Functional classification of antineutrophil cytoplasmic antibody (ANCA) and its relation with clinical parameters of ANCA-associated vasculitis.
Mai Taniguchi, China Washio, Momo Uchizawa, Naho Ogawa, Riku Manabe, Suishin Arai, Hodaka Ogawa, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Yoshihiro Arimura, Koichi Amano, Yukio Yuzawa, Ken-Ei Sada, Tatsuya Atsumi, Hiroaki Dobashi, Masayoshi Harigai, Seiichi Matsuo, Hirofumi Makino, Akihiro Ishizu
Biochemistry and biophysics reports, 45, 102428, 102428, Mar. 2026, [International Magazine]
English, Scientific journal, Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by serum ANCA and systemic small-vessel vasculitis. Neutrophils are primed to express ANCA antigens on the plasma membrane. ANCA binding to the antigens can transduce signals into neutrophils, releasing reactive oxygen species (ROS) and contributing to AAV development. ANCA-mediated signals are transduced via two pathways: ANCA antigens crosslinked by ANCA, and Fcγ receptor (FcγR), to which the Fc portion of ANCA binds. This study aimed to demonstrate the association of ANCA-mediated neutrophil activation pathways with clinical manifestations of AAV, including renal dysfunction and kidney survival at 6 months after treatment. For this purpose, IgG was extracted from the serum of AAV patients before treatment (n = 112), and ROS production from neutrophils exposed to IgG and its suppression by FcγR inhibitors (FcX) were assessed. IgG exhibiting higher ROS production than control IgG was classified as ROS-inducing ANCA and the others as ROS-noninducing ANCA. The former was subclassified into antigen-driven ANCA and FcγR-driven ANCA according to whether the ROS production suppression rate by FcX was <50 % or ≧50 %, respectively. As a result, ANCA was classified into ROS-inducing antigen-driven ANCA (n = 74), ROS-inducing FcγR-driven ANCA (n = 22), and ROS-noninducing ANCA (n = 16). Serum levels of blood urea nitrogen and creatinine were significantly higher in patients with ROS-inducing FcγR-driven ANCA than in those with ROS-noninducing ANCA. Patients with ROS-inducing FcγR-driven ANCA had a significantly lower kidney survival rate 6 months after treatment than other patients. The collective findings suggest that ROS-inducing FcγR-driven ANCA may predict poor kidney prognosis in AAV.

A case of hypertrophic pachymeningitis with neutrophil extracellular traps formation.
Koki Nakamura, Masatoshi Kanda, Yuki Hamakawa, Hidenori Amaike, Ken Nagahata, Hiroyuki Nakamura, China Washio, Yuka Nishibata, Sakiko Masuda, Akihiro Ishizu, Hiroki Takahashi
Rheumatology (Oxford, England), 05 Sep. 2025, [International Magazine]
English, Scientific journal

Artificial intelligence challenge of discriminating cutaneous arteritis and polyarteritis nodosa based on hematoxylin-and-eosin images of skin biopsy specimens.
Wataru Kashiwa, Kenji Hirata, Hiroki Endo, Kohsuke Kudo, Chietsugu Katoh, Tamihiro Kawakami, Hiroyuki Kanno, Kei Takahashi, Tatsuhiko Miyazaki, Eiji Ikeda, Toshiaki Oharaseki, Yayoi Ogawa, Mitsuho Onimaru, Mie Kurata, Daigo Nakazawa, Eri Muso, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Yoshihiro Matsuno, Shunsuke Furuta, Yoshiyuki Abe, Naoto Tamura, Masayoshi Harigai, Akihiro Ishizu
Pathology, research and practice, 269, 155915, 155915, May 2025, [International Magazine]
English, Scientific journal, Diseases that develop necrotizing vasculitis of cutaneous muscular arteries include cutaneous arteritis (CA) and polyarteritis nodosa (PAN). It is difficult to distinguish them based on skin biopsy findings alone. This study demonstrated that artificial intelligence (AI) can discriminate them based on skin biopsy findings and revealed where AI focuses on the image. Ninety-three hematoxylin-and-eosin images of CA and 19 PAN images were used. Among them, 85 CA and 17 PAN images were used to train AI; thereafter, AI was challenged to classify the remaining images. The same test images were evaluated by 26 pathologists with different years of experience. AI accuracy was 75.2 %, whereas that of pathologists was 42.8 %. Gradient-weighted class activation mapping (Grad-CAM) indicated that AI focused on connective tissues around the affected vessels rather than the affected vessels. Twenty-two of the 26 pathologists were randomly divided into two groups of 11 each, one of which referred to Grad-CAM images and was challenged in the second-round test of images different from the first round. The accuracy significantly improved after referring to Grad-CAM images, whereas it was equivalent to the first round without referring to Grad-CAM images. In the survey after the second-round test, pathologists who referred to Grad-CAM images suggested that inflammation and fibrosis in the surrounding connective tissues in PAN might be abundant compared to CA. AI may be useful for histological differentiation between CA and PAN and can help pathologists improve the ability of discriminating CA and PAN based on histological findings of skin biopsy specimens.

Neutrophils and NETs in kidney disease.
Daigo Nakazawa, Sakiko Masuda, Yuka Nishibata, Kanako Watanabe-Kusunoki, Utano Tomaru, Akihiro Ishizu
Nature reviews. Nephrology, 18 Mar. 2025, [International Magazine]
English, Scientific journal, Neutrophils, conventionally regarded as a homogeneous immune cell population, have emerged as a heterogeneous group of cells with distinct gene profiles and immune properties. Activated neutrophils release a spectrum of bioactive substances, including cytokines, chemokines, proteolytic enzymes, reactive oxygen species and neutrophil extracellular traps (NETs), which are composed of decondensed DNA and antimicrobial proteins. NETs have a pivotal role in innate immunity, including in preventing the ascent of uropathogenic bacteria into the kidneys, as they efficiently trap pathogenic microorganisms. However, although indispensable for defence against pathogens, NETs also pose risks of self-damage owing to their cytotoxicity, thrombogenicity and autoantigenicity. Accordingly, neutrophils and NETs have been implicated in the pathogenesis of various disorders that affect the kidneys, including acute kidney injury, vasculitis, systemic lupus erythematosus, thrombotic microangiopathy and in various aetiologies of chronic kidney disease. Pathological alterations in the glomerular vascular wall can promote the infiltration of neutrophils, which can cause tissue damage and inflammation through their interactions with kidney-resident cells, including mesangial cells and podocytes, leading to local cell death. Targeting neutrophil activation and NET formation might therefore represent a new therapeutic strategy for these conditions.

Aneurysmal rupture in microscopic polyangiitis: a case-based review.
Keita Imanishi, Kazuhiro Yasuo, Yusuke Shirai, Satoshi Tanikawa, Momo Uchizawa, Yuka Nishibata, Sakiko Masuda, Zen-Ichi Tanei, Shinya Tanaka, Akihiro Ishizu
Clinical rheumatology, 21 Jan. 2025, [International Magazine]
English, Scientific journal, Microscopic polyangiitis (MPA) affects small and medium vessel, which sometimes leads to arterial aneurysms. In English database, only 15 reports refer to ruptured aneurysms in MPA. We experienced a fatal case with MPA who developed multiple visceral aneurysms, resulting in rupture of the hepatic aneurysm. For the better knowledge of aneurysmal rupture in MPA, we reviewed the feature of 16 cases, including our case. Organ involvement observed was glomerulonephritis 100%, pulmonary involvement 25%, peripheral neuropathy 25%, and purpura 12.5%. Locations of ruptured aneurysms were left gastric artery 31.25%, renal and hepatic artery 18.75% each, intracranial and splenic artery 12.5% each, and gastroepiploic and mesenteric artery 6.25% each. Median time to rupture was 45 days after systemic symptom onset, and 15 days after immunosuppressive treatment induction. Symptoms at rupture were visceral pain 68.75% and hemodynamic instability 62.5%. Pathological findings of ruptured aneurysms were acute vasculitis in 5, no evidence of active inflammation in 3. Causes of death were aneurysmal rupture in 5, treatment complications in 3, and total mortality rate was 50%. In conclusion, the initial presentation of MPA resulting in ruptured aneurysms tends to be renal-limited vasculitis. Aneurysms of abdominal medium-sized arteries tend to rupture, from 4 weeks after systemic symptom onset to 2 weeks after immunosuppressive treatment induction. Most aneurysms are less than 10 mm in diameter, develop asymptomatically in a few days, and are recognized when they rupture. Early induction of immunosuppressive treatment has the potential to shrink aneurysms and prevent rupture.

Cathepsin C inhibition reduces neutrophil serine protease activity and improves activated neutrophil-mediated disorders.
Yuka Nishibata, Suishin Arai, Mai Taniguchi, Issei Nakade, Hodaka Ogawa, Shota Kitano, Yumeka Hosoi, Ayano Shindo, Ryo Nishiyama, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Takafumi Shimizu, William Sinko, Tadashi Nagakura, Yoh Terada, Akihiro Ishizu
Nature communications, 15, 1, 6519, 6519, 22 Aug. 2024, [International Magazine]
English, Scientific journal, Cathepsin C (CatC) is an enzyme which regulates the maturation of neutrophil serine proteases (NSPs) essential for neutrophil activation. Activated neutrophils are key players in the innate immune system, and are also implicated in the etiology of various inflammatory diseases. This study aims to demonstrate a therapeutic potential for CatC inhibitors against disorders in which activated neutrophil-derived neutrophil extracellular traps (NETs) play a significant role. We demonstrate that a CatC inhibitor, MOD06051, dose-dependently suppresses the cellular activity of NSPs, including neutrophil elastase (NE), in vitro. Neutrophils derived from MOD06051-administered rats exhibit significantly lower NE activity and NET-forming ability than controls. Furthermore, MOD06051 dose-dependently ameliorates vasculitis and significantly decreases NETs when administered to a rat model of myeloperoxidase (MPO)-antineutrophil cytoplasmic antibody-associated vasculitis (AAV). These findings suggest that CatC inhibition is a promising strategy to reduce neutrophil activation and improve activated neutrophil-mediated diseases such as MPO-AAV.

