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The Journal of Experimental Medicine Jun 2023Here, we report on a heterozygous interferon regulatory factor 4 (IRF4) missense variant identified in three patients from a multigeneration family with...
Here, we report on a heterozygous interferon regulatory factor 4 (IRF4) missense variant identified in three patients from a multigeneration family with hypogammaglobulinemia. Patients' low blood plasmablast/plasma cell and naïve CD4 and CD8 T cell counts contrasted with high terminal effector CD4 and CD8 T cell counts. Expression of the mutant IRF4 protein in control lymphoblastoid B cell lines reduced the expression of BLIMP-1 and XBP1 (key transcription factors in plasma cell differentiation). In B cell lines, the mutant IRF4 protein as wildtype was found to bind to known IRF4 binding motifs. The mutant IRF4 failed to efficiently regulate the transcriptional activity of interferon-stimulated response elements (ISREs). Rapid immunoprecipitation mass spectrometry of endogenous proteins indicated that the mutant and wildtype IRF4 proteins differed with regard to their respective sets of binding partners. Our findings highlight a novel mechanism for autosomal-dominant primary immunodeficiency through altered protein binding by mutant IRF4 at ISRE, leading to defective plasma cell differentiation.
Topics: Humans; B-Lymphocytes; Cell Differentiation; Interferon Regulatory Factors; Mutation; Plasma Cells
PubMed: 36917008
DOI: 10.1084/jem.20221292 -
Scandinavian Journal of Immunology Sep 2015Persistent humoral immunity depends on the follicular B cell response and on the generation of somatically mutated high-affinity plasma cells and memory B cells. Upon... (Review)
Review
Persistent humoral immunity depends on the follicular B cell response and on the generation of somatically mutated high-affinity plasma cells and memory B cells. Upon activation by an antigen, cognately activated follicular B cells and follicular T helper (TFH ) cells initiate germinal centre (GC) reaction during which high-affinity effector cells are generated. The differentiation of activated follicular B cells into plasma cells and memory B cells is guided by complex selection events, both at the cellular and molecular level. The transition of B cell into a plasma cell during the GC response involves alterations in the microenvironment and developmental state of the cell, which are guided by cell-extrinsic signals. The developmental cell fate decisions in response to these signals are coordinated by cell-intrinsic gene regulatory network functioning at epigenetic, transcriptional and post-transcriptional levels.
Topics: Cell Differentiation; Cellular Microenvironment; Chemokines; Gene Expression Regulation; Gene Regulatory Networks; Germinal Center; Humans; Immunity, Humoral; Lymphocyte Activation; Plasma Cells; Signal Transduction; T-Lymphocytes, Helper-Inducer
PubMed: 26118840
DOI: 10.1111/sji.12336 -
Frontiers in Immunology 2022The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic... (Review)
Review
The modulation of inflammatory (auto)immune reactions by nutrients and gut bacterial metabolites is of great interest for potential preventive and therapeutic strategies. B cell-derived plasma cells are major players in inflammatory (auto)immune responses and can exhibit pro- or anti-inflammatory effects through (auto)antibody-dependent and -independent functions. Emerging evidence indicates a key role of nutrients and microbial metabolites in regulating the differentiation of plasma cells as well as their differentiation to pro- or anti-inflammatory phenotypes. These effects might be mediated indirectly by influencing other immune cells or directly through B cell-intrinsic mechanisms. Here, we provide an overview of nutrients and metabolites that influence B cell-intrinsic signaling pathways regulating B cell activation, plasma cell differentiation, and effector functions. Furthermore, we outline important inflammatory plasma cell phenotypes whose differentiation could be targeted by nutrients and microbial metabolites. Finally, we discuss possible implications for inflammatory (auto)immune conditions.
Topics: Plasma Cells; Autoimmunity; Cell Differentiation; B-Lymphocytes; Nutrients
PubMed: 36466846
DOI: 10.3389/fimmu.2022.1004644 -
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 -
Transplant International : Official... 2022Autoimmune hepatitis (AIH), post-transplant recurrent AIH (rAIH), and plasma cell-rich rejection (PCR) are clinical diagnoses with the shared histopathologic hallmark of...
