scholarly journals Supplying the trip to antibody production—nutrients, signaling, and the programming of cellular metabolism in the mature B lineage

2021 ◽  
Author(s):  
Mark R. Boothby ◽  
Shawna K. Brookens ◽  
Ariel L. Raybuck ◽  
Sung Hoon Cho
Keyword(s):  
B Lymphocytes ◽  
Plasma Cells ◽  
Cell Types ◽  
Nutrient Supply ◽  
Vital Role ◽  
Primary Sources ◽  
Surface Receptors ◽  
Molecular Programming ◽  
B Lineage ◽  
Protection Against Infection

AbstractThe COVID pandemic has refreshed and expanded recognition of the vital role that sustained antibody (Ab) secretion plays in our immune defenses against microbes and of the importance of vaccines that elicit Ab protection against infection. With this backdrop, it is especially timely to review aspects of the molecular programming that govern how the cells that secrete Abs arise, persist, and meet the challenge of secreting vast amounts of these glycoproteins. Whereas plasmablasts and plasma cells (PCs) are the primary sources of secreted Abs, the process leading to the existence of these cell types starts with naive B lymphocytes that proliferate and differentiate toward several potential fates. At each step, cells reside in specific microenvironments in which they not only receive signals from cytokines and other cell surface receptors but also draw on the interstitium for nutrients. Nutrients in turn influence flux through intermediary metabolism and sensor enzymes that regulate gene transcription, translation, and metabolism. This review will focus on nutrient supply and how sensor mechanisms influence distinct cellular stages that lead to PCs and their adaptations as factories dedicated to Ab secretion. Salient findings of this group and others, sometimes exhibiting differences, will be summarized with regard to the journey to a distinctive metabolic program in PCs.

scholarly journals Identification of a novel NF-kappaB p50-related protein in B lymphocytes.

1996 ◽  
Vol 16 (12) ◽  
pp. 7089-7097 ◽  
Author(s):  
R J Phillips ◽  
S Gustafson ◽  
S Ghosh
Keyword(s):  
Transcription Factor ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Protein Complexes ◽  
Cell Types ◽  
Related Protein ◽  
Active Complex ◽  
Inactive Form ◽  
Nf Kappab ◽  
Constitutively Active

In most cell types other than mature B lymphocytes and macrophages, the transcription factor NF-kappaB remains in an inactive form in the cytosol by being bound to the inhibitory proteins IkappaBalpha and IkappaBbeta. To investigate the regulation of constitutively active NF-kappaB in B lymphocytes, we have examined the composition of Rel protein complexes in different mouse B-cell lines. As reported previously, the constitutively active complex in mature B cells was predominantly p50:c-Rel. However, the kappaB binding complex in the plasmacytomas that were examined lacked c-Rel and instead contained only a p50-related protein. This p50-related protein (p55) cross-reacts with three different p50 antisera, exists in both the cytosol and the nucleus, and is the protein that binds to kappaB sites in plasma cells. Transfection of reporter constructs into plasma cells indicates that the p55 complex is also transcriptionally active. The p55 protein can be detected in splenocytes from mice lacking the p105/p50 gene, and therefore it appears to be the product of a distinct gene. The implications of the existence of a NF-kappaB p50-related protein in plasma cells that is capable of binding to kappaB sites and activating transcription are discussed.

scholarly journals Tumor cell heterogeneity in multiple myeloma: antigenic, morphologic, and functional studies of cells from blood and bone marrow

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1925-1935
Author(s):  
MA King ◽  
DS Nelson
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cell ◽  
Tumor Cells ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Cell Types ◽  
Pokeweed Mitogen