Intravenous Administration of Mesenchymal Stem Cell-Derived Exosome Alleviates Spinal Cord Injury by Regulating Neutrophil Extracellular Trap Formation through Exosomal miR-125a-3p.
Yutaka Morishima, Masahito Kawabori, Kazuyoshi Yamazaki, Soichiro Takamiya, Sho Yamaguchi, Yo Nakahara, Hajime Senjo, Daigo Hashimoto, Sakiko Masuda, Yoichiro Fujioka, Yusuke Ohba, Yuki Mizuno, Yuji Kuge, Miki Fujimura
International journal of molecular sciences, 25, 4, 18 Feb. 2024, [International Magazine]
English, Scientific journal, Spinal cord injury (SCI) leads to devastating sequelae, demanding effective treatments. Recent advancements have unveiled the role of neutrophil extracellular traps (NETs) produced by infiltrated neutrophils in exacerbating secondary inflammation after SCI, making it a potential target for treatment intervention. Previous research has established that intravenous administration of stem cell-derived exosomes can mitigate injuries. While stem cell-derived exosomes have demonstrated the ability to modulate microglial reactions and enhance blood-brain barrier integrity, their impact on neutrophil deactivation, especially in the context of NETs, remains poorly understood. This study aims to investigate the effects of intravenous administration of MSC-derived exosomes, with a specific focus on NET formation, and to elucidate the associated molecular mechanisms. Exosomes were isolated from the cell supernatants of amnion-derived mesenchymal stem cells using the ultracentrifugation method. Spinal cord injuries were induced in Sprague-Dawley rats (9 weeks old) using a clip injury model, and 100 μg of exosomes in 1 mL of PBS or PBS alone were intravenously administered 24 h post-injury. Motor function was assessed serially for up to 28 days following the injury. On Day 3 and Day 28, spinal cord specimens were analyzed to evaluate the extent of injury and the formation of NETs. Flow cytometry was employed to examine the formation of circulating neutrophil NETs. Exogenous miRNA was electroporated into neutrophil to evaluate the effect of inflammatory NET formation. Finally, the biodistribution of exosomes was assessed using 64Cu-labeled exosomes in animal positron emission tomography (PET). Rats treated with exosomes exhibited a substantial improvement in motor function recovery and a reduction in injury size. Notably, there was a significant decrease in neutrophil infiltration and NET formation within the spinal cord, as well as a reduction in neutrophils forming NETs in the circulation. In vitro investigations indicated that exosomes accumulated in the vicinity of the nuclei of activated neutrophils, and neutrophils electroporated with the miR-125a-3p mimic exhibited a significantly diminished NET formation, while miR-125a-3p inhibitor reversed the effect. PET studies revealed that, although the majority of the transplanted exosomes were sequestered in the liver and spleen, a notably high quantity of exosomes was detected in the damaged spinal cord when compared to normal rats. MSC-derived exosomes play a pivotal role in alleviating spinal cord injury, in part through the deactivation of NET formation via miR-125a-3p.

Methylprednisolone pulse-enhanced neutrophil extracellular trap formation in mice with imiquimod-induced lupus-like disease, resulting in ischaemia of the femoral head cartilage.
Hodaka Ogawa, Shunichi Yokota, Yumeka Hosoi, Ayano Shindo, Naho Ogawa, Ryodai Yamamura, Tomohiro Shimizu, Issei Nakade, Suishin Arai, Mai Taniguchi, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Norimasa Iwasaki, Akihiro Ishizu
Lupus science & medicine, 10, 2, 28 Dec. 2023, [International Magazine]
English, Scientific journal, OBJECTIVES: Methylprednisolone (mPSL) pulse therapy is an essential option for patients with active systemic lupus erythematosus, but there is a risk of adverse events related to microcirculation disorders, including idiopathic osteonecrosis of the femoral head (ONFH). Recent studies have revealed that excessive neutrophil extracellular traps (NETs) are involved in microcirculation disorders. This study aimed to demonstrate that mPSL pulse could induce NETs in lupus mice and identify the factors contributing to this induction. METHODS: Six mice with imiquimod (IMQ)-induced lupus-like disease and six normal mice were intraperitoneally injected with mPSL on days 39 to 41, and five mice with IMQ-induced lupus-like disease and six normal mice were injected with phosphate-buffered saline. Pathological examinations were conducted to evaluate the ischaemic state of the femoral head and tissue infiltration of NET-forming neutrophils. Proteome analysis was performed to extract plasma proteins specifically elevated in mPSL-administered mice with IMQ-induced lupus-like disease, and their effects on NET formation were assessed in vitro. RESULTS: Mice with IMQ-induced lupus-like disease that received mPSL pulse demonstrated ischaemia of the femoral head cartilage with tissue infiltration of NET-forming neutrophils. Proteome analysis suggested that prenylcysteine oxidase 1 (PCYOX1) played a role in this phenomenon. The reaction of PCYOX1-containing very low-density lipoproteins (VLDL) with its substrate farnesylcysteine (FC) induced NETs in vitro. The combined addition of IMQ and mPSL synergistically enhanced VLDL-plus-FC-induced NET formation. CONCLUSION: PCYOX1 and related factors are worthy of attention to understand the underlying mechanisms and create novel therapeutic strategies for mPSL-mediated microcirculation disorders, including ONFH.

Bruton's tyrosine kinase is a possible therapeutic target in microscopic polyangiitis.
Issei Nakade, Yuto Tamura, Fuyu Hashimoto, Yuko Ariza, Shingo Hotta, Hirofumi Fujigaya, Suishin Arai, Mai Taniguchi, Hodaka Ogawa, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu
Arthritis research & therapy, 25, 1, 215, 215, 06 Nov. 2023, [International Magazine]
English, Scientific journal, BACKGROUND: Bruton's tyrosine kinase (Btk) is an enzyme expressed in leukocytes other than T lymphocytes and plasma cells and involved in B-cell receptor- and Fcγ receptor (FcγR)-mediated signal transduction. Btk inhibitors potentially suppress autoantibody production due to the expected inhibitory ability of B lymphocyte differentiation into antibody-producing plasma cells and reduce FcγR-mediated neutrophil activation, including the release of neutrophil extracellular traps (NETs). Microscopic polyangiitis (MPA) is a systemic small-vessel vasculitis characterized by the pathogenic autoantibody, antineutrophil cytoplasmic antibody (ANCA) that reacts with myeloperoxidase (MPO). MPO and MPO-ANCA immune complex (IC)-induced FcγR-mediated NETs are critically involved in MPA pathogenesis. This study aimed to demonstrate the therapeutic efficacy of the Btk inhibitor tirabrutinib on MPA. METHODS: Various doses of tirabrutinib or vehicle were orally administered to Sprague-Dawley rats daily. Four weeks later, the number of peripheral B lymphocytes was counted, and Btk phosphorylation in B lymphocytes was evaluated by flow cytometry. Human peripheral blood neutrophils were stimulated by MPO and anti-MPO antibody ICs (MPO and anti-MPO-ICs), and Btk and its downstream Vav phosphorylation were assessed by western blotting. The effects of tirabrutinib on MPO and anti-MPO-IC-induced NET formation were examined in vitro. Wistar Kyoto rats were immunized with human MPO to induce experimental MPA and given drug-free or tirabrutinib-containing feed (0.0037% or 0.012%) from day 0 or 28. All rats were euthanized on day 42 for serological and histological evaluation. RESULTS: Tirabrutinib inhibited Btk phosphorylation without decreasing B lymphocytes in vivo. Neutrophil Btk and Vav were phosphorylated when stimulated with MPO and anti-MPO-ICs. Tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA in a dose-dependent manner in vivo. Although MPO-ANCA production was not affected, NET-forming neutrophils in the blood were significantly reduced by tirabrutinib. CONCLUSIONS: The Btk inhibitor tirabrutinib suppressed MPO and anti-MPO-IC-induced NET formation in vitro and ameliorated experimental MPA by reducing NET-forming neutrophils but not decreasing MPO-ANCA titer in vivo. This study suggests that Btk is a possible therapeutic target in MPA.

Demonstration of equivocal anti-glomerular basement membrane antibody positivity as a non-specific reaction through multiple immunologic assays in a case of pediatric asymptomatic hematuria.
Masayuki Sato, Yuka Nishibata, Sakiko Masuda, Tsunehisa Nagamori, Emi Ishibazawa, Yoichiro Yoshida, Hironori Takahashi, Akihiro Ishizu, Satoru Takahashi
Clinical biochemistry, 120, 110650, 110650, Elsevier BV, Oct. 2023, [International Magazine]
English, Scientific journal, BACKGROUND: Anti-glomerular basement membrane (anti-GBM) antibody is essential for the diagnosis of anti-GBM disease. The major epitope consists of the α3 subunits of type IV collagen non-collagenous domain (α 3(IV)NC1). There have been only a few reports of patients false-positive for anti-GBM antibody. CASE REPORT: We experienced an 8-year-old boy who presented with asymptomatic hematuria followed by positivity for anti-GBM antibody as evaluated by a commercially available chemiluminescent enzyme immunoassay (CLEIA). While his condition remained stable other than continuing hematuria, his anti-GBM antibody titer increased. Further examination of another anti-GBM antibody assay (fluoroenzyme immunoassay) showed negative results. Thus, evaluation of the accuracy of his positivity for anti-GBM antibody was required. We conducted the following examinations: A) enzyme-linked immunosorbent assay, B) immunoblotting for recombinant α 1-5(IV)NC1, and C) immunohistochemical analysis of normal kidney tissue sections. Specimens used for the analysis were sera in A and IgG from the patient in B and C, respectively. As a result, no anti-GBM antibody was detected in A. In B, no band specific to α 1-5(IV)NC1 was observed. In C, the kidney tissue was not stained. Taken together, these results led us to judge the positive anti-GBM result in CLEIA of our patient to be a non-specific reaction. CONCLUSION: The commercial assays for anti-GBM antibody can lead to false-positive results. We recommend confirmation of anti-GBM antibody positivity through the use of multiple assays in patients demonstrating an atypical clinical course for anti-GBM disease.

CD47 blockade ameliorates autoimmune vasculitis via efferocytosis of neutrophil extracellular traps.
Satoka Shiratori-Aso, Daigo Nakazawa, Takashi Kudo, Masatoshi Kanda, Yusho Ueda, Kanako Watanabe-Kusunoki, Saori Nishio, Sari Iwasaki, Takahiro Tsuji, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu, Tatsuya Atsumi
JCI insight, 8, 15, 08 Aug. 2023, [International Magazine]
English, Scientific journal, Neutrophil extracellular trap (NET) formation contributes to immune defense and is a distinct form of cell death. Excessive NET formation is found in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), contributing to disease progression. The clearance of dead cells by macrophages, a process known as efferocytosis, is regulated by the CD47-mediated "don't eat me" signal. Hence, we hypothesized that pathogenic NETs in AAV escape from efferocytosis via the CD47 signaling pathway, resulting in the development of necrotizing vasculitis. Immunostaining for CD47 in human renal tissues revealed high CD47 expression in crescentic glomerular lesions of patients with AAV. In ex vivo studies, ANCA-induced netting neutrophils increased the expression of CD47 with the reduction of efferocytosis. After efferocytosis, macrophages displayed pro-inflammatory phenotypes. The blockade of CD47 in spontaneous crescentic glomerulonephritis-forming/Kinjoh (SCG/Kj) mice ameliorated renal disease and reduced myeloperoxidase (MPO)-ANCA titers with a reduction in NETs formation. Thus, CD47 blockade would protect against developing glomerulonephritis in AAV via restored efferocytosis of ANCA-induced NETs.

