研究者詳細 - 武市　拓也

Clinical characteristics of systemic sclerosis patients with anti-NOR90 antibodies

Yamashita, Y; Muro, Y; Koizumi, H; Ogawa-Momohara, M; Takeichi, T; Akiyama, M

JOURNAL OF INVESTIGATIVE DERMATOLOGY 142 巻 ( 12 ) 頁： S204 - S204 2022年12月

Ceramide profiling of stratum corneum in Sj?gren-Larsson syndrome 査読有り国際誌

Arai, A; Takeichi, T; Wakamoto, H; Sassa, T; Ito, Y; Murase, Y; Ogi, T; Akiyama, M; Kihara, A

JOURNAL OF DERMATOLOGICAL SCIENCE 107 巻 ( 3 ) 頁： 114 - 122 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：Journal of Dermatological Science

Background: Sjögren–Larsson syndrome (SLS) is a neurocutaneous disorder whose causative gene is the fatty aldehyde dehydrogenase ALDH3A2 and of which ichthyosis is the major skin symptom. The stratum corneum contains a variety of ceramides, among which ω-O-acylceramides (acylceramides) and protein-bound ceramides are essential for skin permeability barrier formation. Objectives: To determine the ceramide classes/species responsible for SLS pathogenesis and the enzymes that are impaired in SLS. Methods: Genomic DNA was collected from peripheral blood samples from an SLS patient and her parents, and whole-genome sequencing and Sanger sequencing were performed. Lipids were extracted from stratum corneum samples from the SLS patient and healthy volunteers and subjected to ceramide profiling via liquid chromatography coupled with tandem mass spectrometry. Results: A duplication (c.55_130dup) and a missense mutation (p.Lys447Glu) were found in the patient's ALDH3A2 gene. The patient had reduced levels of all acylceramide classes, with total acylceramide levels at 25 % of healthy controls. Reductions were also observed for several nonacylated ceramides: ceramides with phytosphingosine or 6-hydroxysphingosine in the long-chain base moiety were reduced to 24 % and 41 % of control levels, respectively, and ceramides with an α-hydroxy fatty acid as the fatty acid moiety were reduced to 29 %. The fatty acid moiety was shortened in many nonacylated ceramide classes. Conclusion: These results suggest that reduced acylceramide levels are a primary cause of the ichthyosis symptoms of SLS, but reductions in other ceramide classes may also be involved.

DOI： 10.1016/j.jdermsci.2022.08.003

Comment on: Favourable complete remission of anti-OJ antibody-positive myositis after lung cancer resection 査読有り国際誌

Muro, Y; Nishida, K; Yamashita, Y; Koizumi, H; Takeichi, T; Satoh, M; Akiyama, M

RHEUMATOLOGY 61 巻 ( 8 ) 頁： E232 - E234 2022年8月

Extremely mild dominant dystrophic epidermolysis bullosa: Genotype information from whole-exome sequencing of salivary gDNA predicts disease severity 査読有り国際誌

Miyazaki, A; Takeichi, T; Takeuchi, S; Taki, T; Muro, Y; Akiyama, M

JOURNAL OF DERMATOLOGY 49 巻 ( 8 ) 頁： E276 - E277 2022年8月

Eosinophilic granulomatosis with polyangiitis complicated with idiopathic thrombocytopenic purpura and sclerosing cholangitis showing eosinophilic infiltration 査読有り国際誌

Yamashita, Y; Takeichi, T; Ishizu, Y; Suzuki, N; Tsuboi, T; Matsuura, K; Koizumi, H; Muro, Y; Akiyama, M

JOURNAL OF DERMATOLOGY 49 巻 ( 8 ) 頁： E270 - E271 2022年8月

Darier disease successfully treated with a topical agent containing vitamin A (retinyl palmitate), vitamin E, and urea 査読有り国際誌

Miyazaki, A; Taki, T; Takeichi, T; Kono, M; Yagi, H; Akiyama, M

JOURNAL OF DERMATOLOGY 49 巻 ( 8 ) 頁： 779 - 782 2022年8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：Journal of Dermatology

