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      Effect of BAFF blockade on the B cell receptor repertoire and transcriptome in a mouse model of systemic lupus erythematosus

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          Abstract

          Introduction

          Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Anti-B-cell-activating factor (BAFF) therapy effectively depletes B cells and reduces SLE disease activity. This research aimed to evaluate the effect of BAFF blockade on B cell receptor (BCR) repertoire and gene expression.

          Methods

          Through next-generation sequencing, we analyzed gene expression and BCR repertoire in MRL/lpr mice that received long-term anti-BAFF therapy. Based on gene expression profiles, we predicted the relative proportion of immune cells using ImmuCellAI-mouse, validating our predictions via flow cytometry and FluoroSpot.

          Results

          The loss of BCR repertoire diversity and richness, along with increased clonality and differential frequency distribution of the immunoglobulin heavy chain variable (IGHV) segment gene usage, were observed in BAFF-blockade mice. Meanwhile, the distribution of complementarity-determining region 3 (CDR3) length and CDR3 amino acid usage remained unaffected. BAFF blockade resulted in extensive changes in gene expression, particularly that of genes related to B cells and immunoglobulins. Besides, the tumor necrosis factor (TNF)-α responses and interferon (IFN)-α/γ were downregulated, consistent with the decrease in IFN-γ and TNF-α serum levels following anti-BAFF therapy. In addition, BAFF blockade significantly reduced B cell subpopulations and plasmacytoid dendritic cells, and caused the depletion of antibody-secreting cells.

          Discussion

          Our comparative BCR repertoire and transcriptome analyses of MRL/lpr mice subjected to BAFF blockade provide innovative insights into the molecular pathophysiology of SLE.

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          Most cited references71

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          clusterProfiler: an R package for comparing biological themes among gene clusters.

          Increasing quantitative data generated from transcriptomics and proteomics require integrative strategies for analysis. Here, we present an R package, clusterProfiler that automates the process of biological-term classification and the enrichment analysis of gene clusters. The analysis module and visualization module were combined into a reusable workflow. Currently, clusterProfiler supports three species, including humans, mice, and yeast. Methods provided in this package can be easily extended to other species and ontologies. The clusterProfiler package is released under Artistic-2.0 License within Bioconductor project. The source code and vignette are freely available at http://bioconductor.org/packages/release/bioc/html/clusterProfiler.html.
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            Differential expression analysis for sequence count data

            High-throughput sequencing assays such as RNA-Seq, ChIP-Seq or barcode counting provide quantitative readouts in the form of count data. To infer differential signal in such data correctly and with good statistical power, estimation of data variability throughout the dynamic range and a suitable error model are required. We propose a method based on the negative binomial distribution, with variance and mean linked by local regression and present an implementation, DESeq, as an R/Bioconductor package.
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              TRRUST v2: an expanded reference database of human and mouse transcriptional regulatory interactions

              Abstract Transcription factors (TFs) are major trans-acting factors in transcriptional regulation. Therefore, elucidating TF–target interactions is a key step toward understanding the regulatory circuitry underlying complex traits such as human diseases. We previously published a reference TF–target interaction database for humans—TRRUST (Transcriptional Regulatory Relationships Unraveled by Sentence-based Text mining)—which was constructed using sentence-based text mining, followed by manual curation. Here, we present TRRUST v2 (www.grnpedia.org/trrust) with a significant improvement from the previous version, including a significantly increased size of the database consisting of 8444 regulatory interactions for 800 TFs in humans. More importantly, TRRUST v2 also contains a database for TF–target interactions in mice, including 6552 TF–target interactions for 828 mouse TFs. TRRUST v2 is also substantially more comprehensive and less biased than other TF–target interaction databases. We also improved the web interface, which now enables prioritization of key TFs for a physiological condition depicted by a set of user-input transcriptional responsive genes. With the significant expansion in the database size and inclusion of the new web tool for TF prioritization, we believe that TRRUST v2 will be a versatile database for the study of the transcriptional regulation involved in human diseases.
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                Author and article information

                Contributors
                URI : https://loop.frontiersin.org/people/2520930Role: Role: Role: Role:
                Role: Role:
                URI : https://loop.frontiersin.org/people/2558043Role: Role:
                Role: Role:
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                URI : https://loop.frontiersin.org/people/2529894Role: Role: Role:
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                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                09 January 2024
                2023
                : 14
                : 1307392
                Affiliations
                [1] 1 School of Life Sciences and Technology, Tongji University , Shanghai, China
                [2] 2 Biomedical Research Center, Tongji University Suzhou Institute , Suzhou, Jiangsu, China
                [3] 3 Department of Neurology, Tongji Hospital, Tongji University , Shanghai, China
                Author notes

                Edited by: Jing Jing Wang, Flinders University, Australia

                Reviewed by: Lisa K. Blum, Consultant, South San Francisco, CA, United States

                Kirsten Fairfax, University of Tasmania, Australia

                *Correspondence: Hua Gu, gu_hua@ 123456tongji.edu.cn ; Jianmin Fang, jfang@ 123456tongji.edu.cn
                Article
                10.3389/fimmu.2023.1307392
                10803406
                38264661
                32dcaadf-cc6f-4ecc-8d6d-1f4ba3ebe3f6
                Copyright © 2024 Huang, Pi, Xu, Feng, Zhang, Gu and Fang

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 04 October 2023
                : 18 December 2023
                Page count
                Figures: 8, Tables: 0, Equations: 0, References: 71, Pages: 15, Words: 6676
                Funding
                The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work is supported by the National Basic Research Program of China (973 Program) (2015CB553706), the National Natural Science Foundation of China (NSFC82172604), and the Shanghai Science & Technology Basic Research Program (18JC1414400). The authors declare that this study received funding from RemeGen Co., Ltd. The funder was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.
                Categories
                Immunology
                Original Research
                Custom metadata
                Autoimmune and Autoinflammatory Disorders : Autoimmune Disorders

                Immunology
                systemic lupus erythematosus,b cell receptor (bcr) repertoire,transcriptome,b cell-activating factor (baff),mrl/lpr

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