440 results on '"Takeji Nishikawa"'
Search Results
2. Compound heterozygosity for novel splice site mutations ofITGA6in lethal junctional epidermolysis bullosa with pyloric atresia
- Author
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Hiroshi Shimizu, Akira Ishiko, Masashi Akiyama, Junki Ogawa, Takuji Masunaga, and Takeji Nishikawa
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0301 basic medicine ,Integrin ,Dermatology ,Integrin alpha6 ,Biology ,Compound heterozygosity ,Junctional epidermolysis bullosa (medicine) ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Exon ,0302 clinical medicine ,medicine ,Humans ,Skin ,Splice site mutation ,integumentary system ,Infant, Newborn ,Genodermatosis ,General Medicine ,medicine.disease ,Molecular biology ,Phenotype ,030104 developmental biology ,Cancer research ,biology.protein ,Female ,Epidermolysis Bullosa, Junctional ,ITGA6 - Abstract
Junctional epidermolysis bullosa with pyloric atresia (PA-JEB) is a rare congenital bullous disease with gastrointestinal disturbance that has been associated with mutations in ITGA6 or ITGB4 encoding the α6 or β4 subunit of integrin, respectively. Only six ITGA6 mutations in PA-JEB have been reported while many ITGB4 mutations have been identified, and all the ITGA6 mutations were homozygous. Here, we report a case of lethal type PA-JEB, in which immunofluorescence showed the lack of both α6 and β4 integrins resulting from compound heterozygous splice site mutation in ITGA6, c.387G>T and c.2506-1G>C. Maternal c.387G>T induced the skipping of the entire exon 3 and both exons 3 and 4, resulting in premature termination codon and in-frame deletion, respectively. Paternal c.2506-1G>C caused the skipping of the exon 20 and resulted in in-frame deletion. As a reason why the present case showed lethal phenotype despite the in-frame deletion mutation, rapid degradation of neo-synthesized α6 protein and/or impaired transport of integrin were suggested from previous reports, and the lack of localization of integrin α6β4 to the epidermal basement membrane resulted in skin fragility. Our case expands the variety of integrin α6 mutations in PA-JEB.
- Published
- 2016
3. The onset risk of carcinoma in patients continuing tacrolimus topical treatment for oral lichen planus: a case report
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Kazuyuki Tsunoda, Hiromasa Kawana, Hisao Yagishita, Tomoya Soma, Taneaki Nakagawa, Hirofumi Shoji, Takeji Nishikawa, Mayu Morita, Masayori Shirakawa, and Seiji Asoda
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Male ,medicine.medical_specialty ,Administration, Topical ,Biopsy ,Mucocutaneous zone ,Case Report ,chemical and pharmacologic phenomena ,Topical treatment ,Disease ,Tacrolimus ,Surgical Flaps ,Diagnosis, Differential ,Lesion ,030207 dermatology & venereal diseases ,03 medical and health sciences ,0302 clinical medicine ,stomatognathic system ,Candidiasis, Oral ,Squamous cell carcinoma ,Carcinoma ,Humans ,Medicine ,In patient ,Diagnostic Errors ,skin and connective tissue diseases ,General Dentistry ,Dentistry(all) ,business.industry ,030206 dentistry ,Middle Aged ,medicine.disease ,Dermatology ,Lip ,stomatognathic diseases ,surgical procedures, operative ,Oral lichen planus ,Carcinoma, Squamous Cell ,Mouth Neoplasms ,medicine.symptom ,business ,Immunosuppressive Agents ,Lichen Planus, Oral - Abstract
Oral lichen planus is a chronic inflammatory mucocutaneous disease. Topical use of steroids and other immuno-modulating therapies have been tried for this intractable condition. Nowadays, tacrolimus ointment is used more commonly as a choice for treatment. However, a number of discussions have taken place after tacrolimus was reported to be carcinogenic. This report describes a patient who applied tacrolimus ointment to the lower lip after being diagnosed with oral lichen planus in 2008, and whose lesion developed squamous cell carcinoma in 2010. Since the relationship between tacrolimus and cancer development has been reported in only a few cases, including this case report, the clinician must be careful selecting tacrolimus as a second-line treatment for oral lichen planus.
- Published
- 2016
4. Acquired dermal melanocytosis of the face and extremities
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Akira Ishiko, Takeshi Ouchi, Ken Ishii, and Takeji Nishikawa
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Adult ,Skin Neoplasms ,Treatment outcome ,Pigmentations ,Dermatology ,Melanosis ,030207 dermatology & venereal diseases ,03 medical and health sciences ,Rare Diseases ,0302 clinical medicine ,Asian People ,Hyperpigmentation ,medicine ,Humans ,Pigmented lesion ,Zygomatic region ,business.industry ,Anatomy ,Hand ,Treatment Outcome ,medicine.anatomical_structure ,Face ,030220 oncology & carcinogenesis ,Forehead ,Melanocytes ,Extensor surface ,Female ,Laser Therapy ,business - Abstract
Summary Acquired dermal melanocytosis (ADM) is a relatively rare, but well-described disease among adolescent to middle-aged East Asian women, particularly those of Japanese and Chinese descent. Clinically, ADM manifests as multiple punctate and greyish-brown pigmented areas 1–3 mm in diameter occurring on both sides of the forehead and zygomatic region. The subtype of ADM affecting the face and extremities is extremely rare even in East Asian women. We describe three patients with ADM of the face and extremities (ADMFE) and their characteristic clinical features. All patients were Japanese women, and showed multiple greyish-brown pigmentations on both nasal wings and on the extensor surface of the extremities. We found that the clinical features were strikingly uniform, and that a pigmented lesion on the nasal wing can be an important clue to distinguish ADMFE from other hyperpigmented diseases of the hands and feet. One patient was treated with Q-switched ruby laser with excellent outcome. Increased awareness of ADMFE can lead to earlier diagnosis and potential treatment.
- Published
- 2016
5. Superficial mycosis
- Author
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Yasuki, Hata and Takeji, Nishikawa
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Diagnosis, Differential ,Infectious Diseases ,Dermatomycoses ,Humans ,Microbiology ,Skin - Published
- 2015
6. Dermatomycoses and Medically Important Fungi That Are Necessary Subjects of Study for Dermatology Specialists -A Personal Experience
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Takeji Nishikawa
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medicine.medical_specialty ,Antifungal Agents ,Paracoccidioidomycosis ,business.industry ,MEDLINE ,Dermatology ,Disease ,Dermatomycosis ,medicine.disease ,Microbiology ,Infectious Diseases ,Basic research ,Physicians ,Host-Pathogen Interactions ,medicine ,Dermatomycoses ,Humans ,Medicine ,business - Abstract
Among the numerous skin diseases, dermatomycosis is the one caused by fungus (parasite) infecting the skin (host) . Once diagnosis is made, dermatomycosis can be cured with the use of appropriate anti-fungal drugs. Therefore, it is a much more easily treatable disease compareds with intractable skin diseases. From his own experience, the author shows that dermatomycoses are good subspecialties to deal with because many of them are controllable. At the same time, the author points out that basic research on medically important fungi needs to be done as collaborative studies with basic scientists and dermatology specialists. This brief review covers several topics including diagnostics of medical mycoses, imported medical mycoses, tinea, and cutaneous deep mycoses.
- Published
- 2015
7. Unique immunobullous disease in a child with a predominantly IgA response to three desmosomal proteins
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S. Mendelsohn, Fenella Wojnarowska, Takeji Nishikawa, Takashi Hashimoto, C. Gooptu, and Masayuki Amagai
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Pathology ,medicine.medical_specialty ,Dermatology ,Desmoglein ,Autoimmune Diseases ,Dermis ,Desmosome ,Medicine ,Humans ,education ,Child ,Autoantibodies ,Desmocollins ,education.field_of_study ,biology ,medicine.diagnostic_test ,integumentary system ,Desmoglein 3 ,Skin Diseases, Vesiculobullous ,business.industry ,Desmoplakin ,Desmosomes ,medicine.disease ,Immunoglobulin A ,Cytoskeletal Proteins ,Paraneoplastic pemphigus ,medicine.anatomical_structure ,Desmoplakins ,Skin biopsy ,Immunology ,biology.protein ,Female ,Desmocollin ,business ,Desmogleins ,Cell Adhesion Molecules - Abstract
We report the case of a 15-year-old girl who presented at 11 years of age with an interesting, acquired and, to our knowledge, unique blistering disease. It involved both skin and mucous membranes with extensive oral and periungual lesions, clinically resembling paraneoplastic pemphigus. Skin biopsy showed an inflammatory cell infiltrate in the upper dermis with numerous leucocytoclastic nuclear fragments, neutrophilic papillary microabscesses and a small subepidermal bulla. Direct and indirect immunofluorescence studies showed marked intercellular staining with IgA and less prominent staining with IgG. Granular deposition of IgA and, to a lesser extent IgG and C3, was also seen along the basement membrane zone. Immunoblotting and enzyme-linked immunosorbent assay studies showed both IgG and IgA antibodies to desmocollin, desmoglein 3 and desmoplakin. However, despite extensive investigation, no underlying neoplasm was found. Treatment with dapsone and sulphapyridine proved ineffective but methylprednisolone and azathioprine have reduced the blistering. We believe that this patient is unique for her combination of IgA and IgG antibodies to desmoplakin, desmocollin and desmoglein 3, although further studies may provide further clarification.
- Published
- 2016
8. Transgenic rescue of desmoglein 3 null mice with desmoglein 1 to develop a syngeneic mouse model for pemphigus vulgaris
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Masayuki Amagai, Tsuyoshi Hata, Takeji Nishikawa, Kouji Shimoda, Taketo Yamada, Shigeo Koyasu, Koji Nishifuji, and Takashi Sasaki
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Adoptive cell transfer ,medicine.medical_specialty ,Mice, 129 Strain ,Time Factors ,Genotype ,Transgene ,Autoimmunity ,Mice, Transgenic ,Dermatology ,Biology ,Biochemistry ,Mice ,Internal medicine ,Weight Loss ,Immune Tolerance ,Splenocyte ,medicine ,Animals ,Promoter Regions, Genetic ,education ,Molecular Biology ,Mice, Knockout ,education.field_of_study ,Desmoglein 3 ,Desmoglein 1 ,Acantholysis ,Pemphigus vulgaris ,Mouth Mucosa ,medicine.disease ,Adoptive Transfer ,Molecular biology ,Lymphocyte Subsets ,DNA-Binding Proteins ,Mice, Inbred C57BL ,Keratin 5 ,Disease Models, Animal ,Phenotype ,medicine.anatomical_structure ,Endocrinology ,Keratin-5 ,Epidermis ,Keratinocyte ,Hair Follicle ,Pemphigus - Abstract
Background An active disease mouse model of pemphigus vulgaris (PV) was developed using the adoptive transfer of splenocytes from Dsg3 −/− mice with a mixed C57BL/6J (B6) and 129/Sv genetic background into B6-Rag2 −/− mice. Further immunological investigation is needed to resolve the genetic mismatch between host and recipient mice. The B6-Dsg3 −/− mice did not grow old enough to provide splenocytes, probably due to severe oral erosions, with resulting inhibition of food intake. Objective To rescue the B6-Dsg3 −/− mice and to produce syngeneic PV model mice. Methods Transgenic expression of mouse Dsg1 was attempted to compensate for the genetic loss of Dsg3 using the keratin 5 promoter. We evaluated the compensatory ability of Dsg1 in vivo by comparing Dsg1 wt/wt , Dsg1 tg/wt , and Dsg1 tg/tg mice. We generated a PV model via the adoptive transfer of B6-Dsg1 tg/tg Dsg3 −/− splenocytes to B6-Rag2 −/− mice. Results Dsg1 tg/tg and Dsg1 tg/wt mice expressed ectopic Dsg1 on keratinocyte cell surfaces in the lower layers of the epidermis, oral epithelium, and telogen hair follicles. Ectopic Dsg1 blocked the pathogenic effects of AK23 anti-Dsg3 mAb, and improved the body weight loss, telogen hair loss, and survival rate dose-dependently. While the B6-Dsg1 wt/wt Dsg3 −/− mice died by week 2, over 80% of the B6-Dsg1 tg/tg Dsg3 −/− mice survived at week 6. Furthermore, the syngeneic PV model mice showed the characteristic phenotype, including stable anti-Dsg3 antibody production and suprabasilar acantholysis on histology. Conclusion Transgenic expression of Dsg1 rescued the severe B6-Dsg3 −/− phenotype and provided a syngeneic mouse model of PV, which may be a valuable tool for clarifying immunological mechanisms in autoimmunity and tolerance of Dsg3.
