論文 - 高橋　勇人

Case of lamotrigine-induced drug adverse reaction under tocilizumab treatment with clinical and virological features of drug-induced hypersensitivity syndrome

Iriki H., Ouchi T., Ito H., Sawada M., Mukai M., Nomura H., Baba Y., Adachi T., Funakoshi T., Amagai M., Takahashi H.

Journal of Dermatology （Journal of Dermatology）  45 （ 6 ） 738 - 741 2018年06月

共著, 査読有り,  ISSN  03852407

　概要を見る

© 2018 Japanese Dermatological Association The pathological mechanisms and immunological kinetics of drug-induced hypersensitivity syndrome (DIHS), including the relevance of interleukin (IL)-6, remain unclear. We report a case of drug adverse reaction that does not fulfill the diagnostic criteria of DIHS but mimics its characteristic features. Because the patient was under anti-IL-6 therapy at the onset, some symptoms typically seen in DIHS were absent, such as fever and leukocyte count abnormalities. However, the characteristic features of DIHS were clearly observed in the subsequent course, including the repeated recurrence of skin rash, prolonged liver dysfunction and reactivation of herpes viruses. This case suggested that IL-6 role at the onset is not a main factor to determine the subsequent pathomechanism of DIHS and attention should be paid to the preceding therapy for achieving accurate diagnosis.

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Unique clinical and serological features of bullous pemphigoid associated with dipeptidyl peptidase-4 inhibitors

Horikawa H, Kurihara Y, Funakoshi T, Umegaki-Arao N, Takahashi H, Kubo A, Tanikawa A, Kodani N, Minami Y, Meguro S, Itoh H, Izumi K, Nishie W, Shimizu H, Amagai M, Yamagami J

Br J Dermatol 178 （ 6 ） 1462 - 1463 2018年06月

共著, 査読有り,  ISSN  0007-0963

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Azathioprine monotherapy in autoimmune blistering diseases: A feasible option for mild to moderate cases

Kakuta R., Yamagami J., Funakoshi T., Takahashi H., Ohyama M., Amagai M.

Journal of Dermatology （Journal of Dermatology）  45 （ 3 ） 334 - 339 2018年03月

査読有り,  ISSN  03852407

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© 2017 Japanese Dermatological Association Azathioprine (AZP) is used as a corticosteroid (CS)-sparing medication to treat autoimmune blistering diseases. In this study, we examined the efficacy of AZP and the feasibility of using AZP monotherapy (without CS) to treat pemphigus and pemphigoid. We performed a retrospective study of 10 Japanese patients (seven with pemphigus and three with pemphigoid) with mild to moderate disease activity who had been treated using AZP. The treatment efficacy was evaluated based on decreases in the disease activity scores and autoantibody titers. The results demonstrate that seven out of 10 cases (70%) were treated successfully using AZP monotherapy with no severe adverse effects. The disease activity scores of the successfully-treated patients decreased to zero after 1–37.5 months (average, 11.9) and the average disease activity scores in these cases decreased significantly at 2 months (38.2 ± 36.6%) compared with the scores of the three patients who required additional systemic CS therapy (77.5 ± 3.5%) (P < 0.05). Additionally, the autoantibody titers of five cases treated successfully using AZP decreased by half at 6 months. In conclusion, our findings suggest that AZP monotherapy is a viable treatment option for mild to moderate pemphigus and pemphigoid.

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Authors' reply: Paraneoplastic autoimmune multi-organ syndrome is a distinct entity from traditional pemphigus subtypes

Payne, A. S. Kasperkiewicz, M. Ellebrecht, C. T. Takahashi, H. Yamagami, J. Zillikens, D. Amagai, M.

Nat Rev Dis Primers 4   18013 2018年02月

天疱瘡モデルマウスの特徴

高橋 勇人

炎症と免疫 26 （ 1 ） 80 - 85 2018年01月

Langerhans Cells Prevent Autoimmunity via Expansion of Keratinocyte Antigen-Specific Regulatory T Cells

Kitashima D., Kobayashi T., Woodring T., Idouchi K., Doebel T., Voisin B., Adachi T., Ouchi T., Takahashi H., Nishifuji K., Kaplan D., Clausen B., Amagai M., Nagao K.

