Activated PI3Kδ signals compromise plasma cell survival via limiting autophagy and increasing ER stress

2021 ◽  
Vol 218 (12) ◽  
Author(s):  
Fahd Al Qureshah ◽  
Sara Sagadiev ◽  
Christopher D. Thouvenel ◽  
Shuozhi Liu ◽  
Zhaolin Hua ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Plasma Cell ◽  
Cell Biology ◽  
Plasma Cells ◽  
Critical Role ◽  
Secondary Response ◽  
Mtorc1 Signaling ◽  
Humoral Responses ◽  
Antibody Levels

While phosphatidylinositide 3-kinase delta (PI3Kδ) plays a critical role in humoral immunity, the requirement for PI3Kδ signaling in plasma cells remains poorly understood. Here, we used a conditional mouse model of activated PI3Kδ syndrome (APDS), to interrogate the function of PI3Kδ in plasma cell biology. Mice expressing a PIK3CD gain-of-function mutation (aPIK3CD) in B cells generated increased numbers of memory B cells and mounted an enhanced secondary response but exhibited a rapid decay of antibody levels over time. Consistent with these findings, aPIK3CD expression markedly impaired plasma cell generation, and expression of aPIK3CD intrinsically in plasma cells was sufficient to diminish humoral responses. Mechanistically, aPIK3CD disrupted ER proteostasis and autophagy, which led to increased plasma cell death. Notably, this defect was driven primarily by elevated mTORC1 signaling and modulated by treatment with PI3Kδ-specific inhibitors. Our findings establish an essential role for PI3Kδ in plasma cell homeostasis and suggest that modulating PI3Kδ activity may be useful for promoting and/or thwarting specific immune responses.

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.

scholarly journals Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

2022 ◽  
Author(s):  
Amelie Bonaud ◽  
Laetitia Gargowitsch ◽  
Simon Gilbert ◽  
Elanchezhian Rajan ◽  
Pablo Canales-Herrerias ◽  
...  
Keyword(s):  
Plasma Cell ◽  
Cell Biology ◽  
Plasma Cells ◽  
Critical Role ◽  
Serum Antibody ◽  
Cellular Mechanisms ◽  
Antibody Titres ◽  
And Function ◽  
Antibody Secretion ◽  
Cell Maintenance

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

Targeted Overexpression of Mutant Activated N-ras Leads to Aberrant Plasma Cell Biology.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1416-1416
Author(s):  
Michael A. Linden ◽  
Nicole Kirchhof ◽  
Brian G. Van Ness
Keyword(s):  
B Cells ◽  
Plasma Cell ◽  
Cell Biology ◽  
Copy Number ◽  
Plasma Cells ◽  
Developmental Stages ◽  
Ras Gene ◽  
Transgene Copy Number ◽  
Cell Homeostasis ◽  
Ras Mutations

Abstract The ras oncogene regulates a variety of cellular functions, and its dysregulation has been implicated in a variety of human cancers, including multiple myeloma. Indeed, activating ras mutations have been described in 35 – 50% of myeloma patients, 50% of human myeloma cell lines, and 12.5% of patients with monoclonal gammopathy of undetermined significance (MGUS). Given the higher incidence of activating ras mutations in myeloma compared to MGUS, the current models of myelomagenesis suggest that activating ras mutations are involved in the progression of MGUS to myeloma. While there has been a fairly extensive analysis of activating ras mutations in myeloma patients, there have been few studies to investigate the biology of an activated ras mutation in the context of B- and plasma cell development and tumorigenesis. We previously described a transgenic platform that uses the 3′ kappa immunoglobulin light chain enhancer (3′KE) to target transgene expression to B-cells in late developmental stages, including plasma cells (Blood103: 2779, 2004). To study the potential influence of elevated mutant ras expression on B- and plasma cell survival and proliferation, we used the 3′KE to generate a 3′KE/N-ras V12 transgenic mouse. We hypothesized that the presence of the mutant ras gene would affect normal B- and plasma cell homeostasis. Indeed, samples of mononuclear splenocytes from 4-week-old transgenic mice demonstrate a 70% increase in the number of B220+kappa+ B-cells and a 250% increase in the number of CD138+B220hi plasmablastic cells compared to littermate controls. While survival of the 3′KE/N-ras V12 mice appears similar to littermate controls and transgenic animals do not develop tumors at 35 weeks of age, aberrant lymphocyte biology was noted in multiple founder lines. All aged 3′KE/N-ras V12 transgenic founders demonstrated an immunoglobulinemia. Interestingly, the animal with the highest transgene copy number had the least pronounced immunoglobulinemia, while the animal with the lowest transgene copy number had the most pronounced immunoglobulinemia, suggesting an inversely dose-dependent relationship between over-expression of an activated Ras protein and immunoglobulinemia. We performed extensive necropsies and histopathological analyses on all founder mice and aged-matched littermate controls. While no tumors were found in any of the mice, three of the founder mice demonstrated abnormal accumulations of plasma cells in extramedullary sites, such as the kidney. These data indicate that an activated ras transgene can affect B- and plasma cell homeostasis, and this transgenic model could prove useful in studying the role of activating ras mutations in plasma cell tumorigenesis. We are currently using three targeted c-myc gene expression systems to elicit B- and/or plasma cell tumors by co-expressing c-myc and N-ras V12.

