scholarly journals Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

2020 ◽  
Author(s):  
Hector Cordero ◽  
Rodney King ◽  
Pranay Dogra ◽  
Chloe Dufeu ◽  
Sarah See ◽  
...  
Keyword(s):  
B Cells ◽  
Pathogenic Bacteria ◽  
Plasma Cells ◽  
Lymphoid Organ ◽  
Complement Receptors ◽  
Signature Genes ◽  
Molecular Phenotypes ◽  
B Cell Subsets ◽  
Human Neonates ◽  
Antibody Secreting Cells

Abstract The thymus is a central lymphoid organ responsible for the development of T cells. Here, we show that the thymus of human neonates also contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells (ASC) are comprised within a larger subset of B cells lacking expression of the complement receptors CD21 and CD35 and sharing the expression of signature genes defining mouse B1 B cells. Single-cell transcriptomic analyses supported the intrathymic differentiation of CD138+ plasma cells alongside other B cell subsets with distinctive molecular phenotypes. Neonatal thymic plasma cells also included clones reactive to pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.

scholarly journals Intrathymic differentiation of natural antibody-producing plasma cells in human neonates

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Hector Cordero ◽  
Rodney G. King ◽  
Pranay Dogra ◽  
Chloe Dufeu ◽  
Sarah B. See ◽  
...  
Keyword(s):  
T Cells ◽  
B Cells ◽  
Pathogenic Bacteria ◽  
Plasma Cells ◽  
Lymphoid Organ ◽  
Signature Genes ◽  
Molecular Phenotypes ◽  
B Cell Subsets ◽  
Human Neonates

AbstractThe thymus is a central lymphoid organ primarily responsible for the development of T cells. A small proportion of B cells, however, also reside in the thymus to assist negative selection of self-reactive T cells. Here we show that the thymus of human neonates contains a consistent contingent of CD138+ plasma cells, producing all classes and subclasses of immunoglobulins with the exception of IgD. These antibody-secreting cells are part of a larger subset of B cells that share the expression of signature genes defining mouse B1 cells, yet lack the expression of complement receptors CD21 and CD35. Data from single-cell transcriptomic, clonal correspondence and in vitro differentiation assays support the notion of intrathymic CD138+ plasma cell differentiation, alongside other B cell subsets with distinctive molecular phenotypes. Lastly, neonatal thymic plasma cells also include clones reactive to commensal and pathogenic bacteria that commonly infect children born with antibody deficiency. Thus, our findings point to the thymus as a source of innate humoral immunity in human neonates.

scholarly journals Dimethyl fumarate as a first- vs second-line therapy in MS

2018 ◽  
Vol 5 (6) ◽  
pp. e508 ◽  
Author(s):  
Elsebeth Staun-Ram ◽  
Eiman Najjar ◽  
Anat Volkowich ◽  
Ariel Miller
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Dimethyl Fumarate ◽  
Functional Markers ◽  
Immunomodulatory Effects ◽  
Immune Profile ◽  
Line Therapy ◽  
B Cell Subsets

ObjectiveTo elucidate the immunomodulatory effects of dimethyl fumarate (DMF) on B cells in patients with relapsing MS receiving DMF as a “1st-line” vs “2nd-line” therapy.MethodsB cells were isolated from 43 patients with MS at baseline and after 15-week DMF therapy. Phenotype and functional markers and cytokine profile were assessed by flow cytometry. Analysis included clinical and MRI parameters recorded during a 1-year follow-up.Results1st-line and 2nd-line patients presented several differences in their baseline immune profile, which corresponded with differences in their immunologic response to DMF treatment. DMF reduced the proportions of B cells and CD8 T cells whereas increased monocytes. DMF reduced memory B cells, including plasma cells in 2nd-line patients only, whereas strongly increased transitional B cells. Several IL10+ B-cell subsets and TGFβ+ B cells were increased. Proinflammatory LTα+ and TNFα+ B cells were reduced, while IL4+ B cells elevated, whereas IFNγ+ B cells showed opposite effects in 1st-line and 2nd-line patients. HLA and ICAM-1 expression was increased, but % CD86+ B cells reduced. The expression of B-cell activating factor receptor and the proportion of activated CD69 B cells were increased.ConclusionsDMF is associated with increased transitional and IL10+ and TGFβ+ regulatory B cells and a shift toward a more anti-inflammatory immune profile. Cell activation with reduced costimulatory capacity may induce immune hyporesponsiveness. Carryover effects of preceding therapies in 2nd-line patients and the stage of disease influence the immune profile of the patients and the immunomodulatory effects of DMF.

