論文 - 高橋　勇人

ADAM10 partially protects mice against influenza pneumonia by suppressing specific myeloid cell population

Okamori S., Ishii M., Asakura T., Suzuki S., Namkoong H., Kagawa S., Hegab A.E., Yagi K., Kamata H., Kusumoto T., Ogawa T., Takahashi H., Yoda M., Horiuchi K., Hasegawa N., Fukunaga K.

American Journal of Physiology - Lung Cellular and Molecular Physiology （American Journal of Physiology - Lung Cellular and Molecular Physiology）  321 （ 5 ） L872 - L884 2021年11月

ISSN  10400605

　概要を見る

The influenza virus infection poses a serious health threat worldwide. Myeloid cells play pivotal roles in regulating innate and adaptive immune defense. A disintegrin and metalloproteinase (ADAM) family of proteins contributes to various immune responses; however, the role of a disintegrin and metalloproteinase domain-containing protein 10 (ADAM10) in influenza virus infection remains largely unknown. Herein, we investigated its role, focusing on myeloid cells, during influenza virus infection in mice. ADAM10 gene (Adam10)flox/flox/Lyz2-Cre (Adam10DLyz2) and control Adam10flox/flox mice were intranasally infected with 200 plaque-forming units of influenza virus A/H1N1/PR8/34. Adam10DLyz2 mice exhibited a significantly higher mortality rate, stronger lung inflammation, and a higher virus titer in the lungs than control mice. Macrophages and inflammatory cytokines, such as TNF-a, IL-1b, and CCL2, were increased in bronchoalveolar lavage fluid from Adam10DLyz2 mice following infection. CD11b+Ly6G-F4/80+ myeloid cells, which had an inflammatory monocyte/macrophage-like phenotype, were significantly increased in the lungs of Adam10DLyz2 mice. Adoptive transfer experiments suggested that these cells likely contributed to the poorer prognosis in Adam10DLyz2 mice. Seven days after infection, CD11b+Ly6G-F4/80+ lung cells exhibited significantly higher arginase-1 expression levels in Adam10DLyz2 mice than in control mice, whereas an arginase-1 inhibitor improved the prognosis of Adam10DLyz2 mice. Enhanced granulocyte-macrophage colony-stimulating factor (GM-CSF)/GM-CSF receptor signaling likely contributed to this process. Collectively, these results indicate that myeloid ADAM10 protects against influenza virus pneumonia and may be a promising therapeutic target.

• Access to Document (DOI)

Successful treatment of a patient with adult food allergy and severe asthma using omalizumab

Nishie M., Masaki K., Okuzumi S., Mochimaru T., Kabata H., Miyata J., Takahashi H., Fukunaga K.

Asia Pacific Allergy （Asia Pacific Allergy）  11 2021年07月

ISSN  22338276

　概要を見る

Food allergy is a typical immediate-onset allergic disease in which symptoms are provoked by exposure to the sensitized antigens. Although previous reports have shown that omalizumab has helped children with egg or milk allergy achieve oral immunotherapy safely, there is still no established method for induction of remission in adult food allergy. A 51-year-old woman with oral steroid-dependent severe asthma was treated with omalizumab for 6 years. She had shellfish and wheat food allergy and oral allergy syndrome induced by kiwi and other foods associated with latex-fruit syndrome. Since omalizumab treatment, her food allergy symptoms had disappeared. After 7 years of this treatment, disseminated erythema suddenly appeared; omalizumab was discontinued because of suspected drug-induced eruption. After omalizumab interruption, she felt an itching sensation in her throat with worsened asthma control immediately after wheat ingestion. Readministration of omalizumab improved these symptoms. Thus, we raised the possibility that omalizumab not only improved asthma control but also induced pharmacological remission of the patient's food allergy. Omalizumab may be considered as a treatment option for adult patients with food allergies and severe asthma.

• Access to Document (DOI)

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

　概要を見る

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.

• Access to Document (DOI)

Neutrophils initiate and exacerbate Stevens-Johnson syndrome and toxic epidermal necrolysis

Kinoshita M., Ogawa Y., Hama N., Ujiie I., Hasegawa A., Nakajima S., Nomura T., Adachi J., Sato T., Koizumi S., Shimada S., Fujita Y., Takahashi H., Mizukawa Y., Tomonaga T., Nagao K., Abe R., Kawamura T.

