Publications (43)197.94 Total impact
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Article: Three school-age cases of xeroderma pigmentosum variant type.
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ABSTRACT: BACKGROUND: Xeroderma pigmentosum (XP) is a photosensitive genodermatosis with increased susceptibility to skin cancers. Patients are typically diagnosed with XP when they consult a dermatologist for skin cancers. CASE/METHODS: The genetic analysis and 2-8 years of follow-up for three school-age patients with XP-V is described. The patients were referred to us because of increased pigmented freckles; they had not experienced abnormal sunburn or developed skin cancer at their first visit. All patients harbored a genetic mutation in the POLH gene. XPV9KO was diagnosed at age 13 with a homozygous del1661A that creates a stop codon in the non-catalytic domain of POLH. The patient practiced sun protection, effectively preventing the development of skin cancer by age 21. XPV19KO was diagnosed at age 11 with a compound heterozygous mutation of G490T and C1066T, causing POLH truncation in the catalytic domain. This patient developed basal cell carcinoma at ages 12 and 13. XPV18KO was referred to us at age 11 and diagnosed with compound heterozygous variants of c.1246_1311del66 (exon 9 skipping), a novel mutation, and c.661_764 del104 (exon 6 skipping). CONCLUSION: Freckle-like pigmentation on sun-exposed skin is sometimes the only sign of XP-V, and early diagnosis is extremely important for children.Photodermatology Photoimmunology and Photomedicine 06/2013; 29(3):132-9. · 1.30 Impact Factor -
Article: Novel R218X mutation in the fumarate hydratase gene in a patient with Reed's syndrome.
The Journal of Dermatology 10/2012; · 1.49 Impact Factor -
Article: Critical role for mast cells in interleukin-1β-driven skin inflammation associated with an activating mutation in the nlrp3 protein.
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ABSTRACT: Cryopyrin-associated periodic syndromes (CAPS) are caused by aberrant interleukin-1β (IL-1β) production induced by mutations in the NLRP3 protein in humans, but the mechanisms involved remain poorly understood. Using a mouse model, we show a role for the indigenous microbiota and mast cells (MCs) in skin disease associated with mutant Nlrp3 protein. Unlike normal cells, MCs expressing mutant Nlrp3 produced IL-1β in response to lipopolysaccharide or tumor necrosis factor-α (TNF-α). In neonatal mice, the microbiota induced TNF-α and IL-1β and promoted skin disease. MC deficiency greatly reduced disease in Nlrp3 mutant mice, and reconstitution of MC-deficient mice with mutant MCs restored skin disease, which required the expression of IL-1β in MCs. Surprisingly, neutralization of TNF-α abrogated IL-1β production and skin disease in neonatal Nlrp3 mutant mice, but not in affected adult mice. Thus, the microbiota and MCs initiate cellular events leading to dysregulated IL-1β production and skin inflammation in neonatal mice with the CAPS-associated Nlrp3 mutation.Immunity 07/2012; 37(1):85-95. · 21.64 Impact Factor -
Article: Induced pluripotent stem cells from CINCA syndrome patients as a model for dissecting somatic mosaicism and drug discovery.
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ABSTRACT: Chronic infantile neurologic cutaneous and articular (CINCA) syndrome is an IL-1-driven autoinflammatory disorder caused mainly by NLRP3 mutations. The pathogenesis of CINCA syndrome patients who carry NLRP3 mutations as somatic mosaicism has not been precisely described because of the difficulty in separating individual cells based on the presence or absence of the mutation. Here we report the generation of NLRP3-mutant and nonmutant-induced pluripotent stem cell (iPSC) lines from 2 CINCA syndrome patients with somatic mosaicism, and describe their differentiation into macrophages (iPS-MPs). We found that mutant cells are predominantly responsible for the pathogenesis in these mosaic patients because only mutant iPS-MPs showed the disease relevant phenotype of abnormal IL-1β secretion. We also confirmed that the existing anti-inflammatory compounds inhibited the abnormal IL-1β secretion, indicating that mutant iPS-MPs are applicable for drug screening for CINCA syndrome and other NLRP3-related inflammatory conditions. Our results illustrate that patient-derived iPSCs are useful for dissecting somatic mosaicism and that NLRP3-mutant iPSCs can provide a valuable platform for drug discovery for multiple NLRP3-related disorders.Blood 06/2012; 120(6):1299-308. · 9.90 Impact Factor -
Article: Kerion celsi due to Arthroderma incurvatum infection in a Sri Lankan child: species identification and analysis of area-dependent genetic polymorphism.