Tumor cells from six patients with immunoglobulin G (IgG) multiple myeloma were analyzed for surface antigens, cytoplasmic paraprotein, morphology, and response to various culture conditions. The tumor marker was the paraprotein idiotype. Low numbers of tumor cells were found in the blood of most of the patients. In some patients, the circulating tumor cells were solely B lymphocytes, whereas in other patients, they were lymphoid, lymphoplasmacytoid, and plasmacytoid. Dual surface antigen analysis of blood and bone marrow cells confirmed that the tumor may be composed of a spectrum of cell types. Thus, cells may range from surface-idiotype+,CD19+,CD20+, PCA-1-,cytoplasmic- idiotype- lymphocytes, to CD19-,PCA-1+,cytoplasmic-idiotype+ plasma cells that are surface-idiotype- or weakly surface-idiotype+. In one patient, some of the tumor cells co-expressed surface idiotype and CD10. The tumor B lymphocytes were activated in vitro to synthesize paraprotein by pokeweed mitogen (PWM), and by low molecular weight B cell growth factor (BCGF). In contrast, spontaneous synthesis of paraprotein by more mature tumor cells was inhibited by agents that also inhibit nonmyeloma plasma cells. These agents included PWM, gamma interferon, and phorbol ester. The results demonstrate that in multiple myeloma there exist different tumor cell types that are similar, by a variety of criteria, to normal B lineage cells at different stages of differentiation. Thus, further evidence is provided for the hypothesis of myeloma cell differentiation.

scholarly journals Tumor cell heterogeneity in multiple myeloma: antigenic, morphologic, and functional studies of cells from blood and bone marrow

Blood ◽  
1989 ◽  
Vol 73 (7) ◽  
pp. 1925-1935 ◽  
Author(s):  
MA King ◽  
DS Nelson
Keyword(s):  
Multiple Myeloma ◽  
Bone Marrow ◽  
Tumor Cell ◽  
Tumor Cells ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Bone Marrow Cells ◽  
Cell Types ◽  
Pokeweed Mitogen

Abstract Tumor cells from six patients with immunoglobulin G (IgG) multiple myeloma were analyzed for surface antigens, cytoplasmic paraprotein, morphology, and response to various culture conditions. The tumor marker was the paraprotein idiotype. Low numbers of tumor cells were found in the blood of most of the patients. In some patients, the circulating tumor cells were solely B lymphocytes, whereas in other patients, they were lymphoid, lymphoplasmacytoid, and plasmacytoid. Dual surface antigen analysis of blood and bone marrow cells confirmed that the tumor may be composed of a spectrum of cell types. Thus, cells may range from surface-idiotype+,CD19+,CD20+, PCA-1-,cytoplasmic- idiotype- lymphocytes, to CD19-,PCA-1+,cytoplasmic-idiotype+ plasma cells that are surface-idiotype- or weakly surface-idiotype+. In one patient, some of the tumor cells co-expressed surface idiotype and CD10. The tumor B lymphocytes were activated in vitro to synthesize paraprotein by pokeweed mitogen (PWM), and by low molecular weight B cell growth factor (BCGF). In contrast, spontaneous synthesis of paraprotein by more mature tumor cells was inhibited by agents that also inhibit nonmyeloma plasma cells. These agents included PWM, gamma interferon, and phorbol ester. The results demonstrate that in multiple myeloma there exist different tumor cell types that are similar, by a variety of criteria, to normal B lineage cells at different stages of differentiation. Thus, further evidence is provided for the hypothesis of myeloma cell differentiation.

scholarly journals BCMA Is Essential for the Survival of Long-lived Bone Marrow Plasma Cells

2004 ◽  
Vol 199 (1) ◽  
pp. 91-98 ◽  
Author(s):  
Brian P. O'Connor ◽  
Vanitha S. Raman ◽  
Loren D. Erickson ◽  
W. James Cook ◽  
Lehn K. Weaver ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Plasma Cells ◽  
Vital Role ◽  
Term Survival ◽  
B Cell Maturation ◽  
Bone Marrow Plasma ◽  
Immunoglobulin Treatment ◽  
B Lineage

