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Cellular & Molecular Immunology Aug 2023Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid...
Autoantibodies produced by B cells play a pivotal role in the pathogenesis of systemic lupus erythematosus (SLE). However, both the cellular source of antiphospholipid antibodies and their contributions to the development of lupus nephritis (LN) remain largely unclear. Here, we report a pathogenic role of anti-phosphatidylserine (PS) autoantibodies in the development of LN. Elevated serum PS-specific IgG levels were measured in model mice and SLE patients, especially in those with LN. PS-specific IgG accumulation was found in the kidney biopsies of LN patients. Both transfer of SLE PS-specific IgG and PS immunization triggered lupus-like glomerular immune complex deposition in recipient mice. ELISPOT analysis identified B1a cells as the main cell type that secretes PS-specific IgG in both lupus model mice and patients. Adoptive transfer of PS-specific B1a cells accelerated the PS-specific autoimmune response and renal damage in recipient lupus model mice, whereas depletion of B1a cells attenuated lupus progression. In culture, PS-specific B1a cells were significantly expanded upon treatment with chromatin components, while blockade of TLR signal cascades by DNase I digestion and inhibitory ODN 2088 or R406 treatment profoundly abrogated chromatin-induced PS-specific IgG secretion by lupus B1a cells. Thus, our study has demonstrated that the anti-PS autoantibodies produced by B1 cells contribute to lupus nephritis development. Our findings that blockade of the TLR/Syk signaling cascade inhibits PS-specific B1-cell expansion provide new insights into lupus pathogenesis and may facilitate the development of novel therapeutic targets for the treatment of LN in SLE.
Topics: Humans; Mice; Animals; Lupus Nephritis; B-Lymphocyte Subsets; Lupus Erythematosus, Systemic; Autoantibodies; Antibodies, Antiphospholipid; Chromatin; Immunoglobulin G
PubMed: 37291237
DOI: 10.1038/s41423-023-01049-2 -
Frontiers in Immunology 2023Generalized anxiety disorder (GAD) is a prevalent emotional disorder that has received relatively little attention regarding its immunological basis. Recent years have...
BACKGROUND
Generalized anxiety disorder (GAD) is a prevalent emotional disorder that has received relatively little attention regarding its immunological basis. Recent years have seen the widespread use of high-density genetic markers such as SNPs or CNVs for genotyping, as well as the advancement of genome-wide association studies (GWAS) technologies, which have facilitated the understanding of immunological mechanisms underlying several major psychiatric disorders. Despite these advancements, the immunological basis of GAD remains poorly understood. In light of this, we aimed to explore the causal relationship between immune cells and the disease through a Mendelian randomization study.
METHODS
The summary information for GAD (Ncase=4,666, Ncontrol=337,577) was obtained from the FinnGen dataset. Summary statistics for the characterization of 731 immune cells, including morphological parameters (MP=32), median fluorescence intensity (MFI=389), absolute cells (AC=118), and relative cells (RC=192), were derived from the GWAS catalog. The study involved both forward MR analysis, with immune cell traits as the exposure and GAD as the outcome, and reverse MR analysis, with GAD as the exposure and immune cell traits as the outcome. We performed extensive sensitivity analyses to confirm the robustness, heterogeneity, and potential multi-biological effects of the study results. Also, to control for false positive results during multiple hypothesis testing, we adopted a false discovery rate (FDR) to control for statistical bias due to multiple comparisons.
RESULTS
After FDR correction, GAD had no statistically significant effect on immunophenotypes. Several phenotypes with unadjusted low P-values are worth mentioning, including decreased PB/PC levels on B cells(β=-0.289, 95%CI=0.044~0.194, =0.002), reduced PB/PC AC in GAD patients (β=-0.270, 95% CI=0.77~0.92, =0.000), and diminished PB/PC on lymphocytes (β=-0.315, 95% CI=0.77~0.93, =0.001). GAD also exerted a causal effect on CD27 on IgD-CD38br (β=-0.155,95%CI=0.78~0.94,=0.002), CD20-%B cell (β= -0.105,95% CI=0.77~0.94, =0.002), IgD-CD38br%lymphocyte(β=-0.305, 95%CI=0.79~0.95, =0.002), FSC-A level on granulocytes (β=0.200, 95%CI=0.75~0.91, =8.35×10), and CD4RA on TD CD4+(β=-0.150, 95% CI=0.82~1.02, =0.099). Furthermore, Two lymphocyte subsets were identified to be significantly associated with GAD risk: CD24+ CD27+ B cell (OR=1.066,95%CI=1.04~1.10,=1.237×10),CD28+CD4+T cell (OR=0.927, 95%CI=0.89~0.96, =8.085×10).
CONCLUSION
The study has shown the close association between immune cells and GAD through genetic methods, thereby offering direction for future clinical research.
