11 results on '"Hachiro Konaka"'
Search Results
2. SLE stratification based on BAFF and IFN-I bioactivity for biologics and implications of BAFF produced by glomeruli in lupus nephritis
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Eri Itotagawa, Yoshihiko Tomofuji, Yasuhiro Kato, Hachiro Konaka, Kohei Tsujimoto, JeongHoon Park, Daiki Nagira, Takehiro Hirayama, Tatsunori Jo, Toru Hirano, Takayoshi Morita, Masayuki Nishide, Sumiyuki Nishida, Yoshihito Shima, Masashi Narazaki, Yukinori Okada, Hyota Takamatsu, and Atsushi Kumanogoh
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Rheumatology ,Pharmacology (medical) - Abstract
Objective B-cell activating factor (BAFF) is implicated in SLE pathogenesis. Blocking BAFF signalling has contributed to reducing glucocorticoid dosage and preventing organ damage. However, clinical characteristics of patients who may benefit from this therapy are not yet fully elucidated. Therefore, we identified patients with high BAFF-bioactivity to investigate their clinical characteristics and BAFF-producing cells. Methods We established the reporter cell for BAFF and investigated the clinical characteristics of SLE patients with high BAFF-bioactivity. We identified BAFF-expressing kidney cells using publicly available scRNA-seq data and immunohistological analysis. SLE patients were stratified based on the bioactivity of BAFF and type-I IFN (IFN-I) to identify associated characteristic clinical manifestations. Results SLE patients, especially patients with LN, had significantly higher serum BAFF-bioactivity than healthy controls (HC) and non-LN patients. Additionally, single-cell-RNA-seq data and immunohistological analysis of kidney samples from LN patients revealed that BAFF is expressed in glomerular macrophages and mesangial cells. Notably, BAFF bioactivity was elevated in the urine of LN patients compared with that of non-LN patients, while no IFN-I bioactivity was detected in the urine. Furthermore, SLE stratification based on bioactivities of serum BAFF and IFN-I revealed the clinical characteristics of patients: high BAFF represented patients with LN and high IFN-I represented patients with blood and skin manifestations. Conclusions Monitoring urinary BAFF-bioactivity may be valuable in diagnosing LN. Furthermore, stratification based on serum BAFF and IFN-I bioactivities may allow the identification of appropriate patients for biologics targeting BAFF and IFN-I.
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- 2022
3. The proliferative activity levels of each immune cell population evaluated by mass cytometry are linked to the clinical phenotypes of systemic lupus erythematosus
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Akiko Kajihara, Takayoshi Morita, Yasuhiro Kato, Hachiro Konaka, Teruaki Murakami, Yuta Yamaguchi, Shohei Koyama, Hyota Takamatsu, Masayuki Nishide, Yuichi Maeda, Akane Watanabe, Sumiyuki Nishida, Toru Hirano, Yoshihito Shima, Masashi Narazaki, and Atsushi Kumanogoh
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Immunology ,Immunology and Allergy ,General Medicine - Abstract
Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease, and many peripheral immune cell populations (ICPs) are thought to be altered according to the course of the disease. However, it is unclear which ICPs are associated with the clinical phenotypes of SLE. We analyzed peripheral blood mononuclear cells (PBMCs) of 28 SLE patients using mass cytometry and identified 30 ICPs. We determined the proliferative activity of ICPs by measuring the proportion of cells expressing specific markers and Ki-67 among CD45+ cells (Ki-67+ proportion). We observed an increased Ki-67+ proportion for many ICPs of SLE patients and examined the association between their Ki-67+ proportions and clinical findings. The Ki-67+ proportions of five ICPs [classical monocyte (cMo), effector memory CD8+ T cell (CD8Tem), CXCR5− naive B cell (CXCR5− nB), and CXCR5− IgD−CD27− B cell (CXCR5− DNB)] were identified as clinically important factors. The SLE Disease Activity Index (SLEDAI) was positively correlated with cMo and plasma cells (PC). The titer of anti-DNA antibodies was positively correlated with cMo, CXCR5− nB, and CXCR5− DNB. The C4 level was negatively correlated with CXCR5− DNB. The bioactivity of type I interferon was also positively correlated with these ICPs. Fever and renal involvement were associated with cMo. Rash was associated with CD8Tem and CXCR5− DNB. On the basis of the proliferative activity among five ICPs, SLE patients can be classified into five clusters showing different SLE phenotypes. Evaluation of the proliferative activity in each ICP can be linked to the clinical phenotypes of individual SLE patients and help in the treatment strategy.