Darier disease (DD), also called keratosis follicularis, is an autosomal dominant hereditary keratinization disorder that manifests as keratotic papules with plaques in seborrheic areas. There are no validated curative treatments for DD, with the majority of cases treated symptomatically. We report the efficacy of a topical over-the-counter agent which contains retinyl palmitate, vitamin E, and urea for a patient with DD. A 13-year-old girl had brown papules on her scalp, neck, shoulders, and axillae since entering elementary school. A skin biopsy revealed hyperkeratosis, suprabasal acantholysis, and dyskeratosis manifested as corps ronds and grains in the epidermis. Sanger sequencing found the previously reported heterozygous mutation c.1484C>T in ATP2A2. The application of an over-the-counter topical agent containing retinyl palmitate 2750 μg/g (5000 IU/g), tocopheryl acetate 20 mg/g, urea 200 mg/g, and monoammonium glycyrrhizinate 5 mg/g twice daily for 2 months improved the papules without serious adverse events. Oral or topical aromatic vitamin A analogs (retinoids) are often used to treat DD. However, several adverse events are associated with retinoid treatment, and many patients only undergo their intermittent use or discontinue the treatments. Retinyl palmitate is more stable and has a lower irritative profile than other retinoic acids. When applied topically, however, retinyl palmitate cannot penetrate the skin as well as retinol can. Some reports have noted that vitamin E increases the biological availability of vitamin A and that urea helps mechanical percutaneous drug delivery. Our case suggests that retinyl palmitate has a sufficient therapeutic effect when combined with vitamin E and urea. In conclusion, we propose that topical agents containing retinyl palmitate, vitamin E, and urea might have a satisfactory effect on the skin lesions of DD patients, without the serious risks of adverse events.

DOI： 10.1111/1346-8138.16395

Case of ichthyosis with confetti caused by KRT10 mutation, complicated with multiple malignant melanomas 査読有り国際誌

Ito, Y; Takeichi, T; Nakagawa, K; Tanahashi, K; Muro, Y; Ogi, T; Akiyama, M

JOURNAL OF DERMATOLOGY 49 巻 ( 7 ) 頁： E228 - E229 2022年7月

Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2 査読有り国際誌

Suzuki, Y; Takeichi, T; Tanahashi, K; Muro, Y; Suga, Y; Ogi, T; Akiyama, M

INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES 23 巻 ( 14 ) 2022年7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：International Journal of Molecular Sciences

Superficial epidermolytic ichthyosis (SEI) is an autosomal dominant inherited ichthyosis. SEI is caused by mutations in KRT2 and frequently shows erythroderma and widespread blistering at birth. We report the clinical manifestations of two patients from a Japanese family with SEI caused by a hotspot mutation, p.Glu487Lys, in KRT2. In addition, we summarize previous reports on SEI patients with the identical mutation. One of the two patients had disease onset at the age of 7 months. The other patient’s age of onset is unknown, but it was in childhood. Neither of the two patients showed erythroderma. To perform deep phenotyping, we studied the age of onset and the frequency of erythroderma in 34 reported SEI cases with the p.Glu487Lys mutation, including the present cases. Among the cases with sufficient clinical information, 44.4% of the cases that were due to p.Glu487Lys in KRT2 occurred at birth. Erythroderma was observed in 11.1% of the cases with p.Glu487Lys in KRT2.

DOI： 10.3390/ijms23147791

UVB-Induced Skin Autoinflammation Due to Nlrp1b Mutation and Its Inhibition by Anti-IL-1β Antibody 査読有り国際誌

Murase, Y; Takeichi, T; Koseki, J; Miyasaka, Y; Muro, Y; Ohno, T; Shimamura, T; Akiyama, M

FRONTIERS IN IMMUNOLOGY 13 巻頁： 876390 - 876390 2022年6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：Frontiers in Immunology