scholarly journals Complement receptors regulate differentiation of bone marrow plasma cell precursors expressing transcription factors Blimp-1 and XBP-1

2005 ◽  
Vol 201 (6) ◽  
pp. 993-1005 ◽  
Author(s):  
Dominique Gatto ◽  
Thomas Pfister ◽  
Andrea Jegerlehner ◽  
Stephen W. Martin ◽  
Manfred Kopf ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Activation ◽  
Plasma Cells ◽  
Antibody Responses ◽  
Complement Receptors ◽  
Essentially Normal ◽  
Bone Marrow Plasma

Humoral immune responses are thought to be enhanced by complement-mediated recruitment of the CD21–CD19–CD81 coreceptor complex into the B cell antigen receptor (BCR) complex, which lowers the threshold of B cell activation and increases the survival and proliferative capacity of responding B cells. To investigate the role of the CD21–CD35 complement receptors in the generation of B cell memory, we analyzed the response against viral particles derived from the bacteriophage Qβ in mice deficient in CD21–CD35 (Cr2−/−). Despite highly efficient induction of early antibody responses and germinal center (GC) reactions to immunization with Qβ, Cr2−/− mice exhibited impaired antibody persistence paralleled by a strongly reduced development of bone marrow plasma cells. Surprisingly, antigen-specific memory B cells were essentially normal in these mice. In the absence of CD21-mediated costimulation, Qβ-specific post-GC B cells failed to induce the transcriptional regulators Blimp-1 and XBP-1 driving plasma cell differentiation, and the antiapoptotic protein Bcl-2, which resulted in failure to generate the precursor population of long-lived plasma cells residing in the bone marrow. These results suggest that complement receptors maintain antibody responses by delivery of differentiation and survival signals to precursors of bone marrow plasma cells.

scholarly journals Generation of Plasma Cells From Peripheral Blood Memory B Cells: Synergistic Effect of Interleukin-10 and CD27/CD70 Interaction

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 173-180 ◽  
Author(s):  
Kazunaga Agematsu ◽  
Haruo Nagumo ◽  
Yumiko Oguchi ◽  
Takayuki Nakazawa ◽  
Keitaro Fukushima ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Interleukin 10 ◽  
Memory B Cells ◽  
The Other ◽  
Cell Pool ◽  
Activation System ◽  
Antibody Secreting Cells

B cells can differentiate into the antibody-secreting cells, plasma cells, whereas the crucial signals that positively control the entry into the pathway to plasma cells have been unclear. Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). Differentiation into plasma cells by a combination of IL-10 and CD70 transfectants occurred in CD27+ B cells but not in CD27− B cells. Moreover, addition of IL-2 to the IL-10 and CD70-transfect activation system greatly induced differentiation into plasma cells. In the presence of only IL-2, IL-4, or IL-6, CD70 transfectants did not promote differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B-cell pool from peripheral blood B cells primarily activated by IL-2, IL-10, and anti-CD40 monoclonal antibody (MoAb). Finally, CD27 signaling also rescued B cells from IL-10–mediated apoptosis. These data demonstrate that CD27 ligand (CD70) is a key molecule to prevent the IL-10–mediated promotion of apoptosis and to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

scholarly journals Memory persistence and differentiation into antibody-secreting cells accompanied by positive selection in longitudinal BCR repertoires

2022 ◽  
Author(s):  
Artem I. Mikelov ◽  
Evgeniia I. Alekseeva ◽  
Ekaterina A. Komech ◽  
Dmitriy B. Staroverov ◽  
Maria A. Turchaninova ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Inflammatory Diseases ◽  
Affinity Maturation ◽  
Memory B Cells ◽  
Immune Memory ◽  
Memory B Cell ◽  
Antibody Secreting Cells