Science Translational Medicine （Science Translational Medicine）  13 （ 600 ）  2021年06月

ISSN  19466234

　概要を見る

Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening mucocutaneous adverse drug reactions characterized by massive epidermal detachment. Cytotoxic T cells and associated effector molecules are known to drive SJS/TEN pathophysiology, but the contribution of innate immune responses is not well understood. We describe a mechanism by which neutrophils triggered inflammation during early phases of SJS/TEN. Skin-infiltrating CD8+ T cells produced lipocalin-2 in a drug-specific manner, which triggered the formation of neutrophil extracellular traps (NETs) in early lesional skin. Neutrophils undergoing NETosis released LL-37, an antimicrobial peptide, which induced formyl peptide receptor 1 (FPR1) expression by keratinocytes. FPR1 expression caused keratinocytes to be vulnerable to necroptosis that caused further release of LL-37 by necroptotic keratinocytes and induced FPR1 expression on surrounding keratinocytes, which likely amplified the necroptotic response. The NETs-necroptosis axis was not observed in less severe cutaneous adverse drug reactions, autoimmune diseases, or neutrophil-associated disorders, suggesting that this was a process specific to SJS/TEN. Initiation and progression of SJS/TEN keratinocyte necroptosis appear to involve a cascade of events mediated by innate and adaptive immune responses, and understanding these responses may contribute to the identification of diagnostic markers or therapeutic targets for these adverse drug reactions.

• Access to Document (DOI)

MicroRNA-221 and -222 modulate intestinal inflammatory Th17 cell response as negative feedback regulators downstream of interleukin-23

Mikami Y., Philips R.L., Sciumè G., Petermann F., Meylan F., Nagashima H., Yao C., Davis F.P., Brooks S.R., Sun H.W., Takahashi H., Poholek A.C., Shih H.Y., Afzali B., Muljo S.A., Hafner M., Kanno Y., O'Shea J.J.

Immunity （Immunity）  54 （ 3 ） 514 - 525.e6 2021年03月

ISSN  10747613

　概要を見る

MicroRNAs are important regulators of immune responses. Here, we show miR-221 and miR-222 modulate the intestinal Th17 cell response. Expression of miR-221 and miR-222 was induced by proinflammatory cytokines and repressed by the cytokine TGF-β. Molecular targets of miR-221 and miR-222 included Maf and Il23r, and loss of miR-221 and miR-222 expression shifted the transcriptomic spectrum of intestinal Th17 cells to a proinflammatory signature. Although the loss of miR-221 and miR-222 was tolerated for maintaining intestinal Th17 cell homeostasis in healthy mice, Th17 cells lacking miR-221 and miR-222 expanded more efficiently in response to IL-23. Both global and T cell-specific deletion of miR-221 and miR-222 rendered mice prone to mucosal barrier damage. Collectively, these findings demonstrate that miR-221 and miR-222 are an integral part of intestinal Th17 cell response that are induced after IL-23 stimulation to constrain the magnitude of proinflammatory response.

• Access to Document (DOI)

Recent advancement of drug-induced hypersensitivity syndrome

Takahashi H.

Nishinihon Journal of Dermatology （Nishinihon Journal of Dermatology）  83 （ 4 ） 295 - 300 2021年

ISSN  03869784

• Access to Document (DOI)

Cholesterol 25-hydroxylase is a metabolic switch to constrain T cell–mediated inflammation in the skin

Takahashi H., Nomura H., Iriki H., Kubo A., Isami K., Mikami Y., Mukai M., Sasaki T., Yamagami J., Kudoh J., Ito H., Kamata A., Kurebayashi Y., Yoshida H., Yoshimura A., Sun H.W., Suematsu M., O’Shea J.J., Kanno Y., Amagai M.