- Published
- 2011
9. Antigen-independent development of Foxp3+ regulatory T cells suppressing autoantibody production in experimental pemphigus vulgaris
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Satoshi Matsuda, Masayuki Amagai, Naoko Wada, Yujiro Takae, Takeji Nishikawa, Shigeo Koyasu, and Tomoaki Yokoyama
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Adoptive cell transfer ,Immunology ,chemical and pharmacologic phenomena ,Major histocompatibility complex ,T-Lymphocytes, Regulatory ,Immunoglobulin G ,Mice ,Antigen ,Animals ,Immunology and Allergy ,IL-2 receptor ,Antigens ,Autoantibodies ,Mice, Inbred BALB C ,Desmoglein 3 ,biology ,T-cell receptor ,Autoantibody ,FOXP3 ,Forkhead Transcription Factors ,hemic and immune systems ,General Medicine ,Mice, Inbred C57BL ,Disease Models, Animal ,biology.protein ,Pemphigus - Abstract
The CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) play suppressive roles in various types of autoimmunity. It has been reported that Tregs develop in the thymus after high-affinity interaction of their TCR with self-peptide/MHC ligands mostly utilizing TCR-transgenic system. In this study, we examined whether the specific antigen is involved in the development of polyclonal Tregs in pemphigus vulgaris (PV), an autoimmune blistering disease caused by anti-desmoglein 3 (Dsg3) IgG antibodies, as a model system. Adoptive transfer of splenocytes of Dsg3(-)(/-) mice immunized with recombinant mouse Dsg3 to Rag2(-)(/-) recipient mice expressing Dsg3 resulted in the stable production of anti-Dsg3 IgG and the development of PV phenotypes. We show here that Tregs control anti-Dsg3 antibody production in PV model mice: the adoptive transfer of Tregs and the depletion of endogenous Tregs suppressed and augmented, respectively, the anti-Dsg3 antibody production. To examine whether the endogenous expression of Dsg3 is involved in the generation of these PV-relevant Tregs, we compared the potential of wild-type Tregs with that of Tregs from Dsg3(-)(/-) mice. Polyclonal Tregs from Dsg3(-)(/-) mice were more potent than that of wild-type mice, in both adoptive transfer and Treg-depletion experiments, while suppressive activities against IgG production against an irrelevant antigen were similar between Tregs from wild-type and Dsg3(-)(/-) mice. Our observation implies that Tregs capable of suppressing T(h) cells that drive autoantibody production can develop in the absence of the target antigen.
- Published
- 2011
10. Anti-desmoglein IgG autoantibodies in patients with pemphigus in remission
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Takeji Nishikawa, Masayuki Amagai, EJ Kwon, and Jun Yamagami
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Male ,business.industry ,Prednisolone ,Pemphigus vulgaris ,Autoantibody ,Enzyme-Linked Immunosorbent Assay ,Dermatology ,medicine.disease ,Sensitivity and Specificity ,Desmoglein ,Highly sensitive ,Pemphigus ,Infectious Diseases ,Immunoglobulin G ,Immunology ,Active disease ,medicine ,Humans ,Female ,In patient ,Desmogleins ,business ,Pemphigus foliaceus ,Autoantibodies - Abstract
Desmoglein (Dsg) enzyme-linked immunosorbent assay (ELISA) is a highly sensitive and specific method to detect anti-Dsg3 and anti-Dsg1 IgG autoantibodies in pemphigus vulgaris (PV) and pemphigus foliaceus (PF), respectively. Whereas ELISA index values fluctuate in parallel with disease activity, ELISA positivity during clinical remission has been observed.To determine the prevalence of positive Dsg ELISA index values during clinical remission. To ascertain how positive Dsg ELISA scores during remission compare with those during active disease.Dsg ELISA was performed on serum samples of PV and PF patients taken during remission (lesion-freeor= 3 months onor= 15 mg oror= 5 mg/day prednisolone) and active disease. We used a modified ELISA protocol with optimal serum dilutions in sera with very high initial index values, as we previously described.When remission was defined as no eruptionor= 3 months withor= 15 mg/day prednisolone, 20 of 43 PV patients (46.5%) and 4 of 12 PF patients (33.3%) showed Dsg3 and Dsg1 ELISA positivity, respectively. Withor= 5 mg/day, 6 of 17 PV (35.3%) and 1 of 6 PF patients (16.7%) showed Dsg3 and Dsg1 ELISA positivity, respectively. The index value of each ELISA-positive remission serum was consistently lower than that of its corresponding active disease serum. We observed consistent correlation between ELISA index values and indirect immunofluorescence titres.Circulating anti-Dsg IgG autoantibodies are found in a considerable percentage of pemphigus patients in remission, who have high levels of antibody production during active stages.
- Published
- 2008
11. Novel System Evaluating In Vivo Pathogenicity of Desmoglein 3-Reactive T Cell Clones Using Murine Pemphigus Vulgaris
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Yutaka Kawakami, Masayuki Amagai, Yoshiko Fujii, Hayato Takahashi, Takeji Nishikawa, and Masataka Kuwana
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CD4-Positive T-Lymphocytes ,Adoptive cell transfer ,T-Lymphocytes ,T cell ,Immunology ,Receptors, Cell Surface ,Biology ,Cell Line ,Interferon-gamma ,Mice ,In vivo ,medicine ,Animals ,Immunology and Allergy ,education ,Autoantibodies ,Mice, Knockout ,B-Lymphocytes ,education.field_of_study ,Desmoglein 3 ,Pemphigus vulgaris ,Autoantibody ,medicine.disease ,Adoptive Transfer ,Molecular biology ,Recombinant Proteins ,In vitro ,Interleukin-10 ,medicine.anatomical_structure ,Cell culture ,Interleukin-4 ,Pemphigus - Abstract
Autoreactive T cells are thought to be involved in the pathogenesis of autoimmune diseases, but evidence for their direct pathogenicity is almost lacking. Herein we established a unique system for evaluating the in vivo pathogenicity of desmoglein 3 (Dsg3)-reactive T cells at a clonal level in a mouse model for pemphigus vulgaris (PV), an autoimmune blistering disease induced by anti-Dsg3 autoantibodies. Dsg3-reactive CD4+ T cell lines generated in vitro were adoptively transferred into Rag-2−/− mice with primed B cells derived from Dsg3-immunized Dsg3−/− mice. Seven of 20 T cell lines induced IgG anti-Dsg3 Ab production and acantholytic blister, a typical disease phenotype, in recipient mice. Comparison of the characteristics between pathogenic and nonpathogenic Dsg3-reactive T cell lines led to the identification of IL-4 and IL-10 as potential factors associated with pathogenicity. Further in vitro analysis showed that IL-4, but not IL-10, promoted IgG anti-Dsg3 Ab production by primed B cells. Additionally, adenoviral expression of soluble IL-4Rα in vivo suppressed IgG anti-Dsg3 Ab production and the PV phenotype, indicating a pathogenic role of IL-4. This strategy is useful for evaluating the effector function of autoreactive T cells involved in the pathogenesis of various autoimmune diseases.
- Published
- 2008
12. Abnormal keratin expression in circumscribed palmar hypokeratosis
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Atsushi Fujimoto, Mitsuo Sakamoto, Kaori Kameyama, Masayuki Amagai, Akira Ishiko, Yoshimi Benno, Takeji Nishikawa, and Itaru Dekio
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Pathology ,medicine.medical_specialty ,Keratosis ,Keratin-2E ,Hand Dermatoses ,Dermatology ,Biology ,Desquamation ,RNA, Ribosomal, 16S ,Keratin ,medicine ,Humans ,Papillomaviridae ,Aged ,chemistry.chemical_classification ,Corneocyte ,Bacteria ,Staining and Labeling ,integumentary system ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Dyskeratosis ,Staining ,Microscopy, Electron ,chemistry ,DNA, Viral ,Keratins ,Female ,Keratin-2 ,medicine.symptom ,biology.gene ,Polymorphism, Restriction Fragment Length - Abstract
Background Circumscribed palmar or plantar hypokeratosis (CPH) is a rare skin disorder only recently described. Objective To determine the diagnostic features and to provide insight into the pathogenesis of CPH, with analysis of two new Japanese cases. Methods Dermoscopy, immunohistochemistry, electron microscopy, polymerase chain reaction amplification for human papillomavirus (HPV) DNA and 16S microbial rRNA gene profiling were conducted. Results Dermoscopy showed characteristic features using both dry and jelly immersion observation; step-like desquamation and a homogeneous erythema with regularly distributed whitish spots. Immunohistochemistry revealed strong staining with anti-pankeratin antibody (AE1+AE3) and anti-keratin 16 antibody, and decreased expression of keratin 2e. EM revealed a breakage of the corneocytes within their cytoplasm, but structures for cell attachment were intact. HPV and lesion-specific bacteria were not detected. Limitations The number of cases analyzed was two. Conclusion Hyperproliferative epidermal state along with enhanced corneocyte fragility may account for the unique features in CPH.
- Published
- 2007
13. Nomenclature for diseases with IgA antikeratinocyte cell surface autoantibodies
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Takeji Nishikawa and Takashi Hashimoto
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Male ,business.industry ,Cell ,Autoantibody ,Dermatology ,Immunoglobulin A ,medicine.anatomical_structure ,Immunology ,medicine ,Humans ,Female ,business ,Nomenclature ,Pemphigus - Published
- 2015
14. Dose-finding comparative study of 2 weeks of luliconazole cream treatment for tinea pedis - comparison between three groups (1%, 0.5%, 0.1%) by a multi-center randomised double-blind study
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Hideyo Yamaguchi, Iwao Takiuchi, Nobuhiko Higashi, Saburo Kagawa, Hisashi Takahashi, Hideoki Ogawa, Takeji Nishikawa, Shinichi Watanabe, and Katsutaro Nishimoto
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medicine.medical_specialty ,business.industry ,Incidence (epidemiology) ,Luliconazole ,Topical treatment ,Dermatology ,General Medicine ,Group B ,Double blind study ,Dose finding ,chemistry.chemical_compound ,Exact test ,Infectious Diseases ,chemistry ,Medicine ,business ,Adverse effect - Abstract
Summary Luliconazole is a newly developed imidazolyl antifungal agent. A randomised double-blind comparative study was designed to assess the efficacy and safety of 1% luliconazole cream (group A), 0.5% cream (group B) and 0.1% cream (group C), in tinea pedis (interdigital type and plantar type), when used once daily for 2 weeks. Follow-ups were performed at 4 weeks after the end of topical treatment. A total of 241 patients were enrolled and 213 patients were evaluated for efficacy. Rates of improvement of skin lesions in the A, B and C groups assessed at week 4 were 90.5%, 91.0% and 95.8%, respectively. Rates of mycological cure (negative result of microscopy) in the A, B and C groups assessed at week 4 were 79.7%, 76.1%, 72.2% and at week 6 (at 4 weeks after the end of topical treatment) were 87.7%, 94%, 88.9%, respectively. For the mycological effect on tinea pedis of the interdigital type at 2 weeks, the negative conversion of fungi showed a concentration-dependent relationship and indicated a difference in tendency statistically 81.1% (1%– treatment), 62.9% (0.5%– treatment), 58.3% (0.1%– treatment) (Fisher's exact test, P = 0.079) and there was a trend between three groups by Cochran–Mantel–Haenszel method (P = 0.038). The incidence of adverse events in which a causal relationship to this drug could not be ruled out was low (2.6%). All of the adverse events were mild in severity and insignificant clinically.