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ABSTRACT: A three-year-old Sri Lankan boy residing in Japan developed a nodule on his scalp after visiting Sri Lanka. Two months later, the lesion increased in size to 22 × 19 mm(2), and was identified as an erythematous nodule with alopecia. Direct examination of the infected hair shafts indicated fungal hyphae outside the shafts. The fungus was identified as Microsporum gypseum following mycological examination. The sequence of the internal transcribed spacer 1 region of ribosomal RNA gene (ITS1 rDNA) exhibited 95.7-100.0% homology with that of Arthroderma incurvatum. The patient was successfully treated with a 6-week itraconazole course. We also examined DNA samples from eight clinical isolates of A. incurvatum. Alignments of ITS1 sequences of these strains and our isolate, showed gaps in the 64-bp positions 140-142 and 141-143 of the 205-207-bp ITS1 alignment. We performed phylogenetic analysis using the neighbor-jointing (NJ) method based on the ITS1 sequences of the present isolate and twenty related strains. Fifteen A. incurvatum strains were divided into East Asia and non-East Asia clusters. The present isolate belonged to the non-East Asia cluster, suggesting that the patient was infected outside Japan. Moreover, the trees suggested area-dependent genetic polymorphism of A. incurvatum.Medical mycology: official publication of the International Society for Human and Animal Mycology 03/2012; 50(7):690-8. · 2.13 Impact Factor -
Article: The CD40-CD40L axis and IFN-γ play critical roles in Langhans giant cell formation.
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ABSTRACT: The presence of Langhans giant cells (LGCs) is one of the signatures of systemic granulomatous disorders such as tuberculosis and sarcoidosis. However, the pathophysiological mechanism leading to LGC formation, especially the contribution of the T cells abundantly found in granulomas, has not been fully elucidated. To examine the role of T cells in LGC formation, a new in vitro method for the induction of LGCs was developed by co-culturing human monocytes with autologous T cells in the presence of concanavalin A (ConA). This system required close contact between monocytes and T cells, and CD4+ T cells were more potent than CD8+ T cells in inducing LGC formation. Antibody inhibition revealed that a CD40-CD40 ligand (CD40L) interaction and IFN-γ were essential for LGC formation, and the combination of exogenous soluble CD40L (sCD40L) and IFN-γ efficiently replaced the role of T cells. Dendritic cell-specific transmembrane protein (DC-STAMP), a known fusion-related molecule in monocytes, was up-regulated during LGC formation. Moreover, knock-down of DC-STAMP by siRNA inhibited LGC formation, revealing that DC-STAMP was directly involved in LGC formation. Taken together, these results demonstrate that T cells played a pivotal role in a new in vitro LGC formation system, in which DC-STAMP was involved, and occurred via a molecular mechanism that involved CD40-CD40L interaction and IFN-γ secretion.International Immunology 11/2011; 24(1):5-15. · 3.41 Impact Factor -
Article: Maximum growth temperature test for cutaneous Mycobacterium chelonae predicts the efficacy of thermal therapy.
The Journal of Dermatology 07/2011; 39(2):205-6. · 1.49 Impact Factor -
Article: High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study.
