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Cell Apr 2019B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are... (Review)
Review
B cells and the antibodies they produce have a deeply penetrating influence on human physiology. Here, we review current understanding of how B cell responses are initiated; the different paths to generate short- and long-lived plasma cells, germinal center cells, and memory cells; and how each path impacts antibody diversity, selectivity, and affinity. We discuss how basic research is informing efforts to generate vaccines that induce broadly neutralizing antibodies against viral pathogens, revealing the special features associated with allergen-reactive IgE responses and uncovering the antibody-independent mechanisms by which B cells contribute to health and disease.
Topics: Animals; Antibodies, Neutralizing; Antigens; B-Lymphocytes; Germinal Center; Humans; Immunologic Memory; Plasma Cells; T-Lymphocytes; Vaccines
PubMed: 31002794
DOI: 10.1016/j.cell.2019.03.016 -
The Journal of Experimental Medicine Feb 2023The longevity of plasma cells is dependent on their ability to access and reside in so-called niches that are predominantly located in the bone marrow. Here, by...
The longevity of plasma cells is dependent on their ability to access and reside in so-called niches that are predominantly located in the bone marrow. Here, by employing a traceable method to label recently generated plasma cells, we showed that homeostatic plasma cells in the bone marrow and spleen were continuously replenished by newly generated B220hiMHC-IIhi populations that progressively differentiated into B220loMHC-IIlo long-lived plasma cell (LLPC) populations. We also found that, in the bone marrow, germinal center (GC)-independent and GC-dependent plasma cells decayed similarly upon NP-CGG engagement, and both entered the B220loMHC-IIlo LLPC pool. Compared with NP+B220hiMHC-IIhi plasma cells, NP+B220loMHC-IIlo cells were more immobilized in the bone marrow niches and showed better survival potential. Thus, our results suggest that the adhesion status of bone marrow plasma cells is dynamically altered during their differentiation and is associated with provision of survival signals.
Topics: Plasma Cells; Bone Marrow; Cell Differentiation; Bone Marrow Cells; Germinal Center; Cell Survival
PubMed: 36515679
DOI: 10.1084/jem.20221717 -
Frontiers in Immunology 2020
Topics: Animals; Antibodies; Cellular Microenvironment; Humans; Hypersensitivity; Paraproteinemias; Parasitic Diseases; Phenotype; Plasma Cells; Time Factors
PubMed: 33193457
DOI: 10.3389/fimmu.2020.606737 -
European Journal of Immunology Jan 2022Long considered a homogeneous population dedicated to antibody secretion, plasma cell phenotypic and functional heterogeneity is increasingly recognized. Plasma cells... (Review)
Review
Long considered a homogeneous population dedicated to antibody secretion, plasma cell phenotypic and functional heterogeneity is increasingly recognized. Plasma cells were first segregated based on their maturation level, but the complexity of this subset might well be underestimated by this simple dichotomy. Indeed, in the last decade new functions have been attributed to plasma cells including but not limited to cytokine secretion. However, a proper characterization of plasma cell heterogeneity has remained elusive partly due to technical issues and cellular features that are specific to this cell type. Cell intrinsic and cell extrinsic signals could be at the origin of this heterogeneity. Recent advances in technologies such as single cell RNA-seq, ATAC-seq, or ChIP-seq on low cell numbers helped to elucidate the fate decision in other cell lineages and similar approaches could be implemented to evaluate the heterogeneous fate of activated B cells in health and disease. Here, we summarized published work shedding some lights on the stimuli and genetic program shaping B-cell terminal differentiation at the single cell level in mice and men. We also discuss the fate and heterogeneity of plasma cells during immune responses, vaccination, and in the frame of human plasma cell disorders.
Topics: Animals; Cell Differentiation; Chromatin Immunoprecipitation Sequencing; Humans; Immune System Diseases; Plasma Cells; RNA-Seq; Single-Cell Analysis
PubMed: 34694625
DOI: 10.1002/eji.202149216 -
The Journal of Investigative Dermatology Mar 2022B lymphocytes play a central role in immunity owing to their unique antibody-producing capacity that provides protection against certain infections and during... (Review)
Review
B lymphocytes play a central role in immunity owing to their unique antibody-producing capacity that provides protection against certain infections and during vaccination. In autoimmune diseases, B cells can gain pathogenic relevance through autoantibody production, antigen presentation, and proinflammatory cytokine secretion. Recent data indicate that B and plasma cells can function as regulators through the production of immunoregulatory cytokines and/or employing checkpoint molecules. In this study, we review the key findings that define subsets of B and plasma cells with pathogenic and protective functions in autoimmunity. In addition to harsh B-cell depletion, we discuss the strategies that have the potential to reinstall the balance of pathogenic and protective B cells with the potential of more specific and personalized therapies.
