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Fujita K, Kuwabara T, Wang B, Tanaka K, Ito K, Akishima-Fukasawa Y, Mikami T, Akasaka Y, Ishii T. Irradiation Attenuates Systemic Lupus Erythematosus-Like Morbidity in NZBWF1 Mice: Focusing on CD180-Negative Cells. J Immunol Res 2023; 2023:9969079. [PMID: 37886369 PMCID: PMC10599955 DOI: 10.1155/2023/9969079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2022] [Revised: 09/06/2023] [Accepted: 09/07/2023] [Indexed: 10/28/2023] Open
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the production of autoantibodies that can induce systemic inflammation. Ultraviolet-A and X-ray irradiation have been reported to have therapeutic effects in patients with SLE. We previously demonstrated that CD180-negative cells, these are radiosensitive, contribute to the development of SLE-like morbidity in NZBWF1 mice. In this study, the effects of irradiation on SLE-like morbidity manifestations in NZBWF1 mice and on CD180-negative cells were investigated. Whole-body irradiation, excluding the head, attenuated SLE-like morbidity in vivo, as indicated by the prevention of the renal lesion development, inhibition of anti-dsDNA antibody production, reduction of urinary protein levels, and prolongation of the lifespan. Irradiation also reduced the proportion of CD180-negative cells in the spleen. Although other immune cells or molecules may be triggered because of the whole-body irradiation treatment, previous research, and the current results suggest a strong relationship between the radiation-induced decrease in CD180-negative cells and the amelioration of SLE-like morbidities. Clinical trials assessing CD180-negative cells as a therapeutic target for SLE have been hampered by the lack of validated cell markers; nonetheless, the present findings suggest that radiotherapy may be a new therapeutic strategy for managing SLE symptoms.
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Affiliation(s)
- Kazuko Fujita
- Department of Pathology, School of Medicine, Toho University, Ota-Ku, Tokyo 143-8540, Japan
| | - Taku Kuwabara
- Department of Molecular Immunology, School of Medicine, Toho University, Ota-Ku, Tokyo 143-8540, Japan
| | - Bing Wang
- Institute for Radiological Science, National Institutes for Quantum Science and Technology, Chiba-City, Chiba 263-8555, Japan
| | - Kaoru Tanaka
- Institute for Radiological Science, National Institutes for Quantum Science and Technology, Chiba-City, Chiba 263-8555, Japan
| | - Kei Ito
- Department of Pathology, School of Medicine, Toho University, Ota-Ku, Tokyo 143-8540, Japan
- Department of Medical Technology, Faculty of Health Sciences, Tsukuba International University, Ibaragi, Tsuchiura-City 305-8577, Japan
| | - Yuri Akishima-Fukasawa
- Department of Pathology, School of Medicine, Toho University, Ota-Ku, Tokyo 143-8540, Japan
| | - Tetuo Mikami
- Department of Pathology, School of Medicine, Toho University, Ota-Ku, Tokyo 143-8540, Japan
| | - Yoshikiyo Akasaka
- Department of Pathology, School of Medicine, Toho University, Ota-Ku, Tokyo 143-8540, Japan
| | - Toshiharu Ishii
- Department of Pathology, Saiseikai Yokohamashi Tobu Hospital, Kanagawa, Yokohama-City 230-8765, Japan
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Kang N, Liu X, You X, Sun W, Haneef K, Sun X, Liu W. Aberrant B-Cell Activation in Systemic Lupus Erythematosus. KIDNEY DISEASES (BASEL, SWITZERLAND) 2022; 8:437-445. [PMID: 36590680 PMCID: PMC9798842 DOI: 10.1159/000527213] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/30/2022] [Accepted: 09/07/2022] [Indexed: 11/05/2022]
Abstract
Background B lymphocytes (B cells) are essential in humoral response, and their activation is an important first step for the production of antibodies. However, aberrant B-cell activation is common in the development and progression of autoimmune diseases including systemic lupus erythematosus (SLE), which is characterized by the generation of superfluous autoantibodies. SLE exhibits clinical manifestation such as excessive inflammation and tissue damage. This review aims to summarize the recent emerging studies on aberrant B-cell activation and the associated concurrent therapeutic targets in SLE. Summary Aberrant B-cell activation is closely associated with the pathogenesis of SLE. Among a variety of mechanisms, dysregulations of B-cell receptor (BCR), toll-like receptor (TLR), and B-cell activating factor receptor (BAFF-R) pathways are the common and dominating factors involved in aberrant B-cell activation. These aberrant signaling transductions play diverse and integrated roles in the development and the pathogenesis of SLE. Therapies targeting aberrant B-cell activation have shown promising efficacy in achieving the clinical alleviation of SLE, suggesting the discovery of new drug targets from these aberrant signaling pathways is imminent. Here, an integrated survey or review of published high-throughput sequencing database covering RNAs of B cells from SLE versus criteria-matched healthy controls highlights that reported signaling molecules in BCR pathway (VAV2, PLC-γ2), TLR pathway (TLR9, P105, IRF7, TAB1), and BAFF-R pathway (SDF-1α) are attitudinally upregulated in SLE patients. This review thus suggests the concurrent and future therapeutic targets and potential biomarkers in both basic and clinical studies of SLE. Key Messages This review focuses on core B-cell signaling pathways, discussing the progress in the role of aberrant B-cell activation during the pathogenesis of SLE. This review also highlights the signaling molecules from published studies and database for the possible prevention and treatment targets serving the future clinical treatments of SLE.
