HLAクラスII/ミスフォールド蛋白複合体抗体による慢性皮膚潰瘍の病態解明

2020 Fiscal Year Research-status Report

• Project/Area Number: 18K08296
• Research Institution: Osaka University
• Principal Investigator: 荒瀬 規子 大阪大学, 医学系研究科, 助教 (30360481)
• Project Period (FY): 2018-04-01 – 2022-03-31
• Keywords: 皮膚潰瘍 / HLA Class II / ミスフォールド蛋白 / β2GPI

Outline of Annual Research Achievements

申請者らは、HLAクラスII分子にいくつかの細胞内ミスフォールド蛋白質が直接会合することを見つけた。さらにHLAクラスII分子はそれらのミスフォールドタンパク質を細胞表面へ輸送するシャペロン様の機能を有することを見出した(Jiang, Arase et al. Int. Immunol. 2013)。さらにいくつかの自己免疫疾患で、これらミスフォールド蛋白質／HLAクラスII複合体に対して自己抗体が産生されることが判明した。関節リウマチ、抗リン脂質抗体症候群、ANCA関連血管炎、バセドウ病等で患者血清中に特異的ミスフォールド蛋白質／HLAクラスII複合体に対する自己抗体が見つかった(Jin, Arase et al. Proc. Natl. Acad. Sci. USA. 2014, Tanimura et al. Blood 2015, Arthritis Rheumatol 2020, Hiwa, et al. Arthritis Rheumatol 2017他)。一方、原因不明の難治性慢性皮膚潰瘍患者約３割程度の血清中にβ2GPI/HLA Class II複合体抗体が存在した(Arase et al. Br J Dermatol. 2018)。そこでβ2GPI/MHCクラスII複合体の慢性皮膚潰瘍での役割を検討するためにβ2GPI/MHCクラスII複合体をマウスに免疫し、血清中の自己抗体を検討しマウスの症状を観察した。現時点で自己抗体の産生や皮膚症状は認められていない。現在、ミスフォールド蛋白質／HLAクラスII複合体による自己免疫疾患モデルマウス作成予備実験として免疫方法や、アジュバントの検討を行っている。また皮膚潰瘍に関連する新たな自己抗原を検索している。

Current Status of Research Progress

2: Research has progressed on the whole more than it was originally planned.

Reason

β2GPI/MHCクラスII複合体の病的意義や治療法を検討する目的でβ2GPI/MHCクラスII複合体をマウスに種々の方法を用いて免疫した。さらに他の抗原と疾患発症がより明らかな疾患モデルを用いてどの様な方法で免疫する抗原を作成するのが適切かについてマウスに投与する基礎実験を行なっている。さらに慢性皮膚潰瘍と関連する他の自己抗原候補分子に関して検討している。

Strategy for Future Research Activity

疾患発症モデルを樹立するためのミスフォールドタンパク質/MHCクラスII複合体のマウスへの免疫方法樹立に向けて解析を進めている。さらに自己免疫が関与する慢性皮膚潰瘍に関連する新たな自己抗原をクローニングを進めている。

Causes of Carryover

マウスモデル作成に基礎検討が必要となったためそれを行うために次年度での追加実験が必要となった。今年度の実験は既存の消耗品等で賄うことができた。コロナウィルス感染による緊急事態宣言で実験室への立ち入りが制限されたことも影響した。

