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Blood Sep 2020
Topics: Aged; Antigens, CD; Antineoplastic Combined Chemotherapy Protocols; Female; Humans; Leukemia, Plasma Cell; Plasma Cells; Stem Cell Transplantation
PubMed: 32941636
DOI: 10.1182/blood.2020007074 -
Immunological Reviews Sep 2021Antibody-secreting cells (ASC) are the effectors of protective humoral immunity and the only cell type that produces antibodies or immunoglobulins in mammals. In... (Review)
Review
Antibody-secreting cells (ASC) are the effectors of protective humoral immunity and the only cell type that produces antibodies or immunoglobulins in mammals. In addition to their formidable capacity to secrete massive quantities of proteins, ASC are terminally differentiated and have unique features to become long-lived plasma cells (LLPC). Upon antigen encounter, B cells are activated through a complex multistep process to undergo fundamental morphological, subcellular, and molecular transformation to become an efficient protein factory with lifelong potential. The ASC survival potential is determined by factors at the time of induction, capacity to migration from induction to survival sites, and ability to mature in the specialized bone marrow microenvironments. In the past decade, considerable progress has been made in identifying factors regulating ASC longevity. Here, we review the intrinsic drivers, trafficking signals, and extrinsic regulators with particular focus on how they impact the survival potential to become a LLPC.
Topics: Animals; Antibody-Producing Cells; B-Lymphocytes; Bone Marrow; Cell Survival; Immunity, Humoral; Plasma Cells
PubMed: 34337772
DOI: 10.1111/imr.13013 -
American Journal of Transplantation :... Jun 2020Plasma cells (PCs) are the major source of pathogenic allo- and autoantibodies and have historically demonstrated resistance to therapeutic targeting. However,... (Review)
Review
Plasma cells (PCs) are the major source of pathogenic allo- and autoantibodies and have historically demonstrated resistance to therapeutic targeting. However, significant recent clinical progress has been made with the use of second-generation proteasome inhibitors (PIs). PIs provide efficient elimination of plasmablast-mediated humoral responses; however, long-lived bone marrow (BM) resident PCs (LLPCs) demonstrate therapeutic resistance, particularly to first-generation PIs. In addition, durability of antibody (Ab) reduction still requires improvement. More recent clinical trials have focused on conditions mediated by LLPCs and have included mechanistic studies of LLPCs from PI-treated patients. A recent clinical trial of carfilzomib (a second-generation irreversible PI) demonstrated improved efficacy in eliminating BM PCs and reducing anti-HLA Abs in chronically HLA-sensitized patients; however, Ab rebound was observed over several weeks to months following PI therapy. Importantly, recent murine studies have provided substantial insights into PC biology, thereby further enhancing our understanding of PC populations. It is now clear that BMPC populations, where LLPCs are thought to primarily reside, are heterogeneous and have distinct gene expression, metabolic, and survival signatures that enable identification and characterization of PC subsets. This review highlights recent advances in PC biology and clinical trials in transplant populations.