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Affiliation(s)
- Na Kang
- Beijing Key Lab for Immunological Research on Chronic Diseases, School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Xiaohang Liu
- Beijing Key Lab for Immunological Research on Chronic Diseases, School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Xujie You
- Department of Rheumatology, National Centre for Children's Health, Beijing Children's Hospital, Capital Medical University, Beijing, China
| | - Wenbo Sun
- Beijing Key Lab for Immunological Research on Chronic Diseases, School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Kabeer Haneef
- Beijing Key Lab for Immunological Research on Chronic Diseases, School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Beijing, China
| | - Xiaolin Sun
- Department of Rheumatology and Immunology, Beijing Key Lab for Rheumatism and Immune Diagnosis (BZ0135), Peking University People's Hospital, Beijing, China
| | - Wanli Liu
- Beijing Key Lab for Immunological Research on Chronic Diseases, School of Life Sciences, Institute for Immunology, MOE Key Laboratory of Protein Sciences, Beijing Advanced Innovation Center for Structural Biology, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, Tsinghua University, Beijing, China
- Tsinghua-Peking Center for Life Sciences, Beijing, China
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Bale S, Varga J, Bhattacharyya S. Role of RP105 and A20 in negative regulation of toll-like receptor activity in fibrosis: potential targets for therapeutic intervention. AIMS ALLERGY AND IMMUNOLOGY 2021. [DOI: 10.3934/allergy.2021009] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Salazar-Camarena DC, Palafox-Sánchez CA, Cruz A, Marín-Rosales M, Muñoz-Valle JF. Analysis of the receptor BCMA as a biomarker in systemic lupus erythematosus patients. Sci Rep 2020; 10:6236. [PMID: 32277232 PMCID: PMC7148319 DOI: 10.1038/s41598-020-63390-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2019] [Accepted: 03/30/2020] [Indexed: 11/08/2022] Open
Abstract
B cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL) play central roles in B cell development and maturation. Soluble forms of their receptors can be generated by proteolytic cleavage; however, their physiological and clinical roles are unknown. This study aimed to assess the relationships between the receptor soluble B cell maturation antigen (sBCMA) and clinical variables in systemic lupus erythematosus (SLE) patients. Serum cytokine concentrations were measured by ELISA for 129 SLE patients and 34 healthy controls (HCs), and the expression of the receptor BCMA was evaluated on B and plasma cells from 40 subjects. SLE patients showed aberrant expression of the receptor BCMA on B and plasma cells. Soluble levels of the receptor sBCMA and its ligands sAPRIL and sBAFF were increased in SLE patients compared with HCs. Additionally, sBCMA (rs = 0.6177) and sAPRIL (rs = 0.4952) correlated strongly with disease activity. Active SLE patients who achieved low disease activity showed decreased sBCMA (53.30 vs 35.30 ng/mL; p < 0.05) and sBAFF (4.48 vs 2.27 ng/mL; p < 0.05) serum levels after treatment, while sAPRIL expression remained unchanged. At a cutoff value of 22.40 ng/mL, sAPRIL showed high sensitivity (96.12%) and specificity (94.12%) for discrimination between HCs and SLE patients, while sBAFF showed lower sensitivity (82.2%) but higher specificity (94.1%) at a cutoff of 1.195 ng/mL. Relatively high levels of sAPRIL and sBCMA clustered active SLE patients. The receptor sBCMA could be a potential biomarker of disease activity in SLE.