Autoimmune hepatitis (AIH), post-transplant recurrent AIH (rAIH), and plasma cell-rich rejection (PCR) are clinical diagnoses with the shared histopathologic hallmark of plasma cell hepatitis (PCH). As these histologically and serologically indistinguishable diagnoses are differentiated by clinical context, it remains uncertain whether they represent distinct immunologic phenomena. Improved understanding of immunoglobulin subclass 4-producing plasma cells (IgG4-PC) has brought attention to IgG4 as an immunophenotypic biomarker. To date, degree and clinical significance of IgG4-PC infiltration in PCH remain elusive. This retrospective, single-center study assessed IgG4-PC infiltration in AIH, rAIH, and PCR via standardized immunohistochemistry analysis. Identified cases from 2005 to 2020 ( = 47) included AIH (treatment-naïve AIH (tnAIH): n = 15 and AIH-flare on treatment (fAIH); = 10), rAIH ( = 8), and PCR ( = 14) were analyzed and correlated with clinical characteristics. IgG4-Positivity (# IgG4-PC/# pan-IgG-expressing cells) distribution was heterogenous and overlapping [tnAIH: 0.060 (IQR 0.040-0.079), fAIH: 0.000 (0.000-0.033), rAIH: 0.000 (0.000-0.035), PCR: 0.228 (0.039-0.558)]. IgG4-Positivity was inversely correlated with corticosteroid use ( < 0.001). IgG4-Positivity ≥0.500 was associated with rapid AST improvement ( = 0.03). The variable IgG4-Positivity of AIH, rAIH and PCR suggests diverse and overlapping immunopathologic mechanisms and that current diagnostic schemes inadequately capture PCH immunopathology. We propose incorporation of IgG4-Positivity to refine current PCH classification and treatment strategies.
Topics: Hepatitis, Autoimmune; Humans; Immunoglobulin G; Plasma Cells; Retrospective Studies; Transplants
PubMed: 35368647
DOI: 10.3389/ti.2022.10182 -
The FEBS Journal Jul 2022Prophylactic, serological memory relies on maintaining stable reservoirs of plasma cells, capable of constitutively-secreting high-affinity, anti-pathogen antibody for... (Review)
Review
Prophylactic, serological memory relies on maintaining stable reservoirs of plasma cells, capable of constitutively-secreting high-affinity, anti-pathogen antibody for a lifetime. Although antibody titers generated by some vaccines (e.g. measles) can last a lifetime, other vaccinations (e.g. tetanus) need repeated boosting because long-lived plasma cells are not produced or maintained. Moreover, in old age, the ability to generate long-lived humoral responses diminishes. Despite their importance to health, it is unknown how long-lived plasma cells survive over years, whereas most antibody secreting cells die off within weeks after vaccination. In this review, we focus on how known factors regulate the longevity of plasma cell fitness and survival, and how that landscape is shaped by environmental influences, such as inflammation, infection and aging. In addition, we highlight newly discovered cellular dynamics in the bone marrow that may reframe the mechanisms supporting long-lived plasma cell survival and function.
Topics: Antibody-Producing Cells; Bone Marrow; Bone Marrow Cells; Immunologic Memory; Plasma Cells
PubMed: 35114061
DOI: 10.1111/febs.16385 -
Journal of Autoimmunity Apr 2023A majority of circulating IgG is produced by plasma cells residing in the bone marrow (BM). Long-lived BM plasma cells constitute our humoral immune memory and are...
A majority of circulating IgG is produced by plasma cells residing in the bone marrow (BM). Long-lived BM plasma cells constitute our humoral immune memory and are essential for infection-specific immunity. They may also provide a reservoir of potentially pathogenic autoantibodies, including rheumatoid arthritis (RA)-associated anti-citrullinated protein autoantibodies (ACPA). Here we investigated paired human BM plasma cell and peripheral blood (PB) B-cell repertoires in seropositive RA, four ACPA+ RA patients and one ACPA- using two different single-cell approaches, flow cytometry sorting, and transcriptomics, followed by recombinant antibody generation. Immunoglobulin (Ig) analysis of >900 paired heavy-light chains from BM plasma cells identified by either surface CD138 expression or transcriptome profiles (including gene expression of MZB1, JCHAIN and XBP1) demonstrated differences in IgG/A repertoires and N-linked glycosylation between patients. For three patients, we identified clonotypes shared between BM plasma cells and PB memory B cells. Notably, four individuals displayed plasma cells with identical heavy chains but different light chains, which may indicate receptor revision or clonal convergence. ACPA-producing BM plasma cells were identified in two ACPA+ patients. Three of 44 recombinantly expressed monoclonal antibodies from ACPA+ RA BM plasma cells were CCP2+, specifically binding to citrullinated peptides. Out of these, two clones reacted with citrullinated histone-4 and activated neutrophils. In conclusion, single-cell investigation of B-cell repertoires in RA bone marrow provided new understanding of human plasma cells clonal relationships and demonstrated pathogenically relevant disease-associated autoantibody expression in long-lived plasma cells.
