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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 -
Advanced Science (Weinheim,... Sep 2023Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are...
Dermatitis herpetiformis (DH) is an inflammatory skin disorder often considered as an extra intestinal manifestation of celiac disease (CeD). Hallmarks of CeD and DH are auto-antibodies to transglutaminase 2 (TG2) and transglutaminase 3 (TG3), respectively. DH patients have auto-antibodies reactive with both transglutaminase enzymes. Here it is reported that in DH both gut plasma cells and serum auto-antibodies are specific for either TG2 or TG3 with no TG2-TG3 cross reactivity. By generating monoclonal antibodies from TG3-specific duodenal plasma cells of DH patients, three conformational epitope groups are defined. Both TG2-specific and TG3-specific gut plasma cells have few immunoglobulin (Ig) mutations, and the two transglutaminase-reactive populations show distinct selection of certain heavy and light chain V-genes. Mass spectrometry analysis of TG3-specific serum IgA corroborates preferential usage of IGHV2-5 in combination with IGKV4-1. Collectively, these results demonstrate parallel induction of anti-TG2 and anti-TG3 auto-antibody responses involving separate B-cell populations in DH patients.
Topics: Humans; Celiac Disease; Dermatitis Herpetiformis; Immunoglobulin A; Plasma Cells; Protein Glutamine gamma Glutamyltransferase 2; Transglutaminases
PubMed: 37424036
DOI: 10.1002/advs.202300401 -
Current Opinion in Immunology Dec 2019• Memory plasma cells are long-lived but require specialized niches for their survival. • Memory plasma cells are refractory to conventional immunosuppression. •... (Review)
Review
• Memory plasma cells are long-lived but require specialized niches for their survival. • Memory plasma cells are refractory to conventional immunosuppression. • Pathogenic memory plasma cells represent ‘roadblocks’ to response to conventional therapy. • Strategies for (selective) targeting of memory plasma cells are in preclinical and clinical tests.
Topics: Animals; Autoimmune Diseases; Autoimmunity; Cell Survival; Cellular Microenvironment; Humans; Immunologic Memory; Immunomodulation; Organ Specificity; Plasma Cells; Signal Transduction
PubMed: 31675681
DOI: 10.1016/j.coi.2019.09.005 -
Cellular & Molecular Immunology Jul 2018B cells have a critical role in the initiation and acceleration of autoimmune diseases, especially those mediated by autoantibodies. In the peripheral lymphoid system,... (Review)
Review
B cells have a critical role in the initiation and acceleration of autoimmune diseases, especially those mediated by autoantibodies. In the peripheral lymphoid system, mature B cells are activated by self or/and foreign antigens and signals from helper T cells for differentiating into either memory B cells or antibody-producing plasma cells. Accumulating evidence has shown that epigenetic regulations modulate somatic hypermutation and class switch DNA recombination during B-cell activation and differentiation. Any abnormalities in these complex regulatory processes may contribute to aberrant antibody production, resulting in autoimmune pathogenesis such as systemic lupus erythematosus. Newly generated knowledge from advanced modern technologies such as next-generation sequencing, single-cell sequencing and DNA methylation sequencing has enabled us to better understand B-cell biology and its role in autoimmune development. Thus this review aims to summarize current research progress in epigenetic modifications contributing to B-cell activation and differentiation, especially under autoimmune conditions such as lupus, rheumatoid arthritis and type 1 diabetes.
Topics: Animals; Autoimmunity; Cell Differentiation; DNA Methylation; Epigenesis, Genetic; Humans; Immunologic Memory; Lymphocyte Activation; Plasma Cells; Somatic Hypermutation, Immunoglobulin; T-Lymphocytes
PubMed: 29375128
DOI: 10.1038/cmi.2017.133 -
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 -
Frontiers in Immunology 2022Multiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms...
INTRODUCTION
Multiple myeloma (MM) is still an incurable plasma cell malignancy. The efficacy of immunotherapy on MM remains unsatisfactory, and the underlying molecular mechanisms still are not fully understood.
METHODS
In this study, we delineated the dynamic features of immune cell in MM bone marrow (BM) along with elevated tumor cell infiltration by single-cell RNA sequencing (scRNA-seq), and investigated the underlying mechanisms on dysfunction of immune cells associated with myelomagenesis.
