Faculty Profiles - TAKEICHI Takuya

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 Vol. 142 ( 12 ) page： S204 - S204 2022.12

Ceramide profiling of stratum corneum in Sjögren-Larsson syndrome. Reviewed International journal

Ayami Arai, Takuya Takeichi, Hiroyuki Wakamoto, Takayuki Sassa, Yasutoshi Ito, Yuya Murase, Tomoo Ogi, Masashi Akiyama, Akio Kihara

Journal of dermatological science Vol. 107 ( 3 ) page： 114 - 122 2022.9

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Yoshinao Muro, Kazuki Nishida, Yuta Yamashita, Haruka Koizumi, Takuya Takeichi, Minoru Satoh, Masashi Akiyama

Rheumatology (Oxford, England) Vol. 61 ( 8 ) page： E232 - E234 2022.8

Extremely mild dominant dystrophic epidermolysis bullosa: Genotype information from whole-exome sequencing of salivary gDNA predicts disease severity. Reviewed International journal

Akira Miyazaki, Takuya Takeichi, So Takeuchi, Tomoki Taki, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 8 ) page： E276 - E277 2022.8

Eosinophilic granulomatosis with polyangiitis complicated with idiopathic thrombocytopenic purpura and sclerosing cholangitis showing eosinophilic infiltration. Reviewed International journal

Yuta Yamashita, Takuya Takeichi, Yoji Ishizu, Nobuaki Suzuki, Takashi Tsuboi, Kentaro Matsuura, Haruka Koizumi, Yoshinao Muro, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 8 ) page： E270 - E271 2022.8

Darier disease successfully treated with a topical agent containing vitamin A (retinyl palmitate), vitamin E, and urea. Reviewed International journal

Akira Miyazaki, Tomoki Taki, Takuya Takeichi, Michihiro Kono, Hiroaki Yagi, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 8 ) page： 779 - 782 2022.8

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Yasutoshi Ito, Takuya Takeichi, Koichi Nakagawa, Kana Tanahashi, Yoshinao Muro, Tomoo Ogi, Masashi Akiyama

The Journal of dermatology Vol. 49 ( 7 ) page： E228 - E229 2022.7

Deep Phenotyping of Superficial Epidermolytic Ichthyosis due to a Recurrent Mutation in KRT2. Reviewed International journal

Yuika Suzuki, Takuya Takeichi, Kana Tanahashi, Yoshinao Muro, Yasushi Suga, Tomoo Ogi, Masashi Akiyama

International journal of molecular sciences Vol. 23 ( 14 ) 2022.7

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Yuya Murase, Takuya Takeichi, Jun Koseki, Yuki Miyasaka, Yoshinao Muro, Tamio Ohno, Teppei Shimamura, Masashi Akiyama

Frontiers in immunology Vol. 13 page： 876390 - 876390 2022.6

Language：English Publishing type：Research paper (scientific journal)

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. Reviewed International journal

Takuya Takeichi, Kenta Ikeda, Yoshinao Muro, Tomoo Ogi, Shin Morizane, Masashi Akiyama

Journal of the European Academy of Dermatology and Venereology : JEADV Vol. 36 ( 5 ) page： E369 - E371 2022.5

Clinical significance of anti-NOR90 antibodies in systemic sclerosis and idiopathic interstitial pneumonia. Reviewed International journal

Yuta Yamashita, Yasuhiko Yamano, Yoshinao Muro, Mariko Ogawa-Momohara, Takuya Takeichi, Yasuhiro Kondoh, Masashi Akiyama

Rheumatology (Oxford, England) Vol. 61 ( 4 ) page： 1709 - 1716 2022.4

Language：English Publishing type：Research paper (scientific journal) Publisher：OXFORD UNIV PRESS