Research Products

• [Journal Article] Large-scale plasma-metabolome analysis identifies potential biomarkers of psoriasis and its clinical subtypes. (2021)
  • Author(s): [Toshihiro Kishikawa,Noriko Arase,Shigeyoshi Tsuji,Yuichi Maeda,Takuro Nii,Jun Hirata,Ken Suzuki,Kenichi Yamamoto,Tatsuo Masuda,Kotaro Ogawa,Shiro Ohshima,Hidenori Inohara,Atsushi Kumanogoh,Manabu Fujimoto,Yukinori Okada]
  • Journal Title: Journal of dermatological science Volume: 102 Pages: 78~84
  • DOI: 10.1016/j.jdermsci.2021.03.006
  • Peer Reviewed / Open Access
• [Journal Article] A rare case of multiple pyoderma gangrenosum co-mobilized with pseudoxanthoma elasticum (2021)
  • Author(s): [Saki Iga,Atsushi Tanemura,Takumi Kamitani,Madoka Takafuji,Yuma Hanaoka,Noriko Arase,Manabu Fujimoto]
  • Journal Title: JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Volume: 4 Pages: 71~72
  • DOI: 10.1002/cia2.12159
  • Peer Reviewed / Open Access
• [Journal Article] Increased levels of plasma nucleotides in patients with rheumatoid arthritis. (2021)
  • Author(s): [Toshihiro Kishikawa,Yuichi Maeda,Takuro Nii,Noriko Arase,Jun Hirata,et.al.]
  • Journal Title: International immunology Volume: 33 Pages: 119~124
  • DOI: 10.1093/intimm/dxaa059
  • Peer Reviewed / Open Access
• [Journal Article] Immunohistopathological observation of a case recovering from leukotrichia after suction blister transplantation (2021)
  • Author(s): [Atsushi Tanemura,Hanako Koguchi-Yoshioka,Kazunori Yokoi,Eiji Kiyohara,Noriko Arase,Rintaro Ohe,Tamio Suzuki,Manabu Fujimoto]
  • Journal Title: JOURNAL OF DERMATOLOGY Volume: in press Pages: in press
  • DOI: 10.1111/1346-8138.15855
  • Peer Reviewed
• [Journal Article] The beneficial effect of a PDE4 inhibitor in a patient with juvenile-onset intractable pityriasis rubra pilaris without CARD14 mutation (2021)
  • Author(s): [Emi Inoue,Noriko Arase,Yuma Hanaoka,Atsushi Tanemura,Manabu Fujimoto]
  • Journal Title: DERMATOLOGIC THERAPY Volume: 34 Pages: e14714
  • DOI: 10.1111/dth.14714
  • Peer Reviewed
• [Journal Article] Use of a combination of oral psoralen, ultraviolet A and interferon-gamma for the treatment of mycosis fungoides during pregnancy, which probably evoked CD8(+)CD30(+)lymphoproliferative disorder (2021)
  • Author(s): [Kyoko Tonomura,Eiji Kiyohara,Yuya Nakanishi,Atsushi Tanemura,Noriko Arase,Yukinobu Nakagawa,Manabu Fujimoto]
  • Journal Title: JOURNAL OF DERMATOLOGY Volume: 48 Pages: E17-E18
  • DOI: 10.1111/1346-8138.15628
  • Peer Reviewed
• [Journal Article] Local and disease control for nasal melanoma treated with radiation and concomitant anti-programmed death 1 antibody (2020)
  • Author(s): [Yuma Hanaoka,Atsushi Tanemura,Madoka Takafuji,Eiji Kiyohara,Noriko Arase,Osamu Suzuki,Fumiaki Isohashi,Kazuhiko Ogawa,Manabu Fujimoto]
  • Journal Title: JOURNAL OF DERMATOLOGY Volume: 47 Pages: 423-425
  • DOI: 10.1111/1346-8138.15256
  • Peer Reviewed
• [Journal Article] Case of granuloma annulare after using tocilizumab (2020)
  • Author(s): [Kurumi Katsuda,Noriko Arase,Yukinobu Nakagawa,Atsushi Tanemura,Manabu Fujimoto]
