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      Multiple Functions of B Cells in the Pathogenesis of Systemic Lupus Erythematosus

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          Abstract

          Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by excessive autoantibody production and multi-organ involvement. Although the etiology of SLE still remains unclear, recent studies have characterized several pathogenic B cell subsets and regulatory B cell subsets involved in the pathogenesis of SLE. Among pathogenic B cell subsets, age-associated B cells (ABCs) are a newly identified subset of autoreactive B cells with T-bet-dependent transcriptional programs and unique functional features in SLE. Accumulation of T-bet + CD11c + ABCs has been observed in SLE patients and lupus mouse models. In addition, innate-like B cells with the autoreactive B cell receptor (BCR) expression and long-lived plasma cells with persistent autoantibody production contribute to the development of SLE. Moreover, several regulatory B cell subsets with immune suppressive functions have been identified, while the impaired inhibitory effects of regulatory B cells have been indicated in SLE. Thus, further elucidation on the functional features of B cell subsets will provide new insights in understanding lupus pathogenesis and lead to novel therapeutic interventions in the treatment of SLE.

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          Most cited references109

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          Plasma cell differentiation requires the transcription factor XBP-1.

          Considerable progress has been made in identifying the transcription factors involved in the early specification of the B-lymphocyte lineage. However, little is known about factors that control the transition of mature activated B cells to antibody-secreting plasma cells. Here we report that the transcription factor XBP-1 is required for the generation of plasma cells. XBP-1 transcripts were rapidly upregulated in vitro by stimuli that induce plasma-cell differentiation, and were found at high levels in plasma cells from rheumatoid synovium. When introduced into B-lineage cells, XBP-1 initiated plasma-cell differentiation. Mouse lymphoid chimaeras deficient in XBP-1 possessed normal numbers of activated B lymphocytes that proliferated, secreted cytokines and formed normal germinal centres. However, they secreted very little immunoglobulin of any isotype and failed to control infection with the B-cell-dependent polyoma virus, because plasma cells were markedly absent. XBP-1 is the only transcription factor known to be selectively and specifically required for the terminal differentiation of B lymphocytes to plasma cells.
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            A B-cell subset uniquely responsive to innate stimuli accumulates in aged mice.

            We have discovered a distinct mature B-cell subset that accumulates with age, which we have termed age-associated B cells. These cells comprise up to 30% of mature B cells by 22 months. Despite sharing some features with other mature B-cell subsets, they are refractory to BCR and CD40 stimulation. Instead, they respond to TLR9 or TLR7 stimulation and divide maximally on combined BCR and TLR ligation, leading to Ig production and preferential secretion of IL-10 and IL-4. Although similar to follicular B cells in both B-lymphocyte stimulator (BLyS) receptor expression and BLyS binding capacity, these cells do not rely on BLyS for survival. They are neither cycling nor the result of intrinsically altered B lymphopoiesis in aged BM, but instead appear to be generated from mature B cells that exhaustively expand during the individual's lifetime. Finally, they present Ag effectively and favor polarization to a TH17 profile. Together, these findings reveal that while the magnitude of the mature primary B-cell niche is maintained with age, it is increasingly occupied by cells refractory to BCR-driven activation yet responsive to innate receptor stimulation.
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              Regulation of plasma-cell development.

              Plasma cells are the terminally differentiated, non-dividing effector cells of the B-cell lineage. They are cellular factories devoted to the task of synthesizing and secreting thousands of molecules of clonospecific antibody each second. To respond to microbial pathogens with the necessary specificity and rapidity, B cells are exquisitely regulated with respect to both development in the bone marrow and activation in the periphery. This review focuses on the terminal differentiation of B cells into plasma cells, including the different subsets of B cells that become plasma cells, the mechanism of regulation of this transition, the transcription factors that control each developmental stage and the characteristics of long-lived plasma cells.
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                Author and article information

                Journal
                Int J Mol Sci
                Int J Mol Sci
                ijms
                International Journal of Molecular Sciences
                MDPI
                1422-0067
                29 November 2019
                December 2019
                : 20
                : 23
                : 6021
                Affiliations
                [1 ]Department of Rheumatology and Immunology, Second Clinical Medical College of Jinan University, Shenzhen People’s Hospital, Shenzhen 518000, China; kongyang@ 123456hku.hk (K.M.); liu_dz2001@ 123456sina.com (D.L.)
                [2 ]Department of Pathology and Shenzhen Institute of Research and Innovation, The University of Hong Kong, Hong Kong 999077, China; duwenhan@ 123456hotmail.com (W.D.); xhwangbio@ 123456hotmail.com (X.W.)
                [3 ]Department of Rheumatology, Guangzhou First People’s Hospital, School of Medicine, South China University of Technology, Guangzhou, 510000, China; 13631481240@ 123456163.com (S.Y.); caixytracy@ 123456126.com (X.C.)
                [4 ]Department of Rheumatology and Immunology, Southwest Hospital, The First Hospital Affiliated to The Army Medical University, Chongqing 400038, China
                Author notes
                [* ]Correspondence: lijingyi_tmmu@ 123456foxmail.com (J.L.); liweilu@ 123456hku.hk (L.L.); Tel.: +86-852-22552656 (J.L.); +86-023-68765210 (L.L.)
                Author information
                https://orcid.org/0000-0002-0919-6252
                https://orcid.org/0000-0002-5344-3679
                Article
                ijms-20-06021
                10.3390/ijms20236021
                6929160
                31795353
                47e3c9e9-1d8d-4a38-8ec7-8996b726af62
                © 2019 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( http://creativecommons.org/licenses/by/4.0/).

                History
                : 09 September 2019
                : 28 November 2019
                Categories
                Review

                Molecular biology
                systemic lupus erythematosus (sle),autoreactive b cells,age-associated b cells (abcs),regulatory b cells (bregs)

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