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Blood Oct 2021Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation...
Although light-chain amyloidosis (AL) and multiple myeloma (MM) are characterized by tumor plasma cell (PC) expansion in bone marrow (BM), their clinical presentation differs. Previous attempts to identify unique pathogenic mechanisms behind such differences were unsuccessful, and no studies have investigated the differentiation stage of tumor PCs in patients with AL and MM. We sought to define a transcriptional atlas of normal PC development in secondary lymphoid organs (SLOs), peripheral blood (PB), and BM for comparison with the transcriptional programs (TPs) of tumor PCs in AL, MM, and monoclonal gammopathy of undetermined significance (MGUS). Based on bulk and single-cell RNA sequencing, we observed 13 TPs during transition of normal PCs throughout SLOs, PB, and BM. We further noted the following: CD39 outperforms CD19 to discriminate newborn from long-lived BM-PCs; tumor PCs expressed the most advantageous TPs of normal PC differentiation; AL shares greater similarity to SLO-PCs whereas MM is transcriptionally closer to PB-PCs and newborn BM-PCs; patients with AL and MM enriched in immature TPs had inferior survival; and protein N-linked glycosylation-related TPs are upregulated in AL. Collectively, we provide a novel resource to understand normal PC development and the transcriptional reorganization of AL and other monoclonal gammopathies.
Topics: Adult; Humans; Immunoglobulin Light-chain Amyloidosis; Multiple Myeloma; Plasma Cells; Transcriptome; Tumor Cells, Cultured
PubMed: 34133718
DOI: 10.1182/blood.2020009754 -
Immunity Oct 2021Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell...
Diets high in cholesterol alter intestinal immunity. Here, we examined how the cholesterol metabolite 25-hydroxycholesterol (25-HC) impacts the intestinal B cell response. Mice lacking cholesterol 25-hydroxylase (CH25H), the enzyme generating 25-HC, had higher frequencies of immunoglobulin A (IgA)-secreting antigen-specific B cells upon immunization or infection. 25-HC did not affect class-switch recombination but rather restrained plasma cell (PC) differentiation. 25-HC was produced by follicular dendritic cells and increased in response to dietary cholesterol. Mechanistically, 25-HC restricted activation of the sterol-sensing transcription factor SREBP2, thereby regulating B cell cholesterol biosynthesis. Ectopic expression of SREBP2 in germinal center B cells induced rapid PC differentiation, whereas SREBP2 deficiency reduced PC output in vitro and in vivo. High-cholesterol diet impaired, whereas Ch25h deficiency enhanced, the IgA response against Salmonella and the resulting protection from systemic bacterial dissemination. Thus, a 25-HC-SREBP2 axis shapes the humoral response at the intestinal barrier, providing insight into the effect of high dietary cholesterol in intestinal immunity.
Topics: Animals; Cell Differentiation; Cholesterol, Dietary; Hydroxycholesterols; Immunoglobulin A; Intestinal Mucosa; Mice; Peyer's Patches; Plasma Cells; Sterol Regulatory Element Binding Protein 2
PubMed: 34644558
DOI: 10.1016/j.immuni.2021.09.004 -
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 -
Blood Cancer Journal Dec 2021Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most...
Primary plasma cell leukemia (PCL) has a consistently ominous prognosis, even after progress in the last decades. PCL deserves a prompt identification to start the most effective treatment for this ultra-high-risk disease. The aim of this position paper is to revisit the diagnosis of PCL according to the presence of circulating plasma cells in patients otherwise meeting diagnostic criteria of multiple myeloma. We could identify two retrospective series where the question about what number of circulating plasma cells in peripheral blood should be used for defining PCL. The presence of ≥5% circulating plasma cells in patients with MM had a similar adverse prognostic impact as the previously defined PCL. Therefore, PCL should be defined by the presence of 5% or more circulating plasma cells in peripheral blood smears in patients otherwise diagnosed with symptomatic multiple myeloma.
Topics: Aged; Female; Humans; Leukemia, Plasma Cell; Male; Multiple Myeloma; Plasma Cells; Prognosis; Retrospective Studies
PubMed: 34857730
DOI: 10.1038/s41408-021-00587-0 -
Anais Brasileiros de Dermatologia 2016Plasmoacanthoma is an extremely rare verrucous tumor located on periorificial regions characterized by dense dermal plasmacytic infiltrates. Some authors classify it as...
Plasmoacanthoma is an extremely rare verrucous tumor located on periorificial regions characterized by dense dermal plasmacytic infiltrates. Some authors classify it as a form of reactive plasma cell proliferation which represents a heterogeneous spectrum of mucocutaneous disorders. These plasma cell proliferations have been considered to be a benign immunologic inflammatory reaction to known or unknown stimuli. However, the etiology of plasmoacanthoma remains highly speculative. We report the case of a 40-year-old woman who presented with a lobulated warty lesion affecting the lower lip. Biopsy from the lesion was compatible with plasmoacanthoma, which remains an underreported disease in the dermatology literature.
Topics: Acanthoma; Adult; Biopsy; Cell Proliferation; Dermis; Female; Humans; Immunohistochemistry; Lip; Lip Neoplasms; Mouth Mucosa; Plasma Cells; Skin Neoplasms
PubMed: 28300919
DOI: 10.1590/abd1806-4841.20164673 -
The Journal of Experimental Medicine Jan 2024Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic...
Protective immune responses to many pathogens depend on the development of high-affinity antibody-producing plasma cells (PC) in germinal centers (GCs). Transgenic models suggest that there is a stringent affinity-based barrier to PC development. Whether a similar high-affinity barrier regulates PC development under physiologic circumstances and the nature of the PC fate decision has not been defined precisely. Here, we use a fate-mapping approach to examine the relationship between GC B cells selected to undergo additional rounds of affinity maturation, GC pre-PC, and PC. The data show that initial PC selection overlaps with GC B cell selection, but that the PC compartment accumulates a less diverse and higher affinity collection of antibodies over time. Thus, whereas the GC continues to diversify over time, affinity-based pre-PC selection sieves the GC to enable the accumulation of a more restricted group of high-affinity antibody-secreting PC.
Topics: Plasma Cells; Germinal Center; B-Lymphocytes; Antibodies; Antibody-Producing Cells
PubMed: 37938344
DOI: 10.1084/jem.20231838 -
Anais Brasileiros de Dermatologia 2017Zoon vulvitis or vulvitis chronica plasmacellularis is a rare, chronic benign inflammation of the vulvar mucosa, diagnosed histologically, with variable therapeutic...
Zoon vulvitis or vulvitis chronica plasmacellularis is a rare, chronic benign inflammation of the vulvar mucosa, diagnosed histologically, with variable therapeutic responses. It is important to be diagnosed because it mimics the presentation of other genital conditions, such as lichen planus and squamous cell carcinoma, which require specific treatment. We report a case of a female patient with three asymptomatic shallow ulcers on the labia minora. Laboratory tests ruled out infectious diseases and the biopsy was consistent with Zoon Vulvitis.
Topics: Biopsy; Diagnosis, Differential; Female; Humans; Middle Aged; Plasma Cells; Vulva; Vulvitis
PubMed: 29267481
DOI: 10.1590/abd1806-4841.20175622 -
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 -
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