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Affiliation(s)
- Diana Celeste Salazar-Camarena
- Research Institute in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico
| | - Claudia Azucena Palafox-Sánchez
- Research Institute in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico.
| | - Alvaro Cruz
- Research Institute in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico
| | - Miguel Marín-Rosales
- Department of Rheumatology, West Medical Hospital, Ministry of Health, Zapopan, Mexico
| | - José Francisco Muñoz-Valle
- Research Institute in Biomedical Sciences, University Center of Health Sciences, University of Guadalajara, Guadalajara, Mexico
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Peripheral B Cell Subsets in Autoimmune Diseases: Clinical Implications and Effects of B Cell-Targeted Therapies. J Immunol Res 2020; 2020:9518137. [PMID: 32280720 PMCID: PMC7125470 DOI: 10.1155/2020/9518137] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 03/01/2020] [Accepted: 03/10/2020] [Indexed: 12/14/2022] Open
Abstract
Antibody-secreting cells (ASCs) play a fundamental role in humoral immunity. The aberrant function of ASCs is related to a number of disease states, including autoimmune diseases and cancer. Recent insights into activated B cell subsets, including naïve B cell to ASC stages and their resultant cellular disturbances, suggest that aberrant ASC differentiation occurs during autoimmune diseases and is closely related to disease severity. However, the mechanisms underlying highly active ASC differentiation and the B cell subsets in autoimmune patients remain undefined. Here, we first review the processes of ASC generation. From the perspective of novel therapeutic target discovery, prediction of disease progression, and current clinical challenges, we further summarize the aberrant activity of B cell subsets including specialized memory CD11chiT-bet+ B cells that participate in the maintenance of autoreactive ASC populations. An improved understanding of subgroups may also enhance the knowledge of antigen-specific B cell differentiation. We further discuss the influence of current B cell therapies on B cell subsets, specifically focusing on systemic lupus erythematosus, rheumatoid arthritis, and myasthenia gravis.
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Koarada S, Tada Y. Roles of plasmablasts in IgG4-related disease and various immune-based diseases. World J Rheumatol 2016; 6:16-22. [DOI: 10.5499/wjr.v6.i1.16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/22/2015] [Revised: 12/23/2015] [Accepted: 01/07/2016] [Indexed: 02/06/2023] Open
Abstract
IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disease with multiple organ disorders. Recently, in IgG4-RD, increased circulating plasmablasts have been found. The subsets of plasmablasts are negative for RP105 (CD180). A large population of B cells lacking RP105 (RP105-negative B cells) are found in patients with active with systemic lupus erythematosus and other systemic autoimmune diseases, including dermatomyositis, and Sjögren’s syndrome. In other conditions, such as neuromyelitis optica, Kawasaki’s disease, primary biliary cirrhosis and aging, RP105 expression on B cells and monocytes also alters. We review the basic science and clinical significance of RP105-negative B cells including plasmablasts in various immune-based diseases. RP105-negative B cells, especially plasmablasts, play crucial roles in both systemic and organ-specific autoimmune and inflammatory disorders.
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Koarada S, Tashiro S, Nagao N, Suematsu R, Ohta A, Tada Y. Increased RP105-Negative B Cells in IgG4-Related Disease. Open Rheumatol J 2013; 7:55-7. [PMID: 24039640 PMCID: PMC3771239 DOI: 10.2174/1874312901307010055] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/25/2013] [Revised: 07/05/2013] [Accepted: 07/08/2013] [Indexed: 12/17/2022] Open
Abstract
Four patients with IgG4-related disease (IgG4-RD) showed increased percentages of RP105-negative B cells in the peripheral blood. Case 1: A 66-year-old man having retroperitoneal fibrosis had 18.8% of RP105-negative B cells. Oral prednisolone improved the affected lesions and the percentage of RP105-negative B cells decreased (3.2%) after the treatment. Case 2: A 53-year-old man with retroperitoneal fibrosis had 27.9% of RP105-negative B cells. Case 3: A 38-year-old man with follicular hyperplasia showed increased percentage of RP105-negative B cells (8.3%). Case 4: A 60-year-old man with interstitial nephritis had 27.5% of RP105-negative B cells. The treatment decreased the numbers of RP105-negative B cells. Increased numbers of RP105-negatvie B cells is possibly associated with disease activity of IgG4-RD. Analysis of expression of RP105 on B cells may be helpful in evaluation of disease activity of IgG4-RD.
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Affiliation(s)
- S Koarada
- Division of Rheumatology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan
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