Similar deposition of neutrophil extracellular traps in the dermis among COVID-19-associated IgA vasculitis, post-COVID-19 vaccination IgA vasculitis, and COVID-19-unrelated IgA vasculitis.
Tamihiro Kawakami, Kae Yokoyama, Takaharu Ikeda, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
The Journal of dermatology, 50, 5, e151-e152, May 2023, [International Magazine]
English

Regulation of NETosis and Inflammation by Cyclophilin D in Myeloperoxidase-Positive Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
Takashi Kudo, Daigo Nakazawa, Kanako Watanabe-Kusunoki, Masatoshi Kanda, Satoka Shiratori-Aso, Nobuya Abe, Saori Nishio, Jun-Ichiro Koga, Sari Iwasaki, Takahiro Tsuji, Yuichiro Fukasawa, Miwako Yamasaki, Masahiko Watanabe, Sakiko Masuda, Utano Tomaru, Masaaki Murakami, Yasuaki Aratani, Akihiro Ishizu, Tatsuya Atsumi
Arthritis & rheumatology (Hoboken, N.J.), 75, 1, 71, 83, Jan. 2023, [International Magazine]
English, Scientific journal, OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is pathologically characterized by focal fibrinoid necrosis where ANCA-mediated neutrophil extracellular trap (NET) formation and subsequent endothelial necrosis occurs. Cyclophilin D (CypD) plays an important role in mediating cell necrosis and inflammation via opening of mitochondrial permeability transition pores (mPTP). Here, we examined the role of CypD in AAV pathogenesis. METHODS: In vitro, the role and mechanism of CypD in ANCA-stimulated neutrophils were assessed by immunostaining and electron microscopy. A comprehensive RNA sequencing analysis was performed on ANCA-treated murine neutrophils. To investigate the role of CypD in vivo, an-anti-MPO IgG-transfer AAV model or spontaneous AAV model mice were induced in CypD knockout or wild-type mice. RESULTS: In vitro, pharmacological and genetic inhibition of CypD suppressed ANCA-induced NET formation via the suppression of reactive oxygen species/cytochrome c release from the mitochondria. The analysis of RNA sequencing in ANCA-treated murine neutrophils revealed the involvement of inflammatory responses, and CypD deficiency reduced ANCA-induced alterations in gene expression. Furthermore, the upstream regulator analysis revealed the relevance of intracellular calcium (CypD activator) and cyclosporin (CypD inhibitor) in ANCA stimulation, indicating that CypD-dependent mPTP opening is associated with ANCA-induced neutrophil activation and NETosis. In both AAV models, the genetic deletion of CypD ameliorated crescentic glomerulonephritis via the inhibition of CypD-dependent neutrophil and endothelial necrosis. CONCLUSIONS: CypD targeting is a novel and specific therapeutic strategy for AAV via the resolution of necrotizing vasculitis.

Low disease activity of microscopic polyangiitis in patients with anti-myosin light chain 6 antibody that disrupts actin rearrangement necessary for neutrophil extracellular trap formation.
Miku Yoshinari, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Yoshihiro Arimura, Koichi Amano, Yukio Yuzawa, Ken-Ei Sada, Tatsuya Atsumi, Hiroaki Dobashi, Hitoshi Hasegawa, Masayoshi Harigai, Seiichi Matsuo, Hirofumi Makino, Akihiro Ishizu
Arthritis research & therapy, 24, 1, 274, 274, 16 Dec. 2022, [International Magazine]
English, Scientific journal, BACKGROUND: Neutrophil extracellular traps (NETs) are critically involved in microscopic polyangiitis (MPA) pathogenesis, and some patients with MPA possess anti-NET antibody (ANETA). Anti-myosin light chain 6 (MYL6) antibody is an ANETA that affects NETs. This study aimed to determine the significance of anti-MYL6 antibody in MPA. METHODS: The influence of anti-MYL6 antibody on NET formation and actin rearrangement necessary for NET formation was assessed by fluorescent staining. An enzyme-linked immunosorbent assay was established to detect serum anti-MYL6 antibody, and the prevalence of this antibody in MPA was determined. Furthermore, the disease activity and response to remission-induction therapy of MPA were compared between anti-MYL6 antibody-positive and anti-MYL6 antibody-negative MPA patients. RESULTS: Anti-MYL6 antibody disrupted G-actin polymerization into F-actin, suppressing phorbol 12-myristate 13-acetate-induced NET formation. Serum anti-MYL6 antibody was detected in 7 of 59 patients with MPA. The Birmingham vasculitis activity score (BVAS) of anti-MYL6 antibody-positive MPA patients was significantly lower than anti-MYL6 antibody-negative MPA patients. Among the nine BVAS evaluation items, the cutaneous, cardiovascular, and nervous system scores of anti-MYL6 antibody-positive MPA patients were significantly lower than anti-MYL6 antibody-negative MPA patients, although other items, including the renal and chest scores, were equivalent between the two groups. The proportion of patients with remission 6 months after initiation of remission-induction therapy in anti-MYL6 antibody-positive MPA patients was significantly higher than in anti-MYL6 antibody-negative MPA patients. CONCLUSIONS: Collective findings suggested that anti-MYL6 antibody disrupted actin rearrangement necessary for NET formation and could reduce the disease activity of MPA.

Typical cutaneous small-vessel vasculitis induced by combined injection of antiphosphatidylserine/prothrombin complex antibody and anti-LAMP-2 antibody in normal rats.
Tamihiro Kawakami, Issei Nakade, Yuto Tamura, Fuyu Ito, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
The Journal of dermatology, 49, 12, 1233, 1237, Dec. 2022, [International Magazine]
English, Scientific journal, We previously reported that IgA vasculitis and cutaneous arteritis could be dependently associated with the presence of the antiphosphatidylserine/prothrombin complex (anti-PS/PT) antibody and lysosomal-associated membrane protein-2 (LAMP-2). The copy number of LAMP-2 mRNA in skin tissue samples from rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after subcutaneous histone injection was significantly higher than in those without cutaneous vasculitis. We found LAMP-2 protein overexpression in neutrophils and vascular endothelial cells of the affected blood vessels in rats with cutaneous vasculitis induced by intravenous administration of anti-PS/PT antibody after cutaneous priming by histones. We found typical cutaneous small-vessel vasculitis in the skin of rats given intravenous injection of both anti-PS/PT antibody and anti-LAMP-2 antibody after cutaneous priming by histones. We suggested that the introduction of skin local histones and anti-PS/PT antibody in serum could move LAMP-2 to the cell surface of neutrophils and vascular endothelial cells, and that anti-LAMP-2 antibody could bridge these cells through antigen-specific binding in typical cutaneous small-vessel vasculitis.

A Novel Antineutrophil Extracellular Trap Antibody Targeting Myosin Light Chain 6 in Microscopic Polyangiitis.
Miku Yoshinari, Fumihiko Hattanda, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu
The Journal of rheumatology, 49, 11, 1286, 1288, Nov. 2022, [International Magazine]
English

Involvement of neutrophil extracellular traps in the pathogenesis of glomerulonephritis in a case of systemic lupus erythematosus and antineutrophil cytoplasmic antibody-associated vasculitis overlap syndrome.
Arisa Senda, Ryutaro Sasai, Kurumi Kato, Yuka Nishibata, Sakiko Masuda, Akihiro Ishizu, Noriko Takahara
CEN case reports, 11, 3, 339, 346, Aug. 2022, [Domestic magazines]
English, Scientific journal

Possible implication of intermolecular epitope spreading in the production of anti-glomerular basement membrane antibody in anti-neutrophil cytoplasmic antibody-associated vasculitis.
Yuka Nishibata, Mayu Nonokawa, Yuto Tamura, Rio Higashi, Ku Suzuki, Hideyuki Hayashi, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Akihiro Ishizu
Clinical and experimental rheumatology, 40, 4, 691, 704, May 2022, [International Magazine]
English, Scientific journal, OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is sometimes complicated by anti-glomerular basement membrane (GBM) disease. Proteases, including elastase, released from neutrophils activated by ANCA are implicated in the pathogenesis of AAV. Epitopes of anti-GBM antibody exist in the α3-subunit non-collagenous (NC1) domain of collagen type IV [Col (IV)]. This region, called α3(IV)NC1, is structurally cryptic. This study aimed to determine the production mechanism of anti-GBM antibody in AAV. METHODS: We first examined whether α3(IV)NC1 could be revealed by the digestion of formalin-fixed, paraffin-embedded (FFPE) normal kidney sections and Col (IV) by proteases, including neutrophil elastase, using immunohistochemistry (IHC) and enzyme-linked immunosorbent assay (ELISA). Next, the reveal of α3(IV)NC1 and the infiltration of CD11c+ macrophages in the affected kidneys were evaluated by IHC and immunofluorescent staining using FFPE sections. Finally, the production of anti-GBM antibody in AAV rats was determined by ELISA. RESULTS: α3(IV)NC1 was revealed by the digestion of FFPE normal kidney sections and Col (IV) by proteases. Although the reveal of α3(IV)NC1 was observed in sclerotic glomeruli regardless of causative diseases, CD11c+ macrophages near α3(IV)NC1 were characteristics of AAV. Anti-GBM antibody was produced subsequent to ANCA in some AAV rats. IHC demonstrated the reveal of α3(IV)NC1 in affected renal tissues and the infiltration of CD11c+ macrophages around the sites. CONCLUSIONS: The collective findings suggest that, in AAV, proteases released from neutrophils activated by ANCA digest Col (IV) and result in the reveal of α3(IV)NC1, CD11c+ macrophages present GBM epitopes, and then the host's immune system produce anti-GBM antibody.

Presence of neutrophil extracellular traps in superficial venous thrombosis of Behçet's disease.
Tamihiro Kawakami, Kae Yokoyama, Takaharu Ikeda, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
The Journal of dermatology, 49, 7, 741, 745, 17 Apr. 2022, [International Magazine]
English, Scientific journal, Behçet's disease (BD) has a heterogeneous spectrum of disease manifestations featuring the involvement of different organs and can be characterized with different symptoms depending on the clinical department in charge. We retrospectively reviewed BD patients seen at our hospital and investigated the presence of neutrophils producing neutrophil extracellular traps (NET) in those patients. Immunolabeling of myeloperoxidase and histone citrullination proteins was performed on skin biopsies from three BD patients who had skin biopsy-proven superficial vein thrombophlebitis in their erythema nodosum-like lesions. We observed a higher proportion of female patients and a higher incidence of acne-like eruptions among BD patients seen at our dermatology department, while there was a higher incidence of ocular and gastrointestinal involvement among BD patients treated in other departments. We suggest that sex statistical trends could lead to the co-development of different manifestations and may help clinicians choose the best therapeutic approaches, tailoring them to the specific phenotype of the patient rather than one based on single disease manifestations. NET were found in neutrophils of panniculitis concurrent with superficial vein thrombophlebitis. We suggest that the pathogenesis of BD-related thrombosis could be associated with neutrophil activation and NET are released in the panniculitis of affected skin lesions, erythema nodosum-like lesions.