Long-lived humoral immunity is manifested by the ability of bone marrow plasma cells (PCs) to survive for extended periods of time. Recent studies have underscored the importance of BLyS and APRIL as factors that can support the survival of B lineage lymphocytes. We show that BLyS can sustain PC survival in vitro, and this survival can be further enhanced by interleukin 6. Selective up-regulation of Mcl-1 in PCs by BLyS suggests that this α-apoptotic gene product may play an important role in PC survival. Blockade of BLyS, via transmembrane activator and cyclophilin ligand interactor–immunoglobulin treatment, inhibited PC survival in vitro and in vivo. Heightened expression of B cell maturation antigen (BCMA), and lowered expression of transmembrane activator and cyclophilin ligand interactor and BAFF receptor in PCs relative to resting B cells suggests a vital role of BCMA in PC survival. Affirmation of the importance of BCMA in PC survival was provided by studies in BCMA−/− mice in which the survival of long-lived bone marrow PCs was impaired compared with wild-type controls. These findings offer new insights into the molecular basis for the long-term survival of PCs.

Altered Fine Structure of B Lymphocytes Correlated with Defective Terminal Differentiation

1973 ◽  
Vol 31 ◽  
pp. 386-387
Author(s):  
Dale E. Bockman ◽  
L. Y. Frank Wu ◽  
Alexander R. Lawton ◽  
Max D. Cooper
Keyword(s):  
Immune Deficiency ◽  
B Lymphocytes ◽  
Plasma Cells ◽  
Present Report ◽  
Specific Antigen ◽  
Terminal Differentiation ◽  
Second Stage ◽  
Two Stages ◽  
Deficiency Diseases ◽  
Cell Line Generation

B-lymphocytes normally synthesize small amounts of immunoglobulin, some of which is incorporated into the cell membrane where it serves as receptor of antigen. These cells, on contact with specific antigen, proliferate and differentiate to plasma cells which synthesize and secrete large quantities of immunoglobulin. The two stages of differentiation of this cell line (generation of B-lymphocytes and antigen-driven maturation to plasma cells) are clearly separable during ontogeny and in some immune deficiency diseases. The present report describes morphologic aberrations of B-lymphocytes in two diseases in which second stage differentiation is defective.

Nanotheranostic agents for neurodegenerative diseases

2020 ◽  
Vol 4 (6) ◽  
pp. 645-675
Author(s):  
Parasuraman Padmanabhan ◽  
Mathangi Palanivel ◽  
Ajay Kumar ◽  
Domokos Máthé ◽  
George K. Radda ◽  
...  
Keyword(s):  
Drug Delivery ◽  
Neurodegenerative Diseases ◽  
Cell Types ◽  
Specific Cell ◽  
Ageing Population ◽  
Target Tissue ◽  
Therapeutic Approaches ◽  
Surface Receptors ◽  
Theranostic Agents ◽  
Preclinical Animal Models

Neurodegenerative diseases (NDDs), including Alzheimer's disease (AD) and Parkinson's disease (PD), affect the ageing population worldwide and while severely impairing the quality of life of millions, they also cause a massive economic burden to countries with progressively ageing populations. Parallel with the search for biomarkers for early detection and prediction, the pursuit for therapeutic approaches has become growingly intensive in recent years. Various prospective therapeutic approaches have been explored with an emphasis on early prevention and protection, including, but not limited to, gene therapy, stem cell therapy, immunotherapy and radiotherapy. Many pharmacological interventions have proved to be promising novel avenues, but successful applications are often hampered by the poor delivery of the therapeutics across the blood-brain-barrier (BBB). To overcome this challenge, nanoparticle (NP)-mediated drug delivery has been considered as a promising option, as NP-based drug delivery systems can be functionalized to target specific cell surface receptors and to achieve controlled and long-term release of therapeutics to the target tissue. The usefulness of NPs for loading and delivering of drugs has been extensively studied in the context of NDDs, and their biological efficacy has been demonstrated in numerous preclinical animal models. Efforts have also been made towards the development of NPs which can be used for targeting the BBB and various cell types in the brain. The main focus of this review is to briefly discuss the advantages of functionalized NPs as promising theranostic agents for the diagnosis and therapy of NDDs. We also summarize the results of diverse studies that specifically investigated the usage of different NPs for the treatment of NDDs, with a specific emphasis on AD and PD, and the associated pathophysiological changes. Finally, we offer perspectives on the existing challenges of using NPs as theranostic agents and possible futuristic approaches to improve them.