Topics: Animals; Autoantibodies; Humans; Mice; Plasma Cells; Proteasome Inhibitors
PubMed: 32538532
DOI: 10.1111/ajt.15889 -
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 -
Clinical and Experimental Immunology Jan 2016Eosinophils perform numerous tasks. They are involved in inflammatory reactions associated with innate immune defence against parasitic infections and are also involved... (Review)
Review
Eosinophils perform numerous tasks. They are involved in inflammatory reactions associated with innate immune defence against parasitic infections and are also involved in pathological processes in response to allergens. Recently, however, it has become clear that eosinophils also play crucial non-inflammatory roles in the generation and maintenance of adaptive immune responses. Eosinophils, being a major source of the plasma cell survival factor APRIL (activation and proliferation-induced ligand), are essential not only for the long-term survival of plasma cells in the bone marrow, but also for the maintenance of these cells in the lamina propria which underlies the gut epithelium. At steady state under non-inflammatory conditions eosinophils are resident cells of the gastrointestinal tract, although only few are present in the major organized lymphoid tissue of the gut - the Peyer's patches (PP). Surprisingly, however, lack of eosinophils abolishes efficient class-switching of B cells to immunoglobulin (Ig)A in the germinal centres of PP. Thus, eosinophils are required to generate and to maintain mucosal IgA plasma cells, and as a consequence their absence leads to a marked reduction of IgA both in serum and in the gut-associated lymphoid tissues (GALT). Eosinophils thus have an essential part in long-term humoral immune protection, as they are crucial for the longevity of antibody-producing plasma cells in the bone marrow and, in addition, for gut immune homeostasis.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Eosinophils; Humans; Immunity, Humoral; Immunoglobulin A; Intestinal Mucosa; Plasma Cells; Tumor Necrosis Factor Ligand Superfamily Member 13
PubMed: 26291602
DOI: 10.1111/cei.12695 -
Immunological Reviews Mar 2021Antibody-secreting cells (ASCs) or plasma cells secrete antibodies and form a cornerstone of humoral immunity. B cells that receive activation signals in the presence or... (Review)
Review
Antibody-secreting cells (ASCs) or plasma cells secrete antibodies and form a cornerstone of humoral immunity. B cells that receive activation signals in the presence or absence of T cells initiate a differentiation program that requires epigenetic and transcriptional reprogramming in order to ultimately form ASC. Reprogramming is accomplished through the interplay of transcription factors that initiate gene expression programs and epigenetic mechanisms that maintain these programs and cell fates. An important consideration is that all of these factors are operating in the context of cell division. Recent technical advances now allow mechanistic studies to move beyond genetic studies to identify the promoters and enhancer repertoires that are regulated by epigenetic mechanisms and transcription factors in rare cell types and differentiation stages in vivo. This review will detail efforts to integrate transcriptional and epigenetic changes during B cell differentiation with cell division in vivo. What has emerged is a multiphased differentiation model that requires distinct transcription factors and epigenetic programs at each step. The identification of markers that define each phase will help facilitate the manipulation of B cell differentiation for vaccine development or to treat diseases where antibodies are a component.
Topics: Cell Differentiation; Cues; Epigenesis, Genetic; Lymphocyte Activation; Plasma Cells
PubMed: 33278036
DOI: 10.1111/imr.12934 -
Immunological Reviews May 2018Memory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite... (Review)
Review
Memory for antigens once encountered is a hallmark of the immune system of vertebrates, providing us with an immunity adapted to pathogens of our environment. Despite its fundamental relevance, the cells and genes representing immunological memory are still poorly understood. Here we discuss the concept of a circulating, proliferating, and ubiquitous population of effector lymphocytes vs concepts of resting and dormant populations of dedicated memory lymphocytes, distinct from effector lymphocytes and residing in defined tissues, particularly in barrier tissues and in the bone marrow. The lifestyle of memory plasma cells of the bone marrow may serve as a paradigm, showing that persistence of memory lymphocytes is not defined by intrinsic "half-lives", but rather conditional on distinct survival signals provided by dedicated niches. These niches are organized by individual mesenchymal stromal cells. They define the capacity of immunological memory and regulate its homeostasis.
Topics: Animals; Bone Marrow; Bone Marrow Cells; Cell Survival; Homeostasis; Humans; Immunologic Memory; Lymphocyte Activation; Organ Specificity; Plasma Cells; T-Lymphocyte Subsets
PubMed: 29664564
DOI: 10.1111/imr.12656 -
Blood Advances Mar 2023Spatial heterogeneity is a common phenomenon in metastatic solid tumors and an evolving concept in multiple myeloma (MM). The interplay between malignant plasma cells...