Phorbol 12-myristate 13-acetate stimulation under hypoxia induces nuclear swelling with DNA outflow but not extracellular trap formation of neutrophils.
Sakiko Masuda, Kurumi Kato, Misato Ishibashi, Yuka Nishibata, Ayako Sugimoto, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Ichizo Tsujino, Akihiro Ishizu
Experimental and molecular pathology, 125, 104754, 104754, Apr. 2022, [International Magazine]
English, Scientific journal, Neutrophils stand sentinel over infection and possess diverse antimicrobial weapons, including neutrophil extracellular traps (NETs). NETs are composed of web-like extracellular DNA decorated with antimicrobial substances and can trap and eliminate invading microorganisms. Although phorbol 12-myristate 13-acetate (PMA) is a potent NET inducer, previous studies have demonstrated that not all neutrophils exhibit NET formation even if stimulated by PMA at high concentrations. This study first showed that some neutrophils stimulated by PMA displayed a swollen nucleus but not NET formation and that hypoxic environments suppressed the NET release. Next, characterization of PMA-stimulated neutrophils with a swollen nucleus was accomplished by differentiating between suicidal-type NETosis and apoptosis. Furthermore, the significance of the phenomenon was examined using formalin-fixed, paraffin-embedded human lung disease tissues with and without pneumonia. As a result, histone H3 citrullination, DNA outflow, propidium iodide labeling, resistance to DNase I, and suspended actin rearrangement were characteristics of PMA-stimulated neutrophils with a swollen nucleus distinct from neutrophils that underwent either suicidal-type NETosis or apoptosis. Neutrophils stimulated by PMA under hypoxic conditions secreted matrix metalloproteinase-9 cytotoxic to human lung-derived fibroblasts. Further, deposition of neutrophil-derived citrullinated histone H3+ chromatin substances in pulmonary lesions was greater in patients with pneumonia than in patients without pneumonia and positively correlated with hypoxia-inducible factor-1α expression. The collective findings suggested that neutrophils activated under hypoxic conditions could be putative modulators of hypoxia-related disease manifestations.

Neutrophil fixation protocols suitable for substrates to detect anti-neutrophil cytoplasmic antibodies by indirect immunofluorescence.
Yuka Nishibata, Shun Matsuzawa, Yosuke Satomura, Takeshi Ohtsuka, Motoki Kuhara, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
Pathology, research and practice, 228, 153661, 153661, Dec. 2021, [International Magazine]
English, Scientific journal

Spontaneously regressed granulomatosis with polyangiitis: A case report.
Hiroki Ota, Chisa Sato, Akira Igarashi, Sumito Inoue, Sakiko Masuda, Akihiro Ishizu, Masafumi Watanabe
Respiratory investigation, 59, 3, 372, 376, May 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal

Anti-phosphatidylserine/prothrombin complex antibodies in patients with cutaneous vasculitis: Possible involvement in the pathogenesis.
Tamihiro Kawakami, Yuto Tamura, Yupeng Dong, Miku Yoshinari, Yuka Nishibata, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
The Journal of dermatology, 48, 5, 703, 706, May 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal, We assessed the IgG and IgM prevalence of anti-phosphatidylserine/prothrombin complex (aPS/PT) antibodies (Abs) in patients with vasculitis using a novel commercial ELISA kit. To examine whether aPS/PT Abs were involved in the pathogenesis of cutaneous vasculitis, inbred wild-type rats were intravenously administered with a rat IgM class aPS/PT monoclonal Ab established previously or with rat immunoglobulins as controls. To express PS on the surface of vascular endothelium, these rats were given a subcutaneous injection of cell-free histones in advance. Serum IgM aPS/PT Ab levels were elevated in patients with systemic vasculitis with skin involvement and cutaneous arteritis compared to those in patients with systemic vasculitis without skin involvement and healthy controls. There was no significant difference in the serum levels of IgG aPS/PT Abs between the patients and healthy controls. Correspondingly, inbred wild-type rats intravenously administered with the aPS/PT monoclonal IgM Ab after appropriate priming-subcutaneous histone injection developed cutaneous vasculitis. Some rats given rat IgM instead of the aPS/PT monoclonal Ab also developed cutaneous vasculitis, whereas vasculitis did not occur in rats given IgG or only priming by histones. We suggested that IgM aPS/PT Abs could be involved in the pathogenesis of cutaneous vasculitis based on these findings.

RNase in the saliva can affect the detection of severe acute respiratory syndrome coronavirus 2 by real-time one-step polymerase chain reaction using saliva samples.
Yuka Nishibata, Shota Koshimoto, Kenta Ogaki, Erika Ishikawa, Kosuke Wada, Miku Yoshinari, Yuto Tamura, Ryo Uozumi, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
Pathology, research and practice, 220, 153381, 153381, Apr. 2021, [Peer-reviewed], [International Magazine]
English, Scientific journal

Association of Neutrophil Extracellular Traps with the Development of Idiopathic Osteonecrosis of the Femoral Head.
Mayu Nonokawa, Tomohiro Shimizu, Miku Yoshinari, Yamato Hashimoto, Yusuke Nakamura, Daisuke Takahashi, Tsuyoshi Asano, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Norimasa Iwasaki, Akihiro Ishizu
The American journal of pathology, 190, 11, 2282, 2289, Nov. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal

Fluvastatin prevents the development of arthritis in env-pX rats via up-regulation of Rho GTPase-activating protein 12.
Shun Tanimura, Mutsumi Nishida, Tatsunori Horie, Tamotsu Kamishima, Hitomi Matsumoto, Yutaka Morimura, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu
Experimental and molecular pathology, 115, 104454, 104454, Aug. 2020, [Peer-reviewed], [International Magazine]
English, Scientific journal

Relationship between lysosomal-associated membrane protein-2 and anti-phosphatidylserine/prothrombin complex antibody in the pathogenesis of cutaneous vasculitis.
Tamihiro Kawakami, Ayaka Kikuchi, Chie Miyabe, Takaharu Ikeda, Sora Takeuchi, Yuto Tamura, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu
Clinical and experimental rheumatology, 27 Jan. 2020, [Peer-reviewed], [International Magazine]
English, OBJECTIVES: We investigated the relationship between lysosomal-associated membrane protein-2 (LAMP-2) and anti-phosphatidylserine/prothrombin (PS/PT) antibody in the pathogenesis of cutaneous vasculitis. METHODS: Cell surface LAMP-2 expression of human neutrophils was measured using flow cytometry. Twenty inbred wild-type Wistar-King-Aptekman-Hokudai (WKAH) rats were divided into four groups: Group 1, rabbit IgG injection only as negative control (n=5); Group 2, both histone and rabbit IgG injection (n=5); Group 3, anti-LAMP-2 antibody injection only (n=5); and Group 4, both histone and anti-LAMP-2 antibody injection (n=5). Ten WKAH rats were divided into two groups: Group A, histone, anti-PS/PT antibody, and anti-LAMP-2 antibody injection (n=5), and Group B, histone, anti-PS/PT antibody, and rabbit IgG injection as control (n=5). RESULTS: LAMP-2 expression on human neutrophils was induced by cell-free histone exposure in a dose- and time-dependent manner. Histopathological examination revealed the recruitment of neutrophils in cutaneous small vessels in all Group 4 rats. These observations were not evident in systemic organs other than the skin. LAMP-2 expression on the surface of vascular endothelial cells was evident in Group 2, exclusively in the skin, but not in Group 1. Thrombi were detected in various organs in all Groups A and B rats. However, no apparent thrombi were observed in the skin. CONCLUSIONS: Anti-PS/PT and anti-LAMP-2 antibodies are responsible for independent effector mechanisms in the rats given intravenous injection of cell-free histones. We considered that undetermined factors other than cell-free histones could be required for the induction of cutaneous vasculitis by anti-PS/PT and anti-LAMP-2 antibodies.

Native myeloperoxidase is required to make the experimental vasculitis model.
Mayu Nonokawa, Ku Suzuki, Hideyuki Hayashi, Yuka Nishibata, Sakiko Masuda, Daigo Nakazawa, Satoshi Tanaka, Utano Tomaru, Akihiro Ishizu
Arthritis research & therapy, 21, 1, 296, 296, 21 Dec. 2019, [Peer-reviewed], [International Magazine]
English

Detection of Increased Vascular Signal in Arthritis-Prone Rats Without Joint Swelling Using Superb Microvascular Imaging Ultrasonography.
Horie T, Nishida M, Tanimura S, Kamishima T, Tamai E, Morimura Y, Nishibata Y, Masuda S, Nakazawa D, Tomaru U, Atsumi T, Ishizu A
Ultrasound in medicine & biology, 45, 8, 2086, 2093, Aug. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, This study aimed to determine whether ultrasonography (US) can detect increased vascular signal in the synovial tissue before overt synovitis in rheumatoid arthritis (RA). Env-pX rats that spontaneously develop RA-like synovitis were used. Ankle joints of 15 pre-morbid env-pX rats were observed with power Doppler and superb microvascular imaging (SMI) using an ultrahigh-frequency (8-24 MHz) probe. Signal values were counted as the number of pixels. The total number of vessels and vessel area in the synovial tissue were histologically evaluated. Dilated vessels were determined from the mean value of synovial vessels in three wild-type rats. In all env-pX rats, apparent synovial proliferation was not observed. However, vasodilation was evident. Only SMI values were significantly correlated with the number of dilated vessels (r = 0.585, p = 0.022) but not with the total number of vessels. US with SMI using ultrahigh-frequency probe can detect increased vascular signal in the synovial tissue of arthritis-prone rats.

The presence of anti-neutrophil extracellular trap antibody in patients with microscopic polyangiitis.
Hattanda F, Nakazawa D, Watanabe-Kusunoki K, Kusunoki Y, Shida H, Masuda S, Nishio S, Tomaru U, Atsumi T, Ishizu A
Rheumatology (Oxford, England), 58, 7, 1293, 1298, Jul. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, OBJECTIVE: Although ANCA is the major autoantibody in patients with ANCA-associated vasculitis, previous studies have suggested the presence of anti-neutrophil extracellular trap (NET) antibody in patients with microscopic polyangiitis (MPA), one type of ANCA-associated vasculitis. In this study, we aimed to determine the prevalence and pathogenic role of anti-NET antibody (ANETA) in MPA. METHODS: We examined the presence or absence of ANETA in sera obtained from 19 MPA patients by indirect immunofluorescence. We compared the clinical parameters, including age, sex, MPO-ANCA, creatinine, CRP, MPO-DNA complexes and vasculitis activity, in ANETA-positive and ANETA-negative MPA patients. We investigated the serum NET induction and degradation abilities of ANETA-positive and ANETA-negative MPA patients with reference to healthy controls (n = 8). Furthermore, we assessed the relationship between ANETA and the effect of IgG depletion on the serum NET degradation ability. RESULTS: ANETA was present in 10 of the 19 MPA patients. There was no significant difference in the clinical parameters in ANCA-positive and ANCA-negative MPA patients. Although the NET induction ability was higher and the NET degradation ability was lower in MPA sera than those in healthy controls, these abilities were not different between ANETA-positive and ANETA-negative MPA sera. Interestingly, the NET degradation ability in some sera with ANETA was markedly increased by IgG depletion. CONCLUSION: Some MPA patients produce ANETA and some ANETA possess an inhibitory function against the serum NET degradation ability. Although further studies are needed, ANETA is worthy of attention in order to understand the pathophysiology of MPA.