NLRP1 (NACHT and leucine-rich repeat-containing protein family, pyrin domain-containing protein 1) is an innate immune sensor that is involved in the formation of inflammasome complexes. NLRP1 hyperactivity has been reported to cause inherited autoinflammatory diseases including familial keratosis lichenoides chronica and NLRP1-associated autoinflammation with arthritis and dyskeratosis. We generated Nlrp1b (the mouse homologue of human NLRP1) gain-of-function knock-in (Nlrp1b KI) mice with UVB irradiation-induced autoinflammatory skin lesions. We demonstrated that UVB irradiation induces IL-1β upregulation and IL-1β-dependent inflammation via caspase-1 activation in these Nlrp1b KI mice. RNA sequencing revealed the upregulation of inflammasome pathway-related genes, keratinocyte stress marker genes, and keratinocyte differentiation marker genes in the Nlrp1b KI mice after UVB irradiation. The skin inflammation and hyperkeratosis from UVB irradiation in the Nlrp1b KI mice were inhibited by both intraperitoneal and subcutaneous administration of anti-IL-1β antibodies before UVB irradiation. UVB irradiation and the IL-1β pathway are important in the pathogenesis of NLRP1-associated autoinflammatory skin lesions.

DOI： 10.3389/fimmu.2022.876390

Epithelioid cell granuloma formation in CARD14-associated papulosquamous eruptions 査読有り国際誌

Takeichi, T; Ikeda, K; Muro, Y; Ogi, T; Morizane, S; Akiyama, M

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY 36 巻 ( 5 ) 頁： E369 - E371 2022年5月

Clinical significance of anti-NOR90 antibodies in systemic sclerosis and idiopathic interstitial pneumonia 査読有り国際誌

Yamashita, Y; Yamano, Y; Muro, Y; Ogawa-Momohara, M; Takeichi, T; Kondoh, Y; Akiyama, M

RHEUMATOLOGY 61 巻 ( 4 ) 頁： 1709 - 1716 2022年4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：Rheumatology (United Kingdom)

Objective: Anti-NOR90 antibodies are usually found in patients with SSc; however, their clinical relevance remains obscure. We developed an ELISA for measuring them to investigate the clinical features of patients with anti-NOR90 antibodies. Methods: Serum samples from 1252 patients with various conditions from Nagoya University Hospital and 244 patients with idiopathic interstitial pneumonia (IIP) from Tosei General Hospital were included. Anti-NOR90 antibodies were assayed by an ELISA using the recombinant protein produced by in vitro transcription/translation. Results: Five (0.4%) patients in the Nagoya University Hospital cohort had anti-NOR90 antibodies. One patient with diffuse cutaneous SSc, three with limited cutaneous SSc, and one with Raynaud's disease were positive for anti-NOR90 antibodies. Anti-NOR90 antibodies were found more frequently in patients with systemic scleroderma-spectrum disorders (SSDs) than without SSDs (5/316 vs 0/936, P <0.00101) and were found more frequently in patients with SSc than without SSc (4/249 vs 0/528, P <0.0104) in the systemic autoimmune rheumatic diseases cohort. Three of the four anti-NOR90-positive SSc patients had interstitial lung disease (ILD), and two of those four had cancer. Three (1.2%) patients in the Tosei General Hospital cohort had anti-NOR90 antibodies. All three of the anti-NOR90-positive IIP patients had gastrointestinal tract involvement, and two of those three had cancer or skin lesions observed in SSc. Conclusions: Although anti-NOR90 antibodies are rarely found in clinics, our ELISA is useful for their detection. Further studies are needed to confirm the association of anti-NOR90 antibodies with ILD and cancer in SSc and IIP patients.