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- 2022
4. Palmoplantar pustulosis and pustulotic arthro‐osteitis associated with multiple venous occlusion: A case report and literature review
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Emi Inoue, Shiori Hiroumi, Sachina Sato, Misa Hayashi, Hachiro Konaka, Shigeyoshi Tsuji, and Mari Higashiyama
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Dermatology ,General Medicine - Published
- 2023
5. The lysosomal Ragulator complex activates NLRP3 inflammasome in vivo via HDAC6
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Kohei Tsujimoto, Tatsunori Jo, Daiki Nagira, Hachiro Konaka, Jeong Hoon Park, Shin‐ichiro Yoshimura, Akinori Ninomiya, Fuminori Sugihara, Takehiro Hirayama, Eri Itotagawa, Yusei Matsuzaki, Yuki Takaichi, Wataru Aoki, Shotaro Saita, Shuhei Nakamura, Andrea Ballabio, Shigeyuki Nada, Masato Okada, Hyota Takamatsu, Atsushi Kumanogoh, Tsujimoto, Kohei, Jo, Tatsunori, Nagira, Daiki, Konaka, Hachiro, Park, Jeong Hoon, Yoshimura, Shin-Ichiro, Ninomiya, Akinori, Sugihara, Fuminori, Hirayama, Takehiro, Itotagawa, Eri, Matsuzaki, Yusei, Takaichi, Yuki, Aoki, Wataru, Saita, Shotaro, Nakamura, Shuhei, Ballabio, Andrea, Nada, Shigeyuki, Okada, Masato, Takamatsu, Hyota, and Kumanogoh, Atsushi
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Inflammation ,α-tocopherol ,General Immunology and Microbiology ,Inflammasomes ,General Neuroscience ,alpha-Tocopherol ,Peritonitis ,HDAC6 ,Histone Deacetylase 6 ,General Biochemistry, Genetics and Molecular Biology ,NLRP3 inflammasome ,Uric Acid ,Mice, Inbred C57BL ,Mice ,Ragulator complex ,NLR Family, Pyrin Domain-Containing 3 Protein ,Humans ,Animals ,Lysosomes ,Molecular Biology - Abstract
The cellular activation of the NLRP3 inflammasome is spatiotemporally orchestrated by various organelles, but whether lysosomes contribute to this process remains unclear. Here, we show the vital role of the lysosomal membrane-tethered Ragulator complex in NLRP3 inflammasome activation. Deficiency of Lamtor1, an essential component of the Ragulator complex, abrogated NLRP3 inflammasome activation in murine macrophages and human monocytic cells. Myeloid-specific Lamtor1-deficient mice showed marked attenuation of NLRP3-associated inflammatory disease severity, including LPS-induced sepsis, alum-induced peritonitis, and monosodium urate (MSU)-induced arthritis. Mechanistically, Lamtor1 interacted with both NLRP3 and histone deacetylase 6 (HDAC6). HDAC6 enhances the interaction between Lamtor1 and NLRP3, resulting in NLRP3 inflammasome activation. DL-all-rac-α-tocopherol, a synthetic form of vitamin E, inhibited the Lamtor1-HDAC6 interaction, resulting in diminished NLRP3 inflammasome activation. Further, DL-all-rac-α-tocopherol alleviated acute gouty arthritis and MSU-induced peritonitis. These results provide novel insights into the role of lysosomes in the activation of NLRP3 inflammasomes by the Ragulator complex.
