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Fcγriib on B Cells and Myeloid Cells Modulates B Cell Activation And FcγRIIb on B Cells and Myeloid Cells Modulates B Cell Activation and Autoantibody Responses via Different but Synergistic Pathways in Lupus-Prone Yaa This information is current as Mice of September 23, 2021. Qingshun Lin, Mareki Ohtsuji, Hirofumi Amano, Hiromichi Tsurui, Norihiro Tada, Ryota Sato, Hidehiro Fukuyama, Hiroyuki Nishimura, J. Sjef Verbeek and Sachiko Hirose J Immunol published online 29 October 2018 Downloaded from http://www.jimmunol.org/content/early/2018/10/28/jimmun ol.1701487 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2018/10/29/jimmunol.170148 Material 7.DCSupplemental Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 23, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2018 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Published October 29, 2018, doi:10.4049/jimmunol.1701487 The Journal of Immunology FcgRIIb on B Cells and Myeloid Cells Modulates B Cell Activation and Autoantibody Responses via Different but Synergistic Pathways in Lupus-Prone Yaa Mice Qingshun Lin,*,1 Mareki Ohtsuji,† Hirofumi Amano,‡ Hiromichi Tsurui,* Norihiro Tada,x Ryota Sato,{ Hidehiro Fukuyama,{ Hiroyuki Nishimura,† J. Sjef Verbeek,‖,1 and Sachiko Hirose*,1 C57BL/6 (B6).FcgRIIb2/2.Yaa mice spontaneously develop lethal lupus nephritis. To define the cell type–specific role of FcgRIIb in Yaa-associated lupus, we established B cell– (CD19Cre.Yaa), myeloid cell– (C/EBPaCre.Yaa), and dendritic cell– (DC) (CD11cCre.Yaa) specific FcgRIIb-deficient B6.Yaa mouse strains. CD19Cre.Yaa mice developed milder lupus than B6.FcgRIIb2/2. Yaa mice, indicating that FcgRIIb deficiency on B cells is not sufficient for the development of severe disease. Surprisingly, Downloaded from C/EBPaCre.Yaa mice also showed autoantibody production and mild lupus similar to that in CD19Cre.Yaa mice, whereas CD11cCre.Yaa mice stayed disease free. These observations indicate that FcgRIIb deficiency in B cells and myeloid cells, but not DCs, contributes to the severe disease in B6.FcgRIIb2/2.Yaa mice. Flow cytometric analysis showed that the frequency of peripheral Gr-12 but not Gr-1+ monocyte was increased in B6.FcgRIIb2/2.Yaa and C/EBPaCre.Yaa but not CD19Cre.Yaa mice, suggesting a link between FcgRIIb deficiency on myeloid cells and the high frequency of Gr-12 monocytes. RNA sequencing revealed that compared with Gr-1+ monocytes, Gr-12 monocytes expressed higher levels of the B cell–stimulating cytokines http://www.jimmunol.org/ BSF-3, IL-10, and IL-1b, the DC markers CD11c, CD83, and Adamdec1, and the antiapoptotic factors Bcl2 and Bcl6. In conclusion, in Yaa-associated lupus nephritis, FcgRIIb on B cells and myeloid cells modulates B cell activation via different but synergistic pathways. Gr-12 monocytes are the most likely candidate myeloid cells involved. The Journal of Immunology, 2018, 201: 000–000. ice have four types of IgG Fc receptors, FcgRI, Lupus nephritis, the characteristic feature of systemic lupus FcgRIII, FcgRIV, and FcgRIIb (1, 2). The former three erythematosus (SLE), is an IC-mediated renal glomerular and vascular M are activating receptors composed of a ligand-binding inflammatory disease. FcgRIIb encoding gene is identified as a by guest on September 23, 2021 a-chain and a dimer of the FcR g-chain (FcR g) that mediates ac- susceptibility locus for SLE both in mice and humans (3–5). We tivation signals. FcgRIIb is a single-chain receptor, which inhibits previously found that the Fcgr2b gene is polymorphic and that cell activation upon coengagement with the activating FcgRby SLE-prone strains, such as NZB, BXSB, and MRL all share immune complexes (ICs). The balance of stimulatory and inhib- deletion polymorphism in the Fcgr2b promoter region (3). This itory signals determines the outcome of FcgR signaling in mye- causes downregulation of FcgRIIb expression particularly on loid effector cells, which controls IC-mediated cellular responses activated B cells, which results in increased IgG Ab produc- such as Ab-dependent cell-mediated cytotoxicity, Ab-dependent tion (6, 7). The SLE-prone BXSB strain contains not only the cellular phagocytosis, and release of inflammatory mediators. autoimmune-type Fcgr2b locus but also the Y chromosome– On B cells, coengagement of FcgRIIb and the BCR downregulates linked autoimmune acceleration gene (Yaa) mutation. The etio- the production of Abs. logic basis of Yaa is a duplication of the