DOI： 10.1093/rheumatology/keab575

Mutations in SAM syndrome and palmoplantar keratoderma patients suggest genotype/phenotype correlations in DSG1 mutations 査読有り

Case of harlequin ichthyosis in preterm infant with a compound heterozygous ABCA12 missense mutation 査読有り国際誌

Miyazaki, M; Ohkawa, N; Miyabayashi, K; Shoji, H; Takeichi, T; Kantake, M; Akiyama, M; Shimizu, T

JOURNAL OF DERMATOLOGY 49 巻 ( 4 ) 頁： E137 - E139 2022年4月

Takeuchi, S; Takeichi, T; Koike, Y; Takama, H; Tanahashi, K; Okuno, Y; Ishii, N; Muro, Y; Ogi, T; Suga, Y; Akiyama, M

JOURNAL OF THE EUROPEAN ACADEMY OF DERMATOLOGY AND VENEREOLOGY 36 巻 ( 3 ) 頁： E215 - E218 2022年3月

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA 査読有り

Muro Y., Hashimoto T., Izumi S., Ogawa-Momohara M., Takeichi T., Yamashita H., Yasuoka H., Akiyama M.

Clinical and experimental rheumatology 40 巻 ( 2 ) 頁： 219 - 223 2022年2月

Differential Pathomechanisms of Desmoglein 1 Transmembrane Domain Mutations in Skin Disease 査読有り国際誌

Zimmer, SE; Takeichi, T; Conway, DE; Kubo, A; Suga, Y; Akiyama, M; Kowalczyk, AP

JOURNAL OF INVESTIGATIVE DERMATOLOGY 142 巻 ( 2 ) 頁： 323 - + 2022年2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：Journal of Investigative Dermatology

Dominant and recessive mutations in the desmosomal cadherin, desmoglein (DSG) 1, cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. In this study, we compare two dominant missense mutations in the DSG1 transmembrane domain (TMD), G557R and G562R, causing PPK (DSG1PPK-TMD) and SAM syndrome (DSG1SAM-TMD), respectively, to determine the differing pathomechanisms of these mutants. Expressing the DSG1TMD mutants in a DSG-null background, we use cellular and biochemical assays to reveal the differences in the mechanistic behavior of each mutant. Super-resolution microscopy and functional assays showed a failure by both mutants to assemble desmosomes due to reduced membrane trafficking and lipid raft targeting. DSG1SAM-TMD maintained normal expression levels and turnover relative to wildtype DSG1, but DSG1PPK-TMD lacked stability, leading to increased turnover through lysosomal and proteasomal pathways and reduced expression levels. These results differentiate the underlying pathomechanisms of these disorders, suggesting that DSG1SAM-TMD acts dominant negatively, whereas DSG1PPK-TMD is a loss-of-function mutation causing the milder PPK disease phenotype. These mutants portray the importance of the DSG TMD in desmosome function and suggest that a greater understanding of the desmosomal cadherin TMDs will further our understanding of the role that desmosomes play in epidermal pathophysiology.

DOI： 10.1016/j.jid.2021.07.154

Long-term risk of cancer development among anti-Th/To antibody-positive systemic sclerosis patients: comment on the article by Mecoli et al 査読有り国際誌

Yamashita, Y; Muro, Y; Koizumi, H; Takeichi, T; Yamano, Y; Kondoh, Y; Akiyama, M

ARTHRITIS & RHEUMATOLOGY 74 巻 ( 2 ) 頁： 368 - 369 2022年2月

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA 査読有り

Muro Y., Hashimoto T., Izumi S., Ogawa-Momohara M., Takeichi T., Yamashita H., Yasuoka H., Akiyama M.

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 40 巻 ( 2 ) 頁： 219 - 223 2022年2月

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation 査読有り国際共著国際誌

Takeichi, T; Lee, JYW; Okuno, Y; Miyasaka, Y; Murase, Y; Yoshikawa, T; Tanahashi, K; Nishida, E; Okamoto, T; Ito, K; Muro, Y; Sugiura, K; Ohno, T; McGrath, JA; Akiyama, M

FRONTIERS IN IMMUNOLOGY 12 巻頁： 737747 - 737747 2022年1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：Frontiers in Immunology

Heterozygous mutations in JAK1 which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense JAK1 mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical Jak1 knock-in missense mutation (Jak1H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1H595D/+;I596I/+;Y597Y/+ mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in Jak1H595D/+;I596I/+;Y597Y/+ mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of JAK1-associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.

DOI： 10.3389/fimmu.2021.737747