Science Immunology （Science Immunology）  6 （ 64 ）  2021年

　概要を見る

Interleukin-27 (IL-27) is an immunoregulatory cytokine whose essential function is to limit immune responses. We found that the gene encoding cholesterol 25-hydroxylase (Ch25h) was induced in CD4+ T cells by IL-27, enhanced by transforming growth factor–β (TGF-β), and antagonized by T-bet. Ch25h catalyzes cholesterol to generate 25-hydroxycholesterol (25OHC), which was subsequently released to the cellular milieu, functioning as a modulator of T cell response. Extracellular 25OHC suppressed cholesterol biosynthesis in T cells, inhibited cell growth, and induced nutrient deprivation cell death without releasing high-mobility group box 1 (HMGB1). This growth inhibitory effect was specific to actively proliferating cells with high cholesterol demand and was reversed when extracellular cholesterol was replenished. Ch25h-expressing CD4+ T cells that received IL-27 and TGF-β signals became refractory to 25OHC-mediated growth inhibition in vitro. Nonetheless, IL-27–treated T cells negatively affected viability of bystander cells in a paracrine manner, but only if the bystander cells were in the early phases of activation. In mouse models of skin inflammation due to autoreactive T cells or chemically induced hypersensitivity, genetic deletion of Ch25h or Il27ra led to worse outcomes. Thus, Ch25h is an immunoregulatory metabolic switch induced by IL-27 and dampens excess bystander T effector expansion in tissues through its metabolite derivative, 25OHC. This study reveals regulation of cholesterol metabolism as a modality for controlling tissue inflammation and thus represents a mechanism underlying T cell immunoregulatory functions.

• Access to Document (DOI)

The nationwide epidemiological survey of Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan, 2016-2018

Sunaga Y., Kurosawa M., Ochiai H., Watanabe H., Sueki H., Azukizawa H., Asada H., Watanabe Y., Yamaguchi Y., Aihara M., Mizukawa Y., Ohyama M., Hama N., Abe R., Hashizume H., Nakajima S., Nomura T., Kabashima K., Tohyama M., Takahashi H., Mieno H., Ueta M., Sotozono C., Niihara H., Morita E., Kokaze A.

Journal of Dermatological Science （Journal of Dermatological Science）  100 （ 3 ） 175 - 182 2020年12月

ISSN  09231811

　概要を見る

Background: Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse reactions (SCARs). The first national epidemiological survey of SJS/TEN was carried out in 2008. We conducted a new survey to identify changes from the previous survey. Objective: The present survey aimed to estimate the number of SJS/TEN patients in Japan between 2016 and 2018 (primary survey) and to clarify clinical epidemiological profiles (secondary survey). Methods: A primary survey asking for numbers of SJS/TEN patients during the study period was sent to 1205 institutions nationwide. A secondary survey was sent to institutions reporting SJS/TEN patients, seeking detailed information. Results: Yearly prevalence per million was 2.5 for SJS and 1 for TEN. The secondary survey allowed analysis of 315 SJS cases and 174 TEN cases from 160 institutions. Mean age was 53.9 years in SJS, and 61.8 years in TEN. Mortality rate was 4.1 % for SJS and 29.9 % for TEN. In TEN, mean age and mortality rates had increased from the previous survey. The ratio of expected to observed mortality calculated by SCORTEN score was lowest with high-dose steroid therapy (0.40), followed by steroid pulse therapy (0.52). Conclusion: The present findings suggest that the mortality rate of TEN has increased because of increases in mean ages of patients and patients with malignant neoplasm as underlying disease. When comparing the ratio of expected mortality to actual mortality, high-dose steroid therapy achieved the greatest reduction in mortality.

• Access to Document (DOI)

Life-threatening rocuronium-induced anaphylactic shock without cutaneous manifestations successfully reversed with sugammadex: a case report

Takise Y., Kato J., Suhara T., Yamada T., Funakoshi T., Takahashi H., Amagai M., Morisaki H.