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ABSTRACT: Chronic infantile neurologic, cutaneous, articular (CINCA) syndrome, also known as neonatal-onset multisystem inflammatory disease (NOMID), is a dominantly inherited systemic autoinflammatory disease. Although heterozygous germline gain-of-function NLRP3 mutations are a known cause of this disease, conventional genetic analyses fail to detect disease-causing mutations in ∼40% of patients. Since somatic NLRP3 mosaicism has been detected in several mutation-negative NOMID/CINCA syndrome patients, we undertook this study to determine the precise contribution of somatic NLRP3 mosaicism to the etiology of NOMID/CINCA syndrome. An international case-control study was performed to detect somatic NLRP3 mosaicism in NOMID/CINCA syndrome patients who had shown no mutation during conventional sequencing. Subcloning and sequencing of NLRP3 was performed in these mutation-negative NOMID/CINCA syndrome patients and their healthy relatives. Clinical features were analyzed to identify potential genotype-phenotype associations. Somatic NLRP3 mosaicism was identified in 18 of the 26 patients (69.2%). Estimates of the level of mosaicism ranged from 4.2% to 35.8% (mean ± SD 12.1 ± 7.9%). Mosaicism was not detected in any of the 19 healthy relatives (18 of 26 patients versus 0 of 19 relatives; P < 0.0001). In vitro functional assays indicated that the detected somatic NLRP3 mutations had disease-causing functional effects. No differences in NLRP3 mosaicism were detected between different cell lineages. Among nondescript clinical features, a lower incidence of mental retardation was noted in patients with somatic mosaicism. Genotype-matched comparison confirmed that patients with somatic NLRP3 mosaicism presented with milder neurologic symptoms. Somatic NLRP3 mutations were identified in 69.2% of patients with mutation-negative NOMID/CINCA syndrome. This indicates that somatic NLRP3 mosaicism is a major cause of NOMID/CINCA syndrome.Arthritis & Rheumatism 06/2011; 63(11):3625-32. · 7.87 Impact Factor -
Article: Identification of 736T>A mutation of lipase H in Japanese siblings with autosomal recessive woolly hair.
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ABSTRACT: Woolly hair is characterized by fine and tightly curled hair. It has recently been revealed that both LPAR6 and lipase H (LIPH) mutations cause autosomal recessive woolly hair (ARWH)/hypotrichosis. This notion has provided critical evidence to the concept that LPA6 activation by LIPH-catalyzed lipid mediator lysophosphatidic acid has a key role in regulation of hair follicle development. Very recently, novel mutations in exon 6, homozygous 736T>A and compound heterozygous 736T>A and 742C>A have been identified in Japanese ARWH/hypotrichosis patients. Here, we report on siblings (a 7-year-old Japanese girl and her 5-year-old brother) both showing woolly hair. Determination of their genomic sequence showed presence of a homozygous 736T>A transition in exon 6 of the LIPH gene changing cysteine at position 246 to serine, without any mutation in the LPAR6 gene. Additionally, the same mutation was found in one out of a 100 alleles of Japanese healthy controls and identified homozygously in three out of four other Japanese sporadic cases with woolly hair. Collectively, it has been suggested that 736T>A transition is highly specific and common in ARWH/hypotrichosis of Japanese origin.The Journal of Dermatology 02/2011; 38(9):900-4. · 1.49 Impact Factor -
Article: [Early-onset sarcoidosis/Blau syndrome].
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ABSTRACT: Familial Blau syndrome and sporadic early-onset sarcoidosis (EOS) are both systemic granulomatous diseases evoked by the spontaneous activation of mutated NOD2. In Japan, the R334W amino acid substitution is more frequently identified, whereas the R334Q mutation is rare and, in contrast to western countries where disease causing mutations are typically hereditary, most Japanese cases derive from sporadic mutations. Recently, a case with a six-base deletion in the NOD2 gene was reported. This Blau syndrome/EOS patient presented with the unpainful soft swelling of the dorsal side of the wrist and ankles, as well as flexion contracture at the proximal interphalangeal joint that gradually appeared during their clinical course. These features are useful for the differential diagnosis of Blau syndrome/EOS from juvenile idiopathic arthritis. Owing to their characteristic clinical symptoms, Blau and EOS patients can be identified earlier if medical experts become more acquainted with these distinctions. Even though specific treatment based on pathophysiologic mechanism has not been explored yet, early diagnosis will prevent the progression to severe impairment, which can severely affect patients' lives.Japanese Journal of Clinical Immunology 01/2011; 34(5):378-81. -
Article: Lymphocutaneous type of nocardiosis caused by Nocardia vinacea in a patient with polymyositis.
