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Autophagy Nov 2021Scavenger receptors are pattern recognition receptors that recognize both foreign and self-ligands, and initiate different mechanisms of cellular activation, often as...
Scavenger receptors are pattern recognition receptors that recognize both foreign and self-ligands, and initiate different mechanisms of cellular activation, often as co-receptors. The function of scavenger receptor CD36 in the immune system has mostly been studied in macrophages but it is also highly expressed by innate type B cells where its function is less explored. Here we report that CD36 is involved in macro-autophagy/autophagy in B cells, and in its absence, the humoral immune response is impaired. We found that CD36-deficient B cells exhibit a significantly reduced plasma cell formation, proliferation, mitochondrial mobilization and oxidative phosphorylation. These changes were accompanied by impaired initiation of autophagy, and we found that CD36 regulated autophagy and colocalized with autophagosome membrane protein MAP1LC3/LC3 (microtubule-associated protein 1 light chain 3). When we investigated T-cell-dependent immune responses, we found that mice with CD36 deficiency, specifically in B cells, exhibited attenuated germinal center responses, class switching, and antibody production as well as autophagosome formation. These findings establish a critical role for CD36 in B cell responses and may also contribute to our understanding of CD36-mediated autophagy in other cells as well as in B cell lymphomas that have been shown to express the receptor. AICDA/AID: activation-induced cytidine deaminase; ATG5: autophagy related 5; ATP: adenosine triphosphate; BCR: B-cell receptor; CPG: unmethylated cytosine-guanosine; CQ: chloroquine; DC: dendritic cells; FOB: follicular B cells; GC: germinal center; Ig: immunoglobulin; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MFI: mean fluorescence intensity; MZB: marginal zone B cells; NP-CGG: 4-hydroxy-3-nitrophenylacetyl-chicken gamma globulin; OCR: oxygen consumption rate; oxLDL: oxidized low-density lipoprotein; PC: plasma cells; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; SRBC: sheep red blood cells; Tfh: follicular helper T cells; TLR: toll-like receptor.
Topics: Animals; Autophagosomes; Autophagy; B-Lymphocytes; CD36 Antigens; Cell Differentiation; Cell Proliferation; Humans; Immunity, Humoral; Immunoglobulin Class Switching; Mice; Microtubule-Associated Proteins; Plasma Cells; T-Lymphocytes
PubMed: 33535890
DOI: 10.1080/15548627.2021.1885183 -
ELife Aug 2021Despite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to...
Despite the mechanisms of central and peripheral tolerance, the mature B cell compartment contains cells reactive for self-antigen. How these cells are poised not to respond and the mechanisms that restrain B cell responses to low-affinity endogenous antigens are not fully understood. Here, we demonstrate a critical role for the glycan-binding protein galectin-9 in setting the threshold of B cell activation and that loss of this regulatory network is sufficient to drive spontaneous autoimmunity. We further demonstrate a critical role for galectin-9 in restraining not only conventional B-2 B cells, but also innate-like B-1a cells. We show that galectin-9-deficient mice have an expanded population of B-1a cells and increased titers of B-1a-derived autoantibodies. Mechanistically, we demonstrate that galectin-9 regulates BCR and distinct TLR responses in B-1a cells, but not B-1b cells, by regulating the interaction between BCR and TLRs with the regulatory molecules CD5 and CD180, respectively. In the absence of galectin-9, B-1a cells are more readily activated and secrete increased titers of autoantibodies that facilitate autoantigen delivery to the spleen, driving autoimmune responses.
Topics: Age Factors; Animals; Autoimmunity; B-Lymphocytes; Galectins; Germinal Center; Mice; Nephritis; Splenomegaly
PubMed: 34369876
DOI: 10.7554/eLife.64557 -
Cellular & Molecular Immunology Jun 2020In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal... (Review)
Review
In contrast to the previous belief that autoreactive B cells are eliminated from the normal repertoire of B cells, many autoreactive B cells actually escape clonal deletion and develop into mature B cells. These autoreactive B cells in healthy individuals perform some beneficial functions in the host and are homeostatically regulated by regulatory T and B cells or other mechanisms to prevent autoimmune diseases. Autoreactive B-1 cells constitutively produce polyreactive natural antibodies for tissue homeostasis. Recently, autoreactive follicular B cells were reported to participate actively in the germinal center reaction. Furthermore, the selection and usefulness of autoreactive marginal zone (MZ) B cells found in autoimmune diseases are not well understood, although the repertoire of MZ B-cell receptors (BCRs) is presumed to be biased to detect bacterial antigens. In this review, we discuss the autoreactive B-cell populations among all three major B-cell subsets and their regulation in immune responses and diseases.