FP061RECOMBINANT THROMBOMODULIN AMELIORATES VASCULITIS VIA THE INHIBITION OF NEUTROPHIL EXTRACELLULAR TRAPS
Yoshihiro Kusunoki, Kanako Kusunoki, Saori Nishio, Tatsuya Atsumi, Daigo Nakazawa, Fumihiko Hattanda, Akihiro Ishizu, Utano Tomaru, Sakiko Masuda
Nephrology Dialysis Transplantation, 34, Oxford University Press (OUP), 01 Jun. 2019

Formation and Disordered Degradation of Neutrophil Extracellular Traps in Necrotizing Lesions of Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.
Masuda S, Nonokawa M, Futamata E, Nishibata Y, Iwasaki S, Tsuji T, Hatanaka Y, Nakazawa D, Tanaka S, Tomaru U, Kawakami T, Atsumi T, Ishizu A
The American journal of pathology, 189, 4, 839, 846, Apr. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is characterized by the production of ANCAs and systemic necrotizing vasculitis in small vessels. Disordered regulation of neutrophil extracellular traps (NETs) is critically involved in the pathogenesis of AAV. NETs are web-like DNA decorated with antimicrobial proteins; they are extruded from activated neutrophils. The principal degradation factor of NETs in vivo is DNase I; however, NETs resistant to DNase I can persist in tissues and can lead to the production of ANCAs. Deposition of NETs has been demonstrated in glomerular crescents and necrotizing vasculitis in AAV. Here, the amount of NETs in formalin-fixed, paraffin-embedded tissue sections was examined, and the results for AAV were compared with the results for diseases that should be distinguished from AAV. NETs were more abundant in necrotizing vasculitis of AAV than in non-ANCA-associated vasculitis, or in granulomatous angiitis. Pulmonary granulomas in AAV and non-ANCA-associated diseases were further studied. The amount of NETs was significantly greater in necrotizing granulomas of AAV than in granulomas of sarcoidosis without necrosis. Although NETs were formed in necrotizing granulomas of tuberculosis equivalently to those formed in AAV, they were more susceptible to degradation by DNase I than were NETs in AAV. The formation and disordered degradation of NETs in necrotizing lesions are characteristics of AAV and are possibly related to its pathogenesis.

Epitope recognized by anti-glomerular basement membrane (GBM) antibody in a patient with repeated relapse of anti-GBM disease.
Nishibata Y, Masuda S, Nakazawa D, Tanaka S, Tomaru U, Nergui M, Jia X, Cui Z, Zhao MH, Nakabayashi K, Ishizu A
Experimental and molecular pathology, 107, 165, 170, Apr. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal

Pharmaceutical immunoglobulins reduce neutrophil extracellular trap formation and ameliorate the development of MPO-ANCA-associated vasculitis.
Uozumi R, Iguchi R, Masuda S, Nishibata Y, Nakazawa D, Tomaru U, Ishizu A
Modern rheumatology, 30, 3, 1, 7, Apr. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal

018. ANTI-NEUTROPHIL EXTRACELLULAR TRAP ANTIBODY IN PATIENTS WITH MICROSCOPIC POLYANGIITIS
Tatsuya Atsumi, Utano Tomaru, Daigo Nakazawa, Saori Nishio, Kanako Kusunoki, Haruki Shida, Fumihiko Hattanda, Akihiro Ishizu, Sakiko Masuda, Yoshihiro Kusunoki
Rheumatology, 58, Oxford University Press (OUP), 01 Mar. 2019

HIGH DOSE IMMUNOGLOBULINS CAN INHIBIT NEUTROPHIL EXTRACELLULAR TRAP FORMATION, EVENTUALLY PREVENT THE DEVELOPMENT OF MPO-ANCA-ASSOCIATED VASCULITIS
Ryo Uozumi, Sakiko Masuda, Yuka Nishibata, Shun Tanimura, Daigo Nakazawa, Utano Tomaru, Akihiro Ishizu
RHEUMATOLOGY, 58, Mar. 2019
English

Author Correction: Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.
Daigo Nakazawa, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu
Nature reviews. Rheumatology, 15, 2, 123, 123, Feb. 2019, [International Magazine]
English, In the originally published online version of this article there were errors in the Supplementary Information. All three Supplementary Tables had incorrectly numbered references. These errors have now been corrected in the HTML and PDF versions of the manuscript.

Pathogenesis and therapeutic interventions for ANCA-associated vasculitis.
Nakazawa D, Masuda S, Tomaru U, Ishizu A
Nature reviews. Rheumatology, 15, 2, 91, 101, Feb. 2019, [Peer-reviewed], [International Magazine]
English, Scientific journal, Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) affects systemic small vessels and is accompanied by the presence of ANCAs in the serum. This disease entity includes microscopic polyangiitis, granulomatosis with polyangiitis, eosinophilic granulomatosis with polyangiitis and drug-induced AAV. Similar to other autoimmune diseases, AAV develops in patients with a predisposing genetic background who have been exposed to causative environmental factors. The mechanism by which ANCAs cause vasculitis involves ANCA-mediated excessive activation of neutrophils that subsequently release inflammatory cytokines, reactive oxygen species and lytic enzymes. In addition, this excessive activation of neutrophils by ANCAs induces formation of neutrophil extracellular traps (NETs). Although NETs are essential elements in innate immunity, excessive NET formation is harmful to small vessels. Moreover, NETs are involved not only in ANCA-mediated vascular injury but also in the production of ANCAs themselves. Therefore, a vicious cycle of NET formation and ANCA production is considered to be involved in the pathogenesis of AAV. In addition to this role of NETs in AAV, some other important discoveries have been made in the past few years. Incorporating these new insights into our understanding of the pathogenesis of AAV is needed to fully understand and ultimately overcome this disease.

EFFECTS OF RECOMBINANT THROMBOMODULIN ON EXPERIMENTAL AUTOIMMUNE VASCULITIS VIA THE INHIBITION OF NEUTROPHIL EXTRACELLULAR TRAPS
Kanako Watanabe, Daigo Nakazawa, Yoshihiro Kusunoki, Fumihiko Hattanda, Saori Nishio, Sakiko Masuda, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu
NEPHROLOGY DIALYSIS TRANSPLANTATION, 33, 34, 34, May 2018
English

【補体と腎疾患:温故知新】補体系の基本的な理解のために 好中球と補体系
西端 友香, 益田 紗季子, 石津 明洋, 腎と透析, 97, 1, 35, 38, 25 Jul. 2024
(株)東京医学社, Japanese

【皮膚の血流障害】血管炎の病態
益田 紗季子, 石津 明洋, 皮膚科, 5, 4, 325, 329, Apr. 2024
(有)科学評論社, Japanese

SLE・抗リン脂質抗体症候群:基礎 SLEモデルマウスにおける高脂血症はステロイドパルスが誘導する好中球細胞外トラップ(NETs)形成を促進する　　　　　　　　　　　　　　　
小川 帆貴, 小川 奈保, 荒井 粋心, 谷口 舞, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 68回, 508, 508, Mar. 2024
(一社)日本リウマチ学会, Japanese

SLE・抗リン脂質抗体症候群:基礎 ホスファチジルセリン依存性抗プロトロンビン抗体は好中球細胞外トラップを誘導する　　　　　　　　　　　　　　　
荒井 粋心, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 68回, 508, 508, Mar. 2024
(一社)日本リウマチ学会, Japanese

Rising starの集い ANCA関連血管炎におけるNETs形成異常　　　　　　　　　　　　　　　
益田 紗季子, 脈管学, 64, 1, 5, 6, Feb. 2024
(一社)日本脈管学会, Japanese

結腸癌の診断と同時期に発症した抗LAMP-2抗体陽性血管炎の1例　　　　　　　　　　　　　　　
原田 拓弥, 山下 裕之, 上田 聖, 秋山 優弥, 小林 俊昭, 谷口 舞, 西端 友香, 益田 紗季子, 石津 明洋, 金子 礼志, 脈管学, 64, 1, 11, 12, Feb. 2024
(一社)日本脈管学会, Japanese

病理学総論再考 細胞死・細胞障害 NETosisの人為的制御の試み(Reconsideration of General Pathology Cell death and injury: Attempts to artificial control of NETosis)　　　　　　　　　　　　　　　
益田 紗季子, 日本病理学会会誌, 113, 1, 207, 207, Feb. 2024
(一社)日本病理学会, English

ループスマウスへのステロイドパルスは好中球細胞外トラップの形成を増加させる(Steroid pulse enhances neutrophil extracellular trap formation in lupus mice)　　　　　　　　　　　　　　　
小川 奈保, 小川 帆貴, 荒井 粋心, 谷口 舞, 内沢 萌々, 真鍋 陸, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋, 日本病理学会会誌, 113, 1, 297, 297, Feb. 2024
(一社)日本病理学会, English

ベーチェット病における口内炎の原因究明(Investigation into the cause of stomatitis in Behcet's disease)　　　　　　　　　　　　　　　
真鍋 陸, 益田 紗季子, 西端 友香, 荒井 粋心, 谷口 舞, 内沢 萌々, 小川 奈保, 宮前 多佳子, 外丸 詩野, 石津 明洋, 日本病理学会会誌, 113, 1, 297, 297, Feb. 2024
(一社)日本病理学会, English

好中球細胞外トラップのDNase I抵抗性に対する治療的介入(Therapeutic interventions in DNase I resistance of neutrophil extracellular traps)　　　　　　　　　　　　　　　
内沢 萌々, 益田 紗季子, 中村 哲朗, 小川 奈保, 真鍋 陸, 谷口 舞, 荒井 粋心, 西端 友香, 外丸 詩野, 石津 明洋, 日本病理学会会誌, 113, 1, 323, 323, Feb. 2024
(一社)日本病理学会, English

Rising starの集い ANCA関連血管炎におけるNETs形成異常　　　　　　　　　　　　　　　
益田 紗季子, 脈管学, 64, 1, 5, 6, Feb. 2024
(一社)日本脈管学会, Japanese

結腸癌の診断と同時期に発症した抗LAMP-2抗体陽性血管炎の1例　　　　　　　　　　　　　　　
原田 拓弥, 山下 裕之, 上田 聖, 秋山 優弥, 小林 俊昭, 谷口 舞, 西端 友香, 益田 紗季子, 石津 明洋, 金子 礼志, 脈管学, 64, 1, 11, 12, Feb. 2024
(一社)日本脈管学会, Japanese

ANCA関連血管炎におけるNETs形成異常
益田紗季子, 脈管学(Web), 64, 1, 2024

結腸癌の診断と同時期に発症した抗LAMP-2抗体陽性血管炎の1例
原田拓弥, 山下裕之, 上田聖, 秋山優弥, 小林俊昭, 谷口舞, 西端友香, 益田紗季子, 石津明洋, 金子礼志, 脈管学(Web), 64, 1, 2024

複数の測定法による解析で抗糸球体基底膜抗体の偽陽性を確認した無症候性血尿の男児例
佐藤雅之, 西端友香, 益田紗季子, 長森恒久, 津田淳希, 石羽澤映美, 高橋弘典, 石津明洋, 高橋悟, 日本腎臓学会誌(Web), 66, 6-E, 2024

壊疽性膿皮症の皮膚生検標本を使用したneutrophil extracellular traps(NETs)の検証　　　　　　　　　　　　　　　
川上 民裕, 横山 華英, 池田 高治, 益田 紗季子, 石津 明洋, 日本皮膚科学会雑誌, 133, 4, 713, 714, Apr. 2023
(公社)日本皮膚科学会, Japanese

