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Background: Bullous pemphigoid (BP) is an autoimmune bullous disease in which abundant eosinophils accumulate in the blisters. Galectin-10 abounds in the cytoplasm of eosinophils and is released as a result of eosinophil extracellular trap cell death (EETosis)., Objective: To identify EETosis and the pathological roles of galectin-10 in BP., Methods: EETosis and galectin-10 in BP blisters were confirmed by immunofluorescence and transmission electron microscopy. The concentrations of galectin-10 in serum and blister fluid from BP patients were studied by ELISA. The matrix metalloproteinase (MMP) expression in BP blisters was immunohistochemically compared to that in healthy controls. As an in vitro assay, normal human epidermal keratinocytes (NHEKs) and normal human dermal fibroblasts (NHDFs) were stimulated with galectin-10, followed by MMP expression measurement by real-time PCR and ELISA. The signaling pathways activated by galectin-10 were studied using Western blotting and confirmed by inhibition assays., Results: Galectin-10-containing eosinophil infiltration and the extracellular deposition of major basic protein were observed in BP blisters. The ultrastructural characteristics of tissue eosinophils indicated piecemeal degranulation and EETosis. In the BP patients, the concentration of galectin-10 was higher in the blister fluid than in the serum. Several types of MMPs were upregulated in BP blisters. Galectin-10 upregulated the production of MMPs through the pathways of p38 MAPK, ERK and JNK in NHEKs and NHDFs., Conclusion: In the BP blisters, the eosinophils underwent EETosis and released galectin-10. Galectin-10 might contribute to BP blister formation through the production of MMPs by keratinocytes and fibroblasts., (Copyright © 2023 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Dyschromatosis symmetrica hereditaria (DSH) and reticulate acropigmentation of Kitamura (RAK) are rare, inherited pigmentary diseases. DSH shows a mixture of pigmented and depigmented macules on the extremities. RAK shows reticulated, slightly depressed pigmented macules on the extremities. The causative gene of DSH was clarified as ADAR1 by positional cloning including linkage analysis and haplotype analysis in 2003. Ten years later, the causative gene of RAK was identified as ADAM10 by whole-exome sequencing, in 2013. ADAR1 is an RNA-editing enzyme which catalyzes the deamination of adenosine to inosine (A-to-I) in double-stranded RNA substrates during post-transcription processing. Inosine acts as guanine during translation, resulting in codon alterations or alternative splice sites that lead to functional changes in proteins when they occur in coding regions. In 2012, it was clarified that ADAR1 mutations cause Aicardi-Goutières syndrome 6, which is a severe genetic inflammatory disease that affects the brain and the skin. A zinc metalloprotease, a disintegrin and metalloprotease domain-containing protein 10 (ADAM10), is involved in the ectodomain shedding of various membrane proteins and shows various functions in vivo. ADAM10 is known to be involved in the ectodomain shedding of Notch proteins as substrates in the skin. We speculate that the pathogenesis of RAK and Dowling-Degos disease (DDD, a pigmentary disease similar to RAK) is associated with the Notch signaling pathway. In addition, ADAM10 mutations proved to be associated with late-onset Alzheimer disease. This review comprehensively discusses the updated pathophysiology of those genetic pigmentary disorders., (Copyright © 2019 Japanese Society for Investigative Dermatology. Published by Elsevier B.V. All rights reserved.)

