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Journal of Immunology (Baltimore, Md. :... Dec 2021The germinal center (GC) reaction is a coordinated and dynamic ensemble of cells and processes that mediate the maturation and selection of high-affinity GC B cells...
The germinal center (GC) reaction is a coordinated and dynamic ensemble of cells and processes that mediate the maturation and selection of high-affinity GC B cells (GCBs) from lower-affinity precursors and ultimately results in plasma cell and memory cell fates that exit the GC. It is of great interest to identify intrinsic and extrinsic factors that control the selection process. The transcription factor IRF4, induced upon BCR and CD40 signaling, is essential for the acquisition of plasma cell and GCB cell fates. We hypothesized that beyond this early requirement, IRF4 continuously operates at later phases of the B cell response. We show that IRF4 is expressed in GCBs at levels greater than seen in resting cells and plays a role in efficient selection of high-affinity GCBs. Halving gene copy number in an Ag-specific murine B cell model, we found that Ag presentation, isotype switching, GC formation and zonation, somatic hypermutation rates, and proliferation were comparable with cells with a full allelic complement. In contrast, haploinsufficient GCBs exhibited impaired generation of high-affinity cells. Mechanistically, we demonstrate suboptimal Blimp-1 regulation among high-affinity haploinsufficient GCBs. Furthermore, in cotransfer settings, we observed a marked disadvantage of haploinsufficient cells for GC entry, evidential of ineffective recruitment of T cell help. We propose that, analogous to its role in early GC entry, IRF4 continues to function in the late phase of the Ab response to promote productive T follicular helper cell interactions and to activate optimal Blimp-1 expression during GC selection and affinity maturation.
Topics: Animals; B-Lymphocytes; Cell Differentiation; Germinal Center; Haploinsufficiency; Mice; Plasma Cells
PubMed: 34759017
DOI: 10.4049/jimmunol.2100747 -
Journal of Immunology (Baltimore, Md. :... Dec 2021Type I IFN is essential for viral clearance but also contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), via aberrant...
Type I IFN is essential for viral clearance but also contributes to the pathogenesis of autoimmune diseases, such as systemic lupus erythematosus (SLE), via aberrant nucleic acid-sensing pathways, leading to autoantibody production. Type III IFN (IFN-λ) is now appreciated to have a nonredundant role in viral infection, but few studies have addressed the effects of IFN-λ on immune cells given the more restricted expression of its receptor primarily to the epithelium. In this study, we demonstrate that B cells display a prominent IFN gene expression profile in patients with lupus. Serum levels of IFN-λ are elevated in SLE and positively correlate with B cell subsets associated with autoimmune plasma cell development, including CD11cT-betCD21 B cells. Although B cell subsets express all IFN receptors, strongly correlates with the CD11cCD21 B cell expansion, suggesting that IFN-λ may be an unappreciated driver of the SLE IFN signature and B cell abnormalities. We show that IFN-λ potentiates gene transcription in human B cells typically attributed to type I IFN as well as expansion of T-bet-expressing B cells after BCR and TLR7/8 stimulation. Further, IFN-λ promotes TLR7/8-mediated plasmablast differentiation and increased IgM production. CD11c B cells demonstrate IFN-λ hyperresponsive signaling compared with other B cell subsets, suggesting that IFN-λ accelerates plasma cell differentiation through this putative extrafollicular pathway. In summary, our data support type III IFN-λ as a cytokine promoting the Ab-secreting cell pool in human viral and autoimmune disease.