無症候性血尿を呈した抗糸球体基底膜(GBM)抗体陽性症例の血清を用いた抗体解析
西端友香, 佐藤雅之, 長森恒久, 益田紗季子, 外丸詩野, 石津明洋, 脈管学(Web), 63, 1, 2023

COVID-19発症後およびCOVID-19ワクチン接種後IgA血管炎の皮膚生検組織における好中球細胞外トラップの沈着-COVID-19非関連IgA血管炎との比較
益田紗季子, 西端友香, 外丸詩野, 横山華英, 池田高治, 川上民裕, 石津明洋, 脈管学(Web), 63, 1, 2023

無症候性血尿に対する精査で抗糸球体基底膜抗体が陽性だったが,抗体解析により非特異的反応と考えられた男児例
佐藤雅之, 西端友香, 益田紗季子, 長森恒久, 石羽澤映美, 吉田陽一郎, 高橋弘典, 石津明洋, 高橋悟, 日本小児腎臓病学会雑誌(Web), 36, 2023

Production of anti-GBM antibody by intermolecular epitope spreading in ANCA-associated vasculitis
西端友香, 益田紗季子, 外丸詩野, 石津明洋, 日本病理学会会誌, 112, 1, 2023

脊髄損傷モデルに対する間葉系幹細胞由来エクソソームの急性期静脈内投与は好中球の活性化およびNETs形成を抑制する
森島穣, 川堀真人, 山崎和義, 高宮宗一朗, 山口翔, 中原葉, 千丈創, 益田紗季子, 藤岡容一朗, 大場雄介, 日本分子脳神経外科学会プログラム・抄録集, 23rd, 2023

皮膚血管炎動物モデルの完成
川上民裕, 中出一生, 田村宥人, 伊藤吹夕, 西端友香, 益田紗季子, 外丸詩野, 石津明洋, 脈管学(Web), 63, 1, 2023

正常ラットに抗PSPT抗体と抗LAMP2抗体の静脈注射により皮膚血管炎の発症に成功した
川上民裕, 中出一生, 田村宥人, 西端友香, 益田紗季子, 石津明洋, 伊藤吹夕, 外丸詩野, 日本皮膚科学会雑誌, 133, 3, 523, 523, 2023
(公社)日本皮膚科学会, Japanese

正常ラットにヒストン皮下注射後,抗ホスファチジルセリン・プロトロンビン複合体抗体と抗リソソーム膜タンパク質2抗体の静脈注射により,皮膚血管炎の発症に成功した　　　　　　　　　　　　　　　
川上 民裕, 中出 一生, 田村 宥人, 伊藤 吹夕, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋, 日本皮膚免疫アレルギー学会総会学術大会プログラム・抄録集, 52回, 215, 215, Dec. 2022
(一社)日本皮膚免疫アレルギー学会, Japanese

ベーチェット病皮下の血栓性静脈炎におけるNeutrophil Extracellular Trapsの発現
川上 民裕, 横山 華英, 池田 高治, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋, アレルギー, 71, 6-7, 870, 870, Aug. 2022
(一社)日本アレルギー学会, Japanese

結節性多発動脈炎と皮膚動脈炎の皮膚生検画像の人工知能による鑑別　　　　　　　　　　　　　　　
柏 航, 加藤 千恵次, 西端 友香, 益田 紗季子, 外丸 詩野, 川上 民裕, 石津 明洋, 脈管学, 62, 2, 8, 8, Feb. 2022
(一社)日本脈管学会, Japanese

結節性多発動脈炎と皮膚動脈炎の皮膚生検画像の人工知能による鑑別
柏航, 加藤千恵次, 西端友香, 益田紗季子, 外丸詩野, 川上民裕, 石津明洋, 脈管学(Web), 62, 2, 2022

抗ホスファチジルセリン・プロトロンビン複合体抗体による皮膚血管炎動物モデルの完成　　　　　　　　　　　　　　　
川上 民裕, 董 宇鵬, 田村 宥人, 吉成 未来, 西端 友香, 益田 紗季子, 石津 明洋, 外丸 詩野, 日本皮膚科学会雑誌, 132, 1, 91, 91, Jan. 2022
(公社)日本皮膚科学会, Japanese

【新しい手法を駆使した腎臓病研究の最前線】糸球体疾患 ANCAとNETs
石津 明洋, 益田 紗季子, 西端 友香, 腎と透析, 91, 5, 851, 855, Nov. 2021
(株)東京医学社, Japanese

【循環器II-血管・血管腫・弁膜疾患-】小型血管の血管炎
石津 明洋, 益田 紗季子, 西端 友香, 病理と臨床, 39, 11, 1116, 1122, Nov. 2021
(株)文光堂, Japanese

免疫疾患の形態病理学的理解 ヒストン皮下注射と抗ホスファチジルセリン・プロトロンビン複合体抗体静脈注射から完成した皮膚血管炎の動物モデル　　　　　　　　　　　　　　　
川上 民裕, 田村 宥人, 董 宇鵬, 吉成 未来, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋, 日本臨床免疫学会総会プログラム・抄録集, 49回, 58, 58, Oct. 2021
(一社)日本臨床免疫学会, Japanese

膠原病・自己免疫疾患 皮膚血管炎動物モデルの完成と抗ホスファチジルセリン・プロトロンビン複合体抗体
川上 民裕, 田村 宥人, 董 宇鵬, 吉成 未来, 西端 友香, 益田 紗季子, 外丸 詩野, 石津 明洋, アレルギー, 70, 6-7, 809, 809, Aug. 2021
(一社)日本アレルギー学会, Japanese

多発血管炎性肉芽腫症(GPA)の自然退縮における,好中球細胞外トラップ(NETs)分解について 当院で経験した1症例を通して
太田 啓貴, 佐藤 千紗, 五十嵐 朗, 邨野 浩義, 梁 秀鼎, 町田 浩祥, 佐藤 建人, 中野 寛之, 根本 貴子, 西脇 道子, 木村 友美, 山内 啓子, 佐藤 正道, 井上 純人, 渡辺 昌文, 益田 紗季子, 石津 明洋, 日本呼吸器学会誌, 10, 増刊, 241, 241, Apr. 2021
(一社)日本呼吸器学会, Japanese

人工知能による結節性多発動脈炎と皮膚動脈炎の皮膚生検画像の鑑別
新海 隼人, 加藤 千恵次, 川上 民裕, 高橋 啓, 西端 友香, 益田 紗季子, 田中 敏, 外丸 詩野, 石津 明洋, 脈管学, 61, 1, 1, 2, Jan. 2021
(一社)日本脈管学会, Japanese

myosin light chain6を認議する抗好中球細胞外トラップ(NETs)抗体はNETs分解阻害活性を持つ
西端友香, 益田紗季子, 外丸詩野, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 65th, 407, 407, 2021
(一社)日本リウマチ学会, Japanese

Effects of hypoxia on neutrophil extracellular trap formation
益田紗季子, 西端友香, 田中敏, 外丸詩野, 辻野一三, 石津明洋, 日本病理学会会誌, 110, 1, 246, 246, 2021
(一社)日本病理学会, Japanese

Degradation of neutrophil extracellular traps in the spontaneous regression of granulomatosis with polyangiitis: a case report
太田啓貴, 佐藤千紗, 五十嵐朗, 邨野浩義, 梁秀鼎, 町田浩祥, 佐藤建人, 中野寛之, 根本貴子, 西脇道子, 木村友美, 山内啓子, 佐藤正道, 井上純人, 渡辺昌文, 益田紗季子, 石津明洋, 日本呼吸器学会誌(Web), 10, 2021

腎生検組織におけるNeutrophil Extracellular Traps(NETs)の検討　　　　　　　　　　　　　　　
岩崎 沙理, 益田 紗季子, 石津 明洋, 大塚 拓也, 牧田 啓史, 深澤 雄一郎, 辻 隆裕, 日本病理学会会誌, 109, 1, 435, 435, Mar. 2020
(一社)日本病理学会, Japanese

Recombinant thrombomodulin ameliorates autoimmune vasculitis via immune response regulation and tissue injury protection.
Kanako Watanabe-Kusunoki, Daigo Nakazawa, Yoshihiro Kusunoki, Takashi Kudo, Fumihiko Hattanda, Saori Nishio, Sakiko Masuda, Utano Tomaru, Takeshi Kondo, Tatsuya Atsumi, Akihiro Ishizu, Journal of autoimmunity, 108, 102390, 102390, Mar. 2020, [International Magazine]
English

抗GBM抗体が認識するエピトープの表出に関する検討
西端友香, 野々川茉佑, 益田紗季子, 中沢大悟, 田中敏, 外丸詩野, 石津明洋, 脈管学(Web), 60, 2, 2020

ANCA関連血管炎の病因研究 ANCA関連血管炎における好中球細胞外トラップ
魚住諒, 魚住諒, 益田紗季子, 石津明洋, 炎症と免疫, 28, 4, 279, 283, 2020
(株)先端医学社, Japanese

特発性大腿骨頭壊死症の発生における好中球細胞外トラップの関与
清水智弘, 野々川茉佑, 西端友香, 益田紗季子, 高橋大介, 浅野毅, 田中敏, 外丸詩野, 岩崎倫政, 石津明洋, 日本整形外科学会雑誌, 94, 8, S1801, S1801, 2020
(公社)日本整形外科学会, Japanese

Formation of degradation-resistant NETs in pneumonia patients with lung disease
益田紗季子, 石橋美郷, 加藤くるみ, 西端友香, 田中敏, 外丸詩野, 辻野一三, 石津明洋, 日本病理学会会誌, 109, 1, 308, 308, 2020
(一社)日本病理学会, Japanese

Detection of Neutrophil Extracellular Traps in kidney biopsy specimen
岩崎沙理, 益田紗季子, 石津明洋, 大塚拓也, 牧田啓史, 深澤雄一郎, 辻隆裕, 日本病理学会会誌, 109, 1, 2020

抗好中球細胞質抗体(ANCA)に続き抗糸球体基底膜(GBM)抗体が産生されるメカニズム
西端友香, 益田紗季子, 中沢大悟, 外丸詩野, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 64th (CD-ROM), 507, 507, 2020
(一社)日本リウマチ学会, Japanese

薬剤起因性自己免疫疾患におけるNETsの関与
益田紗季子, 石津明洋, 月刊リウマチ科, 61, 1, 64, 68, 2019
(有)科学評論社, Japanese

特発性大腿骨頭壊死症の発生における好中球細胞外トラップの関与
野々川茉佑, 西端友香, 益田紗季子, 石津明洋, 清水智弘, 高橋大介, 浅野毅, 岩崎倫政, 田中敏, 外丸詩野, 北海道医学雑誌, 94, 1, 59, 59, 2019
北海道医学会, Japanese

ANCA関連血管炎(AAV)の壊死性病変部における好中球細胞外トラップ(NETs)の存在と病的意義
益田紗季子, 野々川茉佑, 西端友香, 岩崎沙理, 辻隆裕, 田中敏, 外丸詩野, 川上民裕, 石津明洋, 日本病理学会会誌, 108, 1, 327, 327, 2019
(一社)日本病理学会, Japanese