EBioMedicine （EBioMedicine）  27   293 - 303 2018年01月

査読有り

　概要を見る

© 2017 Langerhans cells (LCs) are antigen-presenting cells in the epidermis whose roles in antigen-specific immune regulation remain incompletely understood. Desmoglein 3 (Dsg3) is a keratinocyte cell-cell adhesion molecule critical for epidermal integrity and an autoantigen in the autoimmune blistering disease pemphigus. Although antibody-mediated disease mechanisms in pemphigus are extensively characterized, the T cell aspect of this autoimmune disease still remains poorly understood. Herein, we utilized a mouse model of CD4+ T cell-mediated autoimmunity against Dsg3 to show that acquisition of Dsg3 and subsequent presentation to T cells by LCs depended on the C-type lectin langerin. The lack of LCs led to enhanced autoimmunity with impaired Dsg3-specific regulatory T cell expansion. LCs expressed the IL-2 receptor complex and the disruption of IL-2 signaling in LCs attenuated LC-mediated regulatory T cell expansion in vitro, demonstrating that direct IL-2 signaling shapes LC function. These data establish that LCs mediate peripheral tolerance against an epidermal autoantigen and point to langerin and IL-2 signaling pathways as attractive targets for achieving tolerogenic responses particularly in autoimmune blistering diseases such as pemphigus.

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Desmoglein 3-Reactive B Cells “Hiding” in Pemphigus Lesions

Takahashi H.

Journal of Investigative Dermatology （Journal of Investigative Dermatology）  137 （ 11 ） 2255 - 2257 2017年11月

査読有り,  ISSN  0022202X

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Pemphigus vulgaris is an autoimmune blistering disease caused by anti-desmoglein 3 IgG autoantibodies. It is accepted that interactions between autoreactive B and T cells are key to humoral autoimmunity targeting desmoglein 3. This orchestrated process usually occurs in secondary lymphoid organs, including the spleen and lymph nodes. Thus, it seems likely that autoreactive B cells reside and produce autoantibodies in these tissues. Yuan et al. analyzed lymphocytes in the lesional skin of patients with pemphigus vulgaris using several experimental techniques and concluded that desmoglein 3-reactive B cells were present. This finding expands our understanding of the pathogenesis of pemphigus and should be considered when following the clinical course of skin lesions and thinking about adjunctive therapy.

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Desmoglein 3-Reactive B cells "Hiding" in pemphigus lesions

Takahashi, H.

J Invest Dermatol 137 （ 11 ） 2255 - 2257 2017年11月

Non-pigmenting fixed drug eruption with mixed features of acute generalized exanthematous pustulosis induced by pseudoephedrine: a case report

Fukuda, R. Ouchi, T. Hirai, I. Funakoshi, T. Honda, A. Tanese, K. Tanikawa, A. Amagai, M. Takahashi, H.

Contact Dermatitis 77 （ 2 ） 123 - 126 2017年08月

査読有り

皮膚科研究における若手育成の試み

高橋 勇人

臨床皮膚科 71 （ 8 ） 574 - 575 2017年07月

Unexpected recalcitrant course of drug-induced erythema multiforme-like eruption and interstitial pneumonia sequentially occurring after nivolumab therapy

Nomura, H. Takahashi, H. Suzuki, S. Kurihara, Y. Chubachi, S. Kawada, I. Yasuda, H. Betsuyaku, T. Amagai, M. Funakoshi, T.

Journal of Dermatology 44 （ 7 ） 818 - 821 2017年07月

査読有り

Pemphigus

Kasperkiewicz, M., Ellebrecht, C.T., Takahashi, H., Yamagami, J., Zillikens, D., Payne, A.S., Amagai, M.

Nature Reviews Disease Primers 3   Article number 17026 2017年05月

Distinct phenotype of epidermolysis bullosa simplex with infantile migratory circinate erythema due to frameshift mutations in the V2 domain of KRT5

Kumagai, Y. Umegaki-Arao, N. Sasaki, T. Nakamura, Y. Takahashi, H. Ashida, A. Tsunemi, Y. Kawashima, M. Shimizu, A. Ishiko, A. Nakamura, K. Tsuchihashi, H. Amagai, M. Kubo, A.

Journal of the European Academy of Dermatology and Venereology 31 （ 5 ） e241 - e243 2017年05月

査読有り,  ISSN  0926-9959

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天疱瘡―デスモグレインに対する細胞性免疫とバリア機能障害

