研究者詳細 - 天谷　雅行

論文 - 天谷　雅行

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IgM to IgG Class Switching Is a Necessary Step for Pemphigus Phenotype Induction in Desmoglein 3-Specific B Cell Receptor Knock-in Mouse

Nomura H., Wada N., Takahashi H., Kase Y., Yamagami J., Egami S., Iriki H., Mukai M., Kamata A., Ito H., Fujii H., Ishikura T., Koseki H., Watanabe T., Yamada T., Ohara O., Koyasu S., Amagai M.

Journal of Immunology （Journal of Immunology） 208 （ 3 ） 582 - 593 2022年02月

ISSN 00221767

Pemphigus vulgaris is an autoimmune blistering disease caused by IgG targeting desmoglein 3 (Dsg3), an adhesion molecule of keratinocytes. Anti-Dsg3 IgG production is prevented in healthy individuals, but it is unclear how Dsg3-specific B cells are regulated. To clarify the immunological condition regulating Dsg3-specific B cells, a pathogenic anti-Dsg3 Ig (AK23) knock-in mouse was generated. AK23 knock-in B cells developed normally without undergoing deletion or acquiring an anergic phenotype in vivo. The knock-in B cells showed Ca2+ influx upon IgM cross-linking and differentiated into AK23-IgG+ B cells after LPS and IL-4 stimulation in vitro that induced a pemphigus phenotype after adoptive transfer into Rag2-/- mice. However, the knock-in mouse itself produced AK23-IgM but little IgG without blisters in vivo. Dsg3 immunization and skin inflammation caused AK23-IgG production and a pemphigus phenotype in vivo. Furthermore, Fcgr2b deficiency or haploinsufficiency spontaneously induced AK23-IgG production and a pemphigus phenotype with poor survival rates in AK23 knock-in mice. To assess Fcgr2b involvement in Ig class-switch efficiency, postswitch transcripts of B cells were quantified and significantly higher in Fcgr2b-/- and Fcgr2b1/mice than wild-type mice in a gene dose-dependent manner. Finally, RNA sequencing revealed reduced expression of FCGR2B and FcγRIIB-related genes in patient B cells. These results indicated that Dsg3-specific B cells do not spontaneously perform pathogenic class switching in vivo, and pemphigus phenotype induction was prevented under normal conditions. Attenuated FcγRIIB signaling is also one of the drivers for pathogenic class switching and is consistent with immunological features identified from clinical samples. This study unveiled a characteristic immune state silencing autoreactive B cells in mice.

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Analysis of clinical characteristics, prognosis and antibody pathogenicity of pemphigus patients positive for anti-desmoglein IgG autoantibodies in remission: a retrospective cohort study

Zhao W.L., Ishii K., Egami S., Xu Z., Funakoshi T., Takahashi H., Tanikawa A., Ishiko A., Amagai M., Yamagami J.

Journal of the European Academy of Dermatology and Venereology （Journal of the European Academy of Dermatology and Venereology） 36 （ 2 ） 271 - 278 2022年02月

ISSN 09269959

Background: The detection of serum anti-desmoglein (Dsg) IgG autoantibodies has been reported to be useful for assessment of disease activity in pemphigus. However, previous studies have reported that anti-Dsg autoantibodies remain detectable in some patients without active pemphigus lesions. Objectives: To investigate the clinical characteristics and antibody pathogenicity of pemphigus patients positive for anti-Dsg IgG autoantibodies in remission. Methods: We retrospectively investigated pemphigus patients with a history of clinical remission who visited the Department of Dermatology of Keio University during 2019 and 2020. The antibody pathogenicity was assessed by bead aggregation assay. Results: When patients were recognized as having entered remission (PDAI = 0 and PSL ≦ 10 mg/day for 2 months), serum autoantibodies against Dsg were detected in 72 of 132 patients (54.5%, positive group; PG), but were not detected in 60 patients (45.5%, negative group; NG). Anti-Dsg antibody titres in remission declined from the active phase in 33 patients in the PG for whom data were available. There were no differences in the chance of reducing PSL to 5 mg/day (P = 0.885) and rate of relapse (P = 0.279) between PG and NG, but fewer patients in PG discontinued corticosteroids (P = 0.004). The ability of patients' sera to block aggregation of Dsg/desmocollin beads was significantly reduced in remission compared to the active phase. However, our results revealed that whole sera in remission still had pathogenic activity in seven of nine patients, and the approximately equal amounts of anti-Dsg antibodies in active phase and remission showed similar pathogenicity. Conclusions: This study will provide guidance in cases where autoantibodies are found to be positive in pemphigus patients during remission or steroid reduction.

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Diagnostic utility of the basophil activation test in natto-induced hypersensitivity

Fukuda R., Ouchi T., Asahina Y., Shiiya C., Takeuchi S., Yasuda-Sekiguchi F., Iriki H., Kouno M., Takahashi S., Tanikawa A., Amagai M., Takahashi H.