抗糸球体基底膜抗体病(抗GBM病)の頻回再発症例の抗GBMが認識するエピトープ
西端友香, 東里緒, 益田紗季子, 中沢大悟, 田中敏, 外丸詩野, 中林公正, 石津明洋, 脈管学(Web), 59, 3, 2019

シクロフィリンDをターゲットとしたANCA関連壊死性血管炎に対する新規治療薬の開発
工藤孝司, 中沢大悟, 白鳥里佳, 楠加奈子, 西尾妙織, 益田紗季子, 外丸詩野, 石津明洋, 渥美達也, 日本臨床免疫学会総会プログラム・抄録集, 47th, 134, 134, 2019
(一社)日本臨床免疫学会, Japanese

抗GBM抗体が認識するエピトープの表出に関する検討
西端友香, 東里緒, 益田紗季子, 中沢大悟, 田中敏, 外丸詩野, 石津明洋, 日本病理学会会誌, 108, 1, 298, 298, 2019
(一社)日本病理学会, Japanese

ANCA関連血管炎の壊死性病変部における好中球細胞外トラップの存在と病的意義
益田紗季子, 益田紗季子, 西端友香, 中沢大悟, 外丸詩野, 川上民裕, 渥美達也, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 63rd, 2019

皮膚血管炎の発症機序における抗リソソーム膜タンパク2抗体(抗LAMP2抗体)と抗ホスファチジルセリン・プロトロンビン複合体抗体(抗PSPT抗体)の役割
川上民裕, 宮部千恵, 池田高治, 菊池彩花, 西端友香, 益田紗季子, 石津明洋, 中沢大悟, 外丸詩野, 日本皮膚科学会雑誌, 129, 12, 2533, 2533, 2019
(公社)日本皮膚科学会, Japanese

ヒストンは好中球細胞上にLAMP2を表出し,抗LAMP2抗体と連携して皮膚小血管炎の発症機序に関与している
川上民裕, 竹内そら, 菊池彩翔, 西端友香, 益田紗季子, 外丸詩野, 石津明洋, 脈管学(Web), 59, 3, 2019

ANCA関連血管炎(AAV)の壊死性病変部における好中球細胞外トラップ(NETs)の存在と病的意義
益田紗季子, 野々川茉佑, 西端友香, 岩崎沙理, 辻隆裕, 田中敏, 外丸詩野, 川上民裕, 石津明洋, 日本病理学会会誌, 107, 1, 330, 330, 26 Apr. 2018
(一社)日本病理学会, Japanese

免疫グロブリン大量静注療法(IVIG)は好中球細胞外トラップ(NETs)の抑制によりMPO‐ANCA関連血管炎を抑制する
魚住諒, 魚住諒, 井口理彩, 益田紗季子, 西端友香, 谷村瞬, 中沢大悟, 外丸詩野, 石津明洋, 日本病理学会会誌, 107, 1, 331, 331, 26 Apr. 2018
(一社)日本病理学会, Japanese

免疫グロブリン大量静注療法(IVIG)は好中球細胞外トラップ(NETs)の抑制によりMPO-ANCA関連血管炎を抑制する　　　　　　　　　　　　　　　
魚住 諒, 井口 理彩, 益田 紗季子, 西端 友香, 谷村 瞬, 中沢 大悟, 外丸 詩野, 石津 明洋, 日本病理学会会誌, 107, 1, 331, 331, Apr. 2018
(一社)日本病理学会, Japanese

免疫グロブリン製剤は好中球細胞外トラップ(NETs)の形成抑制を介してMPO‐ANCA関連血管炎(MPO‐AAV)の発症を抑制する
魚住諒, 魚住諒, 益田紗季子, 西端友香, 谷村瞬, 中沢大悟, 外丸詩野, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62nd, 433, 433, 20 Mar. 2018
(一社)日本リウマチ学会, Japanese

スタチンの関節炎抑制効果とその機序の解明
谷村瞬, 西田睦, 神島保, 西端友香, 益田紗季子, 中沢大悟, 外丸詩野, 渥美達也, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62nd, 778, 778, 20 Mar. 2018
(一社)日本リウマチ学会, Japanese

超高周波プローブを用いたSuperb Micro‐vascular Imagingによる超音波検査でのラット足関節の早期関節炎診断
西田睦, 谷村瞬, 神島保, 西端友香, 益田紗季子, 中沢大悟, 外丸詩野, 渥美達也, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62nd, 485, 485, 20 Mar. 2018
(一社)日本リウマチ学会, Japanese

血管炎1:血管炎のバイオマーカー・病態解析 免疫グロブリン製剤は好中球細胞外トラップ(NETs)の形成抑制を介してMPO-ANCA関連血管炎(MPO-AAV)の発症を抑制する　　　　　　　　　　　　　　　
魚住 諒, 益田 紗季子, 西端 友香, 谷村 瞬, 中沢 大悟, 外丸 詩野, 石津 明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62回, 433, 433, Mar. 2018
(一社)日本リウマチ学会, Japanese

リウマチ性疾患の画像2:関節エコーその他 超高周波プローブを用いたSuperb Micro-vascular Imagingによる超音波検査でのラット足関節の早期関節炎診断　　　　　　　　　　　　　　　
西田 睦, 谷村 瞬, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62回, 485, 485, Mar. 2018
(一社)日本リウマチ学会, Japanese

スタチンの関節炎抑制効果とその機序の解明　　　　　　　　　　　　　　　
谷村 瞬, 西田 睦, 神島 保, 西端 友香, 益田 紗季子, 中沢 大悟, 外丸 詩野, 渥美 達也, 石津 明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 62回, 778, 778, Mar. 2018
(一社)日本リウマチ学会, Japanese

抗好中球細胞質抗体(ANCA)と好中球細胞外トラップ(NETs)
益田紗季子, 石津明洋, 月刊リウマチ科, 59, 2, 200‐205, 205, 28 Feb. 2018
(有)科学評論社, Japanese

BDNFはHUVECにおけるangiogeninの分泌と核移行を誘導する
森綾子, 西岡祐介, 山田真衣, 西端友香, 益田紗季子, 外丸詩野, 本間直幸, 森山隆則, 石津明洋, 日本血管生物医学会学術集会プログラム・抄録集, 26th, 2018

スタチンの関節炎抑制効果と機序の検討
谷村瞬, 渥美達也, 西田睦, 堀江達則, 神島保, 玉井絵里香, 森村豊, 西端友香, 益田紗季子, 石津明洋, 外丸詩野, 北海道医学雑誌, 93, 2, 121, 122, 2018
北海道医学会, Japanese

プロテアーゼによる抗糸球体基底膜抗体病の隔絶抗原の表出
西端友香, 植松千浩, 益田紗季子, 田中敏, 外丸詩野, 石津明洋, 脈管学(Web), 58, 3, 2018

ANCA関連血管炎の壊死性病変部におけるNETsの存在と病的意義
益田紗季子, 野々川茉佑, 西端友香, 岩崎沙理, 辻隆裕, 田中敏, 外丸詩野, 川上民裕, 石津明洋, 脈管学(Web), 58, 3, 2018

スタチン製剤の関節炎抑制効果と機序の検討
谷村瞬, 渥美達也, 西田睦, 堀江達則, 神島保, 齋藤克己, 西端友香, 益田紗季子, 石津明洋, 外丸詩野, 北海道医学雑誌, 92, 2, 105, 105, 01 Nov. 2017
北海道医学会, Japanese

自己免疫疾患とNETosis
楠由宏, 益田紗季子, 外丸詩野, 石津明洋, 月刊リウマチ科, 57, 4, 437‐442, 442, 28 Apr. 2017
(有)科学評論社, Japanese

フローサイトメトリーによる定量的好中球細胞外トラップ測定法
益田紗季子, 西端友香, 松尾淳司, 外丸詩野, 石津明洋, 日本病理学会会誌, 106, 1, 350, 350, 24 Mar. 2017
(一社)日本病理学会, Japanese

抗PSPT抗体による抗リン脂質抗体症候群動物モデルの完成
川上民裕, 石津明洋, 益田紗季子, 外丸詩野, 日本リウマチ学会総会・学術集会プログラム・抄録集, 61st, 605, 605, 18 Mar. 2017
(一社)日本リウマチ学会, Japanese

ANCA関連血管炎(AAV)における抗NETs抗体の存在と病的意義
八反田文彦, 楠由宏, 志田玄貴, 中沢大悟, 西尾妙織, 益田紗季子, 外丸詩野, 渥美達也, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 61st, 431, 431, 18 Mar. 2017
(一社)日本リウマチ学会, Japanese

フローサイトメトリーによる定量的好中球細胞外トラップ測定法　　　　　　　　　　　　　　　
益田 紗季子, 西端 友香, 松尾 淳司, 外丸 詩野, 石津 明洋, 日本病理学会会誌, 106, 1, 350, 350, Mar. 2017
(一社)日本病理学会, Japanese

_7 RAT TYPE II NKT CELL CLONE PATHOGENIC FOR SMALL VESSEL VASCULITIS RECOGNIZES STEROL CARRIER PROTEIN 2
Yusuke Nishioka, Madoka Yamaguchi, Ai Kawakami, Maya Munehiro, Sakiko Masuda, Utano Tomaru, Akihiro Ishizu, RHEUMATOLOGY, 56, 30, 31, Mar. 2017
English, Summary international conference

THE EFFECT OF PEPTIDYLARGININE DEIMINASE INHIBITOR ON NET FORMATION AND MPO-ANCA PRODUCTION IN MOUSE MODEL
Yoshihiro Kusunoki, Daigo Nakazawa, Haruki Shida, Fumihiko Hattanda, Arina Miyoshi, Sakiko Masuda, Saori Nishio, Utano Tomaru, Tatsuya Atsumi, Akihiro Ishizu, RHEUMATOLOGY, 56, 112, 113, Mar. 2017
English, Summary international conference

ESTABLISHMENT OF ANTI-RAT PHOSPHATIDYLSERINE/PROTHROMBIN MONOCLONAL ANTIBODIES AND A THROMBOTIC RAT MODEL INDUCED BY INTRAVENOUS INJECTION OF THE ANTIBODY
Mai Yamada, Tamihiro Kawakami, Kohei Takashima, Yusuke Nishioka, Yuka Nishibata, Sakiko Masuda, Shigeru Yoshida, Akihiro Ishizu, RHEUMATOLOGY, 56, Mar. 2017
English, Summary international conference

抗PSPT抗体は,正常ラットに血栓を発症させる
川上民裕, 山田真衣, 高島滉平, 西岡佑介, 西端友香, 益田紗季子, 吉田繁, 外丸詩野, 石津明洋, 脈管学(Web), 57, 2, 22(J‐STAGE), 2017
Japanese

MPO‐ANCA関連血管炎におけるNETs‐ANCA悪循環
志田玄貴, 八反田文彦, 三次有奈, 楠由宏, 中沢大悟, 佐藤遥, 橋本展洋, 林晃正, 益田紗季子, 石津明洋, 外丸詩野, 北海道医学雑誌, 91, 2, 85‐86, 86, 01 Nov. 2016
北海道医学会, Japanese