Topics: Humans; Genome-Wide Association Study; Mendelian Randomization Analysis; Anxiety Disorders; Granulocytes; B-Lymphocytes
PubMed: 38264647
DOI: 10.3389/fimmu.2023.1338083 -
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 -
Genes & Development Aug 2023Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic... (Review)
Review
Rapid advances in genomics have opened unprecedented possibilities to explore the mutational landscapes in malignant diseases, such as B-cell acute lymphoblastic leukemia (B-ALL). This disease is manifested as a severe defect in the production of normal blood cells due to the uncontrolled expansion of transformed B-lymphocyte progenitors in the bone marrow. Even though classical genetics identified translocations of transcription factor-coding genes in B-ALL, the extent of the targeting of regulatory networks in malignant transformation was not evident until the emergence of large-scale genomic analyses. There is now evidence that many B-ALL cases present with mutations in genes that encode transcription factors with critical roles in normal B-lymphocyte development. These include , , , and , all of which are targeted by translocations or, more commonly, partial inactivation in cases of B-ALL. Even though there is support for the notion that germline polymorphisms in the and genes predispose for B-ALL, the majority of leukemias present with somatic mutations in transcription factor-encoding genes. These genetic aberrations are often found in combination with mutations in genes that encode components of the pre-B-cell receptor or the IL-7/TSLP signaling pathways, all of which are important for early B-cell development. This review provides an overview of our current understanding of the molecular interplay that occurs between transcription factors and signaling events during normal and malignant B-lymphocyte development.
Topics: Humans; Transcription Factors; Gene Expression Regulation; Leukemia; Mutation; Translocation, Genetic; B-Lymphocytes
PubMed: 37673459
DOI: 10.1101/gad.349879.122 -
Frontiers in Immunology 2023A hallmark of T cell dependent (TD) humoral immune responses is the generation of long-lived memory B cells. The generation of these cells occurs primarily in the... (Review)
Review
A hallmark of T cell dependent (TD) humoral immune responses is the generation of long-lived memory B cells. The generation of these cells occurs primarily in the germinal center (GC) reaction, where antigen-activated B cells undergo affinity maturation as a major consequence of the combined processes of proliferation, somatic hypermutation of their immunoglobulin V (IgV) region genes, and selection for improved affinity of their B-cell antigen receptors. As many B cells also undergo class-switching to IgG or IgA in these TD responses, there was traditionally a focus on class-switched memory B cells in both murine and human studies on memory B cells. However, it has become clear that there is also a large subset of IgM-expressing memory B cells, which have important phenotypic and functional similarities but also differences to class-switched memory B cells. There is an ongoing discussion about the origin of distinct subsets of human IgM B cells with somatically mutated IgV genes. We argue here that the vast majority of human IgM-expressing B cells with somatically mutated IgV genes in adults is indeed derived from GC reactions, even though a generation of some mostly lowly mutated IgM B cells from other differentiation pathways, mainly in early life, may exist.
Topics: Adult; Humans; Animals; Mice; B-Lymphocyte Subsets; Memory B Cells; Immunologic Memory; Immunoglobulin M; B-Lymphocytes; Immunoglobulin Variable Region
PubMed: 38143767
DOI: 10.3389/fimmu.2023.1308378 -
Frontiers in Immunology 2023NF-κB signaling is essential to an effective innate and adaptive immune response. Many immune-specific functional and developmental outcomes depend in large on NF-κB.... (Review)
Review
NF-κB signaling is essential to an effective innate and adaptive immune response. Many immune-specific functional and developmental outcomes depend in large on NF-κB. The formidable task of sorting out the mechanisms behind the regulation and outcome of NF-κB signaling remains an important area of immunology research. Here we briefly discuss the role of NF-κB in regulating cell fate decisions at various times in the path of B cell development, activation, and the generation of long-term humoral immunity.
Topics: NF-kappa B; Signal Transduction; B-Lymphocytes; Adaptive Immunity; Cell Differentiation
PubMed: 37533858
DOI: 10.3389/fimmu.2023.1214095 -
Frontiers in Immunology 2023Immunotherapeutic targeting of surface regulatory proteins and pharmacologic inhibition of critical signaling pathways has dramatically shifted our approach to the care... (Review)
Review
Immunotherapeutic targeting of surface regulatory proteins and pharmacologic inhibition of critical signaling pathways has dramatically shifted our approach to the care of individuals with B cell malignancies. This evolution in therapy reflects the central role of the B cell receptor (BCR) signaling complex and its co-receptors in the pathogenesis of B lineage leukemias and lymphomas. Members of the Fc receptor-like gene family () encode cell surface receptors with complex tyrosine-based regulation that are preferentially expressed by B cells. Among them, FCRL1 expression peaks on naïve and memory B cells and is unique in terms of its intracellular co-activation potential. Recent studies in human and mouse models indicate that FCRL1 contributes to the formation of the BCR signalosome, modulates B cell signaling, and promotes humoral responses. Progress in understanding its regulatory properties, along with evidence for its over-expression by mature B cell leukemias and lymphomas, collectively imply important yet unmet opportunities for FCRL1 in B cell development and transformation. Here we review recent advances in FCRL1 biology and highlight its emerging significance as a promising biomarker and therapeutic target in B cell lymphoproliferative disorders.