B-cell mediated immune memory holds both plasticity and conservatism to respond to new challenges and repeated infections. Here, we analyze the dynamics of immunoglobulin heavy chain (IGH) repertoires of memory B cells, plasmablasts and plasma cells sampled several times during one year from peripheral blood of volunteers without severe inflammatory diseases. We reveal a high degree of clonal persistence in individual memory B-cell subsets with inter-individual convergence in memory and antibody-secreting cells (ASCs). Clonotypes in ASCs demonstrate clonal relatedness to memory B cells and are transient in peripheral blood. Two clusters of expanded clonal lineages displayed different prevalence of memory B cells, isotypes, and persistence. Phylogenetic analysis revealed signs of reactivation of persisting memory B cell-enriched clonal lineages, accompanied by new rounds of affinity maturation during proliferation to ASCs. Negative selection contributes to both, persisting and reactivated lineages, saving functionality and specificity of BCRs to protect from the current and future pathogens.

scholarly journals Multiple Myeloma Includes Phenotypically Defined Subsets of Clonotypic CD20+ B Cells that Persist during Treatment with Rituximab

2008 ◽  
Vol 2 ◽  
pp. CMO.S615 ◽  
Author(s):  
Linda M. Pilarski ◽  
Eva Baigorri ◽  
Michael J. Mant ◽  
Patrick M. Pilarski ◽  
Penelope Adamson ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
B Cells ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Light Scatter ◽  
Cell Compartments ◽  
B Lineage ◽  
B Cell Subsets ◽  
Anti Cd20

Potential progenitor B cell compartments in multiple myeloma (MM) are clinically important. MM B cells and some circulating MM plasma cells express CD20, predicting their clearance by treatment with anti-CD20. Here we describe two types of clonotypic CD20+ B cell in peripheral blood of myeloma patients, identified by their expression of CD19 and CD20 epitopes, their expression of CD45RA and their light scatter properties. Thus, the circulating component of the MM clone includes at least two distinct CD19+ CD20+ B cell compartments, as well as CD138+CD20+ plasma cells. To determine whether either or both B cell subsets and the CD20+ plasma cell subset were depleted by anti-CD20 therapy, they were evaluated before, during and after treatment of patients with rituximab (anti-CD20), followed by quantifying B cell subsets over a 5 month period during and after treatment. Overall, all three types of circulating B lineage cells persist despite treatment with rituximab. The inability of rituximab to prolong survival in MM may result from this failure to deplete CD20+ B and plasma cells in MM.

Abstract P785: The B Cell Response to Extracellular Glutamate in the Ischemic Brain

Stroke ◽  
2021 ◽  
Vol 52 (Suppl_1) ◽  
Author(s):  
Vanessa O Torres ◽  
Jadwiga Turchan-Cholewo ◽  
Xiangmei Kong ◽  
Erik J Plautz ◽  
Nancy L Monson ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
B Cells ◽  
B Cell ◽  
Brain Regions ◽  
Ischemic Brain ◽  
Post Stroke ◽  
Aspartate Receptor ◽  
A Cell ◽  
B Cell Subsets ◽  
Antibody Secreting Cells