Allergology International （Allergology International） 71 （ 1 ） 125 - 130 2022年01月

ISSN 13238930

Background: Natto (fermented soybeans)-induced hypersensitivity is characterized by delayed symptom onset that hampers diagnosis. We aimed to clarify the clinical utility of the basophil activation test (BAT) in the diagnosis of natto-induced hypersensitivity. Methods: Five patients with a history of anaphylaxis and chronic urticaria suspected of natto-induced hypersensitivity and seven with chronic spontaneous urticaria clinically unrelated to natto were enrolled in the patient and control groups, respectively. The BAT was performed with two incubation times, 15 min and 1 h, in combination with various concentrations of natto-mucilage extract. Results: In controls, CD203c levels in basophils remained low in the 15-min incubation but were significantly increased in the 1-h incubation. In the patient group, in the 15-min condition, basophil CD203c was significantly upregulated by natto mucilage but not by soybean vs controls (P = 0.001). Low concentrations of natto mucilage were sufficient to upregulate basophil CD203c in the anaphylaxis cases, but high concentrations were required to induce the same effect in the urticaria cases. Finally, the dose-dependent pattern of the BAT results differed significantly between the anaphylaxis and urticaria cases (P = 0.006). Thus, a strong background reaction was observed in the BAT with 1 h incubation; 15 min of incubation was sufficient to identify patients with natto-induced hypersensitivity and may distinguish the clinical phenotype of natto-induced hypersensitivity, i.e., anaphylaxis or urticaria. Conclusions: The BAT with a 15-min incubation period is useful in diagnosing natto-induced hypersensitivity.

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Imatinib mesylate in combination with pembrolizumab in patients with advanced KIT -mutant melanoma following progression on standard therapy: A phase I/II trial and study protocol

Hirai I., Tanese K., Fukuda K., Fusumae T., Nakamura Y., Sato Y., Amagai M., Funakoshi T.

Medicine (United States) （Medicine (United States)） 100 （ 49 ） 2021年12月

ISSN 00257974

Introduction:Genetic alterations of KIT gene are known to be one of the major causes of melanoma. Those are more common in the mucous and acral subtypes and KIT is regarded as major oncogene in Asian melanomas, where the prevalence of these subtypes is high. Up to date, several clinical trials have been conducted to target KIT gene alterations in melanoma with unsatisfied efficacies. Imatinib mesylate, a small-molecule inhibitor of the KIT tyrosine kinase, provides a rapid but not durable clinical response in KIT-mutant melanoma. Meanwhile, recent basic and clinical evidence have revealed another aspect of KIT-targeted therapy, namely the enhancement of antitumor activity of immune checkpoint inhibitors. Herein, we designed clinical trial of co-administrating imatinib mesylate and pembrolizumab (anti-PD-1 antibody) to evaluate its safety and efficacy.Methods and analysis:This is an open-label, single-arm, phase I/II clinical trial involving Japanese patients with metastatic KIT-mutant melanoma that are refractory to standard therapy including anti-PD-1 therapy. Phase I study is a dose-escalation study comprising two dose levels of imatinib mesylate (200 and 400 mg/day, respectively) with fixed dose of pembrolizumab (200 mg every 3 weeks) to evaluate safety and tolerability and determine recommended phase II dose. The primary endpoint of the phase II study is the objective response rate after 4 cycles (3 weeks/cycle) of pembrolizumab and imatinib mesylate at the dose determined in phase I, based on RECIST version 1.1. A Simon's minimax two-stage design is employed to test the null hypothesis of a 5% response rate vs 30% alternative, which will be rejected when a lower confidence limit of two-sided 90% confidence interval of true response rate is over than threshold response rate. The secondary endpoints include progression free survival, overall survival, best overall response and incidence of adverse events. Totally, a target size of 22 patients will be expected.Discussion:If this study shows efficacy and acceptable safety profile, it will contribute to the development of novel treatment option for patients with KIT-mutant melanoma that are refractory to standard therapy.Trial registration:NCT04546074. Date of Registration: September 11, 2020 (https://clinicaltrials.gov/ct2/show/NCT04546074). Date of First Participant Enrollment: December 23, 2020.

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Peripheral tolerance by treg via constraining OX40 signal in autoreactive T cells against desmoglein 3, a target antigen in pemphigus

Iriki H., Takahashi H., Wada N., Nomura H., Mukai M., Kamata A., Ito H., Yamagami J., Matsui T., Kurebayashi Y., Mise-Omata S., Nishimasu H., Nureki O., Yoshimura A., Hori S., Amagai M.

Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America） 118 （ 49 ） 2021年12月

ISSN 00278424

Antigen-specific peripheral tolerance is crucial to prevent the development of organ-specific autoimmunity. However, its function decoupled from thymic tolerance remains unclear. We used desmoglein 3 (Dsg3), a pemphigus antigen expressed in keratinocytes, to analyze peripheral tolerance under physiological antigen-expression conditions. Dsg3-deficient thymi were transplanted into athymic mice to create a unique condition in which Dsg3 was expressed only in peripheral tissue but not in the thymus. When bone marrow transfer was conducted from high-avidity Dsg3-specific T cell receptor–transgenic mice to thymus-transplanted mice, Dsg3-specific CD4+ T cells developed in the transplanted thymus but subsequently disappeared in the periphery. Additionally, when Dsg3-specific T cells developed in Dsg32/2 mice were adoptively transferred into Dsg3-sufficient recipients, the T cells disappeared in an antigen-specific manner without inducing autoimmune dermatitis. However, Dsg3-specific T cells overcame this disappearance and thus induced autoimmune dermatitis in Treg-ablated recipients but not in Foxp3-mutant recipients with dysfunctional Tregs. The molecules involved in disappearance were sought by screening the transcriptomes of wild-type and Foxp3-mutant Tregs. OX40 of Tregs was suggested to be responsible. Consistently, when OX40 expression of Tregs was constrained, Dsg3-specific T cells did not disappear. Furthermore, Tregs obtained OX40L from dendritic cells in an OX40-dependent manner in vitro and then suppressed OX40L expression in dendritic cells and Birc5 expression in Dsg3-specific T cells in vivo. Lastly, CRISPR/Cas9-mediated knockout of OX40 signaling in Dsg3-specific T cells restored their disappearance in Treg-ablated recipients. Thus, Treg-mediated peripheral deletion of autoreactive T cells operates as an OX40-dependent regulatory mechanism to avoid undesired autoimmunity besides thymic tolerance.

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The pathogeneses of pemphigus and pemphigoid diseases

Ujiie H., Yamagami J., Takahashi H., Izumi K., Iwata H., Wang G., Sawamura D., Amagai M., Zillikens D.

Journal of Dermatological Science （Journal of Dermatological Science） 104 （ 3 ） 154 - 163 2021年12月

ISSN 09231811

Autoimmune bullous diseases (AIBDs) are skin disorders which are mainly induced by autoantibodies against desmosomal or hemidesmosomal structural proteins. Previous studies using patients’ samples and animal disease models identified target antigens and elucidated the mechanisms of blister formation. Pemphigus has been the subject of more active clinical and basic research than any other AIBD. These efforts have revealed the pathogenesis of pemphigus, which in turn has led to optimal diagnostic methods and novel therapies, such as rituximab. In bullous pemphigoid (BP), studies with passive-transfer mouse models using rabbit anti-mouse BP180 antibodies and studies with passive-transfer or active mouse models using autoantigen-humanized mice elucidated the immune reactions to BP180 in vivo. Recently, dipeptidyl peptidase-4 inhibitors have attracted attention as a trigger for BP. For epidermolysis bullosa acquisita (EBA), investigations using mouse models are actively under way and several molecules have been identified as targets for novel therapies. In this review, we give an overview and discussion of the recent progress in our understanding of the pathogenesis of pemphigus, BP, and EBA. Further studies on the breakdown of self-tolerance and on the identification of key molecules that are relevant to blister formation may expand our understanding of the etiology of AIBDs and lead to the development of novel therapeutic strategies.

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Comprehensive and long-term surveys of COVID-19 sequelae in Japan, an ambidirectional multicentre cohort study: Study protocol

Nakagawara K., Namkoong H., Terai H., Masaki K., Tanosaki T., Shimamoto K., Lee H., Tanaka H., Okamori S., Kabata H., Chubachi S., Ikemura S., Kamata H., Yasuda H., Kawada I., Ishii M., Ishibashi Y., Harada S., Fujita T., Ito D., Bun S., Tabuchi H., Kanzaki S., Shimizu E., Fukuda K., Yamagami J., Kobayashi K., Hirano T., Inoue T., Kagyo J., Shiomi T., Ohgino K., Sayama K., Otsuka K., Miyao N., Odani T., Oyamada Y., Masuzawa K., Nakayama S., Suzuki Y., Baba R., Nakachi I., Kuwahara N., Ishiguro T., Mashimo S., Minematsu N., Ueda S., Manabe T., Funatsu Y., Koh H., Yoshiyama T., Saito F., Ishioka K., Takahashi S., Nakamura M., Goto A., Harada N., Kusaka Y., Nakano Y., Nishio K., Tateno H., Edahiro R., Takeda Y., Kumanogoh A., Kodama N., Okamoto M., Umeda A., Hagimura K., Sato T., Miyazaki N., Takemura R., Sato Y., Takebayashi T., Nakahara J., Mimura M., Ogawa K., Shimmura S., Negishi K., Tsubota K., Amagai M., Goto R., Ibuka Y., Hasegawa N., Kitagawa Y., Kanai T., Fukunaga K.