- Published
- 2006
15. Unusually located lymphocutaneous nocardiosis caused by Nocardia brasiliensis
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Tomoo Fukuda, Shunichi Miyakawa, Takeji Nishikawa, W. Naka, Yuzuru Mikami, and H. Niizeki
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Male ,Pathology ,medicine.medical_specialty ,Nocardia Infections ,Dermatology ,Nocardia ,Japan ,Skin abrasions ,medicine ,Humans ,Lymphatic Diseases ,Aged ,Aged, 80 and over ,integumentary system ,biology ,Nocardia brasiliensis ,business.industry ,Nocardiosis ,Skin Diseases, Bacterial ,Minocycline ,medicine.disease ,biology.organism_classification ,Nocardiaceae ,Actinomycosis ,business ,Skin lesion ,medicine.drug - Abstract
We report a patient with primary lymphocutaneous Nocardia brasiliensis infection affecting the face and left arm. The mode of infection was via skin abrasions which occurred 2 weeks prior to the development of the skin lesions. Treatment with intravenous minocycline for 4 weeks resulted in a cure. We also review 12 previously reported Japanese cases of lymphocutaneous nocardiosis.
- Published
- 2006
16. Two patients with unusual skin lesions and circulating antikeratinocyte cell surface antibodies: detection of antibodies to the intracellular domain of the pemphigus foliaceus antigen (desmoglein) by studies using fusion proteins
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Takashi Hashimoto, Takeji Nishikawa, and A. Ide
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Keratinocytes ,Male ,Recombinant Fusion Proteins ,Dermatology ,Skin Diseases ,Desmoglein ,Antigen ,Desmosome ,medicine ,Humans ,Aged ,Autoantibodies ,integumentary system ,biology ,Autoantibody ,Molecular biology ,Fusion protein ,Cytoskeletal Proteins ,medicine.anatomical_structure ,Desmoplakins ,Desmoglein 1 ,Immunoglobulin G ,Immunology ,biology.protein ,Female ,Antibody ,Desmogleins ,Keratinocyte - Abstract
We report two patients with unusual skin lesions, who had antikeratinocyte cell surface IgG autoantibodies in their sera. Immunoblot analysis of both a human epidermal extract and a bovine desmosome preparation revealed that the sera of both patients reacted exclusively with the 160-kDa pemphigus foliaceus antigen (desmoglein). We further investigated the antigen molecule using bacterial fusion proteins produced by using bovine desmoglein cDNA, and found that both the sera reacted strongly and exclusively with the intracellular domain of the desmoglein. These results suggest that production of antidesmoglein autoantibodies in the present cases may be an epiphenomenon associated with damage to the keratinocyte cell membrane.
- Published
- 2006
17. A comparative clinical study between 2 weeks of luliconazole 1% cream treatment and 4 weeks of bifonazole 1% cream treatment for tinea pedis
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Hideoki Ogawa, Saburo Kagawa, Nobuhiko Higashi, Katsutaro Nishimoto, Takeji Nishikawa, Hisashi Takahashi, Shinichi Watanabe, Iwao Takiuchi, and Hideyo Yamaguchi
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Adult ,Male ,medicine.medical_specialty ,Antifungal Agents ,Bifonazole 1% cream ,Luliconazole ,Bifonazole ,Dermatology ,Placebo ,Drug Administration Schedule ,law.invention ,Ointments ,Clinical study ,chemistry.chemical_compound ,Trichophyton ,Randomized controlled trial ,law ,medicine ,Humans ,Aged ,Group study ,business.industry ,Imidazoles ,Tinea Pedis ,General Medicine ,Middle Aged ,Treatment Outcome ,Infectious Diseases ,chemistry ,Female ,business ,Skin lesion ,medicine.drug - Abstract
The aim of the study was to compare the efficacy and safety of luliconazole 1% cream and bifonazole 1% cream as applied in the treatment of tinea pedis (interdigital-type and plantar-type). A multi-clinic, randomised single-blind, parallel group study with 34 hospitals and 11 clinics formed the study design. Five hundred and eleven patients with mycologically confirmed tinea pedis were included. Of the 489 evaluable patients, 247 were randomised to luliconazole, and 242 to bifonazole. Luliconazole 1% cream applied once a day for 2 weeks, followed by a placebo cream for 2 weeks, thereafter. Bifonazole 1% cream applied once a day for 4 weeks. Mycological effect (negative result on microscopy) and improvement of skin lesions were measured at weeks 1, 2, 3 and 4. Safety frequency and severity of adverse reactions were also measured. The improvement of skin lesions after 4 weeks was comparably good with rates of 91.5% vs. 91.7% (luliconazole vs. bifonazole). The mycological effect was characterised by high negative rates of 76.1% vs. 75.9% (luliconazole vs. bifonazole). The progression of tinea-related signs and symptom scores differed insignificantly between evaluated luliconazole and bifonazole treatment groups comprising a total of 500 patients. Both substances appeared to be comparably safe and well-tolerated.
- Published
- 2006
18. Tolerance Induction by the Blockade of CD40/CD154 Interaction in Pemphigus Vulgaris Mouse Model
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T. Iwasaki, Masayuki Amagai, Mari Kinoshita, Miyo Aoki-Ota, Takayuki Ota, Takeji Nishikawa, Shigeo Koyasu, Sigeru Tanaka, and Kazuyuki Tsunoda
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Adoptive cell transfer ,medicine.drug_class ,CD40 Ligand ,chemical and pharmacologic phenomena ,Dermatology ,Biology ,Monoclonal antibody ,Biochemistry ,Immune tolerance ,Mice ,Immune Tolerance ,medicine ,Animals ,CD40 Antigens ,education ,Molecular Biology ,Immunosuppression Therapy ,education.field_of_study ,Desmoglein 3 ,Pemphigus vulgaris ,Autoantibody ,Antibodies, Monoclonal ,hemic and immune systems ,Cell Biology ,medicine.disease ,Mice, Mutant Strains ,Disease Models, Animal ,Tolerance induction ,Immunoglobulin G ,Immunology ,biology.protein ,Antibody ,Pemphigus - Abstract
Pemphigus vulgaris (PV) is an autoimmune blistering disease caused by IgG autoantibodies against desmoglein 3 (Dsg3). We have recently developed an active disease mouse model for PV by adoptive transfer of splenocytes from Dsg3(-/-) mice. The purpose of this study was to determine the role of CD40/CD154 interaction in the pathogenic antibody production and development of the disease in PV model mice. When anti-CD154 monoclonal antibody (mAb) was administered to recipient mice prior to adoptive transfer, anti-CD154 mAb almost completely blocked the anti-Dsg3 IgG production and prevented blister formation. The blockade of CD40/CD154 interaction induced tolerance against Dsg3 as the suppression of antibody production was observed through day 70, and it was maintained even after challenge by immunization with recombinant mouse Dsg3 or by adoptive transfer of immunized Dsg3(-/-) splenocytes. Furthermore, the tolerance to Dsg3 was transferable because cotransfer of splenocytes from anti-CD154 mAb-treated mice and naïve Dsg3(-/-) splenocytes significantly suppressed anti-Dsg3 IgG production in recipient mice. In contrast, when anti-CD154 mAb was injected after the mice had developed the PV phenotype, no significant suppression of the production of anti-Dsg3 IgG was observed. These findings indicate that the CD40/CD154 interaction is essential for the induction of pathogenic anti-Dsg3 IgG antibodies and that antigen-specific immune-regulatory cells induced by anti-CD154 mAb would hold a therapeutic option for autoimmune diseases.
- Published
- 2006
19. In Vivo Ultrastructural Localization of the Desmoglein 3 Adhesive Interface to the Desmosome Mid-Line
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Masayuki Amagai, Akira Ishiko, Hitoshi Saito, Takeji Nishikawa, Atsushi Shimizu, Hiroshi Oka, Takayuki Ota, and Kazuyuki Tsunoda
- Subjects
Pathology ,medicine.medical_specialty ,pemphigus vulgaris ,Immunoelectron microscopy ,Dermatology ,Biology ,Biochemistry ,Desmoglein ,Mice ,immunoelectron microscopy ,Desmosome ,Cell Adhesion ,medicine ,Animals ,Microscopy, Immunoelectron ,Cell adhesion ,education ,Molecular Biology ,education.field_of_study ,Desmoglein 3 ,Cell adhesion molecule ,Cadherin ,Pemphigus vulgaris ,Antibodies, Monoclonal ,Desmosomes ,Cell Biology ,medicine.disease ,adhesion molecule ,Cell biology ,Cytoskeletal Proteins ,cadherin ,medicine.anatomical_structure ,Desmoplakins ,Desmogleins - Abstract
Desmoglein (Dsg) is a cadherin cell–cell adhesion molecule located in desmosomes and its precise mechanism for cell–cell adhesion still remains to be elucidated. Opposing cadherin molecules may adhere to the N-terminal EC1 domains, or the entire length of the extracellular (EC) domains may overlap. To solve this controversy, we performed immunoelectron microscopy to map the Dsg3 epitopes in desmosomes. Three different hybridoma cell lines producing anti-Dsg3 monoclonal antibodies (mAb) were intraperitoneally injected into immunodeficient mice and the precise ultrastructural location of bound IgG between the mucosal epithelial cells in vivo was statistically measured and analyzed. The binding site of the AK23 mAb that recognizes the N-terminal EC1 domain was localized to the electron-dense mid-line of desmosomes. The binding sites of AK7 and AK18, which recognize the C-terminal membrane proximal and middle portions of the EC domains, were localized to the desmosomal region proximal to the membrane and the region between the plasma membrane and the dense mid-line, respectively. These results indicate that the N-terminal regions of Dsg3 from opposing cells interact at the dense mid-line of desmosomes where EC1 overlaps.
- Published
- 2005
20. Cutaneous type pemphigus vulgaris: A rare clinical phenotype of pemphigus
- Author
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Kazue Yoshida, Yujiro Takae, Hiroshi Oka, Hitoshi Saito, Akiko Tanikawa, Masayuki Amagai, and Takeji Nishikawa
- Subjects
Male ,Autoimmune disease ,Pathology ,medicine.medical_specialty ,integumentary system ,business.industry ,Acantholysis ,Pemphigus vulgaris ,Mucocutaneous zone ,Autoantibody ,Dermatology ,Middle Aged ,medicine.disease ,Desmoglein ,Pemphigus ,Immunoglobulin G ,medicine ,Humans ,Female ,skin and connective tissue diseases ,business ,Pemphigus foliaceus ,Autoantibodies - Abstract
Pemphigus is an autoimmune blistering disease of the skin, mucous membranes, or both. There are two main categories of pemphigus: pemphigus foliaceus (PF) and pemphigus vulgaris (PV). PV is further subdivided into mucosal dominant and mucocutaneous types, according to the extent of cutaneous lesions. These classes of pemphigus have distinct histopathologic and serologic findings, with most cases falling into these subtypes. We report 4 cases that clinically showed blisters and erosions in the skin only, without mucosal involvement. Histologic examination of cutaneous lesions demonstrated suprabasilar acantholysis, a typical finding for PV. These patients had predominant anti-desmoglein 1 (Dsg1) IgG autoantibodies as well as anti-Dsg3 IgG autoantibodies, as determined by enzyme-linked immunosorbent assay. The desmoglein compensation theory posits that this rare phenotype can be produced by pathogenically weak anti-Dsg3 IgG in the presence of potent anti-Dsg1 IgG autoantibodies. Thus, cutaneous type PV without apparent mucosal involvement is observed as a rare clinical and histologic expression of pemphigus. This expression can be a transient phenotype that may develop from, or evolve into, other subtypes of pemphigus.
- Published
- 2005
21. Skin diseases described in Japan 2004. In Japan beschriebene Dermatosen 2004
- Author
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Yuichi Teraki and Takeji Nishikawa
- Subjects
Prurigo pigmentosa ,Pediatrics ,medicine.medical_specialty ,integumentary system ,business.industry ,Folliculitis ,Dermatology ,Eosinophilic pustular folliculitis ,medicine.disease ,Prurigo ,Medicine ,Kawasaki disease ,Kimura Disease ,medicine.symptom ,business ,Angiolymphoid hyperplasia with eosinophilia ,Hypopigmentation - Abstract
During the last century of modern dermatology, more than 30 skin diseases have been described first by physicians from Japan. Many of those conditions were disorders of pigmentation and keratinization, which are quite common in Oriental patients. Since the late 1940s, a number of skin diseases first reported in Japan have gained attention internationally among them being Kimura disease, hypomelanosis of Ito, Kawasaki disease, adult T-cell leukemia/ lymphoma, eosinophilic pustular folliculitis, prurigo pigmentosa, and Ofuji's papuloerythroderma. In this article, we review skin diseases that were first established as distinct entities in Japan, in order to familiarize readers of the Western literature with these conditions.