Background: Knowledge of changes in lymphatic flow after sentinel lymph node biopsy (SLNB) is important for the development of strategies for postoperative adjuvant therapy in malignant melanoma., Objectives: 41 patients (22 males and 19 females; average age: 67.0 ± 24.0 years) with primary cutaneous malignant melanoma (PCMM) participated in the present study. The primary tumor sites were the upper extremities (9 patients), the lower extremities (20 patients), the trunk (11 patients) and the scalp (1 patient). The tumor thicknesses of the PCMM lesions were from 0.5mm to 9.0mm (average: 3.3 ± 2.5mm). All the participants underwent wide local excision and SLNB., Methods: We studied lymphatic flow before and after SLNB by near-infrared (NIR) imaging in all 41 cases. In addition, we performed NIR imaging of lymphatic flow after the lymph node dissection in one case with sentinel lymph node (SLN) metastasis., Results: Almost no changes in lymphatic flow were seen in 38 of the 41 patients (92.7%) after SLNB. Only in 3 patients (7.3%), one with SLN metastasis and the other two without SLN metastasis, was apparent alteration in the lymphatic flow observed after SLNB. Of the 16 patients without SLN metastasis, only 3 patients showed recurrence of the tumors. Interestingly, 1 of the 2 patients without SLN metastasis but with lymphatic flow alteration had recurrence (regional lymph node metastasis) of the melanoma, whereas only 2 of the 14 patients without SLN metastasis or lymphatic flow alteration had recurrence, 1 with regional lymph node metastasis and the other with distant lymph node metastasis. In 1 case, we re-examined the lymphatic flow after regional lymph node dissection and the lymphatic flow was found to be dramatically changed., Conclusion: We clearly demonstrated that SLNB has only a minimal effect on lymphatic flow. The present results suggest that SLNB does not increase the risk of local recurrence/in-transit metastasis and may support the efficacy of post-SLNB local adjuvant injection to prevent local recurrence and in-transit metastasis., (Copyright © 2015 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.)

Background: Many mutations of the tyrosinase gene have been reported in oculocutaneous albinism type I (OCA1) patient. In the future, a greater number of novel mutations will be found as the search for pathological mutations in the tyrosinase genes of OCA patients from various ethnic origins. For rapid determination in future whether an observed mutation is a polymorphism or a novel pathological one, sequence databases of the gene of various ethnic people are needed., Objective: We established a sequence database of the tyrosinase gene of Japanese as well as Indian people., Method: We collected DNA from 109 Japanese and 103 Indians with normal pigmentation and analyzed their tyrosinase gene using a direct sequencing method., Result: The database shows an apparent difference between the two ethnic groups in polymorphisms of the tyrosinase gene namely, Q402 allele, Y192 allele and IV2+24 insT were found in the Indian population, but not in the Japanese. On the other hand, some Japanese had IV2-21 insT but none of the Indians did. The database supports the notion that the tyrosinase gene evolved and extended separately in the two ethnic groups. And the developing database confirmed that the reported mutations causing Indian and Japanese OCA were not among the polymorphisms in the database, which conversely gives genetical proof of the "genuine" pathological mutations., Conclusion: Eventually, the sequence database we established will contribute to demonstrating novel mutations of albinism in Indians and Japanese.

Tyrosinase is a rate-limiting enzyme in the melanin biosynthetic pathway and a complete defect of the enzyme activity caused by homozygous mutations of the tyrosinase gene is well known to result in tyrosinase-negative oculocutaneous albinism (OCA1A) patients who never develop any melanin pigment in the skin, hair and eyes throughout life. In this paper, we report a novel missense substitution, R239W(CGG --> TGG) of the tyrosinase gene in a patient with tyrosinase-negative OCA.

Dyschromatosis symmetrica hereditaria (DSH) is an autosomal dominant pigmentary disorder, first reported by Toyama in 1910. It is characterized by a mixture of hypopigmented and hyperpigmented macules of various sizes on the backs of the hands and feet. The disease gene of DSH and its chromosomal localization have not yet been identified. A family with DSH and idiopathic torsion dystonia (ITD), a rare neurological disease, was recently reported. Therefore, we speculated that there was a linkage between the DSH gene and the ITD gene, named DYT1 and localized on chromosome 9, and performed linkage analysis between DSH and microsatellite markers on chromosome 9 in three Japanese DSH families (36 patients in total). We obtained a LOD score of < -2 over the whole region of chromosome 9 encompassing DYT1. Thus, we conclude that there is no linkage between DSH and DYT1 as well as any region of chromosome 9.