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Innate and adaptive signals enhance differentiation and expansion of dual-antibody autoreactive B cells in lupus.

Allison Sang | Thomas Danhorn | Jacob N Peterson | Andrew L Rankin | Brian P O'Connor | Sonia M Leach | Raul M Torres | Roberta Pelanda
Nature communications | 2018

Autoreactive B cells have a major function in autoimmunity. A small subset of B cells expressing two distinct B-cell-antigen-receptors (B2R cells) is elevated in many patients with systematic lupus erythematosus (SLE) and in the MRL(/lpr) mouse model of lupus, and is often autoreactive. Here we show, using RNAseq and in vitro and in vivo analyses, signals that are required for promoting B2R cell numbers and effector function in autoimmune mice. Compared with conventional B cells, B2R cells are more responsive to Toll-like receptor 7/9 and type I/II interferon treatment, display higher levels of MHCII and co-receptors, and depend on IL-21 for their homeostasis; moreover they expand better upon T cell-dependent antigen stimulation, and mount a more robust memory response, which are characteristics essential for enhanced (auto)immune responses. Our findings thus provide insights on the stimuli for the expansion of an autoreactive B cell subset that may contribute to the etiology of SLE.

Pubmed ID: 30266981

Associated grants

  • Agency: NIAID NIH HHS, United States
    Id: R01 AI136534
  • Agency: NCI NIH HHS, United States
    Id: P30 CA046934
  • Agency: NIAID NIH HHS, United States
    Id: R56 AI052310
  • Agency: NIAID NIH HHS, United States
    Id: R21 AI078468
  • Agency: NIAID NIH HHS, United States
    Id: T32 AI074491
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI052310
  • Agency: NIAID NIH HHS, United States
    Id: R01 AI052157

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This is a list of tools and resources that we have found mentioned in this publication.


GraphPad Prism (tool)

RRID:SCR_002798

Statistical analysis software that combines scientific graphing, comprehensive curve fitting (nonlinear regression), understandable statistics, and data organization. Designed for biological research applications in pharmacology, physiology, and other biological fields for data analysis, hypothesis testing, and modeling.

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Brainbow mouse resource at Jackson Labs (tool)

RRID:SCR_004894

These Brainbow 1.0 (founder line L) mice allow labeling of individual neuronal types (specifically hippocampal neuron cell bodies, and including motor neurons, dentate gyrus granule cells, pyramidal neurons of the cortex and CA1 area) with approximately 166 distinguishable color variations in cre recombined cells, and may also be useful in conjunction with other Brainbow strains (Stock No. 007901, Stock No. 007911, Stock No. 007921) for neurobiological studies. These Thy1-Brainbow 1.0 (line L) transgenic mice are viable and fertile. The mice possess multiple fluorescent protein sequences uniquely flanked with pairs of incompatible Lox sites alternated to create mutually exclusive recombination events; allowing stochastic expression of multiple fluorescent proteins from a single transgene. Prior to Cre-mediated recombination, the fluorescent protein immediately adjacent to the promoter, dTomato (RFP), is expressed in peripheral and central neurons. When bred to Cre recombinase expressing mice, the resulting offspring can have one of three expression outcomes for each transgene in each cell of the cre expressing tissue(s): dTomato (RFP) (no recombination), mCerulean (CFP), or mYFP. Integration of tandem transgene copies yields combinatorial fluorescent protein expression in each cell, and thus many possible cell colors, providing a way to distinguish adjacent neurons and visualize other cellular interactions. Of note, the single FRT site inserted in the transgene allows tandem transgene copy number reduction through Flp-mediated recombination if desired. These Brainbow 1.0 (founder line L) mice were found to have multiple transgene copies that allow labeling of individual neuronal types (specifically hippocampal neuron cell bodies, and including motor neurons, dentate gyrus granule cells, pyramidal neurons of the cortex and CA1 area) with approximately 166 distinguishable color variations in cre recombined cells, and may also be useful in conjunction with other Brainbow strains (Stock No. 007901, Stock No. 007911, Stock No. 007921) for neurobiological studies. This mouse can be used to support research in many areas including:
Neurobiology Research
* Cre-lox System (loxP-flanked Sequences)
* Fluorescent protein expression in neural tissue
Research Tools
* Cre-lox-System (loxP-flanked Sequences: Test/Reporter)
* Developmental Biology Research (Cre-lox system)
* Developmental Biology Research (transplantation marker for embryonic and adult tissue)
* FLP-FRT System (FRT-flanked Sequences)
* Fluorescent Proteins * Genetics Research (Mutagenesis and Transgenesis: Cre-lox system) * Genetics Research (Tissue/Cell Markers: Cre-lox system) * Genetics Research (Tissue/Cell Markers: astrocyte-specific marker) * Genetics Research (Tissue/Cell Markers: astrocytes) * Genetics Research (Tissue/Cell Markers: astrocytes, neurons) * Genetics Research (Tissue/Cell Markers: glial cells) * Genetics Research (Tissue/Cell Markers: multiple) * Genetics Research (Tissue/Cell Markers: neurons) * Genetics Research (Tissue/Cell Markers: transplantation marker for embryonic and adult tissue) * Neurobiology Research (astrocyte-specific marker) * Neurobiology Research (cell marker) * YFP related Research Tools * Fluorescent Proteins Control: 000664 C57BL/6J (approximate)