- Published
- 2005
22. From the Description Dermatology to the Pathomechanism Orientated Dermatology: Messages from Cases Experienced in the Keio Dermatology Department
- Author
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Takeji Nishikawa
- Subjects
medicine.medical_specialty ,business.industry ,Dermatology department ,Medicine ,Dermatology ,business - Abstract
日本で記載された皮膚疾患,皮膚真菌症,水疱症および膠原病のうちから,印象に残っている症例をその後の経過を含め,あらためて紹介し,それらが皮膚科学にいかなる貢献をしたかを著者の観点からまとめた。好酸球性膿疱性毛包炎(太藤)ならびに色素性痒疹(長島)についてはこれらの疾患が著者の時代における日本発の国際的な皮膚疾患であり,国際レベルでの認知度を含め紹介した。ついで異なった黒色真菌が永い年月を隔てて同一患者に感染したという稀有な症例を取り上げ,さらに分離菌Exophiala jeanselmeiが黒色真菌研究にもたらした成果をあげた。IgAが表皮細胞間に沈着する疾患のなかからは,粘膜疹を認めた小児例を取り上げ,その自己抗体の性状分析が病型分類にもつながった経過を紹介し病名の適性について言及した。最後に環状紅斑を主徴とするシェーグレン症候群とエリテマトーデス合併例の中から,自己抗体と環状紅斑について焦点を当てて考察した。今後も臨床から得られた知見をもとに,病態解明,診断あるいは治療につながる研究が行われ,臨床に還元される成果が得られんことを期待したい。
- Published
- 2005
23. Parallel fluctuation of anti-desmoglein 3 and anti-BP180 autoantibody titres in a patient with bullous pemphigoid
- Author
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Hidemi Anzai, Masayuki Amagai, Akiko Tanikawa, Y. Suzuki, Hayato Takahashi, and Takeji Nishikawa
- Subjects
Pathology ,medicine.medical_specialty ,Pemphigoid ,Dermatology ,medicine.disease_cause ,Autoantigens ,Autoimmunity ,Antigen ,Pemphigoid, Bullous ,medicine ,Humans ,skin and connective tissue diseases ,education ,Aged ,Autoantibodies ,Autoimmune disease ,education.field_of_study ,Desmoglein 3 ,integumentary system ,medicine.diagnostic_test ,business.industry ,Autoantibody ,Non-Fibrillar Collagens ,Cadherins ,medicine.disease ,Immunoglobulin G ,Skin biopsy ,Immunology ,Female ,Bullous pemphigoid ,business - Abstract
We report a 73-year-old Japanese female who developed IgG autoantibodies against BP180 as well as desmoglein 3 (Dsg3). She showed tense blisters on the extremities without apparent mucosal involvement and a skin biopsy indicated subepidermal blisters with eosinophilic spongiosis. Her clinical and histologic features indicated the diagnosis of bullous pemphigoid while anti-Dsg3 IgG might not show an apparent pathogenic effect. Interestingly, titres of anti-Dsg3 IgG fluctuated in parallel with those of anti-BP180 IgG throughout the course with two flares. Although the exact mechanism for autoantibody production is still unknown, the close link in the production of IgG autoantibodies against two independent skin antigens suggests a shared immunoregulatory mechanism against cutaneous autoantigens.
- Published
- 2004
24. Does the position of the premature termination codon in COL7A1 correlate with the clinical severity in recessive dystrophic epidermolysis bullosa?
- Author
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Takeji Nishikawa, Akira Ishiko, Takayuki Ota, and Takuji Masunaga
- Subjects
Male ,Collagen Type VII ,DNA, Complementary ,DNA Mutational Analysis ,Dermatology ,Biology ,Compound heterozygosity ,medicine.disease_cause ,Biochemistry ,Frameshift mutation ,Exon ,Anchoring fibrils ,Genotype ,medicine ,Humans ,Molecular Biology ,Gene ,Genetics ,Mutation ,Base Sequence ,Infant ,Phenotype ,Epidermolysis Bullosa Dystrophica ,Pedigree ,Codon, Nonsense ,Female - Abstract
Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited skin disease caused by mutations in the gene encoding type VII collagen (COL7A1). The mutations are highly variable and this greatly complicates the study of the genotype-phenotype relationships. To date, three recurrent mutations, specific to Japanese RDEB patients have been reported. By comparing the phenotypes of RDEB patients with different recurrent mutations, the upstream positions of the premature termination codons (PTCs) showed strong correlation with the RDEB clinical disease severity. However, such correlations have not been supported by patients with mutations that were different from these recurrent Japanese patients mutations. In this study, we report a case of RDEB with a very mild clinical phenotype, who was a compound heterozygote harbouring both a recurrent Japanese mutation and a novel deletion mutation resulting in a more upstream PTC. The patient and his mother were shown to have a recurrent donor splice site mutation within intron 81 (6573 + 1G > C), a recurrent Japanese mutation that activates a cryptic donor splicing site and results in a downstream PTC. The patient and his father shared a single-nucleotide deletion within exon 64 (5504delA), which causes a downstream frame shift in five amino acids before creating a PTC. Occurrence of the PTCs in mRNA was confirmed by reverse transcription-polymerase chain reaction (RT)-PCR. The patient's skin showed reduced immunofluorescence staining for COL7A1 and reduced number of abnormal or short anchoring fibrils by electron microscopy. Although the position of the mutation 5504delA PTC was located upstream of the previous mutations reported in combination with the 6573 + 1G > C mutation, the two mutations together give an apparently milder clinical phenotype. Therefore, genotype-phenotype relationships in RDEB cannot be explained purely by the position of PTC.
- Published
- 2004
25. Linear discriminant analysis of dermoscopic parameters for the differentiation of early melanomas from Clark naevi
- Author
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Takeji Nishikawa, Seiichiro Kobayashi, Giuseppe Argenziano, Masaru Tanaka, Hiroshi Oka, and H. Peter Soyer
- Subjects
Cancer Research ,medicine.medical_specialty ,Pathology ,Skin Neoplasms ,genetic structures ,Melanoma in situ ,Dermatology ,Diagnosis, Differential ,Breslow Thickness ,medicine ,Humans ,Nevus ,skin and connective tissue diseases ,Melanoma ,neoplasms ,Melanoma diagnosis ,Microscopy ,Nevus, Pigmented ,business.industry ,Stepwise discriminant analysis ,Discriminant Analysis ,food and beverages ,medicine.disease ,Linear discriminant analysis ,Oncology ,Multivariate Analysis ,Pigmented skin ,business - Abstract
As a first step to develop a screening system for pigmented skin lesions, we performed digital discriminant analyses between early melanomas and Clark naevi. A total of 59 cases of melanoma, including 23 melanoma in situ and 36 thin invasive melanomas (Breslow thickness < or =0.75 mm), and 188 clinically equivocal, histopathologically diagnosed Clark naevi were used in our study. After calculating 62 mathematical variables related to the colour, texture, asymmetry and circularity based on the dermoscopic findings of the pigmented skin lesions, we performed multivariate stepwise discriminant analysis using these variables to differentiate melanomas from naevi. The sensitivities and specificities of our model were 94.4 and 98.4%, respectively, for discriminating between melanomas (Breslow thickness < or =0.75 mm) and Clark naevi, and 73.9 and 85.6%, respectively, for discriminating between melanoma in situ and Clark naevi. Our algorithm accurately discriminated invasive melanomas from Clark naevi, but not melanomas in situ from Clark naevi.
- Published
- 2004
26. Pyloric atresia-junctional epidermolysis bullosa syndrome showing novel 594insC/Q425P mutations in integrin beta4 gene (ITGB4)
- Author
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Akira Ishiko, Soo Chan Kim, Hiroshi Shimizu, Takuji Masunaga, Yasuko Takizawa, Jin Sung Lee, and Takeji Nishikawa
- Subjects
Male ,Mothers ,Dermatology ,Biology ,medicine.disease_cause ,Biochemistry ,Frameshift mutation ,Fatal Outcome ,medicine ,Humans ,Missense mutation ,Frameshift Mutation ,Molecular Biology ,Pylorus ,Genetics ,Mutation ,integumentary system ,Integrin beta4 ,Infant, Newborn ,Syndrome ,medicine.disease ,Amino Acid Substitution ,Codon, Terminator ,DNA Transposable Elements ,Mutation testing ,Epidermolysis bullosa ,Epidermolysis Bullosa, Junctional ,Junctional epidermolysis bullosa (veterinary medicine) ,ITGA6 - Abstract
Pyloric atresia-junctional epidermolysis bullosa syndrome (PA-JEB) is an autosomal recessive inherited rare blistering disorder caused by mutations in ITGA6 or ITGB4, genes encoding integrin alpha6 or beta4, respectively. In this study, we have disclosed the mutations in ITGB4 in a Korean patient with PA-JEB. The proband, who showed skin blisters, was diagnosed as having pyloric atresia and died 2 years after birth. Mutational analysis showed a novel 594insC maternal mutation in exon 7, which led to premature termination codon (PTC), and a novel Q425P paternal mutation in exon 11. Q425P mutation was not detected in 200 alleles obtained from a normal healthy Korean control, and was shown to reduce alpha-helix forming ability in integrin beta4 a by Garnier alpha-helicity plot of the protein, indicating that this mutation is pathogenic but not polymorphism. The phenotype in the present case can be explained by (1) the combination of PTC and missense mutation, and (2) amino-acid substitution occurring for the amino acid not preserved in the integrin beta family. Our results contribute to further the accumulation of mutation data for better understanding of the genotype/phenotype correlation in PA-JEB, and may give profound insight into the role of integrins alpha6 and beta4.
- Published
- 2004
27. Conformational epitope mapping and IgG subclass distribution of desmoglein 3 in paraneoplastic pemphigus
- Author
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Masayuki Amagai, Yuko Futei, Takeji Nishikawa, and Takashi Hashimoto
- Subjects
inorganic chemicals ,Paraneoplastic Syndromes ,Enzyme-Linked Immunosorbent Assay ,Dermatology ,Biology ,Desmoglein ,Epitope ,Subclass ,Autoimmune Diseases ,medicine ,Humans ,heterocyclic compounds ,education ,Autoantibodies ,education.field_of_study ,Desmoglein 3 ,Pemphigus vulgaris ,Autoantibody ,Cadherins ,medicine.disease ,enzymes and coenzymes (carbohydrates) ,Pemphigus ,Immunoglobulin G ,Immunology ,Epitope Mapping ,Conformational epitope - Abstract
Background Pemphigus vulgaris (PV) shows autoimmune reaction against desmoglein 3 (Dsg3), whereas paraneoplastic pemphigus (PNP) shows autoimmune reaction against Dsg3 as well as numerous members of the plakin family. It has been demonstrated that in PV, dominant epitopes reside in N-terminal adhesive regions of Dsg3 and that the dominant IgG subclass against Dsg3 is IgG4. Objective We attempted to map conformational epitopes and analyze IgG subclass distribution against Dsg3 in PNP. Method Epitopes on Dsg3 for circulating IgG autoantibodies from PNP (n = 22) were studied with competition enzyme-linked immunosorbent assay (ELISA) using domain-swapped molecules between Dsg3 and Dsg1 and were compared with those for IgG autoantibodies from PV (n = 22). IgG subclass distribution was analyzed with PNP serum by Dsg3 ELISA (n = 17). Results Epitopes on Dsg3 in PNP were distributed more broadly through the extracellular domain of Dsg3 than were those in PV, although the N-terminal extracellular domains of Dsg3 were more frequently recognized than the C-terminal extracellular domains. IgG subclass in PNP was IgG1 and IgG2 dominant. Conclusion Autoimmune response against Dsg3 in PNP is more diversified than that in PV, a finding that suggests PNP and PV have different pathophysiologic mechanisms for triggering production of anti-Dsg3 IgG.
