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新生児スクリーニング検査で同定されたB細胞欠損症
松本 昂之, 西村 豊樹, 山元 綾子, 澤田 浩武, 盛武 浩
日本免疫不全・自己炎症学会雑誌 3 ( 1 ) 16 - 20 2024年2月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：一般社団法人 日本免疫不全・自己炎症学会
新生児スクリーニング（newborn screening：NBS）はおよそ20疾患を対象に公費負担として行われているが，各自治体によって独自に対象疾患を拡大しているのが実状である．宮崎県では，2020年4月から先天性免疫異常症（inborn errors of immunity：IEI）とライソゾーム病を任意で追加している．今回，われわれは宮崎県で実施したNBSによりB細胞欠損症（B-cell deficiency：BCD）を同定した．症例はkappa-deleting recombination excision circles（KRECs）が低値を示し精査対象となった．当科で行った複数回のCD 19陽性B細胞の測定で，一貫してB細胞割合が2％未満でありBCDの診断に至った．診断後は免疫グロブリン補充療法を行いながら，1歳5か月となる現在まで重篤な感染症を合併することなく経過している．自験例のようにNBSを契機としたBCD診断，さらに免疫グロブリン補充による予防介入の報告は本邦初と考えられる．IEIのうちで重症複合免疫不全症とBCDは，重篤な後遺症をきたす例，さらに診断されることなく死亡する例も存在し，早期の診断と治療介入が特に重要である．IEIをNBSの対象疾患として導入することの費用対効果は，世界中で証明されている．今後，日本でもIEIがNBS公費負担の対象になることが期待される．
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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年
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年9月
記述言語：英語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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年8月
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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 査読あり
Nunoi H., Nakamura H., Nishimura T., Matsukura M.
Human Cell 36 ( 2 ) 515 - 527 2022年
記述言語：日本語 掲載種別：研究論文（学術雑誌） 出版者・発行元：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.