Topics: Animals; Mice; Humans; Neoplasms; B-Lymphocytes; Receptors, Fc; Receptors, Cell Surface; Lymphoma; Membrane Proteins
PubMed: 37822931
DOI: 10.3389/fimmu.2023.1251127 -
Proceedings of the National Academy of... Aug 2023Since the pioneering works of Berg and Purcell, discriminating between diffusion followed by binding has played a central role in understanding cell signaling. B cell...
Since the pioneering works of Berg and Purcell, discriminating between diffusion followed by binding has played a central role in understanding cell signaling. B cell receptors (BCR) and antibodies (Ab) challenge that simplified view as binding to the antigen follows after a chain of diffusion and rotations, including whole molecule rotation and independent tilts and twists of their Fab arms due to their Y-shaped structure and flexibility. In this paper, we combine analytical calculations with Brownian simulations to derive the first-passage times due to these three rotations positioning the Fab paratopes at a proper distance and orientation required for antigen binding. Our results indicate that when measuring Ab-Ag effective kinetic binding rates, using experimental methods in which the analyte is in solution only gives values proportional to the intrinsic binding rates, [Formula: see text], and [Formula: see text], for values of [Formula: see text] up to [Formula: see text]. Beyond that, a plateau of the effective 3D on rate between [Formula: see text] and [Formula: see text] is attained. Additionally, for BCR-Ag interactions, the effective 2D on and off binding rates can only be inferred from the corresponding effective 3D on and off rates for values of effective 3D on rates lower than [Formula: see text]. This is highly relevant when trying to relate BCR-antigen-binding strength and B cell response, especially during germinal center reactions. Therefore, there is a pressing need to reexamine our current understanding of the BCR-antigen kinetic rates in germinal centers using the latest experimental assays for BCR-Ag interactions.
Topics: Kinetics; Antibodies; Receptors, Antigen, B-Cell; Signal Transduction; B-Lymphocytes
PubMed: 37616223
DOI: 10.1073/pnas.2220669120 -
Nature Immunology Aug 2023Germinal centers (GCs) require sustained availability of antigens to promote antibody affinity maturation against pathogens and vaccines. A key source of antigens for GC...
Germinal centers (GCs) require sustained availability of antigens to promote antibody affinity maturation against pathogens and vaccines. A key source of antigens for GC B cells are immune complexes (ICs) displayed on follicular dendritic cells (FDCs). Here we show that FDC spatial organization regulates antigen dynamics in the GC. We identify heterogeneity within the FDC network. While the entire light zone (LZ) FDC network captures ICs initially, only the central cells of the network function as the antigen reservoir, where different antigens arriving from subsequent immunizations colocalize. Mechanistically, central LZ FDCs constitutively express subtly higher CR2 membrane densities than peripheral LZ FDCs, which strongly increases the IC retention half-life. Even though repeated immunizations gradually saturate central FDCs, B cell responses remain efficient because new antigens partially displace old ones. These results reveal the principles shaping antigen display on FDCs during the GC reaction.
Topics: Dendritic Cells, Follicular; Germinal Center; Antigens; B-Lymphocytes; Antigen-Antibody Complex
PubMed: 37443283
DOI: 10.1038/s41590-023-01559-1 -
Frontiers in Immunology 2023Germinal centers (GCs) are distinct microanatomical structures that form in the secondary lymphoid organs of endothermic vertebrates (i.e., mammals and some birds).... (Review)
Review
Germinal centers (GCs) are distinct microanatomical structures that form in the secondary lymphoid organs of endothermic vertebrates (i.e., mammals and some birds). Within GCs, B cells undergo a Darwinian selection process to identify clones which can respond to pathogen insult as well as affinity mature the B cell repertoire. The GC response ultimately generates memory B cells and bone marrow plasma cells which facilitate humoral immunological memory, the basis for successful vaccination programs. GCs have not been observed in the secondary lymphoid organs of ectothermic jawed vertebrates (i.e., fishes, reptiles, and amphibians). However, abundant research over the past decades has indicated these organisms can produce antigen specific B cell responses and some degree of affinity maturation. This review examines data demonstrating that the fundamentals of B cell selection may be more conserved across vertebrate phylogeny than previously anticipated. Further, research in both conventional mammalian model systems and comparative models raises the question of what evolutionary benefit GCs provide endotherms if they are seemingly unnecessary for generating the basic functional components of jawed vertebrate humoral adaptive immune responses.
Topics: Animals; Germinal Center; Biological Evolution; B-Lymphocytes; Phylogeny; Bone Marrow Cells; Mammals
PubMed: 37638014
DOI: 10.3389/fimmu.2023.1245704