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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 -
Nature Feb 2024Plasma cells produce large quantities of antibodies and so play essential roles in immune protection. Plasma cells, including a long-lived subset, reside in the bone...
Plasma cells produce large quantities of antibodies and so play essential roles in immune protection. Plasma cells, including a long-lived subset, reside in the bone marrow where they depend on poorly defined microenvironment-linked survival signals. We show that bone marrow plasma cells use the ligand-gated purinergic ion channel P2RX4 to sense extracellular ATP released by bone marrow osteoblasts through the gap-junction protein pannexin 3 (PANX3). Mutation of Panx3 or P2rx4 each caused decreased serum antibodies and selective loss of bone marrow plasma cells. Compared to their wild-type counterparts, PANX3-null osteoblasts secreted less extracellular ATP and failed to support plasma cells in vitro. The P2RX4-specific inhibitor 5-BDBD abrogated the impact of extracellular ATP on bone marrow plasma cells in vitro, depleted bone marrow plasma cells in vivo and reduced pre-induced antigen-specific serum antibody titre with little posttreatment rebound. P2RX4 blockade also reduced autoantibody titre and kidney disease in two mouse models of humoral autoimmunity. P2RX4 promotes plasma cell survival by regulating endoplasmic reticulum homeostasis, as short-term P2RX4 blockade caused accumulation of endoplasmic reticulum stress-associated regulatory proteins including ATF4 and B-lineage mutation of the pro-apoptotic ATF4 target Chop prevented bone marrow plasma cell demise on P2RX4 inhibition. Thus, generating mature protective and pathogenic plasma cells requires P2RX4 signalling controlled by PANX3-regulated extracellular ATP release from bone marrow niche cells.
Topics: Animals; Mice; Adenosine Triphosphate; Autoantibodies; Autoimmunity; Bone Marrow Cells; Cell Lineage; Connexins; Endoplasmic Reticulum; Endoplasmic Reticulum Stress; Mutation; Osteoblasts; Plasma Cells; Receptors, Purinergic P2X4; Signal Transduction
PubMed: 38355795
DOI: 10.1038/s41586-024-07047-2 -
Proceedings of the National Academy of... Jan 2023Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood....
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 soluble N-ethylmaleimide-sensitive factor attachment protein receptor (SNARE) Sec22b as a unique and critical regulator of plasma cell maintenance and function. In the absence of Sec22b, plasma cells were hardly detectable and serum antibody titers were dramatically reduced. Accordingly, -deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b contributes to efficient antibody secretion and is a central regulator of plasma cell maintenance through the regulation of their transcriptional identity and of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil an essential and nonredundant role for Sec22b as a regulator of plasma cell fitness and of the humoral immune response.
Topics: Mice; Animals; Plasma Cells; R-SNARE Proteins; SNARE Proteins; Endoplasmic Reticulum; Biological Transport
PubMed: 36595686
DOI: 10.1073/pnas.2213056120 -
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 -
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 -
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 -
American Journal of Transplantation :... May 2018Plasma cell diseases are a class of hematologic diseases that are sometimes present as preexisting diagnoses prior to organ transplantation, causative factors leading to... (Review)
Review
Plasma cell diseases are a class of hematologic diseases that are sometimes present as preexisting diagnoses prior to organ transplantation, causative factors leading to a need for organ transplantation, or may occur posttransplant as part of the spectrum of posttransplant lymphoproliferative disorders. Herein, we review the most common plasma cell diseases, both as coexisting with other causes of organ failure, but also as a primary underlying cause for organ failure. In many cases, treatment of the underlying clonal disease may be indicated before proceeding with organ transplant. This review aims to provide current and relevant data regarding the management of these conditions in the organ transplant patient, for transplant providers, and those who take care of these patients.
Topics: Graft Rejection; Humans; Multiple Myeloma; Neoplasms, Plasma Cell; Organ Transplantation; Plasma Cells; Risk Factors
PubMed: 29524307
DOI: 10.1111/ajt.14731 -
Trends in Immunology Jan 2018Humoral immunity is generated and maintained by antigen-specific antibodies that counter infectious pathogens. Plasma cells are the major producers of antibodies during... (Review)
Review
Humoral immunity is generated and maintained by antigen-specific antibodies that counter infectious pathogens. Plasma cells are the major producers of antibodies during and after infections, and each plasma cell produces some thousands of antibody molecules per second. This magnitude of secretion requires enormous quantities of amino acids and glycosylation sugars to properly build and fold antibodies, biosynthetic substrates to fuel endoplasmic reticulum (ER) biogenesis, and additional carbon sources to generate energy. Many of these processes are likely to be linked, thereby affording possibilities to improve vaccine design and to develop new therapies for autoimmunity. We review here aspects of plasma cell biology with an emphasis on recent studies and the relationships between intermediary metabolism, antibody production, and lifespan.
Topics: Animals; Antibodies; Antibody Formation; Cell Survival; Endoplasmic Reticulum; Humans; Immunity, Humoral; Plasma Cells; Protein Folding; Stress, Physiological
PubMed: 28919256
DOI: 10.1016/j.it.2017.08.007 -
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