Topics: Animals; Antibody Formation; B-Lymphocytes; Disease; Health; Homeostasis; Humans; Immunity
PubMed: 32382130
DOI: 10.1038/s41423-020-0445-4 -
Frontiers in Immunology 2021B cells form a branch of the adaptive immune system, essential for the body's immune defense against pathogens. B cell dysfunction has been implicated in the... (Review)
Review
B cells form a branch of the adaptive immune system, essential for the body's immune defense against pathogens. B cell dysfunction has been implicated in the pathogenesis of immune mediated liver diseases including autoimmune hepatitis, IgG4-related hepatobiliary disease, primary biliary cholangitis and primary sclerosing cholangitis. B cells may initiate and maintain immune related liver diseases in several ways including the production of autoantibodies and the activation of T cells via antigen presentation or cytokine production. Here we comprehensively review current knowledge on B cell mechanisms in immune mediated liver diseases, exploring disease pathogenesis, B cell therapies, and novel treatment targets. We identify key areas where future research should focus to enable the development of targeted B cell therapies.
Topics: Animals; Autoantibodies; B-Lymphocytes; Cholangitis, Sclerosing; Clinical Trials as Topic; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunotherapy; Liver; Liver Cirrhosis, Biliary; Liver Diseases; Mice
PubMed: 33936097
DOI: 10.3389/fimmu.2021.661196 -
Frontiers in Immunology 2023Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes... (Review)
Review
Autoimmune diseases are heterogeneous disorders believed to stem from the immune system's inability to distinguish between auto- and foreign- antigens. B lymphocytes serve a crucial role in humoral immunity as they generate antibodies and present antigens. Dysregulation of B cell function induce the onset of autoimmune disorders by generating autoantibodies and pro-inflammatory cytokines, resulting in an imbalance in immune regulation. New research in immunometabolism shows that cellular metabolism plays an essential role in controlling B lymphocytes immune reactions by providing the energy and substrates for B lymphocytes activation, differentiation, and function. However, dysregulated immunometabolism lead to autoimmune diseases by disrupting self-tolerance mechanisms. This review summarizes the latest research on metabolic reprogramming of B lymphocytes in autoimmune diseases, identifying crucial pathways and regulatory factors. Moreover, we consider the potential of metabolic interventions as a promising therapeutic strategy. Understanding the metabolic mechanisms of B cells brings us closer to developing novel therapies for autoimmune disorders.
Topics: Humans; Autoimmune Diseases; B-Lymphocytes; Autoantibodies; Immunity, Humoral; Signal Transduction
PubMed: 37680644
DOI: 10.3389/fimmu.2023.1232820 -
Viral Immunology May 2020Gammaherpesviruses are highly prevalent pathogens that establish life-long infection and are associated with diverse malignancies, including lymphoproliferative diseases... (Review)
Review
Gammaherpesviruses are highly prevalent pathogens that establish life-long infection and are associated with diverse malignancies, including lymphoproliferative diseases and B cell lymphomas. Unlike other viruses that either do not infect B cells or infect B cells transiently, gammaherpesviruses manipulate physiological B cell differentiation to establish life-long infection in memory B cells. Disruption of such viral manipulation by genetic or environmental causes is likely to seed viral lymphomagenesis. In this review, we discuss physiological and unique host and viral mechanisms usurped by gammaherpesviruses to fine tune host B cell biology for optimal infection establishment and maintenance.
Topics: B-Lymphocytes; Cell Differentiation; Gammaherpesvirinae; Herpesviridae Infections; Host-Pathogen Interactions; Humans; Lymphocyte Activation; Viral Proteins
PubMed: 31913773
DOI: 10.1089/vim.2019.0126 -
Frontiers in Immunology 2022Systemic sclerosis (SSc) is a rare multisystem autoimmune disease, characterized by fibrosis, vasculopathy, and autoimmunity. Recent advances have highlighted the... (Review)
Review
Systemic sclerosis (SSc) is a rare multisystem autoimmune disease, characterized by fibrosis, vasculopathy, and autoimmunity. Recent advances have highlighted the significant implications of B-cells in SSc. B-cells are present in affected organs, their subpopulations are disrupted, and they display an activated phenotype, and the regulatory capacities of B-cells are impaired, as illustrated by the decrease in the IL-10+ producing B-cell subpopulation or the inhibitory membrane co-receptor density. Recent multi-omics evidence highlights the role of B-cells mainly in the early stage of SSc and preferentially during severe organ involvement. This dysregulated homeostasis partly explains the synthesis of anti-endothelial cell autoantibodies (AECAs) or anti-fibroblast autoantibodies (AFAs), proinflammatory or profibrotic cytokines (interleukin-6 and transforming growth factor-β) produced by B and plasma cells. That is associated with cell-to-cell interactions with endothelial cells, fibroblasts, vascular smooth muscle cells, and other immune cells, altogether leading to cell activation and proliferation, cell resistance to apoptosis, the impairment of regulatory mechanisms, and causing fibrosis of several organs encountered in the SSc. Finally, alongside these exploratory data, treatments targeting B-cells, through their depletion by cytotoxicity (anti-CD20 monoclonal antibody), or the cytokines produced by the B-cell, or their costimulation molecules, seem interesting, probably in certain profiles of early patients with severe organic damage.
