM Munro ◽  
K Rhynhart ◽  
P Schow ◽  
J Daley ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
B Cells ◽  
B Cell ◽  
B Lymphocyte ◽  
Inhibitory Effect ◽  
Germinal Centers ◽  
Follicular Dendritic Cells ◽  
Neoplastic Processes ◽  
Follicular Dendritic

In germinal centers, B lymphocytes are intimately associated with follicular dendritic cells (FDCs). It has been hypothesized that FDCs are involved in the regulation of B-cell growth and differentiation through cell-cell interactions. In this study, highly enriched preparations of FDCs were isolated by cell sorting using the FDC restricted monoclonal antibody DRC-1. When irradiated FDCs were cultured with mitogen stimulated B cells, B cell 3H-TdR uptake was inhibited by up to 80%. This inhibitory effect was not seen when paraformaldehyde fixed FDCs were added to B-cell cultures, suggesting that the FDCs needed to be metabolically active. Moreover, supernatants from cultured FDCs were similarly able to inhibit B-cell proliferation. These results demonstrate that FDCs may downregulate the clonal expansion of B cells that occurs within lymphoid follicles as part of the normal physiologic immune response. Potentially, the loss of the inhibitory role of FDCs in vivo may be of importance in certain infectious and neoplastic processes in which germinal centers are affected.

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