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ABSTRACT: We report a lymphocutaneous type of nocardiosis caused by Nocardia vinacea. A 62-year-old woman with polymyositis presented with some erythematous swellings and subcutaneous abscesses on her right middle finger and the dorsum of her hand, which had persisted for 2 weeks. Culturing of the excised nodule and pus revealed orange to orange-tan colonies with scanty whitish aerial mycelia. The isolate was identified as N. vinacea on the basis of its biochemical and chemotaxonomic characteristics and the results of molecular biological analysis. In our case, oral minocycline (MINO) and trimethoprim-sulfamethoxazole (TMP-SMX) for 7 weeks did not improve the clinical manifestation, even though in vitro susceptibility testing of the isolate predicted its susceptibility to MINO and TMP-SMX. Treatment with partial surgical excision followed by TMP-SMX and meropenem administration was effective. This is the first reported case of a lymphocutaneous type of nocardiosis caused by N. vinacea.Mycopathologia 01/2011; 172(1):47-53. · 1.65 Impact Factor -
Article: Follicular keratosis and bullous formation are typical signs of extragenital lichen sclerosus.
The Journal of Dermatology 11/2010; 38(8):834-6. · 1.49 Impact Factor -
Article: Enhanced NF-κB activation with an inflammasome activator correlates with activity of autoinflammatory disease associated with NLRP3 mutations outside of exon 3: comment on the article by Jéru et al.
Arthritis & Rheumatism 10/2010; 62(10):3123-4; author reply 3124-5. · 7.87 Impact Factor -
Article: The 1st JSID Kisaragi Juku: The junior tutors' perspective.
Journal of dermatological science 06/2010; 58(3):167-70. · 3.71 Impact Factor -
Article: KIT masters mast cells in kids, too.
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ABSTRACT: Adult mastocytosis is usually persistent and caused by c-KIT codon 816-activating mutations. Pediatric mastocytosis is often transient, and the molecular mechanism driving mast cell proliferation in pediatric cases remains unclear. In this issue, Bodemer et al. report novel c-KIT mutations in a large percentage of pediatric cases, identifying both similarities and fundamental differences in the mechanisms causing adult and pediatric mastocytosis.Journal of Investigative Dermatology 03/2010; 130(3):648-50. · 6.31 Impact Factor -
Article: The inflammasome, an innate immunity guardian, participates in skin urticarial reactions and contact hypersensitivity.
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ABSTRACT: Urticarial rash, one of the clinical manifestations characteristic of cryopyrin-associated periodic syndrome (CAPS), is caused by a mutation in the gene encoding for NLRP3 (nucleotide-binding oligomerization domain, leucine-rich repeats containing family, pyrin domain containing 3). This intracellular pattern recognition receptor and its adaptor protein, called apoptosis associated speck-like protein containing a caspase-recruitment and activating domain (ASC), participate in the formation of a multi-protein complex termed the inflammasome. The inflammasome is responsible for activating caspase-1 in response to microbial and endogenous stimuli. From the analysis of cellular mechanisms of urticarial rash in CAPS, we have traced caspase-1 activated IL-1beta in CAPS to a surprising source: mast cells. Recently, two groups have generated gene-targeted mice that harbored Nlrp3 mutations. These mice had very severe phenotypes, with delayed growth and the development of dermatitis, but not urticaria. The reason for the differences in the skin manifestations observed with CAPS and these knock-in mice relates to the findings that the inflammasome also plays a role in contact hypersensitivity, and that IL-18, another cytokine involved with inflammasome-activation of caspase-1, may be a major player in dermatitis development.Allergology International 02/2010; 59(2):105-13. -
Article: Murine fetal skin-derived cultured mast cells: a useful tool for discovering functions of skin mast cells.