Expression of P2X7purinoceptors on human lymphocytes and monocytes: evidence for nonfunctional P2X7receptors

2000 ◽  
Vol 279 (4) ◽  
pp. C1189-C1197 ◽  
Author(s):  
B. J. Gu ◽  
W. Y. Zhang ◽  
L. J. Bendall ◽  
I. P. Chessell ◽  
G. N. Buell ◽  
...  
Keyword(s):  
B Lymphocytes ◽  
Adhesion Molecule ◽  
Human Lymphocytes ◽  
Normal Subjects ◽  
Cell Types ◽  
Surface Expression ◽  
Lymphocytic Leukemia ◽  
Functional Responses ◽  
Intracellular Expression ◽  
Selective Channel

Lymphocytes from normal subjects and patients with B-chronic lymphocytic leukemia (B-CLL) show functional responses to extracellular ATP characteristic of the P2X7receptor (previously termed P2Z). These responses include opening of a cation-selective channel/pore that allows entry of the fluorescent dye ethidium and activation of a membrane metalloprotease that sheds the adhesion molecule L-selectin. The surface expression of P2X7receptors was measured in normal leucocytes, platelets, and B-CLL lymphocytes and correlated with their functional responses. Monocytes showed four- to fivefold greater expression of P2X7than B, T, and NK lymphocytes, whereas P2X7expression on neutrophils and platelets was weak. All cell types demonstrated abundant intracellular expression of this receptor. All 12 subjects with B-CLL expressed lymphocyte P2X7at about the same level as B lymphocytes from normal subjects. P2X7function, measured by ATP-induced uptake of ethidium, correlated closely with surface expression of this receptor in normal and B-CLL lymphocytes and monocytes ( n = 47, r = 0.70; P< 0.0001). However, in three patients the ATP-induced uptake of ethidium into the malignant B lymphocytes was low or absent. The lack of P2X7function in these B lymphocytes was confirmed by the failure of ATP to induce Ba2+uptake into their lymphocytes. This lack of function of the P2X7receptor resulted in a failure of ATP-induced shedding of L-selectin, an adhesion molecule that directs the recirculation of lymphocytes from blood into the lymph node.

scholarly journals Immunologic abnormalities in an animal model of chronic hypoplastic marrow failure induced by busulfan

Blood ◽  
1978 ◽  
Vol 51 (4) ◽  
pp. 601-610 ◽  
Author(s):  
CA Pugsley ◽  
IJ Forbes ◽  
AA Morley
Keyword(s):  
B Lymphocytes ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Cell Injury ◽  
Cell Types ◽  
Peripheral Blood Lymphocytes ◽  
Delayed Type Hypersensitivity ◽  
Splenic Lymphocytes ◽  
Hypoplastic Marrow ◽  
Experimental Murine Model

Abstract The immunology of chronic hypoplastic marrow failure (CHMF, aplastic anemia) was studied in an experimental murine model of the disease induced by busulfan. B lymphocytes of peripheral blood, spleen, and bone marrow were reduced to 30%–40% and T lymphocytes of thymus, spleen, marrow, and blood were decreased to 20%–70% of control values. IgG and IgM antibody titer to sheep red blood cells were reduced to one- third of control levels, and splenic IgG, but not IgM, plaque-forming cells were fewer on day 7 after antigen stimulation. The proliferative responses to phytohemagglutinin or concanavalin A were reduced in cultures of peripheral blood lymphocytes, splenic lymphocytes, and thymocytes, and cutaneous delayed-type hypersensitivity induced by dinitrofluorobenze was not detected in mice with CHMF. The results demonstrate disturbance of a variety of cellular and humoral functions and suggest that the disturbance was due to quantitative and possibly qualitative abnormalities of the cell types subserving these functions. The results suggest that residual cell injury, the lesion underlying experimental CHMF, is not confined to the myeloid stem cell but also involved cells of the lymphoid series.