JA Clinical Reports （JA Clinical Reports）  6 （ 1 ）  2020年12月

　概要を見る

Background: Recognition of rocuronium-induced anaphylaxis is often challenging, owing to its diverse clinical manifestations. Regarding treatment, several reports have described the efficacy of sugammadex, while conflicting reports have also been published. Case: A 71-year-old man was scheduled to undergo split-thickness skin grafting surgery on his hip. During the induction of general anesthesia, the patient developed profound circulatory collapse without any cutaneous manifestations, which required 40 min of cardiopulmonary resuscitation. Later, the patient developed circulatory collapse again during the induction of anesthesia for tracheostomy surgery, which apparently coincided with the administration of rocuronium. Rocuronium-induced anaphylactic shock was suspected, and the administration of sugammadex resulted in swift recovery of hemodynamics. The basophil activation test revealed a positive reaction to rocuronium. Conclusion: The possibility of rocuronium-induced anaphylaxis should be considered when the circulatory collapse coincides with rocuronium administration, even though cutaneous manifestation is absent. Sugammadex can be a treatment option in such atypical cases.

• Access to Document (DOI)

Imiquimod-induced dermatitis impairs thymic tolerance of autoreactive CD4⁺ T cells to desmoglein 3

Iriki H., Mukai M., Ito H., Kurebayashi Y., Amagai M., Takahashi H.

Journal of Dermatological Science （Journal of Dermatological Science）  100 （ 3 ） 166 - 174 2020年12月

ISSN  09231811

　概要を見る

Background: The thymus plays an essential role in removing autoreactive T cells. Autoantigen-expressing thymic epithelial cells (TECs) contribute to the tolerogenic process. The thymus transiently shrinks as an acute thymic involution (ATI) under various inflammatory conditions. However, whether ATI occurs during local skin inflammation remains unclear, as does its influence on thymic immune tolerance. Objective: We investigated whether imiquimod-induced dermatitis causes ATI and impairs thymic immune tolerance against desmoglein 3 (Dsg3), an epidermal autoantigen of pemphigus vulgaris. Methods: 5% imiquimod cream was applied daily, at 62.5 mg/day (high dose group) or 31.25 mg/day (low dose group), for 1 week on the back of wild-type mice, and to wild-type mice that had undergone bone-marrow transplantation from Dsg3-specific T-cell receptor (TCR) transgenic-Rag2−/− mice. Next, thymocytes, TECs and other immune cells were analyzed by flow cytometry. TEC-associated Dsg3 expression was also analyzed by immunofluorescence staining. Results: Thymus weight and thymocyte number in all developmental stages decreased in a dose-dependent manner under imiquimod-induced dermatitis. The number of total TECs, specifically medullary, but not cortical, TECs, decreased in high and low dose groups. Accordingly, the number of Dsg3-experssing UEA-1+keratin 5+mTEC decreased in the thymus during imiquimod-induced dermatitis. Although Dsg3-sepcific transgenic thymocytes was usually deleted in the thymus under physiological condition by central tolerance, Dsg3-sepcific transgenic CD4+CD8− thymocytes significantly increased in number under imiquimod-induced dermatitis. Conclusion: These findings indicate a crosstalk between skin and thymus in adult mice and suggest that skin inflammation may impair thymic tolerance to autoantigens, such as Dsg3.

• Access to Document (DOI)

Targeting inducible costimulator expressed on CXCR5⁺PD-1⁺ T<inf>H</inf> cells suppresses the progression of pemphigus vulgaris

Kim A.R., Han D., Choi J.Y., Seok J., Kim S.E., Seo S.H., Takahashi H., Amagai M., Park S.H., Kim S.C., Shin E.C., Kim J.H.

Journal of Allergy and Clinical Immunology （Journal of Allergy and Clinical Immunology）  146 （ 5 ） 1070 - 1079.e8 2020年11月