Background: Neuronal networks require significant neurotrophic support for functional plasticity after stroke. We showed that B cells exhibit a cell-specific migration pattern in the post-stroke brain. Post-stroke B cell depletion impedes neurogenesis, increases anxiety, and exacerbates memory deficits in mice; deficits generally mediated by brain regions occurring outside the initial infarct. We hypothesize that the post-stroke microenvironment can enhance neurotrophic capacities of B cells to promote plasticity. Methods: Splenic B cells were isolated from 3-5 mo-old male C57Bl/6J mice. B cell N-methyl-D-aspartate receptor (NMDAR) subunits were identified by confocal microscopy. The acute (8 min) Ca 2+ response to 1uM glutamate (glu) +/- NMDAR antagonists (10uM DAPV (competitive NMDAR inhibitor), 30uM ifenprodil (ifen., GluN2B subunit inhibitor), and 10uM TCN201 (GluN2A subunit inhibitor)) was assessed via flow cytometry in B cells (+/- 5ug/mL LPS). B cell viability and neurotrophin (NT)-related genes were assessed by flow cytometry and qPCR, respectively, in B cells (+/- LPS) treated with glu +/- NMDAR antagonists for 24h. Data were analyzed in Graphpad Prism. Results: B cells express functional GluN2A- and GluN2B-containing NMDARs that influx Ca 2+ in response to extracellular glu (*p<0.05). While LPS did not impact NMDAR-dependent Ca 2+ influx in most B cell subsets, Ca 2+ influx was significantly reduced by NMDAR antagonists in LPS-stimulated B cells (Effector B cells (DAPV *p<0.05, ifen **p<0.01), Bregs (DAPV *p<0.05, Ifen *p<0.05), B220 + antibody-secreting cells (ifen *p<0.05, TCN201 *p<0.05)). Furthermore, a 24h glu treatment increased NT (BDNF: 2.28-fold, IL-10: 27.16-fold), NT receptor (TrkB: 1.33-fold) and NMDAR (GluN2A: 2.01-fold, GluN2B: 1.27-fold) expression in LPS-stimulated B cells (vs. untreated controls). Conclusions: Our studies show that B cells respond to glu via NMDARs. Our data suggests that exposure to physiologic levels of glu enhance NMDAR-dependent signaling and upregulate NTs and NT receptors. These results are the first to indicate a glu-induced neurotrophic role for B cells in the ischemic brain. Future studies will determine whether B cell-derived NTs can protect neurons after stroke.

Impact of Autologous Dendritic Cell Immunotherapy (Arcelis™) on B Cell Subsets in HIV-1-Infected Subjects Receiving Antiretroviral Therapy

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 80-80
Author(s):  
Mohamed-Rachid Boulassel ◽  
Bader Yassine-Diab ◽  
Don Healey ◽  
Charles Nicolette ◽  
Rafick-Pierre Sékaly ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
Immune Responses ◽  
B Cell ◽  
Plasma Cells ◽  
Cell Subset ◽  
Cd8 T Cell ◽  
Memory B Cells ◽  
B Cell Subsets ◽  
Hiv 1

Abstract We demonstrated the enhancement of CD8-specific responses following the administration of an immune-based therapy consisting of dendritic cells (DC) electroporated with autologous amplified HIV-1 RNA and CD40 ligand (CD40 L) RNA manufactured by the Arcelis™ process in HIV patients receiving antiretroviral therapy (ART). We conducted a sub study on circulating B cell populations to further assess changes induced by this autologous DC therapy as CD40L is a major B cell co-stimulatory factor. To this end, we assessed B cell subset changes in relation to the proliferative capacity of CD4+ and CD8+ T cells response to DC targets containing the 4 HIV-1 antigens (Gag, Vpr, Rev, Nef). The co-expression of CD19, CD38, IgD, CD10, CD23, CD27, CD5, and CD138 were analyzed by multi-parametric flow cytometry to assess circulating B cell subsets such as naïve resting B-cells (Bm1), activated naïve B cells (Bm2), GC founder cells (Bm2’), centroblasts and centrocytes (Bm3 and Bm4), early memory B cells (eBm5), memory B cells (Bm5), IgD memory cells, plasma cells, and B-1 cells. Changes in B cells subsets were analyzed before and after the four intradermal injections of this immunotherapeutic product containing 1.2 × 107 DC. Ten ART treated subjects with undetectable viral load (< 50 copies/ml), median CD4+ count of 440 cells/μl (range: 316–1102), and with a CD4+ nadir > 200 cells/μl were studied. Throughout the study, no significant changes in CD4+ cell count, CD4/CD8 ratio, and no viral blips were noticed. The percentage of total B cells, Bm1, Bm2, Bm2′, eBm5, IgD memory, plasma cells, and B-1 cell subsets did not significantly change. However, a decrease in the percentage of Bm3 and Bm4 cells was found (0.36 [0.06–0.86] versus 0.11 [0.04–0.36]; P=0.05). Conversely, an important increase in the Bm5 cell subset was evidenced (10.4 [1.6–24.2] versus 18.1 [5.1–27.5]; P=0.005) suggesting a proliferation of B memory cells induced by DC immunization. In addition, the multifunctional and polyvalent CD8+ T cell proliferative responses to the 4 HIV genes used in this immunotherapy were noticed in 8 out of 9 subjects available for analysis and characterized by an effector memory phenotype. No CD4+ T cell immune responses were detected, consistent with the endogenous HLA class I loading of the antigens. Collectively, these results indicate that this immunotherapy induces an increase in the B memory cell population in the absence of inducing any clinically apparent autoimmunity along with strong HIV specific multifunctional CD8+ T cell specific immune responses.