Topics: Adult; Aged; B-Lymphocytes; Cell Differentiation; Female; Humans; Interferons; Lupus Erythematosus, Systemic; Male; Middle Aged; Plasma Cells; Young Adult
PubMed: 34706932
DOI: 10.4049/jimmunol.2100339 -
Frontiers in Immunology 2019Durable humoral immunity is dependent upon the generation of antigen-specific antibody titers, produced by non-proliferating bone marrow resident long-lived plasma cells... (Review)
Review
Durable humoral immunity is dependent upon the generation of antigen-specific antibody titers, produced by non-proliferating bone marrow resident long-lived plasma cells (LLPC). Longevity is the hallmark of LLPC, but why and how they survive and function for years after antigen exposure is only beginning to be understood. LLPC are not intrinsically long-lived; they require continuous signals from the LLPC niche to survive. Signals unique to LLPC survival (vs. PC survival in general) most notably include those that upregulate the anti-apoptotic factor Mcl-1 and activation of the CD28 receptor expressed on LLPC. Other potential factors include expression of BCMA, upregulation of the transcription factor ZBTB20, and upregulation of the enzyme ENPP1. Metabolic fitness is another key component of LLPC longevity, facilitating the diversion of glucose to generate pyruvate during times of stress to facilitate long term survival. A third major component of LLPC survival is the microenvironment/LLPC niche itself. Cellular partners such as stromal cells, dendritic cells, and T regulatory cells establish a niche for LLPC and drive survival signaling by expressing ligands such as CD80/CD86 for CD28 and producing soluble and stromal factors that contribute to LLPC longevity. These findings have led to the current paradigm wherein both intrinsic and extrinsic mechanisms are required for the survival of LLPC. Here we outline this diverse network of signals and highlight the mechanisms thought to regulate and promote the survival of LLPC. Understanding this network of signals has direct implications in increasing our basic understanding of plasma cell biology, but also in vaccine and therapeutic drug development to address the pathologies that can arise from this subset.
Topics: Animals; B-Lymphocyte Subsets; Humans; Plasma Cells; Transcriptome
PubMed: 31130955
DOI: 10.3389/fimmu.2019.00965 -
Cancer Treatment and Research... 2022
Topics: Humans; Plasma Cells
PubMed: 35872008
DOI: 10.1016/j.ctarc.2022.100612 -
Journal of Lower Genital Tract Disease Jan 2022The aim of the study was to identify whether desquamative inflammatory vaginitis (DIV) and plasma cell vulvitis (PCV) are distinct clinicopathologic entities.
OBJECTIVE
The aim of the study was to identify whether desquamative inflammatory vaginitis (DIV) and plasma cell vulvitis (PCV) are distinct clinicopathologic entities.
MATERIALS AND METHODS
The pathology database identified biopsies described as "vaginitis" or "vulvitis" occurring in nonkeratinized epithelium or mucocutaneous junction. Exclusions were age less than 18 years, unavailable slides or records, concurrent neoplasia, or histopathology consistent with other entities. Clinical data included demographics, symptoms, examination, microbiology, treatment, and response. Histopathologic review documented site, epithelial thickness and characteristics, infiltrate, and vascular abnormalities. Cases were analyzed according to histopathologic impression of DIV or PCV based on previous pathologic descriptions.
RESULTS
There were 36 specimens classified as DIV and 18 as PCV from 51 women with mean age of 51 years; 3 (6%) had concurrent biopsies with both. Pain was more common in PCV, but rates of discharge, itch, and bleeding were comparable. Rates of petechiae or erythema were similar and vaginal examination was abnormal in 72% of PCV cases. All DIV and 33% of PCV occurred in squamous mucosa; the remaining PCV cases were from mucocutaneous junction. Mean epithelial thickness, rete ridge appearance, exocytosis, and spongiosis were similar in DIV and PCV. Epithelial erosion, wide-diameter lesions, plasma cells, and stromal hemosiderin occurred in both but were more common in PCV. Lymphocyte-obscured basal layer, narrow-diameter lesions, hemorrhage, and vascular congestion were seen in both, but more common and marked in DIV.
CONCLUSIONS
Desquamative inflammatory vaginitis and PCV have overlapping symptoms, signs, and histopathologic features. They may represent a single condition of hemorrhagic vestibulovaginitis with varying manifestations according to location and severity.