RESULTS
We found that immune cells were activated in those patients with low infiltration of tumor cells, meanwhile suppressed with elevated infiltration of MM cells, which facilitated MM escaping from immune surveillance. Besides PD-1, abnormal expression of kinases, and were involved in the defect of immune cells in MM patients. Importantly, we found aberrant metabolic processes were associated with the immunosuppressive microenvironment in MM patients. Disordered amino acid metabolism promoted the dysfunction of cytotoxicity CD8 T cells as well as lipid metabolism disorder was associated with the dysregulation of NK and DCs in MM. As metabolic checkpoints, kinases would be potential effective strategies for MM immunotherapy.
DISCUSSION
In summary, redressing the disordered metabolism should be the key points to get promising effects in immune-based therapies.
Topics: Humans; Multiple Myeloma; Immunotherapy; Plasma Cells; Bone Marrow; Immunologic Surveillance; Tumor Microenvironment
PubMed: 36532059
DOI: 10.3389/fimmu.2022.1077768 -
Blood Jun 2022
Topics: Humans; Leukemia, Plasma Cell; Plasma Cells
PubMed: 35737405
DOI: 10.1182/blood.2022016032 -
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 -
Proceedings of the National Academy of... Jun 2022Antibodies are produced across multiple isotypes with distinct properties that coordinate initial antigen clearance and confer long-term antigen-specific immune...
Antibodies are produced across multiple isotypes with distinct properties that coordinate initial antigen clearance and confer long-term antigen-specific immune protection. Here, we interrogate the molecular programs of isotype-specific murine plasma cells (PC) following helper T cell-dependent immunization and within established steady-state immunity. We developed a single-cell-indexed and targeted molecular strategy to dissect conserved and divergent components of the rapid effector phase of antigen-specific IgM versus inflammation-modulating programs dictated by type 1 IgG2a/b PC differentiation. During antibody affinity maturation, the germinal center (GC) cycle imparts separable programs for post-GC type 2 inhibitory IgG1 and type 1 inflammatory IgG2a/b PC to direct long-term cellular function. In the steady state, two subsets of IgM and separate IgG2b PC programs clearly segregate from splenic type 3 IgA PC programs that emphasize mucosal barrier protection. These diverse isotype-specific molecular pathways of PC differentiation control complementary modules of antigen clearance and immune protection that could be selectively targeted for immunotherapeutic applications and vaccine design.
Topics: Animals; Antigens; Cell Differentiation; Germinal Center; Immunoglobulin G; Immunoglobulin M; Mice; Plasma Cells; Single-Cell Analysis; T-Lymphocytes, Helper-Inducer
PubMed: 35704755
DOI: 10.1073/pnas.2121260119 -
Journal of Immunology (Baltimore, Md. :... Apr 2022B cell differentiation is associated with substantial transcriptional, metabolic, and epigenetic remodeling, including redistribution of histone 3 lysine 27...
B cell differentiation is associated with substantial transcriptional, metabolic, and epigenetic remodeling, including redistribution of histone 3 lysine 27 trimethylation (H3K27me3), which is associated with a repressive chromatin state and gene silencing. Although the role of the methyltransferase EZH2 (Enhancer of zeste homolog 2) in B cell fate decisions has been well established, it is not known whether H3K27me3 demethylation is equally important. In this study, we showed that simultaneous genetic deletion of the two H3K27 demethylases UTX and JMJD3 (double-knockout [ ] [dKO]) led to a significant increase in plasma cell (PC) formation after stimulation with the T cell-independent Ags LPS and NP-Ficoll. This phenotype occurred in a UTX-dependent manner as UTX single-knockout mice, but not JMJD3 single-knockout mice, mimicked the dKO. Although UTX- and JMJD3-deficient marginal zone B cells showed increased proliferation, dKO follicular B cells also showed increased PC formation. PCs from dKO mice upregulated genes associated with oxidative phosphorylation and exhibited increased spare respiratory capacity. Mechanistically, deletion of and resulted in higher levels of H3K27me3 at proapoptotic genes and resulted in reduced apoptosis of dKO PCs in vivo. Furthermore, UTX regulated chromatin accessibility at regions containing ETS and IFN regulatory factor (IRF) transcription factor family motifs, including motifs of known repressors of PC fate. Taken together, these data demonstrate that the H3K27me3 demethylases restrain B cell differentiation.
Topics: Animals; Chromatin; Histone Demethylases; Histones; Jumonji Domain-Containing Histone Demethylases; Methylation; Mice; Plasma Cells
PubMed: 35346967
DOI: 10.4049/jimmunol.2100948