scholarly journals The oxidative stress response regulates DKK1 expression through the JNK signaling cascade in multiple myeloma plasma cells

Blood ◽  
2007 ◽  
Vol 109 (10) ◽  
pp. 4470-4477 ◽  
Author(s):  
Simona Colla ◽  
Fenghuang Zhan ◽  
Wei Xiong ◽  
Xiaosong Wu ◽  
Hongwei Xu ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Multiple Myeloma ◽  
Wnt Signaling ◽  
Plasma Cells ◽  
Cell Types ◽  
Signaling Cascade ◽  
Jnk Pathway ◽  
Jnk Signaling ◽  
Dkk1 Expression

Abstract Multiple myeloma (MM) plasma cells, but not those from healthy donors and patients with monoclonal gammopathy of undetermined significance or other plasma cell dyscrasias involving the bone marrow, express the Wnt-signaling antagonist DKK1. We previously reported that secretion of DKK1 by MM cells likely contributes to osteolytic lesions in this disease by inhibiting Wnt signaling, which is essential for osteoblast differentiation and survival. The mechanisms responsible for activation and regulation of DKK1 expression in MM are not known. Herein, we could trace DKK1 expression changes in MM cells to perturbations in the JNK signaling cascade, which is differentially modulated through oxidative stress and interactions between MM cells with osteoclasts in vitro. Despite its role as a tumor suppressor and mediator of apoptosis in other cell types including osteoblasts, our data suggest that DKK1, a stress-responsive gene in MM, does not mediate apoptotic signaling, is not activated by TP53, and its forced overexpression could not inhibit cell growth or sensitize MM cells to apoptosis following treatment with thalidomide or lenalidomide. We conclude that specific strategies to modulate persistent activation of the JNK pathway may be beneficial in preventing disease progression and treating myeloma-associated bone disease by inhibiting DKK1 expression.

Diversity, localization and (patho)physiology of mature lymphocyte populations in the bone marrow

Blood ◽  
2021 ◽  
Author(s):  
Christian M. Schürch ◽  
Chiara Caraccio ◽  
Martijn A. Nolte
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Plasma Cells ◽  
Cell Types ◽  
Lymphoid Organ ◽  
Lymphoid Cells ◽  
Term Survival ◽  
Hematopoietic Stem ◽  
Mature Lymphocyte ◽  
Lymphocyte Populations

The bone marrow (BM) is responsible for generating and maintaining lifelong output of blood and immune cells. Besides its key hematopoietic function, the BM acts as an important lymphoid organ, hosting a large variety of mature lymphocyte populations, including B-cells, T-cells, NK(T)-cells and innate lymphoid cells (ILCs). Many of these cell types are thought to only transiently visit the BM, but for others, like plasma cells and memory T-cells, the BM provides supportive niches that promote their long-term survival. Interestingly, accumulating evidence points towards an important role for mature lymphocytes in the regulation of hematopoietic stem cells (HSCs) and hematopoiesis in health and disease. In this review, we describe the diversity, migration, localization and function of mature lymphocyte populations in murine and human BM, focusing on their role in immunity and hematopoiesis. We also address how various BM lymphocyte subsets contribute to the development of aplastic anemia and immune thrombocytopenia, illustrating the complexity of these BM disorders, but also the underlying similarities and differences in their disease pathophysiology. Finally, we summarize the interactions between mature lymphocytes and BM resident cells in HSC transplantation and graft-versus-host disease. A better understanding of the mechanisms by which mature lymphocyte populations regulate BM function will likely improve future therapies for patients with benign and malignant hematological disorders.

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