ISSN  00916749

　概要を見る

Background: Pemphigus vulgaris (PV) is an autoimmune bullous disease mediated by autoantibodies against desmoglein 3 (DSG3). Inducible costimulator (ICOS) is a costimulatory receptor expressed on T cells and influences the activity of T follicular helper (TFH) cells in various autoimmune diseases, but the roles of ICOS and TFH cells in PV remain unclear. Objective: We examined the immunological characteristics, antigen specificity, and pathogenicity of CD4+ T-cell subpopulations, as well as the therapeutic effect of anti-ICOS blocking antibodies in PV. Methods: A mouse model of PV was established by adoptive transfer of immune cells from the skin-draining lymph nodes or spleens of DSG3-expressing skin-grafted Dsg3–/– mice into Rag1–/– mice. The TFH cells and CD4+ T cells in PBMCs from PV patients were examined by flow cytometry. Results: Among CD4+ T cells from the mouse model, ICOS-positive TFH cells were associated with B-cell differentiation and were required for disease induction. Using an MHC class II tetramer, DSG3-specific ICOS+ TFH cells were found to be associated with anti-DSG3 antibody production and expanded in the absence of B cells. In human PV, the frequency of ICOS+CXCR5+PD-1+ memory CD4+ T cells correlated with the autoantibody level. Treatment with anti-ICOS blocking antibodies targeting ICOS+ TFH cells decreased the anti-DSG3 antibody level and delayed disease progression in vivo. Conclusions: Mouse Dsg3-specific ICOS+ TFH cells and human ICOS+CXCR5+PD-1+ TH cells are associated with the anti-DSG3 antibody response in PV. ICOS expressed on CXCR5+PD-1+ TH cells may be a therapeutic target for PV.

• Access to Document (DOI)

Basement membrane zone IgE deposition is associated with bullous pemphigoid disease severity and treatment results

Kamata A., Kurihara Y., Funakoshi T., Takahashi H., Kuroda K., Hachiya T., Amagai M., Yamagami J.

British Journal of Dermatology （British Journal of Dermatology）  182 （ 5 ） 1221 - 1227 2020年05月

共著, 査読有り,  ISSN  00070963

　概要を見る

© 2019 British Association of Dermatologists Background: A subset of patients with bullous pemphigoid (BP) show deposition of IgE in the basement membrane zone (BMZ), yet the relationship between BMZ IgE and the clinical presentation of BP remains unclear. Objectives: To investigate the relationship between IgE deposition, IgE levels in serum, and disease severity in patients with BP. Methods: We investigated IgE autoantibodies in 53 patients with BP by direct immunofluorescence (DIF), indirect immunofluorescence and enzyme-linked immunosorbent assay. Results: Of 53 patients with BP, 23 (43%) had IgE deposition, 10 (19%) of whom were IgE+ and 13 (25%) IgE± according to DIF analyses. Erosion/blister (E/B) Bullous Pemphigoid Disease Area Index (BPDAI) scores were significantly higher in IgE+ patients than in IgE− patients (n = 15), while no significant differences were found for urticaria/erythema BPDAI scores. IgE+ and IgE± patients took longer to reduce their E/B BPDAI score by 75% after systemic corticosteroid treatment. BP180-IgE levels were significantly higher among IgE+ patients than IgE± or IgE− patients (n = 10). Total IgE levels in the serum and blood eosinophil counts did not differ between IgE+, IgE± and IgE− patients. A significant correlation was detected between BP180-IgG and BP180-IgE, but not between BPDAI scores and any of BP180-IgG, BP180-IgE or blood eosinophil count. Conclusions: IgE deposition in the BMZ is associated with higher E/B BPDAI scores and longer treatment periods. We conclude that IgE binding in the BMZ may contribute to BP pathogenesis by promoting blister formation. What's already known about this topic?. BP180-IgE autoantibodies have an important role in the pathogenesis of bullous pemphigoid (BP). A subset of patients with BP display deposition of IgE within the basement membrane zone (BMZ) of skin tissue. What does this study add?. Patients with in vivo IgE deposition in the BMZ displayed higher erosion/blister Bullous Pemphigoid Disease Area Index (BPDAI) scores, while urticaria/erythema BPDAI scores were not significantly different. Patients with in vivo IgE deposition in the BMZ took longer to reduce their erosion/blister BPDAI score by 75% after systemic corticosteroid treatment. BP180-specific IgE levels in serum were higher among patients with linear IgE deposition in the BMZ than in those with granular or no IgE deposition.

