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 ◽  
...  

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.

2021 ◽  
Vol 218 (12) ◽  
Author(s):  
Fahd Al Qureshah ◽  
Sara Sagadiev ◽  
Christopher D. Thouvenel ◽  
Shuozhi Liu ◽  
Zhaolin Hua ◽  
...  

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.


Blood ◽  
2021 ◽  
Author(s):  
Zemin Ren ◽  
Marcel Spaargaren ◽  
Steven T Pals

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.


2020 ◽  
Vol 217 (11) ◽  
Author(s):  
Grace J. Liu ◽  
Markus Jaritz ◽  
Miriam Wöhner ◽  
Benedikt Agerer ◽  
Andreas Bergthaler ◽  
...  

B cell and plasma cell fates are controlled by different transcriptional networks, as exemplified by the mutually exclusive expression and cross-antagonism of the B cell identity factor Pax5 and the plasma cell regulator Blimp1. It has been postulated that repression of Pax5 by Blimp1 is essential for plasma cell development. Here, we challenged this hypothesis by analyzing the IghPax5/+ mouse, which expressed a Pax5 minigene from the immunoglobulin heavy-chain locus. Despite high Pax5 expression, plasma cells efficiently developed in young IghPax5/+ mice at steady state and upon immunization, while their number moderately declined in older mice. Although Pax5 significantly deregulated the plasma cell expression program, key plasma cell regulators were normally expressed in IghPax5/+ plasma cells. While IgM and IgA secretion by IghPax5/+ plasma cells was normal, IgG secretion was modestly decreased. Hence, Pax5 repression is not essential for robust plasma cell development and antibody secretion, although it is required for optimal IgG production and accumulation of long-lived plasma cells.


2015 ◽  
Vol 134 (1) ◽  
pp. 17-24 ◽  
Author(s):  
Geunyoung Jung ◽  
Jin Roh ◽  
Hyangsin Lee ◽  
Minchan Gil ◽  
Doc Hyun Yoon ◽  
...  

Background/Aims: Autophagy is crucial for the survival and function of plasma cells including protection from toxic misfolded immunoglobulin and proper energy metabolism. Multiple myeloma (MM) is an indolent but eventually fatal neoplasm of plasma cells. Autophagy may play a critical role in the survival of MM cells and their response to chemotherapeutic agents. In this study, we correlated the expression of autophagy-related proteins with the prognosis of MM. Methods: In this retrospective cohort study, we examined the expression of the autophagic markers BECLIN 1 and microtubule-associated protein light chain 3 (LC3) in 89 cases of MM biopsied from 2001 to 2004 at the Asan Medical Center. The association of the expression scores of these markers with clinical outcomes was assessed. Results: Patients with strong immunoreactivity to BECLIN 1 or LC3 had a significantly better overall survival (OS) than patients with negative to moderate immunoreactivity (p = 0.036 and 0.018, respectively). This was also true for disease-specific survival (DSS; p = 0.051 and 0.043, respectively). In addition, LC3 immunostaining remained an independent factor impacting OS (p = 0.028) and DSS (p = 0.020) after multivariate analysis. Conclusions: The results of this study suggest that higher immunoreactivity for autophagic markers in MM is associated with superior patient survival.


2020 ◽  
Author(s):  
Ilse Hurbain ◽  
Anne-Sophie Macé ◽  
Maryse Romao ◽  
Lucie Sengmanivong ◽  
Laurent Ruel ◽  
...  

ABSTRACTThe regulation and coordination of developmental processes involves the secretion of morphogens and membrane carriers, including extracellular vesicles, which facilitate their transport over long distance. The long-range activity of the Hedgehog morphogen is conveyed by extracellular vesicles. However, the site and the molecular basis of their biogenesis remains unknown. By combining fluorescence and electron microscopy combined with genetics and cell biology approaches, we investigated the origin and the cellular mechanisms underlying extracellular vesicle biogenesis, and their contribution to Drosophila wing disc development, exploiting Hedgehog as a long-range morphogen. We show that microvilli of Drosophila wing disc epithelium are the site of generation of small extracellular vesicles that transport Hedgehog across the tissue. This process requires the Prominin-like protein, whose activity, together with interacting cytoskeleton components and lipids, is critical for maintaining microvilli integrity and function in secretion. Our results provide the first evidence that microvilli-derived extracellular vesicles contribute to Hedgehog long-range signaling activity highlighting their physiological significance in tissue development in vivo.


Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1416-1416
Author(s):  
Michael A. Linden ◽  
Nicole Kirchhof ◽  
Brian G. Van Ness

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.


2016 ◽  
Vol 213 (11) ◽  
pp. 2229-2248 ◽  
Author(s):  
Elia D. Tait Wojno ◽  
David Artis

Innate lymphoid cells (ILCs) are innate immune cells that are ubiquitously distributed in lymphoid and nonlymphoid tissues and enriched at mucosal and barrier surfaces. Three major ILC subsets are recognized in mice and humans. Each of these subsets interacts with innate and adaptive immune cells and integrates cues from the epithelium, the microbiota, and pathogens to regulate inflammation, immunity, tissue repair, and metabolic homeostasis. Although intense study has elucidated many aspects of ILC development, phenotype, and function, numerous challenges remain in the field of ILC biology. In particular, recent work has highlighted key new questions regarding how these cells communicate with their environment and other cell types during health and disease. This review summarizes new findings in this rapidly developing field that showcase the critical role ILCs play in directing immune responses through their ability to interact with a variety of hematopoietic and nonhematopoietic cells. In addition, we define remaining challenges and emerging questions facing the field. Finally, this review discusses the potential application of basic studies of ILC biology to the development of new treatments for human patients with inflammatory and infectious diseases in which ILCs play a role.