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- 2023
6. The lysosomal Ragulator complex plays an essential role in leukocyte trafficking by activating myosin II
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Masato Okada, Kohei Tsujimoto, Takeshi Nakatani, Atsushi Kumanogoh, Masayuki Nishide, JeongHoon Park, Hachiro Konaka, Tetsuya Kimura, Shyohei Koyama, Yasuhiro Kato, Tatsunori Jo, Hyota Takamatsu, Takayoshi Morita, Yoshitomo Hayama, and Shigeyuki Nada
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Male ,0301 basic medicine ,Leukocyte migration ,Neutrophils ,Science ,Phosphatase ,Antigen-presenting cells ,General Physics and Astronomy ,Motility ,mTORC1 ,macromolecular substances ,Mechanistic Target of Rapamycin Complex 1 ,Article ,General Biochemistry, Genetics and Molecular Biology ,Cell Line ,Mice ,Myosin-Light-Chain Phosphatase ,03 medical and health sciences ,0302 clinical medicine ,Myosin ,Leukocytes ,Animals ,Humans ,Adaptor Proteins, Signal Transducing ,Myosin Type II ,Multidisciplinary ,Chemistry ,Intracellular Signaling Peptides and Proteins ,Cell migration ,Actomyosin ,Dendritic Cells ,General Chemistry ,Ragulator complex ,Cell biology ,Mice, Inbred C57BL ,030104 developmental biology ,Amoeboid migration ,Female ,Myosin-light-chain phosphatase ,Lysosomes ,030217 neurology & neurosurgery ,Signal Transduction - Abstract
Lysosomes are involved in nutrient sensing via the mechanistic target of rapamycin complex 1 (mTORC1). mTORC1 is tethered to lysosomes by the Ragulator complex, a heteropentamer in which Lamtor1 wraps around Lamtor2–5. Although the Ragulator complex is required for cell migration, the mechanisms by which it participates in cell motility remain unknown. Here, we show that lysosomes move to the uropod in motile cells, providing the platform where Lamtor1 interacts with the myosin phosphatase Rho-interacting protein (MPRIP) independently of mTORC1 and interferes with the interaction between MPRIP and MYPT1, a subunit of myosin light chain phosphatase (MLCP), thereby increasing myosin II–mediated actomyosin contraction. Additionally, formation of the complete Ragulator complex is required for leukocyte migration and pathophysiological immune responses. Together, our findings demonstrate that the lysosomal Ragulator complex plays an essential role in leukocyte migration by activating myosin II through interacting with MPRIP., Myosin II–mediated contractility is required for leukocyte migration. Here, authors show that lysosomes are involved in leukocyte migration by providing the platform where Ragulator complex interacts with the myosin phosphatase Rho-interacting protein (MPRIP) independently of mTORC1 and interferes with the interaction between MPRIP and a subunit of myosin light chain phosphatase (MLCP).
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- 2021
7. Inflammatory Thoracic Aortic Aneurysm in a Patient with Advanced Lung Adenocarcinoma Treated with Pembrolizumab
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Ryusuke Ninomiya, Yuhei Kinehara, Satoshi Tobita, Hachiro Konaka, Ryu Jokoji, Takashi Shintani, and Isao Tachibana
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Male ,Lung Neoplasms ,Aortic Aneurysm, Thoracic ,Internal Medicine ,Humans ,Adenocarcinoma of Lung ,Aorta, Thoracic ,General Medicine ,Pemetrexed ,Middle Aged ,Antibodies, Monoclonal, Humanized ,Carboplatin - Abstract
A 57-year-old man with lung adenocarcinoma was treated with chemotherapy and immune checkpoint blockade. After two cycles of carboplatin, pemetrexed, and pembrolizumab, he developed a persistent fever. Chest computed tomography (CT) suggested inflammation of the aortic wall. We treated the patient with corticosteroids. After four cycles of carboplatin, pemetrexed, and pembrolizumab, chest CT showed an aneurysm in the ascending aorta. We diagnosed him with inflammatory thoracic aortic aneurysm induced by pembrolizumab and performed surgical replacement of the ascending aorta. Although this might be a very rare case, we should be aware of aortitis as a potential adverse effect of pembrolizumab.