Topics: Adolescent; Biopsy; Female; Hemorrhage; Humans; Middle Aged; Plasma Cells; Vaginitis; Vulvitis
PubMed: 34928254
DOI: 10.1097/LGT.0000000000000637 -
ELife Jun 2024Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, the factors that control...
Durable serological memory following vaccination is critically dependent on the production and survival of long-lived plasma cells (LLPCs). Yet, the factors that control LLPC specification and survival remain poorly resolved. Using intravital two-photon imaging, we find that in contrast to most plasma cells (PCs) in the bone marrow (BM), LLPCs are uniquely sessile and organized into clusters that are dependent on APRIL, an important survival factor. Using deep, bulk RNA sequencing, and surface protein flow-based phenotyping, we find that LLPCs express a unique transcriptome and phenotype compared to bulk PCs, fine-tuning expression of key cell surface molecules, CD93, CD81, CXCR4, CD326, CD44, and CD48, important for adhesion and homing. Conditional deletion of in PCs following immunization leads to rapid mobilization from the BM, reduced survival of antigen-specific PCs, and ultimately accelerated decay of antibody titer. In naïve mice, the endogenous LLPCs BCR repertoire exhibits reduced diversity, reduced somatic mutations, and increased public clones and IgM isotypes, particularly in young mice, suggesting LLPC specification is non-random. As mice age, the BM PC compartment becomes enriched in LLPCs, which may outcompete and limit entry of new PCs into the LLPC niche and pool.
Topics: Animals; Mice; Plasma Cells; Mice, Inbred C57BL; Receptors, Cell Surface; Cell Survival; Receptors, CXCR4; Spatio-Temporal Analysis
PubMed: 38896451
DOI: 10.7554/eLife.89712 -
Cell Reports Aug 2018Plasma cell survival and the consequent duration of immunity vary widely with infection or vaccination. Using fluorescent glucose analog uptake, we defined multiple...
Plasma cell survival and the consequent duration of immunity vary widely with infection or vaccination. Using fluorescent glucose analog uptake, we defined multiple developmentally independent mouse plasma cell populations with varying lifespans. Long-lived plasma cells imported more fluorescent glucose analog, expressed higher surface levels of the amino acid transporter CD98, and had more autophagosome mass than did short-lived cells. Low amino acid concentrations triggered reductions in both antibody secretion and mitochondrial respiration, especially by short-lived plasma cells. To explain these observations, we found that glutamine was used for both mitochondrial respiration and anaplerotic reactions, yielding glutamate and aspartate for antibody synthesis. Endoplasmic reticulum (ER) stress responses, which link metabolism to transcriptional outcomes, were similar between long- and short-lived subsets. Accordingly, population and single-cell transcriptional comparisons across mouse and human plasma cell subsets revealed few consistent and conserved differences. Thus, plasma cell antibody secretion and lifespan are primarily defined by non-transcriptional metabolic traits.
Topics: Humans; Longevity; Plasma Cells
PubMed: 30157439
DOI: 10.1016/j.celrep.2018.07.084 -
Journal of the American Society of... Mar 2018The unique contributions of memory B cells and plasma cells in kidney diseases remain unclear. In this review, we evaluate the clinical experience with treatments... (Review)
Review
The unique contributions of memory B cells and plasma cells in kidney diseases remain unclear. In this review, we evaluate the clinical experience with treatments directed at B cells, such as rituximab, and at plasma cells, such as proteasome inhibition, to shed light on the role of these two B lineage compartments in glomerular diseases. Specifically, analysis of these targeted interventions in diseases such as ANCA-associated vasculitis, SLE, and antibody-mediated transplant rejection permits insight into the pathogenetic effect of these cells. Notwithstanding the limitations of preclinical models and clinical studies (heterogeneous populations, among others), the data suggest that memory B and plasma cells represent two engines of autoimmunity, with variable involvement in these diseases. Whereas memory B cells and plasma cells appear to be key in ANCA-associated vasculitis and antibody-mediated transplant rejection, respectively, SLE seems likely to be driven by both autoimmune compartments. These conclusions have implications for the future development of targeted therapeutics in immune-mediated renal disease.