- Published
- 2003
28. Immunomolecular mapping of adherens junction and desmosomal components in normal human epidermis
- Author
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Takeji Nishikawa, Hiroshi Shimizu, Sadakazu Aiso, Takuji Masunaga, Yukiko Matsunaga, and Akira Ishiko
- Subjects
Keratinocytes ,Beta-catenin ,Osmium Tetroxide ,Immunoelectron microscopy ,Plakoglobin ,Dermatology ,Biology ,Biochemistry ,Plakophilin ,Adherens junction ,Desmosome ,Freezing ,Cell Adhesion ,medicine ,Humans ,Antigens ,Fluorescent Antibody Technique, Indirect ,Microscopy, Immunoelectron ,Molecular Biology ,Cytoskeleton ,beta Catenin ,Skin ,Cadherin ,Cell Membrane ,Attachment Plaque ,Adherens Junctions ,Desmosomes ,Cadherins ,Immunohistochemistry ,Actins ,Cell biology ,Cytoskeletal Proteins ,Microscopy, Electron ,medicine.anatomical_structure ,Microscopy, Fluorescence ,Trans-Activators ,biology.protein ,Epidermis ,Protein Binding - Abstract
Adherens junctions (AJs) are cell-cell and cell-matrix junctions that are known to comprise the transmembrane and cytoplasmic components linked to the f-actin cytoskeleton. Although the presence of AJs han been confirmed in normal human epidermis, previous studies immunolocalizing AJ-related antigens have been controversial. The purpose of this study was to produce a more precise molecular mapping of AJs and their constituents in relation to desmosomes in normal human epidermal keratinocytes. Using an electron microscope (EM) method to optimally fix plasma membranes. AJ structures were typically seen as a narrowing of the intercellular space between two keratinocytes that was distinct from desmosomes and gap junctions. Such structures were consistently found more frequently in the upper epidermis than in the basal layer. Immunogold electron microscopy showed an absence of the AJ components (E-cadherin and beta-catenin) from desmosomal areas but they were present at interdesmosomal areas at sites of close membrane association. Conversely, the desmosomal components plakoglobin and plakophilin 1 were restricted only to the outer attachment plaque of the desmosome. These results further confirm that AJs have a distinct molecular composition and distribution from desmosomes and that they regularly occur between desmosomes along the keratinocyte plasma membrane to provide alternative cell-cell adhesion mechanisms.
- Published
- 2003
29. Production of recombinant extracellular domains of canine desmoglein 1 (Dsg1) by baculovirus expression
- Author
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Toshiroh Iwasaki, Masayuki Amagai, Koji Nishifuji, and Takeji Nishikawa
- Subjects
Keratinocytes ,Immunology ,Spodoptera ,Biology ,Desmoglein ,Epitope ,law.invention ,Dogs ,law ,Complementary DNA ,Extracellular ,Animals ,Humans ,Secretion ,Dog Diseases ,Fluorescent Antibody Technique, Indirect ,General Veterinary ,Reverse Transcriptase Polymerase Chain Reaction ,Desmoglein 1 ,IIf ,Cadherins ,Molecular biology ,Recombinant Proteins ,Protein Structure, Tertiary ,Immunoglobulin G ,Recombinant DNA ,RNA ,Baculoviridae ,Pemphigus - Abstract
The aim of this study was to generate a recombinant protein to represent the entire extracellular domain of canine desmoglein 1 (Dsg1), a desmosomal cell-cell adhesion molecule, by the baculovirus expression system. Cotransfection of a baculovirus transfer vector containing the cDNA for the entire extracellular domain of canine Dsg1 with baculovirus DNA into insect cells resulted in the secretion of soluble canine Dsg1 into insect culture supernatants. Immunoreactivity of 11 human pemphigus foliaceus (PF) sera against the cell surface of canine keratinocytes was completely removed when the sera were preincubated with the canine Dsg1 baculoprotein. This recombinant canine Dsg1 produced by baculovirus shares the major epitopes of the authentic canine Dsg1 recognized by human PF sera, and will be useful in studying the molecular pathophysiological mechanisms in PF and impetigo in canine patients.
- Published
- 2003
30. Cloning of canine desmoglein 3 and immunoreactivity of serum antibodies in human and canine pemphigus vulgaris with its extracellular domains
- Author
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Masayuki Amagai, Takayuki Ota, Koji Nishifuji, Takeji Nishikawa, and Toshiroh Iwasaki
- Subjects
DNA, Complementary ,Genetic Vectors ,Molecular Sequence Data ,Dermatology ,Biochemistry ,Desmoglein ,Antibodies ,law.invention ,Dogs ,law ,Complementary DNA ,medicine ,Extracellular ,Animals ,Humans ,Amino Acid Sequence ,Cloning, Molecular ,education ,Molecular Biology ,education.field_of_study ,Base Sequence ,Desmoglein 3 ,biology ,Pemphigus vulgaris ,Gene Transfer Techniques ,Cadherins ,medicine.disease ,Precipitin Tests ,Virology ,Molecular biology ,Protein Structure, Tertiary ,Pemphigus ,biology.protein ,Recombinant DNA ,Antibody ,Baculoviridae - Abstract
Background: Pemphigus vulgaris (PV) is an antibody-mediated autoimmune blistering disease of the skin and mucous membrane recognized in humans and several domestic animals, including dogs. The autoimmune target in human PV has been identified as desmoglein (Dsg) 3, a desmosomal cell–cell adhesion molecule, whereas the autoimmune target in canine PV has not yet been identified clearly. Objective: To obtain and sequence the mRNA for the entire coding region of canine Dsg3, and to investigate whether the serum antibodies in human and canine PV recognize the extracellular domains of canine Dsg3. Methods: The cDNA clones for canine Dsg3 were obtained from cultured-canine keratinocytes by reverse transcription-polymerase chain reaction (RT-PCR) and rapid amplification of the cDNA ends (RACE) and were sequenced. Immunoprecipitation-immunoblotting (IP-IB) was performed with nine human PV sera, a canine PV serum and six normal canine sera using canine keratinocyte extracts as well as the entire extracellular domain of canine Dsg3 produced by baculovirus as the substrates. Results: The open reading frame of canine Dsg3 consists of 993 amino acids, and shares 81.2 and 72.6% amino acid identities with human and mouse Dsg3, respectively. IP-IB demonstrated that all of the human and canine PV sera, but none of the normal canine sera tested, immunoprecipitated a 130-kDa protein in canine keratinocyte extracts as well as the recombinant extracellular domains of canine Dsg3. Conclusion: The cDNA sequence and the baculovirus recombinant protein of canine Dsg3 will be useful to characterize the serum autoantibodies in canine PV.
- Published
- 2003
31. Lack of association of the interleukin-1 receptor antagonist gene with palmoplantar pustulosis in Japanese
- Author
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H. Niizeki, K. Hashigucci, Takeji Nishikawa, H. Inoko, N. Inamoto, M. Yokoyama, and T. Naruse
- Subjects
Palmoplantar pustulosis ,medicine.drug_class ,Immunology ,Interleukin ,Biology ,Receptor antagonist ,Pathogenesis ,Interleukin 1 receptor antagonist ,Polymorphism (computer science) ,Genotype ,Genetics ,medicine ,Tumor necrosis factor alpha - Abstract
We analysed a polymorphism of the interleukin (IL)-1 receptor antagonist (IL1RN) gene in 93 Japanese patients with palmoplantar pustulosis (PPP). None of the IL1RN alleles was significantly increased in the patients compared with controls. Because PPP has been reported to be associated with the tumour necrosis factor (TNF) region, we examined the association between the TNF and IL1RN genes. There was a difference in IL1RN*2 positivity between patients with and without the AA genotype of the TNF gene. In contrast, such a difference was not found in controls. These data indicate a possible epistatic effect between TNF and IL1RN linked genes for susceptibility to the pathogenesis of PPP.
- Published
- 2003
32. No involvement of IgG autoantibodies against extracellular domains of desmoglein 2 in paraneoplastic pemphigus or inflammatory bowel diseases
- Author
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Mamoru Watanabe, Takayuki Ota, Masayuki Amagai, and Takeji Nishikawa
- Subjects
Pathology ,medicine.medical_specialty ,Paraneoplastic Syndromes ,Bronchiolitis obliterans ,Enzyme-Linked Immunosorbent Assay ,Dermatology ,Biochemistry ,Desmoglein ,Immunoglobulin G ,medicine ,Humans ,heterocyclic compounds ,Molecular Biology ,Autoantibodies ,Autoimmune disease ,Crohn's disease ,Desmoglein 2 ,biology ,business.industry ,Autoantibody ,Inflammatory Bowel Diseases ,medicine.disease ,Precipitin Tests ,Protein Structure, Tertiary ,Cytoskeletal Proteins ,Pemphigus ,Paraneoplastic pemphigus ,Desmoplakins ,Immunology ,biology.protein ,Desmogleins ,business - Abstract
Background: Patients with paraneoplastic pemphigus (PNP) and inflammatory bowel diseases, such as Crohn's disease (CD) and ulcerative colitis (UC), develop autoantibodies against simple epithelial cells. About 20–30% of patients with PNP develop fatal bronchiolitis obliterans, in which autoantibody-mediated injury is suspected because of in vivo IgG deposition on cell surfaces of bronchial epithelia. Objective: The purpose of this study is to determine whether patients with PNP, CD and UC have IgG autoantibodies against desmoglein 2 (Dsg2), which is expressed in all desmosome-bearing cells including respiratory and intestinal epithelia. Methods: A secreted form of recombinant Dsg2 (rDsg2-His) which contains its entire extracellular domains was produced by baculovirus expression. The reactivity of patients’ sera against rDsg2-His was examined by ELISA as well as immunoprecipitation. Results: An anti-Dsg2 mouse monoclonal antibody, 6D8, showed positive reactivity against rDsg2-His in both methods. However, none of 38 PNP sera reacted with rDsg2-His by ELISA and none of 15 PNP sera tested immunoprecipitated rDsg2-His. Furthermore, none of 12 CD or 27 UC sera reacted with rDsg2-His by ELISA. Conclusion: These findings indicate that IgG autoantibodies against Dsg2 are not involved in PNP, CD or UC and suggest the existence of other unknown cell surface target antigen(s) in bronchiolitis obliterans in PNP.
- Published
- 2003
33. A clinical feature associated with polymorphisms of the TNF region in Japanese patients with palmoplantar pustulosis
- Author
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Hironori Niizeki, Taeko Naruse, Kazuhiro Hashigucci, Nobuko Inamoto, Takeji Nishikawa, Hidetoshi Inoko, and Masao Ota
- Subjects
medicine.medical_specialty ,Pathology ,Palmoplantar pustulosis ,Radio Waves ,Palatine Tonsil ,Immunology ,Provocation test ,Locus (genetics) ,Biology ,Polymerase Chain Reaction ,Asian People ,Internal medicine ,medicine ,Humans ,Psoriasis ,Immunology and Allergy ,Genetic Predisposition to Disease ,Allele ,Promoter Regions, Genetic ,Lymphotoxin-alpha ,Gene ,Polymorphism, Genetic ,Tumor Necrosis Factor-alpha ,Haplotype ,Promoter ,General Medicine ,Phenotype ,Endocrinology ,Tumor necrosis factor alpha ,Microsatellite Repeats - Abstract
We investigated the association of polymorphisms in the tumor necrosis factor (TNF) microsatellite as well as the promoter region of the TNFA gene and the TNFB gene with palmoplantar pustulosis (PPP). In order to clarify the heterogeneity of this disease, we performed a tonsillar provocation test on 78 patients and divided them into two groups according to the results; provocation positive (PP; n = 38) and provocation negative (PN; n = 40). We found that the phenotype frequency of the TNFB2 allele of the TNFB gene in the PN group was significantly higher than in controls (p = 0.0022, corrected p = 0.0044). There was also a significant increase in the frequency of allele B of the TNFA gene (TNFApB) in the PN group when compared with controls (p = 0.0049, corrected p = 0.025). Although there are no significant differences in the frequency of TNFa microsatellites, the frequency of the TNFd7 allele increased and that of the TNFd4 allele decreased in the PN group. An extended haplotype analysis revealed that the TNFd7-TNFApA-TNFB2 haplotype was more frequent in the PN group, implying that the PN group is associated with a low level of TNF-alpha production. These results indicate that detection of polymorphisms at the TNF locus may be a marker for determination of the heterogeneity of the disease, and that the allelic variation may influence the susceptibility.