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- 2022
8. Cell-Free DNA Derived From Neutrophils Triggers Type 1 Interferon Signature in Neuromyelitis Optica Spectrum Disorder
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Hisashi Murata, Makoto Kinoshita, Yoshiaki Yasumizu, Daisuke Motooka, Shohei Beppu, Naoyuki Shiraishi, Yasuko Sugiyama, Keigo Kihara, Satoru Tada, Toru Koda, Hachiro Konaka, Hyota Takamatsu, Atsushi Kumanogoh, Tatsusada Okuno, and Hideki Mochizuki
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Neurology ,Neutrophils ,Neuromyelitis Optica ,Leukocytes, Mononuclear ,Humans ,Neurology (clinical) ,Interferons ,Cell-Free Nucleic Acids - Abstract
Background and ObjectivesRecently accumulating evidence suggests the pivotal role of type 1 interferon (IFN-1) signature in the pathogenesis of neuromyelitis optica spectrum disorder (NMOSD). However, the mechanism of the initial trigger that augments IFN-1 pathway in the peripheral immune system of NMOSD has yet to be elucidated.MethodsClinical samples were obtained from 32 patients with aquaporin-4 antibody–positive NMOSD and 23 healthy subjects. IFN-1 induction in peripheral blood mononuclear cells (PBMCs) by serum-derived cell-free DNA (cfDNA) was assessed in combination with blockades of DNA sensors in vitro. CfDNA fraction was analyzed for DNA methylation profiles by bisulfite sequencing, elucidating the cellular origin of cfDNA. The induction of neutrophil extracellular trap related cell death (NETosis) was further analyzed in NMOSD and control groups, and the efficacy of pharmacologic intervention of NETosis was assessed.ResultsEnhanced IFN-1 induction by cfDNA derived from NMOSD was observed in PBMCs with cofactor of LL37 antimicrobial peptide. DNase treatment, cGAS inhibitor, and Toll-like receptor 9 antagonist efficiently inhibited IFN-1 production. DNA methylation pattern of cfDNA in patients with NMOSD demonstrated that the predominant cellular source of cfDNA was neutrophils. Whole blood transcriptome analysis also revealed neutrophil activation in NMOSD. In addition, enhanced NETosis induction was observed with NMOSD-derived sera, and efficient pharmacologic inhibition of NETosis with dipyridamole was observed.DiscussionOur study highlights the previously unrevealed role of cfDNA predominantly released by neutrophil in the induction of IFN-1 signature in NMOSD and further indicate a novel pharmacologic target in NMOSD.
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- 2021
9. Corrigendum to 'Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies' [J. Autoimmun. 126 (2022) 102774]
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Noriko Arase, Hideaki Tsuji, Hyota Takamatsu, Hui Jin, Hachiro Konaka, Yasuhito Hamaguchi, Kyoko Tonomura, Yorihisa Kotobuki, Ikuko Ueda-Hayakawa, Sumiko Matsuoka, Toru Hirano, Hideki Yorifuji, Hiroyuki Murota, Koichiro Ohmura, Ran Nakashima, Tomoharu Sato, Atsushi Kumanogoh, Ichiro Katayama, Hisashi Arase, and Manabu Fujimoto
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Immunology ,Immunology and Allergy - Published
- 2022
10. Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies
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Noriko Arase, Hideaki Tsuji, Hyota Takamatsu, Hui Jin, Hachiro Konaka, Yasuhito Hamaguchi, Kyoko Tonomura, Yorihisa Kotobuki, Ikuko Ueda-Hayakawa, Sumiko Matsuoka, Toru Hirano, Hideki Yorifuji, Hiroyuki Murota, Koichiro Ohmura, Ran Nakashima, Tomoharu Sato, Atsushi Kumanogoh, Ichiro Katayama, Hisashi Arase, and Manabu Fujimoto
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Myositis ,Ribonucleoproteins ,Immunoglobulin G ,Immunology ,Humans ,Immunology and Allergy ,HLA-DR Antigens ,Autoantibodies ,Autoimmune Diseases - Abstract
Intracellular proteins are often targeted by autoantibodies in autoimmune diseases; however, the mechanism through which intracellular molecules are targeted remains unknown. We previously found that several intracellular misfolded proteins are transported to the cell surface by HLA class II molecules and are recognized by autoantibodies in some autoimmune diseases, such as rheumatoid arthritis, antiphospholipid syndrome, and microscopic polyangiitis. Ro52 is an intracellular Fc receptor that is a target antigen for myositis-associated autoantibodies. We analyzed the role of HLA class II molecules in the autoantibody recognition of Ro52. Ro52 alone was not transported to the cell surface by HLA class II molecules; however, it was transported to the cell surface in the presence of both IgG heavy chain and HLA class II molecules to form a Ro52/IgG/HLA-DR complex. The Ro52/IgG/HLA-DR complex was specifically recognized by autoantibodies from some patients with inflammatory myopathies. We then evaluated 120 patients with inflammatory myopathies with four types of myositis-specific antibodies and analyzed the autoantibodies against the Ro52/IgG/HLA-DR complex. The specific antibodies against the Ro52/IgG/HLA-DR complex were detected in 90% and 93% of patients who were positive for anti-MDA5 and anti-ARS antibodies, respectively. In individual patients with these two inflammatory myopathies, changes in serum titers of anti-Ro52/IgG/HLA-DR-specific antibodies were correlated with the levels of KL-6 (R = 0.51 in anti-MDA5 antibody-positive DM patients, R = 0.67 in anti-ARS antibody-positive PM/DM patients with respiratory symptoms) and CK (R = 0.63 in anti-ARS antibody-positive PM/DM patients with muscle symptoms) over time. These results suggest that antibodies against Ro52/IgG/HLA-DR expressed on the cell surface could be involved in the pathogenesis of inflammatory myopathy subgroups.