Spatial heterogeneity is a common phenomenon in metastatic solid tumors and an evolving concept in multiple myeloma (MM). The interplay between malignant plasma cells (PCs) and the microenvironment has not yet been analyzed in MM. For this purpose, we performed bone marrow aspirates and imaging-guided biopsies of corresponding lesions in newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM) patients. PCs were isolated and subjected to whole-exome sequencing (WES). Non-PCs were studied with next-generation flow (NGF) and T-cell receptor sequencing (TCRseq) to analyze the connection between malignant and nonmalignant cells in the bone marrow and in lesions. Although we observed a strong overlap from WES, NGF, and TCRseq in patients with intramedullary disease, WES revealed significant spatial heterogeneity in patients with extramedullary disease. NGF showed significant immunosuppression in RRMM compared with NDMM as indicated by fewer myeloid dendritic cells, unswitched memory B cells, Th9 cells, and CD8 effector memory T cells but more natural killer and regulatory T cells. Additionally, fewer T-cell receptor (TCR) sequences were detected in RRMM compared with NDMM and healthy individuals. After induction therapy, TCR repertoire richness increased to levels of healthy individuals, and NGF showed more regulatory T cells and myeloid-derived suppressor cells, regardless of depth of response. Clinical significance of imaging-guided biopsies of lesions was demonstrated by detection of monoclonal PCs in patients without measurable residual disease (MRD) in aspirates from the iliac crest as well as identification of secondary primary malignancies in MRD- patients. Furthermore, site-specific clones with different drug susceptibilities and genetically defined high-risk features were detected by our workflow.
Topics: Humans; Multiple Myeloma; Bone Marrow; Plasma Cells; Neoplasms, Plasma Cell; Tumor Microenvironment
PubMed: 35868022
DOI: 10.1182/bloodadvances.2022007457 -
Frontiers in Immunology 2023To achieve longevity, IgA plasma cells require a sophisticated anatomical microenvironment that provides cytokines, cell-cell contacts, and nutrients as well as... (Review)
Review
To achieve longevity, IgA plasma cells require a sophisticated anatomical microenvironment that provides cytokines, cell-cell contacts, and nutrients as well as metabolites. The intestinal epithelium harbors cells with distinct functions and represents an important defense line. Anti-microbial peptide-producing paneth cells, mucus-secreting goblet cells and antigen-transporting microfold (M) cells cooperate to build a protective barrier against pathogens. In addition, intestinal epithelial cells are instrumental in the transcytosis of IgA to the gut lumen, and support plasma cell survival by producing the cytokines APRIL and BAFF. Moreover, nutrients are sensed through specialized receptors such as the aryl hydrocarbon receptor (AhR) by both, intestinal epithelial cells and immune cells. However, the intestinal epithelium is highly dynamic with a high cellular turn-over rate and exposure to changing microbiota and nutritional factors. In this review, we discuss the spatial interplay of the intestinal epithelium with plasma cells and its potential contribution to IgA plasma cell generation, homing, and longevity. Moreover, we describe the impact of nutritional AhR ligands on intestinal epithelial cell-IgA plasma cell interaction. Finally, we introduce spatial transcriptomics as a new technology to address open questions in intestinal IgA plasma cell biology.
Topics: Plasma Cells; Intestines; Intestinal Mucosa; Cytokines; Immunoglobulin A
PubMed: 36875083
DOI: 10.3389/fimmu.2023.1114348 -
Hematology. American Society of... Dec 2022The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can... (Review)
Review
The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can expect deeper responses, longer remissions, and improved overall survival. Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens. Its role as a maintenance therapy is currently being explored. Subsequently, a variety of novel antibody therapeutics have evolved from the success of daratumumab, using similar concepts to target the malignant plasma cell clone. Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7. Antibody-drug conjugates, complex molecules composed of an antibody tethered to a cytotoxic drug, target malignant cells and deliver a lethal payload. The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope-such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)-on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.
Topics: Humans; Multiple Myeloma; Neoplasm Recurrence, Local; Antibodies, Bispecific; Immunotherapy; Plasma Cells
PubMed: 36485135
DOI: 10.1182/hematology.2022000334