• Access to Document (DOI)

Successful treatment with secukinumab of three psoriatic patients undergoing dialysis

Mukai M, Kurihara Y, Ito Y, Shintani Y, Takahashi H, Kubo A, Amagai M, Umegaki-Arao N

（J Dermatol）  47 （ 1 ） e26 - e28 2020年01月

共著, 査読有り,  ISSN  0385-2407

• Access to Document (DOI)

Development of an electronic medical record-based algorithm to identify patients with Stevens-Johnson syndrome and toxic epidermal necrolysis in Japan

Fukasawa T., Takahashi H., Kameyama N., Fukuda R., Furuhata S., Tanemura N., Amagai M., Urushihara H.

PLoS ONE （PLoS ONE）  14 （ 8 ） e0221130 2019年08月

共著, 査読有り,  ISSN  1932-6203

　概要を見る

© 2019 Fukasawa et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), severe drug reactions, are often misdiagnosed due to their rarity and lack of information on differential diagnosis. The objective of the study was to develop an electronic medical record (EMR)-based algorithm to identify patients with SJS/TEN for future application in database studies. From the EMRs of a university hospital, two dermatologists identified all 13 patients with SJS/TEN seen at the Department of Dermatology as the case group. Another 1472 patients who visited the Department of Dermatology were identified using the ICD-10 codes for diseases requiring differentiation from SJS/TEN. One hundred of these patients were then randomly sampled as controls. Based on clinical guidelines for SJS/TEN and the experience of the dermatologists, we tested 128 algorithms based on the use of ICD-10 codes, clinical courses for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic odds ratio (DOR) of each algorithm were calculated, and the optimal algorithm was defined as that with high PPV and maximal sensitivity and specificity. One algorithm, consisting of a combination of clinical course for SJS/TEN, medical encounters for mucocutaneous lesions from SJS/TEN, and items to exclude paraneoplastic pemphigus, but not ICD-10 codes, showed a sensitivity of 76.9%, specificity of 99.0%, PPV of 40.5%, NPV of 99.8%, and DOR of 330.00. We developed a potentially optimized algorithm for identifying SJS/TEN based on clinical practice records. The almost perfect specificity of this algorithm will prevent bias in estimating relative risks of SJS/TEN in database studies. Considering the small sample size, this algorithm should be further tested in different settings.

• Access to Document (DOI)

Autoimmunity and immunological tolerance in autoimmune bullous diseases

Takahashi H., Iriki H., Mukai M., Kamata A., Nomura H., Yamagami J., Amagai M.

International immunology （International immunology）  31 （ 7 ） 431 - 437 2019年07月

共著, 査読有り,  ISSN  0953-8178

　概要を見る

© The Japanese Society for Immunology. 2019. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com. Autoimmune diseases are devastating conditions in which the immune system is directed against the host, leading to life-threatening destruction of organs. Although autoantigens are ill-defined in most autoimmune diseases, this is not the case in the skin. Autoimmune bullous diseases have been extensively studied with detailed characterization of autoantigens, the epitopes that are targeted, and the mechanisms of action that mediate autoimmune tissue destruction. Pemphigus is an autoimmune bullous disease caused by circulating IgG that targets two desmosomal proteins, desmoglein 1 and 3, which are crucial for cell-cell adhesion of keratinocytes. Binding of auto-antibodies to desmogleins impairs keratinocyte adhesion, leading to severe blistering disease. Mouse models that recapitulate the human disease have been instrumental in elucidating the detailed pathophysiology. Taking advantage of the fact that desmogleins are specifically targeted in pemphigus, studying humoral and cellular autoimmunity against these autoantigens provides us with an opportunity to understand not only the effector mechanisms of B and T cells in mediating pathology but also how autoreactive lymphocytes are regulated during development in the thymus and post-development in the periphery. This review introduces pemphigus and its subtypes as prototypic autoimmune diseases from which recent basic and translational developments should provide insight into how autoimmunity develops.

• Access to Document (DOI)

Patient voice on management of facial dermatological adverse events with targeted therapies: a qualitative study

Yagasaki K., Takahashi H., Ouchi T., Yamagami J., Hamamoto Y., Amagai M., Komatsu H.