BMJ Open Respiratory Research （BMJ Open Respiratory Research） 8 （ 1 ） 2021年11月

Introduction The rapid spread of COVID-19 posed a global burden. Substantial number of people died of the disease in the acute phase of infection. In addition, a significant proportion of patients have been reported to suffer from post-acute phase symptoms, sequelae of COVID-19, which may negatively influence the quality of daily living and/or socioeconomic circumstances of the patients. However, no previous study has comprehensively and objectively assessed the quality of life of patients by using existing international scales. Further, evidence of socioeconomic consequences among patients with COVID-19 is scarce. To address the multidimensional issues from sequelae of COVID-19, evidence from comprehensive surveys beyond clinical perspectives is critical that investigates health, and social determinants of disease progression as well as socioeconomic consequences at a large scale. Methods and analysis In this study, we plan to conduct a nationwide and comprehensive survey for the sequelae of COVID-19 in a total of 1000 patients diagnosed at 27 hospitals throughout Japan. This study will evaluate not only the health-related status of patients from clinical perspectives but also the Health-related Quality of Life (HRQoL) scores, socioeconomic status and consequences to discuss the sequelae of the disease and the related risk factors. The primary endpoint is the frequency of long-term complications of COVID-19 infection. The secondary endpoints are risk factors for progression to sequelae of COVID-19 infection. The study will provide robust and important evidence as a resource to tackle the issues from the sequelae of COVID-19 from the multi-dimensional perspectives. Ethics and dissemination This trial was approved by the Keio University School of Medicine Ethics Committee (20200243, UMIN000042299). The results of this study will be reported at a society meeting or published in a peer-reviewed journal.

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Filaggrin-gene mutation has minimal effect on the disease severity in the lesions of atopic dermatitis

Ota M., Sasaki T., Ebihara T., Yokosawa E., Murakami Y., Matsunaka H., Chinuki Y., Amagai M., Morita E.

Journal of Dermatology （Journal of Dermatology） 48 （ 11 ） 1688 - 1699 2021年11月

ISSN 03852407

Loss-of-function mutations of filaggrin (FLG) gene (FLG) are the strongest known genetic risk factor for atopic dermatitis (AD). It is still debatable how FLG gene mutations and the resulting abnormal amount of FLG protein contribute to skin barrier function and symptoms of AD. In this study, we examined the effects of loss-of-function mutations of FLG gene on the severity of skin lesions and skin barrier function in 55 patients with AD by evaluating eight patients with AD with FLG gene mutations and 47 patients with AD without mutations. The results showed that the FLG gene mutation did not affect the duration of AD, severity of AD, degree of local inflammatory symptoms, skin water content and trans-epidermal water loss of the lesions. Next, in these eight mutation carriers and the 47 non-carriers, stratum corneum was collected from the three site of skin lesions using tape-stripping method, and the amounts of FLG protein and total amino acid contained in the stratum corneum was measured to investigate the effect of the FLG gene mutation on the amount of FLG gene product in the local lesion. FLG abnormalities had little effect on FLG protein and total amino acid content in the stratum corneum in the lesional skin. The amount of the FLG products, especially amino acids derived from FLG, in the stratum corneum of AD lesional skin is influenced by development of dermatitis. The results obtained from this study supports that the activation of Th2-dominant inflammatory cells, together with FLG abnormality, plays a role in suppressing the production of FLG in skin lesions.

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Frequent FGFR3 and Ras Gene Mutations in Skin Tags or Acrochordons

Aoki S., Hirata Y., Kawai T., Nakabayashi K., Hata K., Suzuki H., Kosaki K., Amagai M., Kubo A.

Journal of Investigative Dermatology （Journal of Investigative Dermatology） 141 （ 11 ） 2756 - 2760.e8 2021年11月

ISSN 0022202X

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Efficacy of hydroxychloroquine for treating annular erythema associated with Sjögren’s syndrome

Arakawa H., Tanese K., Tanaka R., Murakami K., Sujino K., Miyamoto J., Amagai M., Tanikawa A.

