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Faculty of Medicine School of Medicine Department of Developmental and Urological-Reproductive Medicine, Pediatrics |
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Assistant Professor |
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External Link |
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NISHIMURA Toyoki
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Papers 【 display / non-display 】
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B-cell deficiency identified by newborn screening
Matsumoto Takayuki, Nishimura Toyoki, Yamamoto Ayako, Sawada Hirotake, Moritake Hiroshi
JSIAD Journal 3 ( 1 ) 16 - 20 2024.2
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Japanese Society for Immunodeficiency and Autoinflammatory Diseases
Newborn screening（NBS）is carried out at public expense for approximately 20 diseases in Japan; however, each prefecture independently conducts additional NBS including several more diseases. Miyazaki Prefecture has optionally included inborn errors of immunity（IEIs）and lysosomal storage diseases since April 2020. We herein report a baby who suffered from B-cell deficiency（BCD）that was identified by NBS conducted in Miyazaki Prefecture. The baby had low levels of kappa-deleting recombination excision circles（KRECs）and was referred to our hospital. Several measurements of CD19-positive B cells in the peripheral blood consistently showed values <2%, leading to the diagnosis of BCD. Periodic immunoglobulin replacement successfully led to a healthy outcome without serious infection developing over a period of more than 17 months. This is the first case of BCD identified by NBS and that underwent prophylactic gamma globulin replacement in Japan. Severe combined immunodeficiency disease and BCD are IEIs known to cause severe sequelae, and patients sometimes die without a correct diagnosis being made; therefore, their early diagnosis and early treatment are extremely important. The inclusion of IEIs in NBS has proven to be cost-effective all over the world. In the future, it is expected that IEIs will be covered by NBS public funds in Japan as well.
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Uchiyama T., Kawai T., Nakabayashi K., Nakazawa Y., Goto F., Okamura K., Nishimura T., Kato K., Watanabe N., Miura A., Yasuda T., Ando Y., Minegishi T., Edasawa K., Shimura M., Akiba Y., Sato-Otsubo A., Mizukami T., Kato M., Akashi K., Nunoi H., Onodera M.
Molecular Therapy 31 ( 12 ) 3424 - 3440 2023
Language：English Publishing type：Research paper (scientific journal) Publisher：Molecular Therapy
Stem cell gene therapy using the MFGS-gp91phox retroviral vector was performed on a 27-year-old patient with X-linked chronic granulomatous disease (X-CGD) in 2014. The patient's refractory infections were resolved, whereas the oxidase-positive neutrophils disappeared within 6 months. Thirty-two months after gene therapy, the patient developed myelodysplastic syndrome (MDS), and vector integration into the MECOM locus was identified in blast cells. The vector integration into MECOM was detectable in most myeloid cells at 12 months after gene therapy. However, the patient exhibited normal hematopoiesis until the onset of MDS, suggesting that MECOM transactivation contributed to clonal hematopoiesis, and the blast transformation likely arose after the acquisition of additional genetic lesions. In whole-genome sequencing, the biallelic loss of the WT1 tumor suppressor gene, which occurred immediately before tumorigenesis, was identified as a potential candidate genetic alteration. The provirus CYBB cDNA in the blasts contained 108 G-to-A mutations exclusively in the coding strand, suggesting the occurrence of APOBEC3-mediated hypermutations during the transduction of CD34-positive cells. A hypermutation-mediated loss of oxidase activity may have facilitated the survival and proliferation of the clone with MECOM transactivation. Our data provide valuable insights into the complex mechanisms underlying the development of leukemia in X-CGD gene therapy.
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Narazaki H, Akioka S, Akutsu Y, Araki M, Fujieda M, Fukuhara D, Hara R, Hashimoto K, Hattori S, Hayashibe R, Imagawa T, Inoue Y, Ishida H, Ito S, Itoh Y, Kawabe T, Kitoh T, Kobayashi I, Matsubayashi T, Miyamae T, Mizuta M, Mori M, Murase A, Nakagishi Y, Nagatani K, Nakano N, Nishimura T, Nozawa T, Okamoto N, Okura Y, Sawada H, Sawanobori E, Sugita Y, Tanabe Y, Tomiita M, Yamaguchi KI, Yasuoka R, Yokoyama K
Modern rheumatology 33 ( 5 ) 1021 - 1029 2022.9
Language：English Publishing type：Research paper (scientific journal) Publisher：Modern Rheumatology
Objectives: Although epidemiological surveys of paediatric rheumatic diseases in Japan have been conducted, they were single surveys with no continuity. This is the first report of the Pediatric Rheumatology Association of Japan registry database, which was established to continuously collect data for paediatric rheumatic diseases. Methods: Pediatric Rheumatology International Collaborate Unit Registry version 2 (PRICUREv2) is a registry database established by the Pediatric Rheumatology Association of Japan. The registry data were analysed for the age of onset, time to diagnosis, sex differences, seasonality, and other factors. Results: Our data showed the same trend regarding rates of paediatric rheumatic diseases reported in Japan and other countries. The age of onset was lower in juvenile idiopathic arthritis (JIA) and juvenile dermatomyositis and higher in systemic lupus erythematosus and Sjögren's syndrome. The time to diagnosis was relatively short in JIA and systemic lupus erythematosus but longer in juvenile dermatomyositis and Sjögren's syndrome. Rheumatoid factor-positive polyarticular JIA showed a seasonality cluster with regard to onset. Conclusion: PRICUREv2 aided the retrieval and evaluation of current epidemiological information on patients with paediatric rheumatic diseases. It is expected that the data collection will be continued and will be useful for expanding research in Japan.