scholarly journals Generation of Plasma Cells From Peripheral Blood Memory B Cells: Synergistic Effect of Interleukin-10 and CD27/CD70 Interaction

Blood ◽  
1998 ◽  
Vol 91 (1) ◽  
pp. 173-180 ◽  
Author(s):  
Kazunaga Agematsu ◽  
Haruo Nagumo ◽  
Yumiko Oguchi ◽  
Takayuki Nakazawa ◽  
Keitaro Fukushima ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
B Cells ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Interleukin 10 ◽  
Memory B Cells ◽  
The Other ◽  
Cell Pool ◽  
Activation System ◽  
Antibody Secreting Cells

Abstract B cells can differentiate into the antibody-secreting cells, plasma cells, whereas the crucial signals that positively control the entry into the pathway to plasma cells have been unclear. Triggering via CD27 by CD27 ligand (CD70) on purified peripheral blood B cells yielded an increase in the number of plasma cells in the presence of interleukin-10 (IL-10). Differentiation into plasma cells by a combination of IL-10 and CD70 transfectants occurred in CD27+ B cells but not in CD27− B cells. Moreover, addition of IL-2 to the IL-10 and CD70-transfect activation system greatly induced differentiation into plasma cells. In the presence of only IL-2, IL-4, or IL-6, CD70 transfectants did not promote differentiation into plasma cells. On the other hand, CD40 signaling increased the expansion of a B-cell pool from peripheral blood B cells primarily activated by IL-2, IL-10, and anti-CD40 monoclonal antibody (MoAb). Finally, CD27 signaling also rescued B cells from IL-10–mediated apoptosis. These data demonstrate that CD27 ligand (CD70) is a key molecule to prevent the IL-10–mediated promotion of apoptosis and to direct the differentiation of CD27+ memory B cells toward plasma cells in cooperation with IL-10.

scholarly journals BLyS inhibition eliminates primary B cells but leaves natural and acquired humoral immunity intact

2008 ◽  
Vol 105 (40) ◽  
pp. 15517-15522 ◽  
Author(s):  
Jean L. Scholz ◽  
Jenni E. Crowley ◽  
Mary M. Tomayko ◽  
Natalie Steinel ◽  
Patrick J. O'Neill ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Plasma Cells ◽  
Memory B Cells ◽  
Natural Antibody ◽  
Memory Cells ◽  
B1 Cells ◽  
Antibody Secreting Cells ◽  
Versus Antigen

We have used an inhibiting antibody to determine whether preimmune versus antigen-experienced B cells differ in their requisites for BLyS, a cytokine that controls differentiation and survival. Whereas in vivo BLyS inhibition profoundly reduced naïve B cell numbers and primary immune responses, it had a markedly smaller effect on memory B cells and long-lived plasma cells, as well as secondary immune responses. There was heterogeneity within the memory pools, because IgM-bearing memory cells were sensitive to BLyS depletion whereas IgG-bearing memory cells were not, although both were more resistant than naïve cells. There was also heterogeneity within B1 pools, as splenic but not peritoneal B1 cells were diminished by anti-BLyS treatment, yet the number of natural antibody-secreting cells remained constant. Together, these findings show that memory B cells and natural antibody-secreting cells are BLyS-independent and suggest that these pools can be separately manipulated.

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