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Frontiers in Immunology 2023The development of B cells, their activation and terminal differentiation into antibody-producing plasma cells are characterized by alternating phases of proliferation... (Review)
Review
The development of B cells, their activation and terminal differentiation into antibody-producing plasma cells are characterized by alternating phases of proliferation and quiescence that are controlled by complex transcriptional networks. The spatial and anatomical organization of B cells and plasma cells inside lymphoid organs as well as their migration within lymphoid structures and between organs are prerequisites for the generation and the maintenance of humoral immune responses. Transcription factors of the Krüppel-like family are critical regulators of immune cell differentiation, activation, and migration. Here, we discuss the functional relevance of Krüppel-like factor 2 (KLF2) for B cell development, B cell activation, plasma cell formation and maintenance. We elaborate on KLF2-mediated regulation of B cell and plasmablast migration in the context of immune responses. Moreover, we describe the importance of KLF2 for the onset and the progression of B cell-related diseases and malignancies.
Topics: B-Lymphocytes; Cell Differentiation; Kruppel-Like Transcription Factors; Plasma Cells; Transcription Factors; Humans
PubMed: 37251374
DOI: 10.3389/fimmu.2023.1172641 -
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 -
Cytometry. Part B, Clinical Cytometry May 2023Flow cytometry has been indispensable in diagnosing B cell lymphoma and plasma cell neoplasms. The advances in novel multicolor flow cytometry have also made this... (Review)
Review
Flow cytometry has been indispensable in diagnosing B cell lymphoma and plasma cell neoplasms. The advances in novel multicolor flow cytometry have also made this technology a robust tool for monitoring minimal/measurable residual disease in chronic lymphocytic leukemia and multiple myeloma. However, challenges using conventional gating strategies to isolate neoplastic B or plasma cells are emerging due to the rapidly increasing number of antibody therapeutics targeting single or multiple classic B/plasma cell-lineage markers, such as CD19, CD20, and CD22 in B cells and CD38 in plasma cells. This review is the first of a two-part series that summarizes the most current targeted therapies used in B and plasma cell neoplasms and proposes detailed alternative approaches to overcome post-targeted therapy analysis challenges by flow cytometry. The second review in this series (Chen et al.) focuses on challenges encountered in the use of targeted therapy in precursor B cell neoplasms.
Topics: Humans; Plasma Cells; Antigens, CD; Flow Cytometry; B-Lymphocytes; Neoplasms, Plasma Cell; Neoplasm, Residual; Immunophenotyping
PubMed: 36321879
DOI: 10.1002/cyto.b.22097 -
Leukemia Mar 2022The role of infection and chronic inflammation in plasma cell disorders (PCD) has been well-described. Despite not being a diagnostic criterion, infection is a common... (Review)
Review
The role of infection and chronic inflammation in plasma cell disorders (PCD) has been well-described. Despite not being a diagnostic criterion, infection is a common complication of most PCD and represents a significant cause of morbidity and mortality in this population. As immune-based therapeutic agents are being increasingly used in multiple myeloma, it is important to recognize their impact on the epidemiology of infections and to identify preventive measures to improve outcomes. This review outlines the multiple factors attributed to the high infectious risk in PCD (e.g. the underlying disease status, patient age and comorbidities, and myeloma-directed treatment), with the aim of highlighting future prophylactic and preventive strategies that could be implemented in the clinic. Beyond this, infection and pathogens as an entity are believed to also influence disease biology from initiation to response to treatment and progression through a complex interplay involving pathogen exposure, chronic inflammation, and immune response. This review will outline both the direct and indirect role played by oncogenic pathogens in PCD, highlight the requirement for large-scale studies to decipher the precise implication of the microbiome and direct pathogens in the natural history of myeloma and its precursor disease states, and understand how, in turn, pathogens shape plasma cell biology.
Topics: Adaptive Immunity; Animals; Humans; Immunity, Innate; Infections; Inflammation; Multiple Myeloma; Plasma Cells
PubMed: 35110727
DOI: 10.1038/s41375-021-01506-9 -
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 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 -
Immunology Letters Aug 2023Plasma cells are the antibody secretors of the immune system. Continuous antibody secretion over years can provide long-term immune protection but could also be held...
Plasma cells are the antibody secretors of the immune system. Continuous antibody secretion over years can provide long-term immune protection but could also be held responsible for long-lasting autoimmunity in case of self-reactive plasma cells. Systemic autoimmune rheumatic diseases (ARD) affect multiple organ systems and are associated with a plethora of different autoantibodies. Two prototypic systemic ARDs are systemic lupus erythematosus (SLE) and Sjögren's disease (SjD). Both diseases are characterized by B-cell hyperactivity and the production of autoantibodies against nuclear antigens. Analogues to other immune cells, different subsets of plasma cells have been described. Plasma cell subsets are often defined dependent on their current state of maturation, that also depend on the precursor B-cell subset from which they derived. But, a universal definition of plasma cell subsets is not available so far. Furthermore, the ability for long-term survival and effector functions may differ, potentially in a disease-specific manner. Characterization of plasma cell subsets and their specificity in individual patients can help to choose a suitable targeting approach for either a broad or more selective plasma cell depletion. Targeting plasma cells in systemic ARDs is currently challenging because of side effects or varying depletion efficacies in the tissue. Recent developments, however, like antigen-specific targeting and CAR-T-cell therapy might open up major benefits for patients beyond current treatment options.
Topics: Humans; Plasma Cells; Autoimmunity; Autoantibodies; Lupus Erythematosus, Systemic; Sjogren's Syndrome; Respiratory Distress Syndrome; Autoimmune Diseases
PubMed: 37315847
DOI: 10.1016/j.imlet.2023.06.005 -
Acta Biochimica Et Biophysica Sinica Nov 2023Ulcerative colitis (UC) develops as a result of complex interactions between various cell types in the mucosal microenvironment. In this study, we aim to elucidate the...
Ulcerative colitis (UC) develops as a result of complex interactions between various cell types in the mucosal microenvironment. In this study, we aim to elucidate the pathogenesis of ulcerative colitis at the single-cell level and unveil its clinical significance. Using single-cell RNA sequencing and high-dimensional weighted gene co-expression network analysis, we identify a subpopulation of plasma cells (PCs) with significantly increased infiltration in UC colonic mucosa, characterized by pronounced oxidative stress. Combining 10 machine learning approaches, we find that the PC oxidative stress genes accurately distinguish diseased mucosa from normal mucosa (independent external testing AUC=0.991, sensitivity=0.986, specificity=0.909). Using MCPcounter and non-negative matrix factorization, we identify the association between PC oxidative stress genes and immune cell infiltration as well as patient heterogeneity. Spatial transcriptome data is used to verify the infiltration of oxidatively stressed PCs in colitis. Finally, we develop a gene-immune convolutional neural network deep learning model to diagnose UC mucosa in different cohorts (independent external testing AUC=0.984, sensitivity=95.9%, specificity=100%). Our work sheds light on the key pathogenic cell subpopulations in UC and is essential for the development of future clinical disease diagnostic tools.
Topics: Humans; Colitis, Ulcerative; Plasma Cells; Deep Learning; Gene Expression Profiling; Intestinal Mucosa
PubMed: 37814814
DOI: 10.3724/abbs.2023237