Topics: Autoantibodies; B-Lymphocytes; Cytokines; Endothelial Cells; Fibrosis; Humans; Scleroderma, Systemic
PubMed: 35903091
DOI: 10.3389/fimmu.2022.933468 -
Nature Jul 2020Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer. Here we analyse 1,148 patient-derived B-cell...
Malignant transformation of cells typically involves several genetic lesions, whose combined activity gives rise to cancer. Here we analyse 1,148 patient-derived B-cell leukaemia (B-ALL) samples, and find that individual mutations do not promote leukaemogenesis unless they converge on one single oncogenic pathway that is characteristic of the differentiation stage of transformed B cells. Mutations that are not aligned with this central oncogenic driver activate divergent pathways and subvert transformation. Oncogenic lesions in B-ALL frequently mimic signalling through cytokine receptors at the pro-B-cell stage (via activation of the signal-transduction protein STAT5) or pre-B-cell receptors in more mature cells (via activation of the protein kinase ERK). STAT5- and ERK-activating lesions are found frequently, but occur together in only around 3% of cases (P = 2.2 × 10). Single-cell mutation and phospho-protein analyses reveal the segregation of oncogenic STAT5 and ERK activation to competing clones. STAT5 and ERK engage opposing biochemical and transcriptional programs that are orchestrated by the transcription factors MYC and BCL6, respectively. Genetic reactivation of the divergent (suppressed) pathway comes at the expense of the principal oncogenic driver and reverses transformation. Conversely, deletion of divergent pathway components accelerates leukaemogenesis. Thus, persistence of divergent signalling pathways represents a powerful barrier to transformation, while convergence on one principal driver defines a central event in leukaemia initiation. Pharmacological reactivation of suppressed divergent circuits synergizes strongly with inhibition of the principal oncogenic driver. Hence, reactivation of divergent pathways can be leveraged as a previously unrecognized strategy to enhance treatment responses.
Topics: Animals; B-Lymphocytes; Cell Line, Tumor; Cell Transformation, Neoplastic; Enzyme Activation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Leukemia, B-Cell; Mice; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Proto-Oncogene Proteins c-bcl-6; Proto-Oncogene Proteins c-myc; STAT5 Transcription Factor; Signal Transduction
PubMed: 32699415
DOI: 10.1038/s41586-020-2513-4 -
Current Opinion in Immunology Oct 2021Stringent regulation of IgE antibody production is critical for constraining allergic responses. This review discusses recent advances in understanding cell-intrinsic... (Review)
Review
Stringent regulation of IgE antibody production is critical for constraining allergic responses. This review discusses recent advances in understanding cell-intrinsic and extrinsic mechanisms that regulate the genesis and fate of IgE B cells. B cell-intrinsic regulation of IgE is orchestrated by the IgE B Cell Receptor (BCR). Through its antigen-independent signaling and low surface expression, the IgE BCR drives IgE B cells to differentiate into short-lived plasma cells and/or undergo apoptosis, restricting IgE-expressing cells from entering long-lived compartments. The pivotal extrinsic regulators of IgE responses are T follicular helper cells (T). T produce IL-4 and IL-21, which, respectively, are the major activating and inhibitory cytokines for IgE class-switching. Other newly identified T follicular subsets also contribute to IgE regulation. Although IgE responses are normally constrained, recent studies suggest that specific conditions can induce the formation of IgE responses with enhanced affinity or longevity, effectively 'breaking the rules' of IgE regulation.
Topics: Animals; Antibody Formation; Apoptosis; B-Lymphocytes; Cytokines; Disease Susceptibility; Gene Expression Regulation; Germinal Center; Humans; Hypersensitivity; Immunoglobulin E; Immunologic Memory; Immunomodulation; Plasma Cells; Receptors, Antigen, B-Cell
PubMed: 34216934
DOI: 10.1016/j.coi.2021.06.005 -
Cells May 2021Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of... (Review)
Review
Autoreactive B cells are key drivers of pathogenic processes in autoimmune diseases by the production of autoantibodies, secretion of cytokines, and presentation of autoantigens to T cells. However, the mechanisms that underlie the development of autoreactive B cells are not well understood. Here, we review recent studies leveraging novel techniques to identify and characterize (auto)antigen-specific B cells. The insights gained from such studies pertaining to the mechanisms involved in the escape of tolerance checkpoints and the activation of autoreactive B cells are discussed. In addition, we briefly highlight potential therapeutic strategies to target and eliminate autoreactive B cells in autoimmune diseases.
Topics: Animals; Autoimmune Diseases; Autoimmunity; B-Lymphocytes; Humans; Immune Checkpoint Proteins; Immune Tolerance; Lymphocyte Activation; Phenotype
PubMed: 34068035
DOI: 10.3390/cells10051190