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- 2022
11. Pathological and therapeutic implications of eosinophil-derived semaphorin 4D in eosinophilic chronic rhinosinusitis
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Yujiro Naito, Takayoshi Morita, Hyota Takamatsu, Yohei Maeda, Atsushi Kumanogoh, Yoshimitsu Nakanishi, Takeshi Nakatani, Yu Futami, Maiko Naito, Hidenori Inohara, Masaki Hayama, Daisuke Okuzaki, Hachiro Konaka, Takeshi Tsuda, Sho Obata, Masayuki Nishide, Yasuhiko Suga, Ayaka Nakatani, Yasuhiro Kato, Takashi Shikina, Yoshitomo Hayama, Kazuya Takeda, Shohei Koyama, Mayuko Izumi, Shingo Satoh, and Satoshi Nojima
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Adult ,Male ,0301 basic medicine ,Immunology ,SEMA4D ,Semaphorins ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Antigens, CD ,Eosinophilia ,Eosinophilic ,medicine ,Animals ,Humans ,Immunology and Allergy ,Nasal polyps ,Sinusitis ,Rhinitis ,Mice, Inbred BALB C ,biology ,business.industry ,Transendothelial and Transepithelial Migration ,Middle Aged ,Eosinophil ,medicine.disease ,Recombinant Proteins ,Eosinophils ,Ovalbumin ,030104 developmental biology ,medicine.anatomical_structure ,Chronic Disease ,biology.protein ,Immunohistochemistry ,Female ,Nasal Lavage Fluid ,Antibody ,business ,hormones, hormone substitutes, and hormone antagonists ,030215 immunology - Abstract
Background Eosinophilic chronic rhinosinusitis (ECRS) is a subtype of chronic rhinosinusitis. Clinical markers for ECRS disease activity and treatment strategies have not been sufficiently established. Although semaphorins are originally identified as neuronal guidance factors, it is becoming clear that they play key roles in immune regulation and inflammatory diseases. Objective We sought to investigate the pathological functions and therapeutic potential of semaphorin 4D (SEMA4D) in ECRS. Methods Serum soluble SEMA4D levels in patients with paranasal sinus diseases were measured by ELISA. The expression of SEMA4D in blood cells and nasal polyp tissues was assessed by flow cytometry and immunohistochemistry, respectively. Generation of soluble SEMA4D was evaluated in matrix metalloproteinase-treated eosinophils. Endothelial cells were stimulated with recombinant SEMA4D, followed by eosinophil transendothelial migration assays. Allergic chronic rhinosinusitis was induced in mice using Aspergillus protease with ovalbumin. The efficacy of treatment with anti-SEMA4D antibody was evaluated histologically and by nasal lavage fluid analysis. Results Serum soluble SEMA4D levels were elevated in patients with ECRS and positively correlated with disease severity. Tissue-infiltrated eosinophils in nasal polyps from patients with ECRS stained strongly with anti-SEMA4D antibody. Cell surface expression of SEMA4D on eosinophils from patients with ECRS was reduced, which was due to matrix metalloproteinase-9–mediated cleavage of membrane SEMA4D. Soluble SEMA4D induced eosinophil transendothelial migration. Treatment with anti-SEMA4D antibody ameliorated eosinophilic infiltration in sinus tissues and nasal lavage fluid in the ECRS animal model. Conclusions Eosinophil-derived SEMA4D aggravates ECRS. Levels of serum SEMA4D reflect disease severity, and anti-SEMA4D antibody has therapeutic potential as a treatment for ECRS.
- Published
- 2020
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