ANCA関連血管炎―最近の話題―1 好中球細胞外トラップ
益田紗季子, 石津明洋, 月刊アレルギーの臨床, 36, 485, 419‐423, 423, 20 May 2016
(株)北隆館, Japanese

自己血管内皮細胞反応性小型血管炎惹起性type II NKT細胞が認識する分子の同定
西岡佑介, 山口まどか, 川上愛, 宗廣真矢, 山田真衣, 益田紗季子, 外丸詩野, 石津明洋, 日本病理学会会誌, 105, 1, 353, 353, 12 Apr. 2016
(一社)日本病理学会, Japanese

抗ラクトフェリン抗体は好酸球性多発血管炎性肉芽腫症において好中球細胞外トラップの形成を促進し,疾患活動性に関与する
志田玄貴, 中沢大悟, 八反田文彦, 楠由宏, 益田紗季子, 外丸詩野, 川上民裕, 渥美達也, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 60th, 479, 479, 18 Mar. 2016
(一社)日本リウマチ学会, Japanese

Peptigylarginine deiminase 4阻害薬は好中球細胞外トラップの形成阻害を介してMPO‐ANCA産生を抑制する
楠由宏, 中沢大悟, 志田玄貴, 八反田文彦, 益田紗季子, 外丸詩野, 西尾妙織, 渥美達也, 石津明洋, 日本リウマチ学会総会・学術集会プログラム・抄録集, 60th, 479, 479, 18 Mar. 2016
(一社)日本リウマチ学会, Japanese

Glandular papilloma(columnar cell papilloma)の1例
KATO TAKASHI, MASUDA SAKIKO, YOSHIOKA ASUKA, HIRAO TOMOMI, HIDA IKUHARU, ICHIHARA MAKOTO, GOTODA YUKO, MURAOKA SHUNJI, 日本臨床細胞学会雑誌, 53, Suppl.2, 584, 584, 10 Oct. 2014
(公社)日本臨床細胞学会, Japanese

初発診断および再発評価に細胞診が有用だった子宮頸部原発小細胞癌の1例
MASUDA SAKIKO, KATO TAKASHI, YOSHIOKA ASUKA, HIRAO TOMOMI, ICHIHARA SHIN, GOTODA YUKO, MURAOKA SHUNJI, 日本臨床細胞学会雑誌, 53, Suppl.1, 266, 266, 23 Apr. 2014
(公社)日本臨床細胞学会, Japanese

A case report of matrix-producing carcinoma of the breast
MINOSHIMA ATSUSHI, MASUDA SAKIKO, KATO TAKASHI, YOSHIOKA ASUKA, HIRAO TOMOMI, ICHIHARA SHIN, GOTODA HIROKO, MURAOKA SHUNJI, 日本臨床細胞学会雑誌, 53, 1, 41, 46, 22 Jan. 2014
<b><i>Background</i></b> : Matrix-producing carcinoma (MPC) of the breast is a rare subtype of breast cancer, accounting for 0.03 to 0.2% of all breast cancers.<br>We report a case of MPC and its cytopathological features.<br><b><i>Case</i></b> : A 53-year-old female presented with a hard mass in her left breast. Papanicolaou staining of fine-needle-aspiration cytology specimens showed atypical single cells and cell clusters in a pale green-stained myxoid background. There were three types of cell clusters : carcinomatous, chondromatous, and intermediate clusters in a chondroid matrix.<br>Histologically, the tumor had a chondromatous element at the center and a carcinomatous element in the peripheral region. The tumor demonstrated overt carcinoma with direct transition to a cartilaginous stromal matrix without an intervening spindle cell zone or osteoclastic cells ; based on these findings, we diagnosed the tumor as MPC.<br><b><i>Conclusion</i></b> : It is possible to suspect MPC when both carcinomatous and chondromatous cell clusters appear on the same glass slide with transitional images of these cells. Thus, MPC may be suspected clinically based on its characteristic properties., 特定非営利活動法人 日本臨床細胞学会, Japanese

乳腺基質産生癌の一例
MINOSHIMA ATSUSHI, MASUDA SAKIKO, KATO TAKASHI, YOSHIOKA ASUKA, HIRAO TOMOMI, ICHIHARA MAKOTO, GOTODA YUKO, MURAOKA SHUNJI, 日本臨床細胞学会雑誌, 52, Suppl.1, 197, 197, 17 May 2013
(公社)日本臨床細胞学会, Japanese

Plasma-dependent, antibody- and Fcγ receptor-mediated translocation of CD8 molecules from T cells to monocytes
岩崎 沙理, 益田 紗季子, 馬場 智久, 外丸 詩野, 勝俣 一晃, 笠原 正典, 石津 明洋, 北海道醫學雜誌 = Acta medica Hokkaidonensia, 87, 2, 68, 68, 01 Apr. 2012
北海道医学会, Japanese

Fcγ受容体を介したtrogocytosisの意義と制御機構の解析
MASUDA SAKIKO, IWASAKI SARI, SATO JURI, TOMARU UTANO, KASAHARA MASANORI, ISHIZU AKIHIRO, 日本病理学会会誌, 100, 1, 316, 316, 26 Mar. 2011
(一社)日本病理学会, Japanese

ヒト末梢血に検出されるCD8陽性単球・顆粒球の解析
MASUDA SAKIKO, IWASAKI SATOSHI, BABA TOMOHISA, KATSUMATA KAZUAKI, TOMARU UTANO, KASAHARA MASANORI, ISHIZU AKIHIRO, 日本病理学会会誌, 99, 1, 217, 217, 26 Mar. 2010
(一社)日本病理学会, Japanese

ヒト末梢血におけるCD8陽性単球の解析
IWASAKI SARI, MASUDA SAKIKO, BABA TOMOHISA, KATSUMATA KAZUAKI, TOMARU UTANO, KASAHARA MASANORI, ISHIZU AKIHIRO, 臨床病理, 57, 補冊, 136, 136, 28 Jul. 2009
(一社)日本臨床検査医学会, Japanese

ヒト末梢血に検出されるCD8陽性単球の解析
IWASAKI SARI, BABA TOMOHISA, MASUDA SAKIKO, KATSUMATA KAZUAKI, TOMARU UTANO, KASAHARA MASANORI, ISHIZU AKIHIRO, 日本病理学会会誌, 98, 1, 279, 279, 20 Mar. 2009
(一社)日本病理学会, Japanese

ANCA関連血管炎(AAV)の壊死性病変部における好中球細胞外トラップ(NETs)の存在と病的意義　　　　　　　　　　　　　　　
益田 紗季子
日本病理学会, 2018, Japanese, Oral presentation
[Domestic Conference]

ANCA関連血管炎(AAV)の壊死性病変部における好中球細胞外トラップ(NETs)の存在と病的意義　　　　　　　　　　　　　　　
益田 紗季子
血管病理研究会, 2017, Japanese, Oral presentation
[Domestic Conference]

フローサイトメトリーによる定量的好中球細胞外トラップ測定法　　　　　　　　　　　　　　　
益田 紗季子
日本病理学会, 2017, Japanese, Oral presentation
[Domestic Conference]

フローサイトメトリーによる定量的好中球細胞外トラップ測定法　　　　　　　　　　　　　　　
益田 紗季子
MPO研究会, 2016, Japanese, Oral presentation
[Domestic Conference]

初発診断および再発評価に細胞診が有用だった子宮頸部原発小細胞癌の１例　　　　　　　　　　　　　　　
益田 紗季子
日本臨床細胞学会, 2014, Japanese, Poster presentation
[Domestic Conference]

ヒト末梢血におけるCD8陽性単球・顆粒球の解析　　　　　　　　　　　　　　　
益田 紗季子
日本病理学会, 2010, English, Oral presentation
[Domestic Conference]

分解抵抗性を示す好中球細胞外トラップを標的としたANCA関連血管炎の新規治療開発
科学研究費助成事業
01 Apr. 2025 - 31 Mar. 2028
益田 紗季子
日本学術振興会, 基盤研究(C), 北海道大学, 25K11717

ベーチェット病患者唾液の好中球細胞外トラップ誘導能の低下原因の解明
科学研究費助成事業
01 Apr. 2022 - 31 Mar. 2025
益田 紗季子
日本学術振興会, 若手研究, 北海道大学, 22K16337

Reveal of the pathogenesis of MPO-ANCA-associated vasculitis and development of novel therapeutic strategies
Grants-in-Aid for Scientific Research
01 Apr. 2021 - 31 Mar. 2024
石津 明洋, 益田 紗季子, 外丸 詩野, 中沢 大悟
①MPO-ANCAはどのように好中球を活性化するのかについて、TNF-αでプライミングした好中球に液相または抗原固相により免疫複合体を形成した状態でMPO-ANCAを反応させ、好中球細胞外トラップ（NETs）の形成と細胞内シグナル分子のリン酸化を指標として好中球の活性化を評価した。その結果、どちらの場合もMPO-ANCAはNETsを誘導したが、抗原固相により免疫複合体を形成した状態で好中球に反応させた場合にシグナル分子がリン酸化されることを確認した。
②MPO-ANCAにより誘導されるNETsに血管炎惹起性はあるかについて、MPO-ANCA誘導モデルの病変糸球体にNETsの沈着があることを証明した。
③MPO-ANCA関連血管炎（MPO-AAV）におけるNETs除去障害の原因は何かについて、MPO-AAVの肺病変部に認められたDNase I抵抗性NETsと結核の肺病変部に認められたDNase I感受性NETs、そしてin vitroで誘導したDNase I感受性あるいは抵抗性NETsを用いてプロテオーム解析を行った。NETsにDNase I抵抗性をもたらす候補タンパク18種を抽出し、これらのリコンビナントタンパクをNETs誘導時に添加したところ、5つのタンパクで通常のNETsではなく類円形のDNase I抵抗性NETsが形成された。さらに、そのうちの一つのタンパクに対する阻害抗体をNETs誘導時に加えると、類円形NETsおよび通常型NETsの形成が抑制された。
これらの知見に基づき、MPO-AAVの病態形成機序に即した分子標的治療を開発するため、前臨床試験を開始した。
Japan Society for the Promotion of Science, Grant-in-Aid for Scientific Research (B), Hokkaido University, 21H02958

Elucidation of DNase resistance acquisition mechanism of neutrophil extracellular traps in ANCA-associated vasculitis
Grants-in-Aid for Scientific Research
01 Apr. 2019 - 31 Mar. 2022
Masuda Sakiko
The proteins of DNase I-sensitive NETs or DNase I-resistant NETs were compared by proteomics analysis, and narrowed down 18 protein candidates that are considered to confer DNase I resistance to NETs. When candidate proteins were added during NET induction, the formation of normal NET was suppressed by the five proteins, and the formation of abnormal NET resistant to DNase I became the main component. Addition of an inhibitory antibody to one of these proteins during NETs induction suppressed the formation of normal and abnormal NETs.
Japan Society for the Promotion of Science, Grant-in-Aid for Early-Career Scientists, Hokkaido University, 19K16575