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Increase of MZB1 in B Cells in Systemic Lupus Erythematosus

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Increase of MZB1 in B Cells in Systemic Lupus Erythematosus Miyagawa-Hayashino et al. Arthritis Research & Therapy (2018) 20:13 DOI 10.1186/s13075-018-1511-5 RESEARCHARTICLE Open Access Increase of MZB1 in B cells in systemic lupus erythematosus: proteomic analysis of biopsied lymph nodes Aya Miyagawa-Hayashino1,2,7*, Hajime Yoshifuji3, Koji Kitagori1,3, Shinji Ito4, Takuma Oku1,5, Yoshitaka Hirayama1,5, Adeeb Salah2, Toshiki Nakajima3, Kaori Kiso6, Norishige Yamada6, Hironori Haga2 and Tatsuaki Tsuruyama6 Abstract Background: Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease in which dysregulation of B cells has been recognized. Here, we searched for potential biomarkers of SLE using liquid chromatography-tandem mass spectrometry (LC-MS). Methods: Lymph nodes from SLE patients and controls were analyzed by LC-MS. To validate the identified molecules, immunoblotting and immunohistochemistry were performed and B cells from SLE patients were analyzed by quantitative RT-PCR. B-cell subsets from NZB/W F1 mice, which exhibit autoimmune disease resembling human SLE, were analyzed by flow cytometry. Endoplasmic reticulum (ER) stress was induced by tunicamycin and the serum concentration of anti-dsDNA antibodies was determined by ELISA. TUNEL methods and immunoblotting were used to assess the effect of tunicamycin. Results: MZB1, which comprises part of a B-cell-specific ER chaperone complex and is a key player in antibody secretion, was one of the differentially expressed proteins identified by LC-MS and confirmed by immunoblotting. Immunohistochemically, larger numbers of MZB1+ cells were located mainly in interfollicular areas and scattered in germinal centers in specimens from SLE patients compared with those from controls. MZB1 colocalized with CD138+ plasma cells and IRTA1+ marginal zone B cells. MZB1 mRNA was increased by 2.1-fold in B cells of SLE patients with active disease (SLE Disease Activity Index 2000 ≥ 6) compared with controls. In aged NZB/W F1 mice, splenic marginal zone B cells and plasma cells showed elevated MZB1 levels. Tunicamycin induced apoptosis of MZB1+ cells in target organs, resulting in decreased serum anti-dsDNA antibody levels. Additionally, MZB1+ cells were increased in synovial tissue specimens from patients with rheumatoid arthritis. Conclusions: MZB1 may be a potential therapeutic target in excessive antibody-secreting cells in SLE. Keywords: Formalin-fixed paraffin-embedded, Lupus-prone mice, Proteomic analysis, Systemic lupus erythematosus, SLE lymphadenopathy, TUNEL, Unfolded protein response Background Aberrant innate immune responses play an important role Systemic lupus erythematosus (SLE) is a systemic inflam- in SLE, contributing tissue injury via release of proinflam- matory autoimmune disease characterized by production matory cytokines and aberrant activation of T and B cells, of autoantibodies directed against nucleic acid-associated with the latter leading to pathogenic autoantibody produc- autoantigens that cause multiple organ damage, including tion [2]. Autoreactive B cells differentiate into pathogenic skin, joints, kidney, and the central nervous system [1]. memory and plasma cells via germinal center responses [3]. B-cell depletion is an attractive therapeutic option in * Correspondence: [email protected] SLE. However, targeting human CD20 (rituximab), which 1 Center for Innovation in Immunoregulative Technology and Therapeutics, is expressed on almost all B-cell lineages except early pro- Graduate School of Medicine, Kyoto University, Yoshida-konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan B cells, plasmablasts, and plasma cells, has shown disap- 2Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan pointing results in two randomized clinical trials of lupus Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Miyagawa-Hayashino et al. Arthritis Research & Therapy (2018) 20:13 Page 2 of 11 [4, 5], although there has been a question about both trial nanoflow reversed-phase LC (NanoLC-Ultra 2D-Plus; design and clinical outcome measures [2]. Recent clinical Eksigent, Dublin, CA, USA) equipped with cHiPLC trials using belimumab, a fully humanized monoclonal Nanoflex (Eksigent). Eluted peptides were analyzed by a antibody directed against B-lymphocyte stimulator (BLyS; quadrupole time-of-flight hybrid mass spectrometer also known as BAFF), proved beneficial [6–9]. Dual B-cell (Triple TOF5600+ system; AB