高橋 勇人 天谷雅行

実験医学 35 （ 7 ） 1143 - 1149 2017年04月

関節リウマチ患者に生じたメトトレキサート関連リンパ増殖性疾患と考えられた1例

畠中美帆 角田梨沙 高橋勇人 谷川瑛子 竹内勤 亀山香織 天谷雅行

臨床皮膚科 70 （ 13 ） 1067 - 1071 2016年12月

ISSN  0021-4973

　概要を見る

76歳,女性.18年前に発症した関節リウマチ(rheumatoid arthritis:RA)に対し10年前よりメトトレキサート(MTX),1年前よりアバタセプト(ABT)で加療していた.初診3週間程前から両下腿に皮疹を認め,当院を受診した.四肢に一部表面に痂皮を付着した,浸潤を触れる暗赤色結節が多発散在していた.組織はCD20,bcl-2,EBER陽性の異型細胞が皮下織中心に増殖し,びまん性大細胞型B細胞リンパ腫に一致し,MTX関連リンパ増殖性疾患と診断した.ABTの投与を延期し,MTXを中止後,結節は完全に消退した.現在ABTを継続投与中だが再燃していない.過去の文献を調べえた限り,その発症には,原病の免疫異常および長期にわたる罹病期間,MTXを介したEpstein-Barrウイルスの再活性化などが複合的に関連した可能性があると推察された.(著者抄録)

天疱瘡におけるデスモグレイン3特異的T細胞の臓器を越えた病原的役割

高橋勇人 天谷雅行

医学のあゆみ 259 （ 2 ） 159 - 164 2016年10月

ISSN  0039-2359

　概要を見る

尋常性天疱瘡(PV)は、デスモグレイン(Dsg)3に対する自己抗体により生じる自己免疫性水疱症のひとつである。著者らはモデルマウスを用いて、B細胞による自己抗体産生を誘導するDsg3特異的CD4+T細胞を解析してきた。近年、樹立したDsg3特異的T細胞クローン(Dsg3H1 T細胞)を利用して、Dsg3特異的T細胞受容体トランスジェニックマウスを作成した。Dsg3H1 T細胞はB細胞による自己抗体産生を介して水疱形成を誘導するのみならず、表皮に直接浸潤し皮膚炎(interface dermatitis)を誘導することが明らかとなった。天疱瘡の亜型である腫瘍随伴性天疱瘡(PNP)においては水疱と皮膚炎がともに認められるが、その複雑な病態がDsg3特異的T細胞により誘導されることが考えられた。さらに、PNPに認められる致死的な肺障害は、肺に生じた異所性扁平上皮化生に対して表皮抗原に反応するT細胞により誘導されることが示唆された。(著者抄録)

Case of lymphoplasmacytic plaque in children: Analysis of the distribution of infiltrating immune cells

Mukai, M. Tanese, K. Umegaki-Arao, N. Kubo, A. Takahashi, H. Amagai, M.

J Dermatol 43 （ 11 ） 1368 - 1370 2016年04月

査読有り,  ISSN  0385-2407

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Condylomata lata on the ankle: an unusual location

Ikeda, E. Goto, A. Suzaki, R. Sawada, M. Dekio, I. Ishizaki, S. Fujibayashi, M. Takahashi, H. Tanaka, M.

Dermatol Pract Concept 6 （ 2 ） 49 - 51 2016年04月

査読有り,  ISSN  2160-9381

　概要を見る

A 43-year-old Japanese man presented with reddish nodules on the ankle. The nodules had a yellowish crust and eroded surface. Dermoscopy revealed red to milky-red globules at the periphery and some glomerular vessels in the center and a whitish-pink network, which corresponded to capillary dilatation in the papillary dermis and prominent acanthosis, respectively. These structures were surrounded by a yellowish peripheral structureless area and multiple white, small, round structures in the center, corresponding to the macerated horny layer and keratin plugs. Blood samples were positive for rapid plasma reagin (1:64), Treponema pallidum hemagglutination assay (1:20480), and fluorescent treponemal antibody-absorption (1:1280). A lesional skin biopsy specimen showed irregular acanthosis and papillomatosis. The Warthin-Starry and anti-Treponema pallidum antibody stains on the biopsy specimen revealed many spirochetes in the lower epidermis and the papillary dermis. A diagnosis of secondary syphilis with condylomata lata was made. After one week of treatment with oral benzylpenicillin benzathine hydrate (Bicillin((R)) G granules 400,000 units; Banyu Pharmaceutical Co., Ltd, Tokyo, Japan), 1.6 million units (U) daily, the ankle lesions had resolved with a small ulcer and pigmentation. Although syphilis is a relatively common disease, this case study reports an unusual presentation as well as dermoscopy findings.

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重症薬疹の特徴と初期診療のポイント

高橋勇人

ペインクリニック 36 （ 11 ） 1469 - 1480 2015年11月

デスモグレイン3特異的T細胞によって誘導される多彩な皮膚病理

高橋勇人 天谷雅行

実験医学 33 （ 12 ） 1948 - 1953 2015年08月