Journal of Dermatology （Journal of Dermatology） 48 （ 10 ） 1526 - 1532 2021年10月

ISSN 03852407

Annular erythema is one of the cutaneous manifestations of Sjögren’s syndrome (SS). Topical corticosteroids and tacrolimus, and oral corticosteroids, have been used as treatments for this condition. However, the safety and efficacy of these treatments remains unsatisfactory, and further development of therapies are desired. In this study, we performed a retrospective analysis of 16 annular erythema associated with SS (AESS) patients treated with hydroxychloroquine (HCQ). Disease activity was assessed using a modified version of the Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI), which we termed the modified CLASI (m-CLASI). HCQ treatment improved AESS lesions in all 16 patients. The mean m-CLASI score was reduced by 85.6% at the 12-week follow-up relative to baseline (p < 0.01). Notably, 60% (6/10 cases) of patients with AESS lesions limited to the facial area achieved complete remission within 4 weeks. In the analysis of six patients who had taken oral prednisolone before starting HCQ, all were able to reduce the dose within 52 weeks without relapse. Particularly, 75% (3/4 cases) of patients with prednisolone dose of more than 5 mg/day could reduce their dose to less than 5 mg/day in combination with HCQ. For the safety concerns, two patients experienced grade 1 diarrhea during the 52-week observation period. However, neither serious adverse events nor adverse events requiring discontinuation of treatment occurred. The results of the present study suggest that HCQ may not only be highly effective as a single agent, but may also be useful as a steroid-sparing agent in refractory case requiring long-term steroid administration, making it a good treatment option for AESS.

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A multicenter, open-label, uncontrolled, single-arm phase 2 study of tirabrutinib, an oral Bruton's tyrosine kinase inhibitor, in pemphigus

Yamagami J., Ujiie H., Aoyama Y., Ishii N., Tateishi C., Ishiko A., Ichijima T., Hagihara S., Hashimoto K., Amagai M.

Journal of Dermatological Science （Journal of Dermatological Science） 103 （ 3 ） 135 - 142 2021年09月

ISSN 09231811

Background: The treatment of pemphigus is based on systemic corticosteroid use and adjuvant therapies, but some patients are resistant to conventional therapy. Tirabrutinib is a highly selective oral Bruton's tyrosine kinase inhibitor that may be clinically effective in treating pemphigus by suppressing B-cell signaling. Objective: We investigated the efficacy and safety of tirabrutinib in patients with refractory pemphigus. Methods: This was a multicenter, open-label, single-arm phase 2 study of Japanese patients with refractory pemphigus receiving appropriate treatment with an oral corticosteroid and adjuvant therapies. Patients received postprandial oral tirabrutinib 80 mg once daily for 52 weeks. After 16 weeks of tirabrutinib treatment, the corticosteroid dose was tapered to ≤10 mg/day of prednisolone equivalent. Results: In total, 16 patients were evaluated (mean age, 52.5 years; 50 % male). The complete remission rate after 24 weeks of treatment (primary endpoint) was 18.8 % (3/16; 95 % confidence interval, 6.6 %–43.0 %). By Week 52, eight patients (50.0 %) achieved complete remission and 10 patients (62.5 %) achieved remission. Over 52 weeks of treatment, the mean prednisolone dose decreased from 17.03 to 7.65 mg/day. Incidences of adverse events (AEs) and adverse drug reactions were 87.5 % and 43.8 %, respectively. A relationship with tirabrutinib was ruled out for all serious AEs and Grade ≥3 AEs. Conclusion: Treatment with tirabrutinib enabled remission and reduced oral corticosteroid exposure over time and did not result in any major safety concerns in patients with refractory pemphigus. Thus, oral tirabrutinib may be a new treatment option for patients with refractory pemphigus.

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Neonatal Linear IgA Bullous Dermatosis Mediated by Breast Milk-Borne Maternal IgA

Egami S., Suzuki C., Kurihara Y., Yamagami J., Kubo A., Funakoshi T., Nishie W., Matsumura K., Matsushima T., Kawaida M., Sakamoto M., Amagai M.

JAMA Dermatology （JAMA Dermatology） 157 （ 9 ） 1107 - 1111 2021年09月

ISSN 21686068

Importance: Neonatal linear immunoglobulin A (IgA) bullous dermatosis (LABD) is a rare disease that can be fatal when associated with respiratory failure. All previously reported cases of neonatal LABD have been in newborns with healthy asymptomatic mothers, and the pathogenic IgA was of unknown origin. Objective: To clarify the origin of IgA associated with LABD in neonates born of healthy asymptomatic mothers. Design, Setting, and Participants: This case study analyzed the laboratory findings of a single breast-fed newborn male with neonatal LABD admitted to the Keio University Hospital in Tokyo and his healthy asymptomatic mother. The healthy newborn developed life-threatening blisters and erosions of the skin and mucous membranes on day 4 after birth. Blood serum, skin, and maternal breast milk were examined for IgA autoantibodies. Main Outcomes and Measures: Histopathologic and immunofluorescence analyses of specimens (serum, skin, and breast milk) from the patient and his mother. Results: Histopathologic evaluation of the newborn's skin revealed subepidermal blisters with neutrophil infiltrates, and immunofluorescence testing showed linear IgA deposition along the basement membrane zone (BMZ), which lead to the diagnosis of neonatal LABD. Indirect immunofluorescence using normal human skin after treatment with 1-mol/L sodium chloride showed the patient to have circulating IgA binding to the dermal side of BMZ. Immunohistochemical staining proved the deposition of secretory IgA in the neonatal skin by demonstrating the presence of J chain - not been seen in other LABD cases - indicating that the autoantibodies producing the blisters were derived from the maternal breast milk. Although no circulating IgA against the skin was detected in mother's sera, the breast milk contained IgA that reacted with the dermal side of the BMZ. No new blister formation was observed after cessation of breastfeeding. Conclusions and Relevance: The results of this case study suggest a passive transfer of pathogenic IgA to a newborn from an asymptomatic mother via breast milk. In prior reports, no serum from asymptomatic mothers of newborns with LABD had IgA autoantibodies binding to skin components; however, in this case, we found that the maternal breast milk contained IgA autoantibodies associated with neonatal LABD. In neonatal LABD, maternal breast milk should be examined for IgA autoantibodies and breast milk feeding should be discontinued as soon as neonatal LABD is suspected..