OBJECTIVE: Anti-NOR90 antibodies are usually found in patients with systemic sclerosis (SSc); however, their clinical relevance remains obscure. We developed an enzyme-linked immunosorbent assay (ELISA) for measuring them to investigate the clinical features of patients with anti-NOR90 antibodies. METHODS: Serum samples from 1,252 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, 3 with limited cutaneous SSc, and 1 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 4 anti-NOR90-positive SSc patients had interstitial lung disease (ILD), and 2 of those 4 had cancer. Three (1.2%) patients in the Tosei General Hospital cohort had anti-NOR90 antibodies. All 3 of the anti-NOR90-positive IIP patients had gastrointestinal tract involvement, and 2 of those 3 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 Reviewed

Case of harlequin ichthyosis in preterm infant with a compound heterozygous ABCA12 missense mutation. Reviewed International journal

Moeka Miyazaki, Natsuki Ohkawa, Kazuki Miyabayashi, Hiromichi Shoji, Takuya Takeichi, Masato Kantake, Masashi Akiyama, Toshiaki Shimizu

The Journal of dermatology Vol. 49 ( 4 ) page： E137 - E139 2022.4

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

Journal of the European Academy of Dermatology and Venereology Vol. 36 ( 3 ) page： E215 - E218 2022.3

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA Reviewed

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

Clinical and experimental rheumatology Vol. 40 ( 2 ) page： 219 - 223 2022.2

Differential pathomechanisms of desmoglein-1 transmembrane domain mutations in skin disease. Reviewed International journal

Stephanie E Zimmer, Takuya Takeichi, Daniel E Conway, Akiharu Kubo, Yasushi Suga, Masashi Akiyama, Andrew P Kowalczyk

The Journal of investigative dermatology Vol. 142 ( 2 ) page： 323 - + 2022.2

Language：English Publishing type：Research paper (scientific journal) Publisher：ELSEVIER SCIENCE INC

Dominant and recessive mutations in the desmosomal cadherin, desmoglein-1 (DSG1), cause the skin diseases palmoplantar keratoderma (PPK) and severe dermatitis, multiple allergies, and metabolic wasting (SAM) syndrome, respectively. Here, 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 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 DSG1WT, 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 while 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. Reviewed International journal

Yuta Yamashita, Yasuhiko Yamano, Yoshinao Muro, Haruka Koizumi, Takuya Takeichi, Yasuhiro Kondoh, Masashi Akiyama

Arthritis & rheumatology (Hoboken, N.J.) Vol. 74 ( 2 ) page： 368 - 369 2022.2

Language：English Publisher：WILEY

We read the report by Mecoli et al on the relationship between cancer and anti-Th/To antibodies (AThAs) in patients with systemic sclerosis (SSc) (1). It is interesting that the presence of AThAs was reported to confer a protective effect against cancer development in those patients. However, cancer development in AThA-positive patients was significantly suppressed only within the first 3 years after SSc onset, and there was no significant difference in the number of deceased between the AThA-positive and AThA-negative patients.

DOI： 10.1002/art.41945

Anti-Zo antibodies in Japanese myositis patients detected by a newly developed ELISA Reviewed

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

CLINICAL AND EXPERIMENTAL RHEUMATOLOGY Vol. 40 ( 2 ) page： 219 - 223 2022.2

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation. Reviewed International coauthorship International journal

Takuya Takeichi, John Y W Lee, Yusuke Okuno, Yuki Miyasaka, Yuya Murase, Takenori Yoshikawa, Kana Tanahashi, Emi Nishida, Tatsuya Okamoto, Komei Ito, Yoshinao Muro, Kazumitsu Sugiura, Tamio Ohno, John A McGrath, Masashi Akiyama

Frontiers in immunology Vol. 12 page： 737747 - 737747 2022.1

Language：English Publishing type：Research paper (scientific journal) Publisher：FRONTIERS MEDIA SA

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 (Jak1 H595D/+;I596I/+;Y597Y/+ mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the Jak1 H595D/+;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 Jak1 H595D/+;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