Regulation of CXCR3 and CXCR4 expression during terminal differentiation of memory B cells into plasma cells

Blood ◽  
2005 ◽  
Vol 105 (10) ◽  
pp. 3965-3971 ◽  
Author(s):  
Gwendolin Muehlinghaus ◽  
Luisa Cigliano ◽  
Stephan Huehn ◽  
Anette Peddinghaus ◽  
Heike Leyendeckers ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Plasma Cell ◽  
Chemokine Receptor ◽  
Plasma Cells ◽  
Cxcr4 Expression ◽  
Memory B Cells ◽  
Interleukin 4 ◽  
Limiting Factor ◽  
Ifn Γ

Abstract C-X-C motif chemokine receptor 3 (CXCR3) and CXCR4 expressed on immunoglobulin G (IgG)–plasma-cell precursors formed in memory immune responses are crucial modulators of the homing of these cells. Here, we studied the regulation of the expression of these chemokine receptors during the differentiation of human memory B cells into plasma cells. We show that CXCR3 is absent on CD27- naive B cells but is expressed on a fraction of memory B cells, preferentially on those coexpressing IgG1. On differentiation into plasma-cell precursors, CXCR3+ memory B cells maintain the expression of this chemokine receptor. CXCR3- memory B cells up-regulate CXCR3 and migrate toward concentration gradients of its ligands only when costimulated with interferon γ (IFN-γ), but not interleukin 4 (IL-4), IL-1β, IL-6, IFN-α, IFN-β, or tumor necrosis factor α (TNF-α). In contrast, the differentiation of CXCR4- B cells into plasma cells is generally accompanied by the induction of CXCR4 expression. These results show that lack of CXCR4 expression on plasma-cell precursors is not a limiting factor for plasma-cell homing and that the expression of CXCR3 on memory B cells and plasma-cell precursors is induced by IFN-γ, provided in human T helper type 1 (Th1)–biased immune responses. Once induced in memory B cells, CXCR3 expression remains part of the individual cellular memory.

scholarly journals Blimp-1-Dependent Plasma Cell Differentiation Is Required for Efficient Maintenance of Murine Gammaherpesvirus Latency and Antiviral Antibody Responses

2009 ◽  
Vol 84 (2) ◽  
pp. 674-685 ◽  
Author(s):  
Andrea M. Siegel ◽  
Udaya Shankari Rangaswamy ◽  
Ruth J. Napier ◽  
Samuel H. Speck
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Critical Role ◽  
Antibody Responses ◽  
Plasma Cell Differentiation ◽  
Murine Gammaherpesvirus ◽  
Infected Cells