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ABSTRACT: Mast cells are widely distributed throughout the body, being preferentially localized at host-environment interfaces. They have long been known as major effector cells in IgE-mediated allergic responses. However, accumulating evidence has provided many new insights into their functions. They are now known to be involved in diverse pathological processes, for example, innate and adaptive immunity. Utility of mast cell-deficient mice and mast cell-knock-in mice has provided powerful models to demonstrate compelling evidence for their in vivo relevance. Conversely, primary cultures of tissue-derived mast cells provide excellent models for in vitro studies of functions at both cellular and molecular levels. Because mast cells exhibit phenotypical and functional heterogeneity in different anatomical sites, it is important to obtain tissue-specific mast cells to clarify their function in tissue. In this regard, researchers have established several methods to prepare mast cells from different tissues, which are technically difficult to obtain at high purity and yield. To overcome these difficulties, we have developed a primary culture system to obtain large numbers of mast cells at high purity from murine fetal skin. In this review, we describe characteristics of such mast cells and their utility in mast cell biology.Journal of Investigative Dermatology 03/2009; 129(5):1120-5. · 6.31 Impact Factor -
Article: Mast cells mediate neutrophil recruitment and vascular leakage through the NLRP3 inflammasome in histamine-independent urticaria
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ABSTRACT: Urticarial rash observed in cryopyrin-associated periodic syndrome (CAPS) caused by nucleotide-binding oligomerization domain-leucine-rich repeats containing pyrin domain 3 (NLRP3) mutations is effectively suppressed by anti-interleukin (IL)-1 treatment, suggesting a pathophysiological role of IL-1beta in the skin. However, the cellular mechanisms regulating IL-1beta production in the skin of CAPS patients remain unclear. We identified mast cells (MCs) as the main cell population responsible for IL-1beta production in the skin of CAPS patients. Unlike normal MCs that required stimulation with proinflammatory stimuli for IL-1beta production, resident MCs from CAPS patients constitutively produced IL-1beta. Primary MCs expressed inflammasome components and secreted IL-1beta via NLRP3 and apoptosis-associated speck-like protein containing a caspase recruitment domain when stimulated with microbial stimuli known to activate caspase-1. Furthermore, MCs expressing disease-associated but not wild-type NLRP3 secreted IL-1beta and induced neutrophil migration and vascular leakage, the histological hallmarks of urticarial rash, when transplanted into mouse skin. Our findings implicate MCs as IL-1beta producers in the skin and mediators of histamine-independent urticaria through the NLRP3 inflammasome.The Journal of Experimental Medicine. 01/2009; 206(5):1037-46. -
Article: Role of the NOD2 genotype in the clinical phenotype of Blau syndrome and early-onset sarcoidosis.
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ABSTRACT: Blau syndrome and its sporadic counterpart, early-onset sarcoidosis (EOS), share a phenotype featuring the symptom triad of skin rash, arthritis, and uveitis. This systemic inflammatory granulomatosis is associated with mutations in the NOD2 gene. The aim of this study was to describe the clinical manifestations of Blau syndrome/EOS in Japanese patients and to determine whether the NOD2 genotype and its associated basal NF-kappaB activity predict the Blau syndrome/EOS clinical phenotype. Twenty Japanese patients with Blau syndrome/EOS and NOD2 mutations were recruited. Mutated NOD2 was categorized based on its basal NF-kappaB activity, which was defined as the ratio of NF-kappaB activity without a NOD2 ligand, muramyldipeptide, to NF-kappaB activity with muramyldipeptide. All 9 mutations, including E383G, a novel mutation that was identified in 20 patients with Blau syndrome/EOS, were detected in the centrally located NOD region and were associated with ligand-independent NF-kappaB activation. The median age of the patients at disease onset was 14 months, although in 2 patients in Blau syndrome families (with mutations R334W and E383G, respectively) the age at onset was 5 years or older. Most patients with Blau syndrome/EOS had the triad of skin, joint, and ocular symptoms, the onset of which was in this order. Clinical manifestations varied even among familial cases and patients with the same mutations. There was no clear relationship between the clinical phenotype and basal NF-kappaB activity due to mutated NOD2. However, when attention was focused on the 2 most frequent mutations, R334W and R334Q, R334W tended to cause more obvious visual impairment. NOD2 genotyping may help predict disease progression in patients with Blau syndrome/EOS.Arthritis & Rheumatism 01/2009; 60(1):242-50. · 7.87 Impact Factor -
Article: Chemical burn caused by glycidyl methacrylate.
Contact Dermatitis 12/2008; 59(5):316-7. · 3.51 Impact Factor
Top co-authors
Top Journals
Institutions
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2008–2010
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Chiba University
- Department of Dermatology
Chiba-shi, Chiba-ken, Japan
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2002–2007
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Kyoto University
- • Department of Pediatrics
- • Department of Dermatology
Kyoto, Kyoto-fu, Japan
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2004–2005
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Tokyo University of Agriculture and Technology
- • Division of Animal Life Science
- • Department of Veterinary Medicine
Tokyo, Tokyo-to, Japan
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