SCIEX, Framingham, immunotherapy was confirmed to be superior to individ- MA, USA). ual anti-CD20 depletion or BAFF blockade in a murine lupus model [10]. Upon binding to its receptors, TACI, Identification and quantification of peptides BAFF receptor, and B-cell maturation antigen, BLyS acti- Tandem mass spectra were searched against the vates signals for B-cell survival and maturation with beli- Uniprot-KB/Swissprot human proteomic database mumab effect via depletion of recently formed, rather (2014–June) from the European Bioinformatics Institute. than memory, B cells or long-lived plasma cells in SLE ProteinPilot software version 4.5β (AB SCIEX) was used [6–8]. Recently, proteasome inhibitors bortezomib, delan- for the database search. False discovery rates (FDRs) zomib, and carfilzomib have shown to be effective in re- were determined after peptide/protein identification fractory SLE patients [11] or lupus-prone mice by using the Proteomic System Performance Evaluation depleting plasma cells [12–14]. Plasma cells are sensitive Pipeline provided as a part of ProteinPilot software (AB to proteasome inhibitors because of their high rate of anti- SCIEX). Label-free quantification of peptides was per- body synthesis [11–14]. formed using Progenesis QI for Proteomics software In the study of murine lupus-prone models, the spleen (Nonlinear Dynamics, Newcastle upon Tyne, UK). Pro- is examined to understand the underlying mechanisms tein abundance was determined by the relative quantifi- of lupus [15–21]. Although localized or generalized cation using the nonconflicting peptides. Proteins lymphadenopathy is a common symptom, seen at some identified by at least two distinct peptides (confidence ≥ stage in the evolution of the disease in about 60% of SLE 95%) were used in the following analyses. The details of patients [22], for SLE patients lymphoid organs (e.g., the analysis were described previously [24]. spleen and lymph node) are rarely biopsied, only if ma- lignancy should be ruled out. The pathology database in Validation using immunoblotting in human tissues our institution contained five archives of biopsied speci- Analysis of MZB1, one of the highly confident and dif- mens from patients with lymphadenopathy associated ferentially expressed proteins between SLE patients and with SLE, which were collected to rule out malignancy. controls in LC-MS, was chosen for a validation study. Formalin-fixed paraffin-embedded (FFPE) tissues ar- Immunoblot analysis was performed using proteins ex- chived in pathology department laboratories worldwide tracted from lymph nodes from SLE patients and con- may provide an extremely valuable resource for bio- trols using the Qproteome FFPE Tissue Kit (Qiagen, marker discovery for rare diseases [23]. Recent develop- Venlo, the Netherlands). The antibodies used were ments in methodologies using FFPE tissue in mass MZB1 (Proteintech, Rosemont, IL, USA) and beta-actin spectrometry-based proteomics led us to examine poten- (Abcam, Cambridge, UK). Protein bands were visualized tial biomarkers and new therapeutic targets of SLE [24]. using a chemiluminescence substrate (Nacalai Tesque, Here, we applied liquid chromatography-tandem mass Kyoto, Japan), and images were obtained using Ez- spectrometry (LC-MS) to analyze lymph node tissue Capture MG (Daihan Scientific Co., Ltd, Seoul, South from SLE patients and identified MZB1 as a potential Korea). Visualized bands were analyzed using CS biomarker of SLE. Analyzer (Atto Corporation, Tokyo, Japan). Methods Patient samples and immunohistochemistry Proteomic sample preparation and LC-MS For immunohistochemistry, the expression profile of SLE lymphadenopathy is lymph node enlargement asso- MZB1 was investigated by the REAL EnVision/HRP de- ciated with SLE. Reactive follicular hyperplasia is the tection system (DakoCytomation, Glostrup, Denmark). most frequent finding [22]. Lymph nodes from patients Lymph nodes from patients with SLE lymphadenopathy diagnosed with SLE (n = 3) and controls (n = 3) were (n = 5) or controls (n = 5) were used for a validation used for LC-MS analysis. The controls were lymph study of LC-MS results. In addition, excised tonsil speci- nodes dissected during thyroidectomy for papillary car- mens from patients with tonsillar hypertrophy (n = 4), cinoma with no metastasis found. Proteins from FFPE biopsy specimens for polyarteritis nodosa (skin, n =6; tissue were extracted using the Liquid Tissue MS Pro- skeletal muscle, n = 1), muscle biopsies for dermatomyo- tein Prep Kit (Expression
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