  • Journal Title: JOURNAL OF DERMATOLOGY Volume: 47 Pages: E117-E119
  • DOI: 10.1111/1346-8138.15252
  • Peer Reviewed
• [Journal Article] Genotype and phenotype analysis of patients with pediatric cutaneous mastocytosis, especially wild-type KIT patients (2020)
  • Author(s): [Noriko Arase,Mari Wataya-Kaneda,Hiroyuki Murota,Yukinobu Nakagawa,Toshifumi Yamaoka,Saori Itoi-Ochi,Kouyuki Hirayasu,Hisashi Arase,Manabu Fujimoto,Ichiro Katayama]
  • Journal Title: JOURNAL OF DERMATOLOGY Volume: 47 Pages: 426-429
  • DOI: 10.1111/1346-8138.15266
  • Peer Reviewed
• [Journal Article] A case of zonisamide-induced toxic epidermal necrolysis with acute respiratory failure (2020)
  • Author(s): [Miki Kume,Yukinobu Nakagawa,Eiji Kiyohara,Noriko Arase,Mari Wataya-Kaneda,Moto Yaga,Masahiro Yanagawa,Manabu Fujimoto]
  • Journal Title: ALLERGOLOGY INTERNATIONAL Volume: 69 Pages: 642-644
  • DOI: 10.1016/j.alit.2020.04.007
  • Peer Reviewed
• [Journal Article] Rare case of segmental vitiligo in which lesional enlargement occurred after suction blister transplantation (2020)
  • Author(s): [Kurumi Katsuda,Atsushi Tanemura,Madoka Takafuji,Yuma Hanaoka,Eiji Kiyohara,Noriko Arase,Manabu Fujimoto]
  • Journal Title: JOURNAL OF DERMATOLOGY Volume: 47 Pages: E340-E342
  • DOI: 10.1111/1346-8138.15489
  • Peer Reviewed
• [Journal Article] Immunohistochemical analysis of rhododendrol-induced leukoderma in improved and aggravated cases (2020)
  • Author(s): [Masahito Yasuda,Akiko Sekiguchi,Chikako Kishi,Sayaka Toki,Noriko Arase,Aya Takahashi,Fei Yang,Atsushi Tanemura,Masahiro Hayashi,Yuko Abe,Toshihisa Hamada,Tamio Suzuki,Ichiro Katayama,Osamu Ishikawa]
  • Journal Title: JOURNAL OF DERMATOLOGICAL SCIENCE Volume: 99 Pages: 140-143
  • DOI: 10.1016/j.jdermsci.2020.06.011
  • Peer Reviewed
• [Journal Article] The beta(2)-Glycoprotein I/HLA-DR Complex As A Major Autoantibody Target in Obstetric Antiphospholipid Syndrome (2020)
  • Author(s): [Kenji Tanimura,Shigeru Saito,Mikiya Nakatsuka,Takeshi Nagamatsu,Tomoyuki Fujii,Atsushi Fukui,Masashi Deguchi,Yuki Sasagawa,Noriko Arase,Hisashi Arase,Hideto Yamada]
  • Journal Title: ARTHRITIS & RHEUMATOLOGY Volume: 72 Pages: 1882-1891
  • DOI: 10.1002/art.41410
  • Peer Reviewed
• [Journal Article] First case of symmetrical acral keratoderma in Japan with filaggrin mutation who showed marked improvement in skin manifestations using moisturizer (2020)
  • Author(s): [Kazuya Akaji,Noriko Arase,Jin Teng Peh,Eiji Kiyohara,Hiroyuki Murota,Toshifumi Nomura,Manabu Fujimoto]
  • Journal Title: JOURNAL OF DERMATOLOGY Volume: 47 Pages: E291-E293
  • DOI: 10.1111/1346-8138.15410
  • Peer Reviewed
• [Journal Article] Achievement of remission with surgical resection of a lung adenocarcinoma without systemic treatment in a rare case of anti-TIF1-gamma antibody-positive dermatomyositis (2020)
  • Author(s): [Kyoko Tonomura,Yorihisa Kotobuki,Soichiro Funaki,Kurumi Katsuda,Noriko Arase,Eiji Kiyohara,Ikuko Ueda,Manabu Fujimoto]