Blood ◽  
2014 ◽  
Vol 124 (12) ◽  
pp. 1873-1879 ◽  
Author(s):  
Lawrence H. Boise ◽  
Jonathan L. Kaufman ◽  
Nizar J. Bahlis ◽  
Sagar Lonial ◽  
Kelvin P. Lee

Abstract Multiple myeloma is a plasma cell malignancy in which significant advances have been observed during the last 15 years. Our understanding of the disease has been advanced through its molecular characterization. We have also seen improvements in patient care with the development of 2 new classes of active agents, proteasome inhibitors and immunomodulatory drugs (IMiDs), resulting in a significant improvement in overall survival of myeloma patients such that it can now be debated as to whether some subsets of myeloma patients can be cured. However, the advances in our understanding of myeloma biology occurred in parallel with advances in treatment as opposed to being directly informed by the research. Moreover, the molecular characterization of malignant plasma cells would not have predicted the effectiveness of these novel therapies. We hypothesize that proteasome inhibitors and IMiDs are highly active because malignant plasma cells are constrained by many of the characteristics of their normal counterparts and these novel therapies target both normal plasma cell biology and the cancer biology of myeloma. Thus, a better understanding of normal plasma cell biology will likely yield as many actionable targets as mapping the genomic landscape of this disease.


2019 ◽  
Vol 47 (6) ◽  
pp. 1635-1650 ◽  
Author(s):  
Xiaohong Peng ◽  
Xiaoshuai Huang ◽  
Ke Du ◽  
Huisheng Liu ◽  
Liangyi Chen

Taking advantage of high contrast and molecular specificity, fluorescence microscopy has played a critical role in the visualization of subcellular structures and function, enabling unprecedented exploration from cell biology to neuroscience in living animals. To record and quantitatively analyse complex and dynamic biological processes in real time, fluorescence microscopes must be capable of rapid, targeted access deep within samples at high spatial resolutions, using techniques including super-resolution fluorescence microscopy, light sheet fluorescence microscopy, and multiple photon microscopy. In recent years, tremendous breakthroughs have improved the performance of these fluorescence microscopies in spatial resolution, imaging speed, and penetration. Here, we will review recent advancements of these microscopies in terms of the trade-off among spatial resolution, sampling speed and penetration depth and provide a view of their possible applications.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3516-3516
Author(s):  
James J. Driscoll ◽  
Konstantinos Lefkimmiatis ◽  
Mariateresa Fulciniti ◽  
Rao Prabhala ◽  
Dheeraj Pelluru ◽  
...  

Abstract The pursuit of rationale, targeted therapies relies on a detailed understanding of the mechanisms that subvert normal growth control and lead to development of Multiple Myeloma (MM). To further define the mechanistic steps that contribute to MM pathogenesis, we examined mRNA expression profiles of CD138+ plasma cells obtained from normal, Monoclonal Gammopathy of Unknown Significance (MGUS), and MM patient samples. Using genomic results in combination with molecular and cellular-based assays, we demonstrate a critical role for UBC9 and the sumoylation pathway in myeloma cell growth and survival. Notably, Reverse Transcriptase Polymerase Chain Reaction (RT-PCR) demonstrated a ten-fold induction in UBC9; a gene that encodes the sole Sumo-conjugating enzyme in human cells. We demonstrated an elevation of UBC9 in both MM primary patient cells and in a number of patient-derived MM cell lines. In addition, a number of other sumoylation pathway components were induced in primary MM cells at the gene and protein level relative to normal plasma cells. We believe that induction of UBC9 is an early genetic event in the pathogenesis of MM since the induction was observed at the gene and protein level in plasma cells from patients with MGUS. Importantly, UBC9 induction was functionally significant since a different pattern of sumoylation was observed in total cell lysate from MM patient plasma cells relative to that of normal plasma cells. Furthermore, overexpresion of a mutant form of UBC9 deficient in Sumo-conjugating activity increased the sensitivity of plasma cells to apoptosis by chemotherapeutic agents and these cells were impaired in other essential functions that included cellular proliferation, DNA synthesis, resistance to apoptosis and adhesion to bone marrow stroma. Immunoblotting of MM patient cell lysates also demonstrated a similar induction of the UBC9 gene product (Ubc9) as well as induction of the Sumo ligases Nse2 and PIAS1. These studies identify UBC9 as a target upregulated early in the pathogenesis of MM and indicate a critical role for sumoylation in disrupting the controls that govern normal plasma cell growth. To further develop prognostically relevant molecular signatures and classifications of MM subtypes, we analyzed the survival outcome of patients that expressed induced levels of UBC9, as well as other sumoylation components, and demonstrate significantly reduced survival of such patients following current treatment modalities. The results provide evidence for critical role of UBC9 and sumoylation in MM pathogenesis. Furthermore, sumoylation pattern may serve as a therapeutic target in MM, help stratify clinical management and provide a framework for the identification of sumoylation pathway targets that govern MM cell growth and progression.


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