- Published
- 2003
34. Suppression of the Immune Response Against Exogenous Desmoglein 3 in Desmoglein 3 Knockout Mice: An Implication for Gene Therapy
- Author
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Miyo Aoki, Takeji Nishikawa, Manabu Ohyama, Takayuki Ota, Masayuki Amagai, Kazuyuki Tsunoda, Shigeo Koyasu, and Reiko Harada
- Subjects
Male ,DNA, Complementary ,Transgene ,Genetic enhancement ,Dermatology ,Skin Diseases ,Biochemistry ,Gene product ,Mice ,skin graft ,Immune system ,recessive genodermatosis ,Immunopathology ,Immune Tolerance ,Animals ,CD154 ,education ,Molecular Biology ,Mice, Knockout ,education.field_of_study ,immunosuppression ,Desmoglein 3 ,biology ,Antibodies, Monoclonal ,Genetic Therapy ,Skin Transplantation ,Cell Biology ,Cadherins ,Mice, Inbred C57BL ,Immunoglobulin G ,Immunology ,Knockout mouse ,biology.protein ,Female ,CD40 ligand ,Antibody - Abstract
Gene therapies for recessive genetic diseases may provoke unwanted immune responses against the introduced gene product because patients, especially those with null mutation of a certain protein, have no tolerance for the protein of interest. This study used desmoglein 3 knockout (Dsg3-/-) mice as a disease model for a genetic defect in DSG3, to investigate whether nonviral gene therapy induces an immune response against Dsg3 and whether the reaction against Dsg3 can be prevented. When mouse Dsg3 cDNA was injected in the skin of Dsg3-/- mice, 50% of treated Dsg3-/- mice developed anti-Dsg3 IgG, which can bind native Dsg3 in vivo. To prevent this response, we used an anti-CD40L monoclonal antibody, MR1, which blocks the costimulatory interaction between CD40 and CD40L. To evaluate the effect of MR1, we grafted Dsg3+/+skin on Dsg3-/- mice, to mimic stable gene transfer of Dsg3. After skin grafting, all the recipient Dsg3-/- mice were treated with either MR1 (n=8) or control hamster IgG (n=8). All of the control IgG-treated mice developed circulating anti-Dsg3 IgG about 2 wk after grafting, and IgG deposition was observed on the surfaces of keratinocytes in the grafted Dsg3+/+skin. Such anti-Dsg3 IgG production was significantly prevented, however, when the recipient mice were treated with MR1. These findings suggested that gene therapies for recessive diseases may provoke an immune response against the transgene product, and that the CD40-CD40L interaction might be a reasonable target for effective prevention of such undesirable immune responses, leading, in turn, to a successful gene therapy.
- Published
- 2003
35. Pyogenic lymphoma of the skin: a peculiar variant of primary cutaneous neutrophil-rich CD30+ anaplastic large-cell lymphoma. Clinicopathological study of four cases and review of the literature
- Author
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G. Burg, Marshall E. Kadin, P.J Frosch, Werner Kempf, Dmitry V. Kazakov, Reinhard Dummer, Takeji Nishikawa, and S Lange-Ionescu
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Skin Neoplasms ,CD30 ,Neutrophils ,medicine.medical_treatment ,Ki-1 Antigen ,Dermatology ,Cutaneous lymphoma ,hemic and lymphatic diseases ,Tumor Cells, Cultured ,Humans ,Medicine ,Interleukin 8 ,Histiocyte ,business.industry ,Interleukin-8 ,Large-cell lymphoma ,Interleukin ,Middle Aged ,medicine.disease ,Abscess ,Lymphoma ,Cytokine ,Female ,Lymphoma, Large B-Cell, Diffuse ,Facial Neoplasms ,business - Abstract
Systemic anaplastic large-cell lymphoma (ALCL) in human immunodeficiency virus (HIV)-infected individuals showing an extensive infiltrate of neutrophils has been reported and referred to as 'neutrophil-rich' CD30+ ALCL. Secondary cutaneous involvement has been found in a subset of these cases. We report the clinicopathological features of four immunocompetent patients with primary cutaneous neutrophil-rich ALCL and present a new histological subtype with a dissolute growth pattern of CD30+ tumour cells. Four HIV-negative patients presented with rapidly growing solitary or multiple tumours located on the face. Ulceration of the lesions with purulent discharge was a typical finding. Various inflammatory dermatoses were considered clinically in all cases. The histological hallmark was a large number of neutrophils in the infiltrate that masked neoplastic CD30+ anaplastic cells. In two cases, a dissolute growth pattern of anaplastic tumour cells was observed. In two cases, a strong correlation between tumour growth and interleukin (IL)-8 cytokine pattern as well as the production of IL-8 by tumour cells was demonstrated. The diagnosis of neutrophil-rich ALCL is challenging clinically and histologically as the tumour cell compartment is masked by an extensive inflammatory infiltrate of neutrophils and other reactive cells such as histiocytes which may be mainly due to release of IL-8 by tumour cells. The term 'pyogenic' designates the typical feature of this distinct neutrophil-rich ALCL, namely abscess formation ('pyo-') by cytokines (IL-8) produced by tumour cells ('-genic'). The clinical behaviour of this type is the same as in primary cutaneous CD30+ ALCL with classical histological presentation.
- Published
- 2003
36. Unilateral bullous pemphigoid without erythema and eosinophil infiltration in a hemiplegic patient
- Author
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Jun Yamagami, Daisuke Tsuruta, Takashi Hashimoto, and Takeji Nishikawa
- Subjects
Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,biology ,Erythema ,business.industry ,Dermatology ,General Medicine ,Eosinophil ,Immunofluorescence ,medicine.disease ,Epitope ,medicine.anatomical_structure ,Antigen ,medicine ,biology.protein ,Bullous pemphigoid ,Antibody ,medicine.symptom ,business ,Infiltration (medical) - Abstract
In this report, we describe an 88-year-old male stroke patient with unilateral bullous pemphigoid limited to the hemiplegic side. Physical examinations revealed multiple tense bullae with clear and/or bloody contents without apparent erythema on the right thigh and lower leg, accompanied by erosions on the right chest. Histopathologically, no eosinophils were infiltrated into and around the subepidermal bullae. Immunofluorescence revealed deposited and circulating immunoglobulin (Ig)G anti-basement membrane zone antibodies. Immunoblot assays using various antigen sources and enzyme-linked immunosorbent assay revealed that IgG antibodies in this case reacted with unique epitopes between NC16a and C-terminal domains on the 120-kDa LAD-1, the extracellular truncated form of BP180. Three observations were unique in our case. First, the distribution of bullae in our patient was limited to the hemiplegic side. Second, there was no apparent erythema clinically and no eosinophilic infiltration histopathologically. Third, the patient achieved remission without the use of oral corticosteroids. The unusual epitopes in this case may contribute to these phenomena.
- Published
- 2012
37. BP180 ELISA using bacterial recombinant NC16a protein as a diagnostic and monitoring tool for bullous pemphigoid
- Author
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Masakazu Kobayashi, Koji Hashimoto, Masayuki Amagai, Takashi Hashimoto, Keiko Kuroda-Kinoshita, Yuji Shirakata, and Takeji Nishikawa
- Subjects
Adult ,Male ,Pemphigoid ,Dystonin ,Enzyme-Linked Immunosorbent Assay ,Nerve Tissue Proteins ,Dermatology ,Autoantigens ,Sensitivity and Specificity ,Biochemistry ,Bacterial Proteins ,Antigen ,Pemphigoid, Bullous ,Humans ,Medicine ,Molecular Biology ,Pemphigus foliaceus ,Aged ,Aged, 80 and over ,Collagen disease ,business.industry ,Pemphigus vulgaris ,Collagen Diseases ,Autoantibody ,Middle Aged ,Non-Fibrillar Collagens ,medicine.disease ,Recombinant Proteins ,Protein Structure, Tertiary ,Cytoskeletal Proteins ,Epitope mapping ,Case-Control Studies ,Immunology ,Female ,Collagen ,Bullous pemphigoid ,Carrier Proteins ,business - Abstract
Bullous pemphigoid (BP) is an acquired autoimmune subepidermal blistering disease against hemidesmosomal cytoplasmic BP230 and transmembrane BP180 proteins. Epitope mapping studies have shown that the membrane-proximal noncollagenous (NC) 16a domain of BP180 harbors clusters of antigenic sites recognized by the vast majority of BP sera. In this study, we developed an enzyme-linked immunosorbent assay (ELISA) using bacterial recombinant NC16a protein and evaluated its clinical benefit for diagnosis and monitoring disease activity. Fifty four (84.4%) of 64 sera from BP patients were positive, while only one (1.1%) of 91 sera from collagen disease patients and five (1.5%) of 336 sera from normal control barely exceeded the cut-off value. None of 69 pemphigus vulgaris sera and none of 42 pemphigus foliaceus sera exceeded the cut-off value. Thus, the sensitivity and specificity of NC16a ELISA were 84.4 and 98.9%, respectively. The correlation between ELISA scores and disease activity along the time course was examined using seven BP patients. NC16a ELISA scores tended to fluctuate in parallel with the disease activity along the time course and reflected the disease activity much better than indirect immunofluorescence. These findings indicate that NC16a ELISA will be a valuable tool not only for the diagnosis of patients with BP but also for the monitoring of the disease activity.
- Published
- 2002
38. Upregulation of P-cadherin expression in the lesional skin of pemphigus, Hailey-Hailey disease and Darier’s disease
- Author
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Margaret J. Wheelock, Megumi Hakuno, Takeji Nishikawa, Hiroshi Shimizu, and Masashi Akiyama
- Subjects
education.field_of_study ,Pathology ,medicine.medical_specialty ,Histology ,integumentary system ,business.industry ,Acantholysis ,Pemphigus vulgaris ,Dermatology ,medicine.disease ,Pathology and Forensic Medicine ,Pemphigus ,medicine.anatomical_structure ,Desmosome ,Hailey–Hailey disease ,Desmoglein 1 ,Desmoglein 3 ,Medicine ,business ,education ,Pemphigus foliaceus - Abstract
Background: Autoimmune blistering diseases, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), are known to be caused by binding of autoantibodies to the desmosomal cadherins, desmoglein 3 and desmoglein 1, respectively. Recently, mutations in the genes coding Ca2+ pumps leads to inherited blistering diseases, Hailey-Hailey disease (HHD) and Darier’s disease (DD). Cadherins are a family of Ca2+-dependent cell adhesion molecules and P-cadherin is one of the major cadherins expressed in the epidermis. Although detailed mechanisms of acantholysis of these blistering diseases have not been fully clarified, abnormal expression of cadherins caused by altered Ca2+ concentration due to the binding of autoantibodies to cell surface or by mutations in Ca2+ pumps is suggested to be involved in mechanisms of acantholysis of these atuoimmune and inherited blistering diseases. The purpose of the present study was to determine whether altered P-cadherin expression is present in these diseases. Method: Distribution patterns of P-cadherin in skin specimens from patients with PV (n=2), PF (n=2), HHD (n=4) and DD (n=3), were examined with confocal laser scanning microscopy using two anti-P-cadherin antibodies, 6A9 and NCC-CAD-299. Results: In normal control skin, P-cadherin expression was restricted to the basal layer. In contrast, positive immunostaining of P-cadherin was observed not only in the basal cells, but also in the suprabasal cells in lesional skin of all the acantholytic diseases. Conclusions: The present results clearly demonstrated that upregulation of P-cadherin expression occurs in the acantholysis in all the four blistering diseases PV, PF, HHD and DD. Upregulation of P-cadherin may be involved in the pathomechanism of both the autoimmune blistering diseases and the inherited blistering diseases.