ABSTRACT Recent evidence from the study of Epstein-Barr virus and Kaposi's sarcoma-associated herpesvirus supports a model in which terminal differentiation of B cells to plasma cells leads to virus reactivation. Here we address the role of Blimp-1, the master transcriptional regulator of plasma cell differentiation, in murine gammaherpesvirus 68 (MHV68) latency and reactivation. Blimp-1 expression in infected cells was dispensable for acute virus replication in the lung following intranasal inoculation and in the spleen following intraperitoneal inoculation with MHV68. However, we observed a role for Blimp-1 in both the establishment of latency and reactivation from latency in vivo. Additionally, plasma cell-deficient mice also exhibited a significant defect in the establishment of latency in the spleen, as well as reactivation from latency, similar to mice that lacked Blimp-1 only in MHV68-infected cells. In the absence of plasma cells, MHV68 infection failed to elicit a strong germinal center response and fewer B cells in the germinal center were MHV68 infected. Notably, the absence of a functional Blimp-1 gene only in MHV68-infected cells led to a decrease in both B-cell and CD4+ T-cell responses during the establishment of latency. Finally, Blimp-1 expression in infected cells played a critical role in the maintenance of both MHV68 latency in the spleen and antibody responses to MHV68. Together, these studies support a model wherein episodic Blimp-1-mediated plasma cell differentiation leads to MHV68 reactivation, which serves to both renew the latency reservoirs and stimulate long-lived plasma cells to secrete virus-specific antibody.

scholarly journals Syndecan-1 and stromal heparan sulfate proteoglycans: key moderators of plasma cell biology and myeloma pathogenesis

Blood ◽  
2021 ◽  
Author(s):  
Zemin Ren ◽  
Marcel Spaargaren ◽  
Steven T Pals
Keyword(s):  
Heparan Sulfate ◽  
B Cell ◽  
Plasma Cell ◽  
Cell Biology ◽  
Plasma Cells ◽  
Specific Growth ◽  
B Cell Development ◽  
B Cell Antigen Receptor ◽  
Growth And Survival ◽  
Bm Niche

Plasma cells no longer express a B-cell-antigen-receptor and are hence deprived of signals crucial for survival throughout B-cell development. Instead, normal plasma cells, as well as their malignant myeloma counterparts, heavily rely on communication with the bone-marrow (BM) microenvironment for survival. The plasma cell heparan-sulfate-proteoglycan (HSPG) syndecan-1 (CD138), and HSPGs in the BM-microenvironment, acts as master regulator of this communication by co-opting specific growth- and survival-factors from the BM-niche. This designates syndecan-1/HSPGs, and their synthesis-machinery, as potential treatment targets in MM.

scholarly journals Potential anti-EBV effects associated with elevated interleukin-21 levels: a case report

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Kristian Assing ◽  
Christian Nielsen ◽  
Marianne Jakobsen ◽  
Charlotte B. Andersen ◽  
Kristin Skogstrand ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Plasma Cell ◽  
Germinal Center ◽  
Plasma Cells ◽  
Cell Formation ◽  
Memory B Cells ◽  
Memory B Cell

Abstract Background Germinal center derived memory B cells and plasma cells constitute, in health and during EBV reactivation, the largest functional EBV reservoir. Hence, by reducing germinal center derived formation of memory B cells and plasma cells, EBV loads may be reduced. Animal and in-vitro models have shown that IL-21 can support memory B and plasma cell formation and thereby potentially contribute to EBV persistence. However, IL-21 also displays anti-viral effects, as mice models have shown that CD4+ T cell produced IL-21 is critical for the differentiation, function and survival of anti-viral CD8+ T cells able to contain chronic virus infections. Case presentation We present immunological work-up (flow-cytometry, ELISA and genetics) related to a patient suffering from a condition resembling B cell chronic active EBV infection, albeit with moderately elevated EBV copy numbers. No mutations in genes associated with EBV disease, common variable immunodeficiency or pertaining to the IL-21 signaling pathway (including hypermorphic IL-21 mutations) were found. Increased (> 5-fold increase 7 days post-vaccination) CD4+ T cell produced (p < 0.01) and extracellular IL-21 levels characterized our patient and coexisted with: CD8+ lymphopenia, B lymphopenia, hypogammaglobulinemia, compromised memory B cell differentiation, absent induction of B-cell lymphoma 6 protein (Bcl-6) dependent peripheral follicular helper T cells (pTFH, p = 0.01), reduced frequencies of peripheral CD4+ Bcl-6+ T cells (p = 0.05), compromised plasmablast differentiation (reduced protein vaccine responses (p < 0.001) as well as reduced Treg frequencies. Supporting IL-21 mediated suppression of pTFH formation, pTFH and CD4+ IL-21+ frequencies were strongly inversely correlated, prior to and after vaccination, in the patient and in controls, Spearman’s rho: − 0.86, p < 0.001. Conclusions To the best of our knowledge, this is the first report of elevated CD4+ IL-21+ T cell frequencies in human EBV disease. IL-21 overproduction may, apart from driving T cell mediated anti-EBV responses, disrupt germinal center derived memory B cell and plasma cell formation, and thereby contribute to EBV disease control.