Journal of Patient-Reported Outcomes （Journal of Patient-Reported Outcomes）  3 （ 1 ） 27 2019年05月

共著, 査読有り,  ISSN  2509-8020

　概要を見る

Background: With the increased use of targeted therapies in oncology, dermatological adverse events (dAEs) have drawn attention. Because the face is crucial for human identity and social interactions, facial dAEs have significant impact on a patient’s quality of life. This study aimed to explore patients’ experience with regard to the management of targeted oncological therapy-induced facial dAEs. Methods: In this qualitative study, 20 patients at a university hospital in Japan with advanced/metastatic cancer and targeted therapy-induced facial dAEs were individually interviewed to collect data. Thematic analysis was used to analyze the data. Results: Patients with cancer and targeted oncological therapy-induced facial dAEs who were referred to the Department of Dermatology had certain expectations from specialist services. Three key themes were identified: professional input and advice, empathetic commitment to individual management, and integrated care across specialties. Conclusions: The referred patients with cancer and facial dAEs needed more in-depth information and advice from dermatological services and were reassured by the empathetic commitment to individual management in integrated care across specialties. These findings suggest that attention to the patient’s perspective with a “sick person first” attitude and a collaborative effort across different specialties is important to minimize the effects of facial dAEs on the quality of life of patients with cancer.

• Access to Document (DOI)

好酸球増多症と多発性単神経炎,紫斑を伴った末梢性T細胞リンパ腫非特定型の1例

柳澤絵里加, 栗原佑一, 舩越建, 高橋勇人, 加野美希, 深井達夫, 戸澤圭一, 清水隆之, 天谷雅行, 海老原全

臨床皮膚科 73 （ 6 ） 457 - 464 2019年05月

共著, 査読有り,  ISSN  0021-4973

Gamma-delta T cell large granular lymphocyte leukaemia with multiple cutaneous nodules that showed spontaneous regression

Suzuki C, Hirai I, Nomura H, Ouchi T, Okayama M, Okamoto S, Amagai M, Tanese K, Takahashi H

J Eur Acad Dermatol Venereol 33 （ 3 ） e134 - e137 2019年03月

共著, 査読有り,  ISSN  0926-9959

• Access to Document (DOI)

Regulatory T cell deficiency and autoimmune skin disease: beyond scurfy mouse and IPEX

Hashimoto, T. Takahashi, H. Sakaguchi, S.

J Allergy Clin Immunol Epub 2018年09月

査読有り

Vancomycin Mediates IgA Autoreactivity in Drug-Induced Linear IgA Bullous Dermatosis

Yamagami J., Nakamura Y., Nagao K., Funakoshi T., Takahashi H., Tanikawa A., Hachiya T., Yamamoto T., Ishida-Yamamoto A., Tanaka T., Fujimoto N., Nishigori C., Yoshida T., Ishii N., Hashimoto T., Amagai M.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  138 （ 7 ） 1473 - 1480 2018年07月

共著, 査読有り,  ISSN  0022202X

　概要を見る

© 2018 The Authors Vancomycin (VCM) is known to induce linear IgA bullous dermatosis (LAD). However, in contrast to conventional LAD, in which circulating IgA autoantibodies against basement membrane proteins are commonly detected, patient sera from VCM-induced LAD yields negative results in indirect immunofluorescence microscopy, and the targeted autoantigen remains undetermined. By using sera from a typical patient with VCM-induced LAD, we identified that co-incubation of sera with VCM resulted in linear IgA deposition at the basement membrane zone by indirect immunofluorescence. Patient sera reacted with the dermal side of 1 mol/L NaCl-split skin and with the recombinant noncollagenous (i.e., NC1) domain of type VII collagen by both immunoblot and ELISA in the presence of VCM. The investigation of an additional 13 patients with VCM-induced LAD showed that 10 out of the 14 sera (71.4%) reacted with the NC1 domain of type VII collagen by ELISA when spiked with VCM, whereas only 4 (28.6%) tested positive without it. The enhancement of reactivity to NC1 by VCM, as determined by optical density via ELISA, was observed in 10 out of the 14 sera (71.4%). These findings indicate that type VII collagen is a target autoantigen in VCM-induced LAD and that VCM mediates IgA autoreactivity against type VII collagen, providing an insight into mechanisms involved in drug-induced autoimmune disease.

• Access to Document (DOI)