Topics: Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Cytokines; Humans; Plasma Cells
PubMed: 34955289
DOI: 10.1016/j.jid.2021.05.038 -
Immunological Reviews Sep 2021Antibody-secreting plasma cells are a central component of short- and long-term adaptive immunity. Yet, many fundamental questions about how activated B cells decide to... (Review)
Review
Antibody-secreting plasma cells are a central component of short- and long-term adaptive immunity. Yet, many fundamental questions about how activated B cells decide to yield functional plasma cells have yet to be answered. Likewise, the biochemical processes underpinning the ability of plasma cells to generate and secrete large numbers of antibodies, the capacity of some plasma cell to sustain antibody secretion, presumably without interruption, for decades, and the capacity of long-lived plasma cells to avoid apoptosis despite the high-energy demands associated with sustained robust antibody synthesis and secretion each remain mysterious processes. Our objective here is to review what is currently known about these processes with an emphasis on the earliest phases of plasma cell genesis. Along the way, we will work toward developing a model that ties the biochemistry of plasma cell function and survival. The chief idea imbedded in this model is that progress toward understanding plasma cell survival mechanisms may require increased focus on the unique cell autonomous processes inherent in plasma cell differentiation and function.
Topics: Antibody Formation; Antibody-Producing Cells; B-Lymphocytes; Cell Differentiation; Lymphocyte Activation; Plasma Cells
PubMed: 34313339
DOI: 10.1111/imr.12992 -
Trends in Immunology Apr 2019Helper T cell induced plasma cells (PCs) that secrete class-switched neutralizing antibody are paramount to effective immunity. Following class-switch recombination... (Review)
Review
Helper T cell induced plasma cells (PCs) that secrete class-switched neutralizing antibody are paramount to effective immunity. Following class-switch recombination (CSR), antigen-activated B cells differentiate into extrafollicular PCs or mature in germinal centers (GCs) to produce high-affinity memory B cells and follicular PCs. Many studies focus on the core transcriptional programs that drive central PC functions of longevity and antibody secretion. However, it is becoming clear that these central programs are further subdivided across antibody isotype with separable transcriptional trajectories. Divergent functions emerge at CSR, persist through PC terminal differentiation and further assort memory PC function following antigen recall. Here, we emphasize recent work that assorts divergent isotype-specific PC function across four major modules of immune protection.
Topics: Animals; Humans; Plasma Cells; T-Lymphocytes, Helper-Inducer
PubMed: 30846256
DOI: 10.1016/j.it.2019.01.012 -
Journal of Clinical Immunology May 2016Autophagy is a highly conserved pathway that recycles cytosolic material and organelles via lysosomal degradation. Once simplistically viewed as a non-selective survival... (Review)
Review
Autophagy is a highly conserved pathway that recycles cytosolic material and organelles via lysosomal degradation. Once simplistically viewed as a non-selective survival strategy in dire straits, autophagy has emerged as a tightly regulated process ensuring organelle function, proteome plasticity, cell differentiation and tissue homeostasis, with key roles in physiology and disease. Selective target recognition, mediated by specific adapter proteins, enables autophagy to orchestrate highly specialized functions in innate and adaptive immunity. Among them, the shaping of plasma cells for sustainable antibody production through a negative control on their differentiation program. Moreover, memory B cells and long-lived plasma cells require autophagy to exist. Further, the plasma cell malignancy, multiple myeloma deploys abundant autophagy, essential for homeostasis, survival and drug resistance.
Topics: Animals; Autophagosomes; Autophagy; B-Lymphocytes; Carrier Proteins; Cell Transformation, Neoplastic; Humans; Immune System; Neoplasms, Plasma Cell; Plasma Cells; Protein Binding; Signal Transduction
PubMed: 26984755
DOI: 10.1007/s10875-016-0254-9 -
Blood Sep 2014Multiple 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... (Review)
Review
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.
Topics: Humans; Immunoglobulin Light Chains; Immunologic Factors; Multiple Myeloma; Mutation; Plasma Cells; Proteasome Inhibitors
PubMed: 25097176
DOI: 10.1182/blood-2014-05-578732 -
Immunological Reviews Mar 2019Plasma cells are terminally differentiated B lymphocytes that constitutively secrete antibodies. These antibodies can provide protection against pathogens, and their... (Review)
Review
Plasma cells are terminally differentiated B lymphocytes that constitutively secrete antibodies. These antibodies can provide protection against pathogens, and their quantity and quality are the best clinical correlates of vaccine efficacy. As such, plasma cell lifespan is the primary determinant of the duration of humoral immunity. Yet dysregulation of plasma cell function can cause autoimmunity or multiple myeloma. The longevity of plasma cells is primarily dictated by nutrient uptake and non-transcriptionally regulated metabolic pathways. We have previously shown a positive effect of glucose uptake and catabolism on plasma cell longevity and function. In this review, we discuss these findings with an emphasis on nutrient uptake and its effects on respiratory capacity, lifespan, endoplasmic reticulum stress, and antibody secretion in plasma cells. We further discuss how some of these pathways may be dysregulated in multiple myeloma, potentially providing new therapeutic targets. Finally, we speculate on the connection between plasma cell intrinsic metabolism and systemic changes in nutrient availability and metabolic diseases.
Topics: Animals; Antibody Formation; Autoimmunity; Cell Respiration; Endoplasmic Reticulum Stress; Glucose; Humans; Multiple Myeloma; Nutritional Physiological Phenomena; Plasma Cells
PubMed: 30874356
DOI: 10.1111/imr.12732