- Published
- 2001
39. Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus
- Author
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Yuko Futei, Ken Ishii, Masayuki Amagai, Keiko Kuroda-Kinoshita, Takeji Nishikawa, and Kazuhiko Ohya
- Subjects
Enzyme-Linked Immunosorbent Assay ,Dermatology ,Biology ,Biochemistry ,Desmoglein ,Subclass ,Immunoglobulin G ,Antibody Specificity ,medicine ,Humans ,education ,Molecular Biology ,Pemphigus foliaceus ,Autoantibodies ,education.field_of_study ,Desmoglein 3 ,integumentary system ,Pemphigus vulgaris ,Autoantibody ,Cadherins ,medicine.disease ,Pemphigus ,Immunology ,biology.protein - Abstract
Pemphigus vulgaris (PV) and pemphigus foliaceus (PF) are autoimmune skin diseases caused by autoantibodies against desmoglein (Dsg) 3 and Dsg1. We have previously developed ELISAs using recombinant Dsg3 and Dsg1 expressed by baculovirus as a diagnostic tool for pemphigus. In this study, we determined the frequency of coexistence of IgA class as well as distribution of IgG subclass. Two out of 49 PV and PF sera tested had anti-Dsg1 IgA in addition to anti-Dsg1 IgG. Interestingly, one of them showed prominent pustular formation. Among IgG subclass, IgG4 was predominant and found in all of the 30 PV and 19 PF sera tested, followed by IgG1, detected in 25 out of 30 PV and 12 out of 19 PF sera. Even though IgG2 and IgG3 were detected in 13 and one PV and 6 and 4 PF sera, respectively, the ELISA titers had barely exceeded the cutoff value in most of the cases. There was no IgG subclass shift during the course of the disease in seven cases examined. These findings indicate that IgG4 subclass is the predominant autoantibodies in both PV and PF, while IgG1 is also frequently found.
- Published
- 2001
40. Clinical phenotype and anti-desmoglein autoantibody profile in paraneoplastic pemphigus
- Author
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Manabu Ohyama, Masayuki Amagai, Grant J. Anhalt, Hossein C. Nousari, Takeji Nishikawa, and Takashi Hashimoto
- Subjects
Adult ,Male ,Pathology ,medicine.medical_specialty ,Adolescent ,Paraneoplastic Syndromes ,Mucocutaneous zone ,Dermatology ,Desmoglein ,Immunophenotyping ,medicine ,Humans ,Aged ,Autoantibodies ,business.industry ,Desmoglein 1 ,Pemphigus vulgaris ,Autoantibody ,Antibody titer ,Middle Aged ,medicine.disease ,Cytoskeletal Proteins ,Pemphigus ,Paraneoplastic pemphigus ,Desmoplakins ,Immunology ,Female ,Desmogleins ,business ,Cell Adhesion Molecules - Abstract
Background: Paraneoplastic pemphigus (PNP) has similar features to pemphigus vulgaris (PV), including circulating anti-desmoglein (Dsg) IgG as pathogenic autoantibodies. When PV is divided into mucosal dominant type and mucocutaneous type, mucosal dominant type has only anti-Dsg3 IgG, whereas the mucocutaneous type has both anti-Dsg3 and anti-Dsg1 IgG. Objective: The purpose of this study was to determine whether there is a difference in anti-Dsg autoantibody profile between mucosal dominant PNP and mucocutaneous PNP. Methods: Twenty-one patients with PNP were categorized as mucosal dominant and mucocutaneous types based on clinical information. Antibody titers against Dsg3 and Dsg1 were measured by enzyme-linked immunosorbent assay by means of recombinant Dsg1 and Dsg3. Results: There were 9 cases of mucosal dominant type and 12 cases of mucocutaneous type. Eight of 9 cases of mucosal dominant type were positive for anti-Dsg3 IgG, but 3 of them were also positive for anti-Dsg1 IgG. All 12 cases of mucocutaneous type were positive for anti-Dsg3 IgG, whereas only 6 of them were positive for anti-Dsg1 IgG. Conclusion: There was no clear association between the clinical phenotype and anti-Dsg antibody profile in PNP as seen in PV. This finding suggests that besides anti-Dsg IgG other pathologic mechanisms such as lichenoid reaction or interface dermatitis may be involved in the blister formation in PNP. (J Am Acad Dermatol 2001;44:593-8.)
- Published
- 2001
41. Beyond the year 2000: Japanese dermatology
- Author
-
Takeji Nishikawa
- Subjects
medicine.medical_specialty ,Asia ,Japan ,business.industry ,International Cooperation ,Humans ,Medicine ,Dermatology ,business ,Societies, Medical ,Forecasting - Published
- 2001
42. Chapter 9: COMPUTER-AIDED SURGERY AND TISSUE EXPANSION IN AURICULAR RECONSTRUCTION FOR IMCROTIA
- Author
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Masayuki Amagai, Jun-ichi Hata, Megumi Hakuno, Takeji Nishikawa, Akinori Hashiguchi, Kanji Wakabayashi, and Masakazu Kobayashi
- Subjects
Liver injury ,Pathology ,medicine.medical_specialty ,medicine.diagnostic_test ,business.industry ,medicine.drug_class ,Azathioprine ,General Medicine ,Disease ,medicine.disease ,Vinblastine ,Pemphigus ,Hailey–Hailey disease ,Skin biopsy ,medicine ,Corticosteroid ,business ,medicine.drug - Abstract
We report a case of a 59-year-old man with a severe generalized form of Hailey-Hailey disease that was complicated by fatal liver injury. Erosive lesions were first noted in the axillary and perianal regions at 15 year of age, and Hailey-Hailey disease was diagnosed based on the clinical features and histologic findings in skin biopsy specimens. The patient was treated with at first topical steroids and later a low dose of a corticosteroid, but the skin lesions gradually became generalized. At 45 years of age liver dysfunction was detected after azathioprine and vinblastine treatment for the generalized skin lesions. The liver injury gradually progressed and finally the patient died. The gene responsible for Hailey-Hailey disease was recently identified as ATP2C1, and it encodes a Ca(2+)-transport ATPase with broad expression, including in skin and liver. This finding suggests that mutation of the ATP2C1 gene may give rise to an extracutaneous phenotype, such as the liver dysfunction observed in severe cases, including our own. Further accumulation of cases is necessary to determine whether this is true.
- Published
- 2001
43. The Extracellular Domain of BPAG2 has a Loop Structure in the Carboxy Terminal Flexible Tail In Vivo
- Author
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Akira Ishiko, Hiroshi Shimizu, Takuji Masunaga, Takeji Nishikawa, Katsushi Owaribe, Masashi Akiyama, and Shuko Nonaka
- Subjects
Pathology ,medicine.medical_specialty ,Dystonin ,Immunoelectron microscopy ,Nerve Tissue Proteins ,Dermatology ,Autoantigens ,Biochemistry ,Mice ,Laminin ,medicine ,Animals ,Humans ,Amino Acid Sequence ,Molecular Biology ,Basement membrane ,integumentary system ,biology ,Hemidesmosome ,Cell Biology ,Immunogold labelling ,Hemidesmosomes ,Non-Fibrillar Collagens ,Lamina lucida ,Molecular biology ,Protein Structure, Tertiary ,Cytoskeletal Proteins ,medicine.anatomical_structure ,biology.protein ,Lamina densa ,Carrier Proteins ,Extracellular Space - Abstract
The 180 kDa bullous pemphigoid antigen is a hemidesmosome-associated transmembranous protein with a molecule length estimated to be 190-230 nm, which is much longer than the transverse length of the lamina lucida and lamina densa. The purpose of this study was to clarify the precise in vivo structure of the 180 kDa bullous pemphigoid antigen in normal human skin. We used three monoclonal antibodies directed to (i) the intracellular globular head of the 180 kDa bullous pemphigoid antigen, (ii) the mid-portion of the flexible tail of the antigen, corresponding approximately to amino acids 1000-1320, and (iii) the carboxyl terminal end, corresponding approximately to amino acids 1320-1500 of the antigen. Using low temperature postembedding immunoelectron microscopy, we quantitated the distribution of immunogold labeling of these monoclonal antibodies in normal human skin. The results showed that the monoclonal antibodies (i) bound to the intracellular portion of the hemidesmosome at a mean distance of 20 nm from the plasma membrane, (ii) bound to the lamina densa beneath the hemidesmosome at a mean distance of 65 nm from the plasma membrane, and (iii) bound to the lamina densa-lamina lucida interface at a mean distance of 39 nm from the plasma membrane. Considering the reported size of the 180 kDa bullous pemphigoid antigen, our results indicate that the extracellular domain of the antigen has at least one loop structure in the lamina densa in vivo. This unique structure of the antigen is thought to contribute to dermo- epidermal adhesion by intertwining with other basement membrane components.
- Published
- 2000
44. Polymorphisms in the TNFA promoter region is not associated with palmoplantar pustulosis
- Author
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T. Tojo, T. Urushibara, K. Hashigucci, H. Niizeki, K. Akiya, M. Yokoyama, Takeji Nishikawa, Hidetoshi Inoko, Y. Yamazaki, Yuichiro Yamasaki, and Taeko Naruse
- Subjects
Genetics ,Immunology ,Intron ,Single-nucleotide polymorphism ,Promoter ,General Medicine ,Biology ,Biochemistry ,law.invention ,Genetic marker ,law ,Genotype ,Immunology and Allergy ,Enhancer ,Gene ,Polymerase chain reaction - Abstract
Polymorphisms of the 5′-flanking promoter/enhancer region of the TNFA gene were determined in 80 Japanese patients with pulmoplantar pustulosis (PPP). The 5′-flanking region of the TNFA gene from –1107 to –66 was amplified by polymerase chain reaction (PCR) method. Nucleotide sequencing data from the PCR products revealed that 5 single nucleotide polymorphisms at position –1031, –863, –857, –307 and –237. None of the nucleotide substitutions were significantly increased in PPP patients when compared with those in controls. To clarify the linkage among the neighboring genetic marker, we analyzed the association between the polymorphisms in the TNFA promoter region and the NcoI polymorphism in the first intron of the TNFB gene as well as HLA-DR9. The genotype at –1031C is strongly associated with TNFB1 and negatively associated with TNFB2 which is reported to be associated with PPP. These data indicate that TNFA gene centromeric to TNFB is not associated with PPP and the susceptible gene of PPP is located between TNFB and HLA-B.
- Published
- 2000
45. Subepidermal blistering disease with autoantibodies against a novel dermal 200-kDa antigen
- Author
-
Takashi Hashimoto, Kim B. Yancey, M. Peter Marinkovich, Yoshie Kawahara, Zhuxiang Nie, Detlef Zillikens, and Takeji Nishikawa
- Subjects
Adult ,Keratinocytes ,Male ,Pathology ,medicine.medical_specialty ,Linear IgA bullous dermatosis ,Dermatitis Herpetiformis ,Dermatology ,Biochemistry ,Autoimmune Diseases ,Antigen ,Psoriasis ,Immunoblot Analysis ,Dermatitis herpetiformis ,Pemphigoid, Bullous ,medicine ,Humans ,Antigens ,Fluorescent Antibody Technique, Indirect ,skin and connective tissue diseases ,Molecular Biology ,Cells, Cultured ,Aged ,Autoantibodies ,Skin ,Skin Diseases, Vesiculobullous ,integumentary system ,biology ,business.industry ,Autoantibody ,Middle Aged ,medicine.disease ,Molecular Weight ,Immunoglobulin G ,Immunology ,biology.protein ,Female ,Bullous pemphigoid ,Antibody ,business - Abstract
A number of autoimmune subepidermal blistering diseases are characterized by the distinct autoantigens of the cutaneous basement membrane zone. Recently, a few cases with autoantibodies against a novel 200-kDa dermal protein have been reported. We collected nine cases of subepidermal blistering disease with IgG antibodies against this 200-kDa antigen. In this report, we describe the clinical and immunological appearances in these cases. Five cases showed bullous pemphigoid-like features, one case resembled dermatitis herpetiformis, and another case showed mixed features of bullous pemphigoid and linear IgA bullous dermatosis. It was interesting to note that psoriasis coexisted in four cases. By indirect immunofluorescence on 1 M NaCl split skin, IgG antibodies from all sera reacted with the dermal side of the split. By immunoblot analysis, IgG antibodies recognized a 200-kDa protein of dermal extract. IgG affinity-purified antibodies on the 200-kDa immunoblot membrane stained the dermal side of 1 M NaCl split skin. Various examinations suggested that the 200-kDa antigen is not identical to any chains of laminins-1, -5 or -6. This autoimmune subepidermal blistering disease against the dermal 200-kDa protein may form a new distinct entity, which often associates with psoriasis.