DOI： 10.1093/mr/roac112
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Nunoi H., Xie P., Nakamura H., Aratani Y., Fang J., Nishimura T., Kataoka H., Maeda H., Matsukura M.
Inflammation 45 ( 4 ) 1668 - 1679 2022.8
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Inflammation
Chronic granulomatous disease (CGD) is a primary immunodeficiency wherein phagocytes are unable to produce reactive oxygen species (ROS) owing to a defect in the nicotinamide adenine dinucleotide phosphate oxidase (NADPH) complex. Patients with CGD experience bacterial and fungal infections and excessive inflammatory disorders. Bone marrow transplantation and gene therapy are theoretically curative; however, residual pathogenic components cause inflammation and/or organic damage in patients. Moreover, antibiotic treatments may not help in preventing excessive inflammation due to the residual presence of fungal cell wall β-glucan. Thus, better treatment strategies against CGD are urgently required. Polyethylene glycol–conjugated recombinant porcine d-amino acid oxidase (PEG-pDAO) supplies ROS to defective NADPH oxidase in neutrophils of patients with CGD, following which the neutrophils regain bactericidal activity in vitro. In this study, we employed an in vivo nonviable Candida albicans (nCA)–induced lung inflammation model of gp91-phox knockout CGD mice and supplied novel PEG conjugates of Fusarium spp. d-amino acid oxidase (PEG-fDAO), as it exhibits higher enzyme activity than PEG-pDAO. The body weight, lung weight, and lung pathology were evaluated using three experimental strategies with the in vivo lung inflammation model to test the efficacy of the ROS-generating enzyme replacement therapy with PEG-fDAO. The lung weight and pathological findings suggest the condition was ameliorated by administration PEG-fDAO, followed by intraperitoneal injection of d-phenylalanine or d-proline. Although a more precise protocol is essential, these data reveal the targeted delivery of PEG-fDAO to the nCA-induced inflammation site and show that PEG-fDAO can be used to treat inflammation in CGD in vivo.
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Recent topics and advanced therapies in chronic granulomatous disease Reviewed
Nunoi H., Nakamura H., Nishimura T., Matsukura M.
Human Cell 36 ( 2 ) 515 - 527 2022
Language：Japanese Publishing type：Research paper (scientific journal) Publisher：Human Cell
Chronic granulomatous disease (CGD) is a primary immunodeficiency characterized by the inability of phagocytes to produce reactive oxygen species (ROS) owing to a defect in any of the five components (CYBB/gp91phox, CYBA/p22phox, NCF1/p47phox, NCF2/p67phox, and NCF4/p40phox) and a concomitant regulatory component of Rac1/2 and CYBC1/Eros of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex. Patients with CGD are at an increased risk of life-threatening infections caused by catalase-positive bacteria and fungi and of inflammatory complications such as CGD colitis. Antimicrobial and azole antifungal prophylaxes have considerably reduced the incidence and severity of bacterial and improved fungal infections and overall survival. CGD studies have revealed the precise epidemiology and role of NADPH oxidase in innate immunity which has led to a new understanding of the importance of phagocyte oxygen metabolism in various host-defense systems and the fields leading to cell death processes. Moreover, ROS plays central roles in the determination of cell fate as secondary messengers and by modifying of various signaling molecules. According to this increasing knowledge about the effects of ROS on the inflammasomal system, immunomodulatory treatments, such as IFN-γ and anti-IL-1 antibodies, have been established. This review covers the current topics in CGD and the relationship between ROS and ROS-mediated pathophysiological phenomena. In addition to the shirt summary of hematopoietic stem cell transplantation and gene therapy, we introduce a novel ROS-producing enzyme replacement therapy using PEG-fDAO to compensate for NADPH oxidase deficiency.