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 Appearance of Human Plasma Cells Following Differentiation of Human B Cells in NOD/SCID Mouse Spleen

2003 ◽  
Vol 10 (2-4) ◽  
pp. 197-202 ◽  
Author(s):  
Kentaro Kikuchi ◽  
Zhe-Xiong Lian ◽  
Xiao-Song He ◽  
Aftab A. Ansari ◽  
Miyuki Ishibashi ◽  
...  
Keyword(s):  
B Cells ◽  
Plasma Cell ◽  
Mononuclear Cells ◽  
Plasma Cells ◽  
Human Peripheral Blood ◽  
Natural Killer Cell Activity ◽  
Killer Cell ◽  
Cell Activity ◽  
Scid Mice ◽  
Human B Cells

Relatively little is known for the differentiation and maturation process of human B cells to plasma cells. This is particularly important in reconstitution work involving transfer of autoantibodies. To address this issue, we transplanted human peripheral blood mononuclear cells (PBMC) directly into the spleen of irradiated NOD/SCID mice depleted of natural killer cell activity. Within 6 weeks, naïve B cells differentiated into memory B cells and, importantly, the numbers of human CD138+plasma cells in spleen increased by 100 fold after transplantation. Plasma cell numbers correlated with the detection of human IgM and IgG in serum, indicating that human B cells had differentiated into mature plasma cells in the murine spleen. In addition to CD19+plasma cells, a distinct CD19-plasma cell population was detected, suggesting that downregulation of CD19 associated with maturation of plasma cells occurred. When purified human B cells were transplanted, those findings were not observed. Our results indicate that differentiation and maturation of human B cells and plasma cells can be investigated by transplantation of human PBMC into the spleen of NOD/SCID mice. The model will be useful for studying the differentiation of human B cells and generation of plasma cells.

scholarly journals Self-reactive and polyreactive B cells are generated and selected in the germinal center during γ-herpesvirus infection

2019 ◽  
Vol 32 (1) ◽  
pp. 27-38 ◽  
Author(s):  
Shuhei Sakakibara ◽  
Teruhito Yasui ◽  
Hideyuki Jinzai ◽  
Kristy O’Donnell ◽  
Chao-Yuan Tsai ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Germinal Center ◽  
Plasma Cells ◽  
Somatic Hypermutation ◽  
Recombinant Antibodies ◽  
The Self ◽  
Herpesvirus Infection ◽  
A Minor ◽  
Auto Antibody

Abstract Immune responses against certain viruses are accompanied by auto-antibody production although the origin of these infection-associated auto-antibodies is unclear. Here, we report that murine γ-herpesvirus 68 (MHV68)-induced auto-antibodies are derived from polyreactive B cells in the germinal center (GC) through the activity of short-lived plasmablasts. The analysis of recombinant antibodies from MHV68-infected mice revealed that about 40% of IgG+ GC B cells were self-reactive, with about half of them being polyreactive. On the other hand, virion-reactive clones accounted for only a minor proportion of IgG+ GC B cells, half of which also reacted with self-antigens. The self-reactivity of most polyreactive clones was dependent on somatic hypermutation (SHM), but this was dispensable for the reactivity of virus mono-specific clones. Furthermore, both virus-mono-specific and polyreactive clones were selected to differentiate to B220lo CD138+ plasma cells (PCs). However, the representation of GC-derived polyreactive clones was reduced and that of virus-mono-specific clones was markedly increased in terminally differentiated PCs as compared to transient plasmablasts. Collectively, our findings demonstrate that, during acute MHV68 infection, self-reactive B cells are generated through SHM and selected for further differentiation to short-lived plasmablasts but not terminally differentiated PCs.

Sign in / Sign up

Export Citation Format

Share Document