  • Journal Title: JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Volume: 3 Pages: 117-119
  • DOI: 10.1002/cia2.12134
  • Peer Reviewed
• [Journal Article] An Optimized Crovalimab Dose and Regimen Reduced the Formation of Drug-Target-Drug Complexes in Patients with Paroxysmal Nocturnal Hemoglobinuria from the Phase I/II COMPOSER Trial (2020)
  • Author(s): [Jun-Ichi Nishimura,Antoine Soubret,Simon Buatois,Jean-Eric Charoin,Sasha Sreckovic,Christoph Bucher,Jules Hernandez-Sanchez,Gregor Jordan,Julia Ramos,Noriko Arase,Masaki Hotta,Yoshitaka Isaka,Yoshikazu Ito,Yuzuru Kanakura,Jin Seok Kim,Taroh Kinoshita,Eiichi Morii,et.al.]
  • Journal Title: BLOOD Volume: 136 Pages: null
  • DOI: 10.1182/blood-2020-136265
  • Peer Reviewed
• [Journal Article] Case of X-linked hypohidrotic ectodermal dysplasia, along with facial bilateral reticular pigmentation (2020)
  • Author(s): [Tomo Kamitani,Noriko Arase,Toshifumi Nomura,Jin Teng Peh,Ichiro Katayama,Mari Wataya-Kaneda,Manabu Fujimoto]
  • Journal Title: JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Volume: 3 Pages: 41-42
  • DOI: 10.1002/cia2.12097
  • Peer Reviewed
• [Journal Article] A case of giant porokeratosis coexisting disseminated superficial porokeratosis (2020)
  • Author(s): [Saori Itoi-Ochi,Atsushi Tanemura,Noriko Arase,Manabu Fujimoto]
  • Journal Title: JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Volume: 3 Pages: 139-141
  • DOI: 10.1002/cia2.12141
  • Peer Reviewed
• [Journal Article] A case of drug-induced hypersensitivity syndrome due to diaminodiphenyl sulfone complicated by acute respiratory failure with atypical erythema around existing prurigo (2020)
  • Author(s): [Kazuya Akaji,Noriko Arase,Yukinobu Nakagawa,Atsushi Tanemura,Ichiro Katayama,Manabu Fujimoto]
  • Journal Title: JOURNAL OF CUTANEOUS IMMUNOLOGY AND ALLERGY Volume: 3 Pages: 45-47
  • DOI: 10.1002/cia2.12106
  • Peer Reviewed
• [Journal Article] Trial of Nemolizumab and Topical Agents for Atopic Dermatitis with Pruritus (2020)
  • Author(s): Kabashima K, Matsumura T, Komazaki H, Kawashima M; Nemolizumab-JP01 Study Group.
  • Journal Title: N Engl J Med. Volume: 383 Pages: 141-150
  • DOI: 10.1056/NEJMoa1917006.
  • Peer Reviewed
• [Presentation] ヘパリン類似物質が奏功した symmetrical acral keratoderma の1例 (2020)
  • Author(s): 赤路和哉、荒瀬規子、Peh Jin Teng、清原英司、室田浩之、乃村俊史、藤本 学
  • Organizer: 第84回日本皮膚科学会東部支部学術大会
• [Presentation] アプレミラストが奏効した若年性毛孔性紅色粃糠疹の1例 (2020)
  • Author(s): 井上栄美、荒瀬規子、花岡佑真、種村 篤、藤本 学
  • Organizer: 第84回日本皮膚科学会東京支部学術大会
• [Presentation] An Optimized Crovalimab Dose and Regimen Reduced the Formation of Drug-Target-Drug Complexes in Patients with Paroxysmal Nocturnal Hemoglobinuria From the Phase I/II COMPOSER Trial. (2020)
  • Author(s): Jun-ichi Nishimura, Antoine Soubret, Simon Buatois, Jean-Eric Charoin, Sasha Sreckovic, Christoph Bucher, Jules Hernandez-Sanchez, Gregor Jordan, Julia Ramos, Noriko Arase, Masaki Hotta, Yoshitaka Isaka, Yoshikazu Ito, Yuzuru Kanakura, Jin Seok Kim, Taroh Kinoshita, Eiichi Morii, et.al.
  • Organizer: 62nd Ash Annual Meeting and Exposition
  • Int'l Joint Research