TLR7 gene due to a *Department of Pathology, Juntendo University School of Medicine, Tokyo 113-8421, The sequences presented in this article have been submitted to the National Center Japan; †Toin Human Science and Technology Center, Department of Biomedical En- for Biotechnical Information’s Gene Expression Omnibus (https://www.ncbi.nlm.nih. gineering, Toin University of Yokohama, Yokohama 225-8502, Japan; ‡Department of gov/geo/query/acc.cgi?acc=GSE116757) under accession number GSE116757. Internal Medicine and Rheumatology, Juntendo University School of Medicine, Tokyo x Address correspondence and reprint requests to Dr. Sachiko Hirose at the current 113-8421, Japan; Atopy Research Center, Juntendo University School of Medicine, { address: Department of Biomedical Engineering, Toin University of Yokohama, 1614 Tokyo 113-8421, Japan; Laboratory for Lymphocyte Differentiation, RIKEN Center ‖ Kurogane-cho, Aoba-ku, Yokohama 225-8502, Japan. E-mail address: sacchi@toin. for Integrative Medical Sciences, Yokohama 230-0045, Japan; and Department of ac.jp Human Genetics, Leiden University Medical Center, 2333ZA Leiden, the Netherlands The online version of this article contains supplemental material. 1Current address: Toin Human Science and Technology Center, Department of Biomedical Engineering, Toin University of Yokohama, Yokohama, Japan. Abbreviations used in this article: ACR, albumin/creatinine ratio; B6, C57BL/6; BSF-3, B cell–stimulating factor-3; DC, dendritic cell; FcR g, FcR g-chain; FPKM, ORCIDs: 0000-0002-6457-0630 (H.F.); 0000-0003-0934-6924 (J.S.V.). fragment per kilobase of exon per million reads; GC, germinal center; GO, gene Received for publication October 25, 2017. Accepted for publication September 22, ontology; GSEA, Gene Set Enrichment Analysis; IC, immune complex; MOMA-1, 2018. metallophilic macrophage Ab; PANTHER, protein analysis through evolutionary relationships; PAS, periodic acid–Schiff; PNA, peanut agglutinin; RNP, ribonucleo- This work was supported by grants from the Ministry of Education, Culture, Science, protein; SLAM, signaling lymphocytic activation molecule; SLE, systemic lupus Sports, Science and Technology of Japan (26460493 and 15K08432) and a grant from erythematosus; Yaa, Y chromosome–linked autoimmune accelerating gene. the Ministry of Health, Labour and Welfare of Japan (16ek0109019s0703). Q.L., H.F., J.S.V., and S.H. designed, conducted, and analyzed experiments and wrote Copyright Ó 2018 by The American Association of Immunologists, Inc. 0022-1767/18/$37.50 the manuscript; M.O., H.T., N.T., and R.S. conducted and analyzed experiments and approved the manuscript; H.A. and H.N. designed and interpreted experiments and approved the manuscript. www.jimmunol.org/cgi/doi/10.4049/jimmunol.1701487 2 FcgRIIb ON B CELLS AND MYELOID CELLS translocation of the TLR7-containing region in the X chromosome B cells, monocytes, neutrophils, macrophages, and DCs were examined by to the Y chromosome (8, 9). Because the SLE phenotype in BXSB staining PBLs or spleen cells with fluorescent-conjugated mAbs against male mice was almost completely reversed by substitution of the B220 (RA3-6B2), CD11b (M1/70), CD11c (HL3), and Gr-1 (RB6-8C5), and with biotin-conjugated anti-FcgRIIb (Ly17.2) mAb followed by autoimmune-type Fcgr2b with C57BL/6 (B6)-type Fcgr2b (10), the streptavidin-allophycocyanin. For spleen cell subset analysis, cells were autoimmune-type Fcgr2b is a crucial susceptibility factor for SLE stained with fluorescent-conjugated mAbs against CD3 (17A2), CD4 in BXSB male mice. However, BXSB female mice carrying the (RM4-5), B220, ICOS (398.4A), Foxp3 (FJK-16s), CD25 (PC61), CD138 autoimmune-type Fcgr2b do not develop SLE because of the lack of (281-2), CD11b, and CD11c and peanut agglutinin (PNA). For staining of the intracellular marker Foxp3, cells were surface stained with mAbs against TLR7 duplication due to the X chromosome inactivation mechanisms CD4 and CD25 followed by intracellular staining with mAb against Foxp3 that equalize gene expression, indicating that the autoimmune-type using the FOXP3 Fix/Perm Buffer Set and protocol (BioLegend). For PBL Fcgr2b locus contributes to SLE susceptibility through a strong ep- subset analysis, cells were stained with fluorescent-conjugated mAbs against b istatic interaction with the Yaa locus. B220, CD11b, Gr-1, CD115 (AFS98), I-A (K25-8.7), NK1.1 (PK136), In addition to the polymorphic Fcgr2b gene, the downstream
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