Topics: Humans; Autoantibodies; Plasma Cells; Citrulline; Bone Marrow; Arthritis, Rheumatoid; Clone Cells; Immunoglobulin G; Peptides, Cyclic
PubMed: 37001434
DOI: 10.1016/j.jaut.2023.103022 -
Journal of Translational Medicine Feb 2022B cell maturation antigen (BCMA), a transmembrane glycoprotein member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17), highly expressed on the plasma... (Review)
Review
B cell maturation antigen (BCMA), a transmembrane glycoprotein member of the tumor necrosis factor receptor superfamily 17 (TNFRSF17), highly expressed on the plasma cells of Multiple myeloma (MM) patients, as well as the normal population. BCMA is used as a biomarker for MM. Two members of the TNF superfamily proteins, including B-cell activating factor (BAFF) and A proliferation-inducing ligand (APRIL), are closely related to BCMA and play an important role in plasma cell survival and progression of MM. Despite the maximum specificity of the monoclonal antibody technologies, introducing the tumor-specific antigen(s) is not applicable for all malignancies, such as MM that there plenty of relatively specific antigens such as GPCR5D, MUC1, SLAMF7 and etc., but higher expression of BCMA on these cells in comparison with normal ones can be regarded as a relatively exclusive marker. Currently, different monoclonal antibody (mAb) technologies applied in anti-MM therapies such as daratuzumab, SAR650984, GSK2857916, and CAR-T cell therapies are some of these tools that are reviewed in the present manuscript. By the way, the structure, function, and signaling of the BCMA and related molecule(s) role in normal plasma cells and MM development, evaluated as well as the potential side effects of its targeting by different CAR-T cells generations. In conclusion, BCMA can be regarded as an ideal molecule to be targeted in immunotherapeutic methods, regarding lower potential systemic and local side effects.
Topics: B-Cell Maturation Antigen; Humans; Immunotherapy; Immunotherapy, Adoptive; Multiple Myeloma; Plasma Cells
PubMed: 35144648
DOI: 10.1186/s12967-022-03285-y -
Mucosal Immunology Apr 2022Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral...
Krüppel-like factor 2 (KLF2) is a potent regulator of lymphocyte differentiation, activation and migration. However, its functional role in adaptive and humoral immunity remains elusive. Therefore, by using mice with a B cell-specific deletion of KLF2, we investigated plasma cell differentiation and antibody responses. We revealed that the deletion of KLF2 resulted in perturbed IgA plasma cell compartmentalization, characterized by the absence of IgA plasma cells in the bone marrow, their reductions in the spleen, the blood and the lamina propria of the colon and the small intestine, concomitant with their accumulation and retention in mesenteric lymph nodes and Peyer's patches. Most intriguingly, secretory IgA in the intestinal lumen was almost absent, dimeric serum IgA was drastically reduced and antigen-specific IgA responses to soluble Salmonella flagellin were blunted in KLF2-deficient mice. Perturbance of IgA plasma cell localization was caused by deregulation of CCR9, Integrin chains αM, α4, β7, and sphingosine-1-phosphate receptors. Hence, KLF2 not only orchestrates the localization of IgA plasma cells by fine-tuning chemokine receptors and adhesion molecules but also controls IgA responses to Salmonella flagellin.
Topics: Animals; Flagellin; Immunoglobulin A; Intestinal Mucosa; Kruppel-Like Transcription Factors; Mice; Peyer's Patches; Plasma Cells
PubMed: 35347229
DOI: 10.1038/s41385-022-00503-0 -
American Journal of Transplantation :... Aug 2020Despite new immunotherapies aimed at B and T cells, plasma cells and their lifelong antibody secretion constitute a major immune barrier to long-term graft survival. In... (Review)
Review
Despite new immunotherapies aimed at B and T cells, plasma cells and their lifelong antibody secretion constitute a major immune barrier to long-term graft survival. In this mini-review, we survey the recent advances that have been made in the biology and immunometabolism of long-lived plasma cells, and outline aspects of plasma cell function that can be exploited for clinical benefit in recipients of solid organ transplants. A handful of ongoing studies are already targeting plasma cells to achieve desensitization and reduce the alloantibody burden in individuals posttransplant. In reviewing the recent strides made in our understanding of the molecular basis of plasma cell survival, we will place our discussions in the context of existing preclinical and clinical studies.
Topics: Graft Rejection; Graft Survival; Humans; Isoantibodies; Organ Transplantation; Plasma Cells; T-Lymphocytes
PubMed: 32034987
DOI: 10.1111/ajt.15813