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Adoptive cell therapy using tumor-infiltrating lymphocytes for melanoma refractory to immune-checkpoint inhibitors

Hirai I., Funakoshi T., Kamijuku H., Fukuda K., Mori M., Sakurai M., Koda Y., Kato J., Mori T., Watanabe N., Noji S., Yaguchi T., Iwata T., Ohta S., Fujita T., Tanosaki R., Handa M., Okamoto S., Amagai M., Kawakami Y.

Cancer Science （Cancer Science） 112 （ 8 ） 3163 - 3172 2021年08月

ISSN 13479032

To evaluate the feasibility of adoptive cell therapy (ACT) using ex vivo-expanded tumor-infiltrating lymphocytes (TILs) in Japanese patients with melanoma who failed immune-checkpoint inhibitor therapy, an open-label, single-arm, pilot study was conducted. We investigated the immunological and genetic factors of the pretreatment tumor and expanded TILs that may be associated with the clinical response. The treatment protocol comprised preparation of TIL culture, lympho-depleting non-myeloablative preconditioning with cyclophosphamide and fludarabine, TIL infusion, and intravenous administration of low-dose IL-2. Three patients of clinical subtypes mucosal, superficial spreading, and acral melanoma underwent TIL-ACT. Most severe adverse events, including fever and leukopenia, were manageable with the supportive regimen specified in the protocol, suggesting that the TIL-ACT regimen is suitable for Japanese patients with melanoma. One patient showed a short-term partial response, one relatively long-stable disease, and one experienced disease progression. Whole-exome and transcriptional sequencing of isolated tumor cells and immunohistochemical analyses before TIL-ACT revealed various immunostimulatory factors, including a high tumor mutation burden and immune cell-recruiting chemokines, as well as various immunosuppressive factors including TGF-β, VEGF, Wnt/β-catenin, and MAPK signaling and epithelial-to-mesenchymal transition, which might influence the efficacy of TIL-ACT. Our results imply mechanisms for the antitumor effect of and resistance to TIL-ACT. Further studies of immune-resistant mechanisms of TIL-ACT are warranted. This study is registered with the UMIN Clinical Trial Registry (UMIN 000011431).

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爪甲紅色線条を呈した爪乳頭腫の1例

椎谷千尋, 種本紗枝, 宮本樹里亜, 天谷雅行, 齋藤昌孝

皮膚科の臨床（金原出版(株)） 63 （ 9 ） 1417 - 1419 2021年08月

ISSN 0018-1404

＜文献概要＞45歳,男性。左拇指爪甲の爪半月から爪甲遠位端まで伸びる幅2mmの紅色線条がみられた。爪甲遠位端には爪甲下に角質の付着を認め,同部位に非常に強い圧痛の訴えがあった。ダーモスコピーでは爪甲の下面が軽度陥凹しており,陥凹部では角質塊がみられた。紅色線条をすべて切除したところ,病理では紅色線条部の爪甲の低形成に加えて,爪床表皮の乳頭状増殖と真皮浅層の毛細血管拡張の所見を認めた。臨床および病理所見より,爪乳頭腫と診断した。術後速やかに疼痛は消失し,明らかな爪甲の変形も残さなかった。爪甲紅色線条を呈する疾患はいくつか知られており,そのひとつが爪乳頭腫である。爪乳頭腫はその病因や病態が未だ不明なこともあり,貴重な症例と考え報告した。

Autosomal dominant familial acanthosis nigricans caused by a C-terminal nonsense mutation of FGFR3

Tahara U., Yasuda M., Yamada Y., Aoki S., Sato S., Amagai M., Kubo A.