Topics: Animals; Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis; Antibodies, Monoclonal; Autoimmunity; B-Lymphocytes; Cell Lineage; Graft Rejection; Humans; Immunologic Memory; Kidney Transplantation; Lupus Nephritis; Molecular Targeted Therapy; Plasma Cells
PubMed: 29326157
DOI: 10.1681/ASN.2017040367 -
Current Opinion in Immunology Dec 2014Immunoglobulin E (IgE) is pathogenic in allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and food allergy. Recent studies using genetically... (Review)
Review
Immunoglobulin E (IgE) is pathogenic in allergic diseases such as asthma, allergic rhinitis, atopic dermatitis, and food allergy. Recent studies using genetically modified IgE reporter mice indicate that the majority of serum IgE in mice is produced by short-lived IgE plasma cells, with minor contributions from long-lived IgE plasma cells, and implicate IgG1 and IgE memory B cells as potential sources of IgE memory. Clinical studies using antibodies against IL-13 or the IL-4 and IL-13 receptor subunit IL-4Rα, as well as an antibody against the M1 prime domain of human membrane IgE, indicate that, similar to mice, a proportion of IgE in humans is derived from ongoing IgE immune responses and short-lived plasma cells. Targeting IgE production may lead to new therapies for the treatment of allergic diseases.
Topics: Animals; Humans; Hypersensitivity; Immunoglobulin E; Immunologic Memory; Interleukin-13; Interleukin-4; Mice; Plasma Cells; Receptors, Cell Surface
PubMed: 25156315
DOI: 10.1016/j.coi.2014.08.001 -
Frontiers in Immunology 2022The differentiation of B cells into antibody-secreting plasma cells depends on cell division-coupled, epigenetic and other cellular processes that are incompletely...
INTRODUCTION
The differentiation of B cells into antibody-secreting plasma cells depends on cell division-coupled, epigenetic and other cellular processes that are incompletely understood.
METHODS
We have developed a CRISPR/Cas9-based screen that models an early stage of T cell-dependent plasma cell differentiation and measures B cell survival or proliferation versus the formation of CD138+ plasmablasts. Here, we refined and extended this screen to more than 500 candidate genes that are highly expressed in plasma cells.
RESULTS
Among known genes whose deletion preferentially or mostly affected plasmablast formation were the transcription factors Prdm1 (BLIMP1), Irf4 and Pou2af1 (OBF-1), and the Ern1 gene encoding IRE1a, while deletion of XBP1, the transcriptional master regulator that specifies the expansion of the secretory program in plasma cells, had no effect. Defective plasmablast formation caused by Ern1 deletion could not be rescued by the active, spliced form of XBP1 whose processing is dependent on and downstream of IRE1a, suggesting that in early plasma cell differentiation IRE1a acts independently of XBP1. Moreover, we newly identified several genes involved in NF-kB signaling (Nfkbia), vesicle trafficking (Arf4, Preb) and epigenetic regulators that form part of the NuRD complex (Hdac1, Mta2, Mbd2) to be required for plasmablast formation. Deletion of ARF4, a small GTPase required for COPI vesicle formation, impaired plasmablast formation and blocked antibody secretion. After Hdac1 deletion plasmablast differentiation was consistently reduced by about 50%, while deletion of the closely related Hdac2 gene had no effect. Hdac1 knock-out led to strongly perturbed protein expression of antagonistic transcription factors that govern plasma cell versus B cell identity (by decreasing IRF4 and BLIMP1 and increasing BACH2 and PAX5).
DISCUSSION
Taken together, our results highlight specific and non-redundant roles for Ern1, Arf4 and Hdac1 in the early steps of plasma cell differentiation.
Topics: CRISPR-Cas Systems; B-Lymphocytes; Plasma Cells; Cell Differentiation; Antibodies
PubMed: 36685499
DOI: 10.3389/fimmu.2022.1083119