- Published
- 2000
46. Dissociation of intra- and extracellular domainsof desmosomal cadherins and E-cadherin inHailey-Hailey disease and Darier’s disease
- Author
-
James K. Wahl, Masayuki Amagai, Margaret J. Wheelock, Megumi Hakuno, M. Akiyama, Hiroshi Shimizu, and Takeji Nishikawa
- Subjects
integumentary system ,Cadherin ,Desmoplakin ,Plakoglobin ,Dermatology ,Biology ,Desmoglein ,Molecular biology ,medicine.anatomical_structure ,Desmosome ,Desmoglein 1 ,Immunology ,medicine ,biology.protein ,Desmocollin ,Desmosomal Cadherins - Abstract
In order to clarify the pathomechanism of acantholysis in Hailey-Hailey disease (HHD) and Darier's disease (DD), the distribution of desmosomal and adherens junction-associated proteins was studied in the skin of patients with HHD (n = 4) and DD (n = 3). Domain-specific antibodies were used to determine the cellular localization of the desmosomal transmembrane glycoproteins (desmogleins 1 and 3 and desmocollin), desmosomal plaque proteins (desmoplakin, plakophilin and plakoglobin) and adherens junction-associated proteins (E-cadherin, alpha-catenin, beta-catenin and actin). A significant difference in staining patterns between intra- and extracellular domains of desmosomal cadherins and E-cadherin was demonstrated in acantholytic cells in both HHD and DD, but not in those in pemphigus vulgaris and pemphigus foliaceus samples used as controls. In acantholytic cells in HHD and DD, antibodies against attachment plaque proteins and intracellular epitopes of desmosomal cadherins exhibited diffuse cytoplasmic staining, whereas markedly reduced staining was observed with antibodies against extracellular epitopes of the desmogleins. Similarly, membrane staining of an intracellular epitope of E-cadherin was preserved, while immunoreactivity of an extracellular epitope of E-cadherin was destroyed. While the DD gene has been identified as ATP2A2, the gene for HHD has not been clarified. The dissociation of intra- and extracellular domains of desmosomal cadherin and E-cadherin is characteristic of the acantholytic cells in HHD and DD, and not of pemphigus. This common phenomenon in HHD and DD might be closely related to the pathophysiological mechanisms in both conditions.
- Published
- 2000
47. Use of autoantigen-knockout mice in developing an active autoimmune disease model for pemphigus
- Author
-
Kazuyuki Tsunoda, Masayuki Amagai, Koji Nishifuji, Shigeo Koyasu, Takeji Nishikawa, and Harumi Suzuki
- Subjects
Molecular Sequence Data ,Fluorescent Antibody Technique ,Enzyme-Linked Immunosorbent Assay ,Spleen ,Autoantigens ,Antibodies ,Article ,Autoimmune Diseases ,Mice ,medicine ,Animals ,Lymphocytes ,education ,Mice, Knockout ,Autoimmune disease ,education.field_of_study ,Desmoglein 3 ,biology ,Desmoglein 1 ,Pemphigus vulgaris ,General Medicine ,Cadherins ,medicine.disease ,Recombinant Proteins ,DNA-Binding Proteins ,Disease Models, Animal ,Pemphigus ,Phenotype ,medicine.anatomical_structure ,Immunology ,Knockout mouse ,biology.protein ,Immunization ,Antibody ,Hair - Abstract
The development of experimental models of active autoimmune diseases can be difficult due to tolerance of autoantigens, but knockout mice, which fail to acquire tolerance to the defective gene product, provide a useful tool for this purpose. Using knockout mice lacking desmoglein 3 (Dsg3), the target antigen of pemphigus vulgaris (PV), we have generated an active disease model for this autoantibody-mediated disease. Dsg3(-/-) mice, but not Dsg3(+/-) littermates, produced anti-Dsg3 IgG that binds native Dsg3, when immunized with recombinant mouse Dsg3. Splenocytes from the immunized Dsg3(-/-) mice were then adoptively transferred into Rag-2(-/-) immunodeficient mice expressing Dsg3. Anti-Dsg3 IgG was stably produced in the recipient mice for more than 6 months without further boosting. This IgG bound to Dsg3 in vivo and disrupted the cell-cell adhesion of keratinocytes. Consequently, the recipient mice developed erosions in their oral mucous membranes with typical histologic findings of PV. In addition, the recipient mice showed telogen hair loss, as found in Dsg3(-/-) mice. Collectively, the recipient mice developed the phenotype of PV due to the pathogenic anti-Dsg3 IgG. This model will be valuable for developing novel therapeutic strategies. Furthermore, our approach can be applied broadly for the development of various autoimmune disease models.
- Published
- 2000
48. Development of chimeric molecules for recognition and targeting of antigen-specific B cells in pemphigus vulgaris
- Author
-
Takayuki Ota, Masayuki Amagai, Harumi Suzuki, Nana Shimizu, Margaret J. Wheelock, James K. Wahl, Shigeo Koyasu, Shinobu Gamou, Takeji Nishikawa, and Charlotte Proby
- Subjects
education.field_of_study ,biology ,medicine.drug_class ,Surface Immunoglobulin ,Pemphigus vulgaris ,Dermatology ,medicine.disease ,Monoclonal antibody ,Virology ,Molecular biology ,Desmoglein ,Epitope ,Desmoglein 3 ,biology.protein ,medicine ,Pseudomonas exotoxin ,Antibody ,education - Abstract
Pemphigus vulgaris (PV) is an autoimmune blistering disease characterized by circulating pathogenic IgG antibodies against desmoglein 3 (Dsg3). The purpose of this study was to develop chimeric molecules for specific recognition and elimination of autoimmune B cells in PV. Mouse hybridoma cell lines producing anti-Dsg3 antibody (5H10, 12A2) were developed as an in vitro model system for targeting B cells. Dsg3-GFP, a baculoprotein containing the entire extracellular domain of Dsg3 fused with green fluorescence protein, recognized and targeted the hybridoma cells through their surface immunoglobulin receptors in an antigen-specific way. The epitopes of these monoclonal antibodies were mapped on the amino terminal EC1 and part of EC2, a region considered functionally important in cadherins. Chimeric toxin molecules containing the mapped region (Dsg3deltaN1) and modified Pseudomonas exotoxin were produced in bacteria (Dsg3deltaN1-PE40-KDEL, PE3 7-Dsg3deltaN1-KDEL) and tested in vitro on hybridoma cell lines. The chimeric toxins, but not Dsg3deltaN1 alone, showed dose-dependent toxic activity with a reduction in hybridoma cell number to 40-60% of toxin-negative control cultures, compared with little or no effect on anti-Dsg3-negative hybridoma cells. Furthermore, these toxins showed toxic effects on anti-Dsg3 IgG-producing B cells from Dsg3deltaN1-immunized mice, with a 60% reduction in cell number compared with Dsg3deltaN1 alone. Thus, specific recognition and targeting of antigen-specific B cells in PV was demonstrated; this strategy may hold promise as a future therapeutic option for PV and other autoimmune diseases.
- Published
- 2000
49. Two cases of Trichophyton mentagrophytes Infection Contracted from a Hamster and a Chinchilla
- Author
-
Takeji Nishikawa, Yasuki Hata, Masayuki Amagai, Reiko Harada, and Wataru Naka
- Subjects
Pathology ,medicine.medical_specialty ,Adolescent ,Phodopus ,Erythema ,Itraconazole ,medicine.medical_treatment ,Hamster ,Neticonazole ,Microbiology ,Rodent Diseases ,Lesion ,chemistry.chemical_compound ,Tinea ,Trichophyton ,Chinchilla ,Cricetinae ,medicine ,Animals ,Humans ,Child ,biology ,business.industry ,Human-Animal Bond ,medicine.disease ,biology.organism_classification ,Treatment Outcome ,Infectious Diseases ,chemistry ,Female ,Tinea capitis ,medicine.symptom ,business ,Topical steroid ,medicine.drug - Abstract
We report two cases of Trichophyton mentagrophytes infection. Case 1: A 10-year-old girl visited Tokyo Electric Power Hospital in June 1994 for evaluation of an erythematous lesion on her head. Three months of topical steroid therapy exacerbated the lesion with pustular formation. Histopathological and mycological examination revealed that the patient had tinea capitis caused by T. mentagrophytes. T. mentagrophytes was also isolated from her pet, a hamster. Case 2: A-14-year-old girl was referred to Shonan Clinic in January 1996 with scaly erythema on her face. She had been treated with neticonazole hydrochloride at another clinic, but the lesion became worse. Direct microscopic examination of the scale was negative at that time, so treatment with topical steroid was started. After 10 days, the lesion was almost cured, but one month later it recurred with an annular distribution. KOH preparation of the scale revealed mycelia and T. mentagrophytes was isolated on culture. T. mentagrophytes was also isolated from her pet, a chinchilla. In both cases, the oral administration of itraconazole at 50 mg/day was effective. The isolated pathogen was identified as Arthroderma vanbreuseghemii with species-specific primers of chitin synthase 1 gene. T. mentagrophytes is one of the most common dermatophytes isolated from man and animals. Rodents like the hamster and the chinchilla have recently become popular as pets in Japan. We should be aware that rodents may carry this kind of fungal pathogen as they become even more popular as pets.
- Published
- 2000
50. Epidermolysis bullosa simplex associated with muscular dystrophy: Phenotype-genotype correlations and review of the literature
- Author
-
Hiroshi Hachisuka, Takeji Nishikawa, Hiroshi Shimizu, Jouni Uitto, Yasuko Takizawa, Masako Udono, Mitsuru Kawai, Satoru Murata, and Leena Pulkkinen
- Subjects
Pathology ,medicine.medical_specialty ,Genotype ,Fluorescent Antibody Technique ,macromolecular substances ,Dermatology ,medicine.disease_cause ,Muscular Dystrophies ,Epidermolysis bullosa simplex ,Intermediate Filament Proteins ,medicine ,Humans ,Allele ,Muscular dystrophy ,Child ,Gene ,Mutation ,business.industry ,Hemidesmosome ,Muscle weakness ,Plectin ,Middle Aged ,medicine.disease ,Immunohistochemistry ,Phenotype ,Epidermolysis Bullosa Simplex ,Female ,medicine.symptom ,business - Abstract
Background: Epidermolysis bullosa simplex associated with muscular dystrophy (EBS-MD; OMIM# 226670) is an autosomal recessive disorder caused by genetic defects in the plectin gene. Because EBS-MD is relatively rare, and gene defects have been elucidated only in a limited number of patients, the precise phenotype-genotype correlations have not yet been fully elucidated. Objective: The purpose of this study was to define clinical features of EBS-MD and to clarify its phenotype-genotype correlations. Methods: Clinical, ultrastructural, immunohistochemical, and molecular features of 4 unrelated Japanese patients with EBS-MD were recorded. In addition, 6 cases with defined plectin gene mutations reported in the literature were reviewed. Results: In skin of the EBS-MD patients, the blister formation always occurs just above the hemidesmosomes, and expression of plectin is absent or markedly reduced in all cases examined. All 10 patients, including 6 cases in the literature, showed generalized blistering at birth or soon thereafter, and experienced nail deformities. In addition, decayed teeth (5 cases), urethral strictures (3), mild palmoplantar hyperkeratosis (2), infantile respiratory complications (2), alopecia (1), and laryngeal webs (1) were present. All 8 patients who were older than 9 years demonstrated considerable muscle weakness, and the majority of them ended up being wheelchair bound. Among the 10 patients, 7 were products of consanguineous marriage, 9 have premature termination codon (PTC) mutations in both alleles of the plectin gene, and 7 cases were homozygous for the mutation. One patient who is homozygous for a 2719del9 in-frame deletion mutation that resulted in elimination of 3 amino acids, QEA, could still walk at the age of 46 and showed milder clinical severity. Conclusion: EBS-MD reveals clinical features not only characteristic of EBS and MD, but also other manifestations including urethral, dental, and respiratory complications. The majority of patients are products of consanguineous marriage and have homozygous plectin gene mutations. Whereas patients with PTC mutations in both alleles typically showed severe clinical features of EBS-MD and ended up being wheelchair bound, a homozygous patient for an in-frame deletion mutation showed positive, yet attenuated, plectin expression and milder clinical phenotype. Thus plectin immunofluorescence, combined with identification of the underlying plectin mutations, is of value in predicting the severity of the muscle involvement that occurs later in life of patients with EBS-MD. (J Am Acad Dermatol 1999;41:950-6.)
- Published
- 1999
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