Journal of Human Genetics （Journal of Human Genetics） 66 （ 8 ） 831 - 834 2021年08月

ISSN 14345161

FGFR3 encodes a transmembrane receptor tyrosine kinase that has six autophosphorylation sites of tyrosine. Among them, Y770 is a negative regulatory site for the downstream signaling of FGFR3. Constitutive active mutations in FGFR3 are involved in human developmental disorders including familial acanthosis nigricans, an autosomal dominant disorder characterized by general hyperpigmentation with mild acanthosis of the epidermis. Here, we report two unrelated cases of familial acanthosis nigricans with a heterozygous c.2302G>T (p.E768*) mutation in FGFR3 (NM_000142.5). FGFR3 mRNA purified from the skin lesion neither showed aberrant splicing nor nonsense-mediated mRNA decay, indicating that the FGFR3 mutant simply lacked the C-terminal 768–806 amino acids including Y770. While all of the known pathogenic mutations were missense mutations in FGFR3 showing autosomal dominant trait, the c.2302G>T mutation of FGFR3 is a unique autosomal dominant nonsense mutation that causes familial acanthosis nigricans probably via loss of negative regulatory autophosphorylation site of FGFR3.

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Risk of Stevens-Johnson syndrome and toxic epidermal necrolysis associated with anticonvulsants in a Japanese population: Matched case–control and cohort studies

Fukasawa T., Takahashi H., Takahashi K., Tanemura N., Amagai M., Urushihara H.

Allergology International （Allergology International） 70 （ 3 ） 335 - 342 2021年07月

ISSN 13238930

Background: Evidence for the risk and incidence of anticonvulsant-induced Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) in Japan is scarce. Methods: We conducted a matched case–control study using a large-scale Japanese claims database. SJS/TEN cases were identified using a claims-based algorithm developed in a previous study (sensitivity 76.9%, specificity 99.0%). Conditional logistic regression with Firth's bias correction to address an issue of rare events was used to estimate odds ratios (ORs) for SJS/TEN for each anticonvulsant use (90 days before the index date) versus non-use. 90-day cumulative incidence of SJS/TEN per 100,000 new users was calculated for 33 anticonvulsants. Causality between anticonvulsant use and SJS/TEN in each exposed case was assessed using the algorithm of drug causality for epidermal necrolysis (ALDEN) score. Results: From 5,114,492 subjects, we selected 71 SJS/TEN cases and 284 controls. We observed significantly increased ORs for SJS/TEN among new users of carbamazepine (OR 68.00) and lamotrigine (OR 36.00) with ALDEN scores of “probable” or higher. Cumulative incidence of SJS/TEN was 93.83 for carbamazepine and 84.33 for lamotrigine. One case newly exposed to phenytoin which developed SJS/TEN was rated “unlikely” in ALDEN causality, resulting in cumulative incidence of 66.27. Cumulative incidence of SJS/TEN was 25.23 for levetiracetam, 7.52 for clonazepam, and 1.23 for diazepam, but their ALDEN scores were “very unlikely”. Conclusions: This study is the first to document the differential risk of SJS/TEN for anticonvulsants in a real-world setting in Japan. Exposure to carbamazepine and lamotrigine was associated with an increased risk of SJS/TEN.

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Atopic dermatitis: Role of the skin barrier, environment, microbiome, and therapeutic agents

Luger T., Amagai M., Dreno B., Dagnelie M.A., Liao W., Kabashima K., Schikowski T., Proksch E., Elias P.M., Simon M., Simpson E., Grinich E., Schmuth M.

Journal of Dermatological Science （Journal of Dermatological Science） 102 （ 3 ） 142 - 157 2021年06月

ISSN 09231811

Atopic dermatitis (AD) is a chronic, inflammatory skin disorder characterized by eczematous and pruritic skin lesions. In recent decades, the prevalence of AD has increased worldwide, most notably in developing countries. The enormous progress in our understanding of the complex composition and functions of the epidermal barrier allows for a deeper appreciation of the active role that the skin barrier plays in the initiation and maintenance of skin inflammation. The epidermis forms a physical, chemical, immunological, neuro-sensory, and microbial barrier between the internal and external environment. Not only lesional, but also non-lesional areas of AD skin display many morphological, biochemical and functional differences compared with healthy skin. Supporting this notion, genetic defects affecting structural proteins of the skin barrier, including filaggrin, contribute to an increased risk of AD. There is evidence to suggest that natural environmental allergens and man-made pollutants are associated with an increased likelihood of developing AD. A compromised epidermal barrier predisposes the skin to increased permeability of these compounds. Numerous topical and systemic therapies for AD are currently available or in development; while anti-inflammatory therapy is central to the treatment of AD, some existing and novel therapies also appear to exert beneficial effects on skin barrier function. Further research on the skin barrier, particularly addressing epidermal differentiation and inflammation, lipid metabolism, and the role of bacterial communities for skin barrier function, will likely expand our understanding of the complex etiology of AD and lead to identification of novel targets and the development of new therapies.

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A unique mode of keratinocyte death requires intracellular acidification

Matsui T., Kadono-Maekubo N., Suzuki Y., Furuichi Y., Shiraga K., Sasaki H., Ishida A., Takahashi S., Okada T., Toyooka K., Sharif J., Abe T., Kiyonari H., Tominaga M., Miyawaki A., Amagai M.