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HTSeq (tool)

RRID:SCR_005514

THIS RESOURCE IS NO LONGER IN SERVICE. Documented on February 28,2023. Software Python package that provides infrastructure to process data from high-throughput sequencing assays. While the main purpose of HTSeq is to allow you to write your own analysis scripts, customized to your needs, there are also a couple of stand-alone scripts for common tasks that can be used without any Python knowledge.

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Systems Transcriptional Activity Reconstruction (tool)

RRID:SCR_005622

A next-generation web-based application that aims to provide an integrated solution for both visualization and analysis of deep-sequencing data, along with simple access to public datasets.

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Thermo Fisher Scientific (tool)

RRID:SCR_008452

Commercial vendor and service provider of laboratory reagents and antibodies. Supplier of scientific instrumentation, reagents and consumables, and software services.

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FlowJo (tool)

RRID:SCR_008520

Software for single-cell flow cytometry analysis. Its functions include management, display, manipulation, analysis and publication of the data stream produced by flow and mass cytometers.

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QIAGEN (tool)

RRID:SCR_008539

A commercial organization which provides assay technologies to isolate DNA, RNA, and proteins from any biological sample. Assay technologies are then used to make specific target biomolecules, such as the DNA of a specific virus, visible for subsequent analysis.

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Sigma-Aldrich (tool)

RRID:SCR_008988

American chemical, life science and biotechnology company owned by Merck KGaA. Merger of Sigma Chemical Company and Aldrich Chemical Company. Provides organic and inorganic chemicals, building blocks, reagents, advanced materials and stable isotopes for chemical synthesis, medicinal chemistry and materials science, antibiotics, buffers, carbohydrates, enzymes, forensic tools, hematology and histology, nucleotides, proteins, peptides, amino acids and their derivatives.

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Agilent Technologies (tool)

RRID:SCR_013575

Company provides laboratories worldwide with analytical instruments and supplies, clinical and diagnostic testing services, consumables, applications and expertise in life sciences and applied chemical markets.

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Morpheus (tool)

RRID:SCR_014975

Modeling and simulation environment for study of multi scale and multicellular systems. Users can construct and simulate models of gene regulation, signaling pathways, tissue patterning and morphogenesis and explore the effects of multiscale feedbacks between these processes. Morpheus can render 2D and 3D models using graphical user interface.

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DESeq2 (tool)

RRID:SCR_015687

Software package for differential gene expression analysis based on the negative binomial distribution. Used for analyzing RNA-seq data for differential analysis of count data, using shrinkage estimation for dispersions and fold changes to improve stability and interpretability of estimates.

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