Proceedings of the National Academy of Sciences of the United States of America （Proceedings of the National Academy of Sciences of the United States of America） 118 （ 17 ） 2021年04月

ISSN 00278424

The stratum corneum (SC), the outermost epidermal layer, consists of nonviable anuclear keratinocytes, called corneocytes, which function as a protective barrier. The exact modes of cell death executed by keratinocytes of the upper stratum granulosum (SG1 cells) remain largely unknown. Here, using intravital imaging combined with intracellular Ca2+- and pH-responsive fluorescent probes, we aimed to dissect the SG1 death process in vivo. We found that SG1 cell death was preceded by prolonged (∼60 min) Ca2+ elevation and rapid induction of intracellular acidification. Once such intracellular ionic changes were initiated, they became sustained, irreversibly committing the SG1 cells to corneocyte conversion. Time-lapse imaging of isolated murine SG1 cells revealed that intracellular acidification was essential for the degradation of keratohyalin granules and nuclear DNA, phenomena specific to SC corneocyte formation. Furthermore, intravital imaging showed that the number of SG1 cells exhibiting Ca2+ elevation and the timing of intracellular acidification were both tightly regulated by the transient receptor potential cation channel V3. The functional activity of this protein was confirmed in isolated SG1 cells using whole-cell patch-clamp analysis. These findings provide a theoretical framework for improved understanding of the unique molecular mechanisms underlying keratinocyte-specific death mode, namely corneoptosis.

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Staphylococcus cohnii is a potentially biotherapeutic skin commensal alleviating skin inflammation

Ito Y., Sasaki T., Li Y., Tanoue T., Sugiura Y., Skelly A.N., Suda W., Kawashima Y., Okahashi N., Watanabe E., Horikawa H., Shiohama A., Kurokawa R., Kawakami E., Iseki H., Kawasaki H., Iwakura Y., Shiota A., Yu L., Hisatsune J., Koseki H., Sugai M., Arita M., Ohara O., Matsui T., Suematsu M., Hattori M., Atarashi K., Amagai M., Honda K.

Cell Reports （Cell Reports） 35 （ 4 ） 2021年04月

Host-microbe interactions orchestrate skin homeostasis, the dysregulation of which has been implicated in chronic inflammatory conditions such as atopic dermatitis and psoriasis. Here, we show that Staphylococcus cohnii is a skin commensal capable of beneficially inhibiting skin inflammation. We find that Tmem79−/− mice spontaneously develop interleukin-17 (IL-17)-producing T-cell-driven skin inflammation. Comparative skin microbiome analysis reveals that the disease activity index is negatively associated with S. cohnii. Inoculation with S. cohnii strains isolated from either mouse or human skin microbiota significantly prevents and ameliorates dermatitis in Tmem79−/− mice without affecting pathobiont burden. S. cohnii colonization is accompanied by activation of host glucocorticoid-related pathways and induction of anti-inflammatory genes in the skin and is therefore effective at suppressing inflammation in diverse pathobiont-independent dermatitis models, including chemically induced, type 17, and type 2 immune-driven models. As such, S. cohnii strains have great potential as effective live biotherapeutics for skin inflammation.

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造影CTで検出困難であった活動性出血が外科的介入時に判明したdeep dissecting hematomaの1例

小川夕貴, 伏間江貴之, 舩越建, 加藤達也, 岡部圭介, 小林秀, 天谷雅行, 山上淳

臨床皮膚科（(株)医学書院） 75 （ 4 ） 285 - 289 2021年04月

ISSN 0021-4973

＜文献概要＞60歳,男性.ワルファリンカリウム内服中.初診1ヵ月前に左足外顆の皮下腫瘤を自覚した.初診2週間前に近医を受診し,ガングリオン疑いで穿刺された.その後,皮下腫瘤は増大傾向となり,疼痛も出現したため前医整形外科を受診した.MRIにて陳旧性血腫を認め,当科紹介受診した.初診時,左足外顆に径5cm大,びらんを伴う暗紫紅色の皮下腫瘤を認め,発赤と腫脹を伴っていた.造影CTで活動性出血を示唆する所見なく,皮下血腫の二次感染を疑い抗生剤投与と圧迫療法を開始したが増悪傾向で第7病日に局所麻酔下で血腫除去術を施行した.術中,深部動脈からの活動性出血を認め結紮処理した.脂肪組織と筋膜の間に血腫を生じており,自験例をdeep dissecting hematomaと診断した.血腫が出血源を圧迫していたため出血が持続的ながら緩徐であり,画像検査で活動性出血を同定できなかったと考えられた.臨床的に血腫の拡大を疑う場合は,画像所見にかかわらず早期の外科的治療介入が重要と考えた.

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