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

2021 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 – 2023-03-31
• Keywords: 抗Ro52/IgG/HLA-クラスII複合体抗体 / 皮膚筋炎 / 抗MDA5抗体陽性無筋炎型皮膚筋炎 / 抗ARS抗体症候群 / 間質性肺炎 / 筋症状 / 細胞質内蛋白

Outline of Annual Research Achievements

申請者らは細胞内で生成されるミスフォールド蛋白質がHLAクラスII分子と会合して細胞表面に輸送される現象を見出した。さらにそれらのHLAクラスII/ミスフォールド蛋白複合体は種々の膠原病で自己抗体の標的となった。今回細胞内Fc受容体Ro52蛋白がIgG/HLAクラスII分子と複合体を形成し細胞表面に輸送されることを新たに発見した。さらにこれらのRo52/IgG/HLAクラスII複合体はシェーグレン症候群や皮膚筋炎患者患者において自己抗体の標的抗原となった。皮膚筋炎では、抗Ro52/IgG/HLAクラスII複合体抗体は抗MDA5抗体陽性無筋炎型皮膚筋炎や抗ARS抗体症候群患者血清で優位に陽性だった。皮膚筋炎患者の血清Ro52/IgG/HLAクラスII複合体抗体はシェーグレン症候群患者血清と比較して、リコンビナントRo52蛋白で吸収した後も高い割合でRo52/IgG/HLAクラスII複合体を認識し、皮膚筋炎患者血清にはRo52/IgG/HLAクラスII複合体を特異的に認識する抗体が多く含まれることがわかった。皮膚筋炎患者の血清抗Ro52/IgG/HLAクラスII複合体抗体の抗体価の推移を調べると、間質性肺炎や筋症状の病勢変化と関連して推移することが判明した。このことより皮膚筋炎において抗Ro52/IgG/HLAクラスII複合体特異抗体が病原性を有する可能性が考えられた。今まで細胞質内蛋白が自己抗体の標的となる機序は不明だったが、今回新たにHLAクラスIIとミスフォールド蛋白の複合体にさらに細胞質内蛋白が会合し３者が複合体を形成することで細胞質内蛋白が細胞表面に輸送され、自己抗体の標的となる新たな機序が判明した。このことを踏まえてさらに慢性皮膚潰瘍で自己抗体の標的となるHLAクラスII/ミスフォールド蛋白複合体を見つけて行く。

Current Status of Research Progress

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

Reason

今回新たに細胞質内蛋白がHLAクラスII/ミスフォールド蛋白複合体により細胞表面へ輸送される機序が明らかとなった。このことは新しいHLAクラスII/ミスフォールド蛋白複合体抗体を見つける上で重要と考えられた。

Strategy for Future Research Activity

慢性皮膚潰瘍患者の血清中の新しいHLAクラスII/ミスフォールド蛋白複合体抗体を細胞質内蛋白も含めて探索し、皮膚潰瘍発症機構を解明して行く。

Causes of Carryover

2021年度は新たなHLAクラスII/ミスフォールド蛋白複合体の解析を今まで購入していた備品や消耗品に多少追加する程度で研究を遂行できた。そこで次年度さらに新しい複合体を見つけるスクリーニングのために費用を当てることとした。

Research Products

• [Journal Article] Blistering Papulosquamous Erythema with Arthralgia: A Quiz. (2022)
  • Author(s): [Yukiho Kurosaki,Yosuke Ishitsuka,Yasuhiro Kato,Noriko Arase,Manabu Fujiomto]
  • Journal Title: Acta dermato-venereologica Volume: 102 Pages: adv00690
  • DOI: 10.2340/actadv.v102.936
  • Peer Reviewed / Open Access
• [Journal Article] Familial Michelin tire baby syndrome. (2022)
  • Author(s): [Mami Hayashi,Mari Wataya-Kaneda,Hanako Koguchi-Yoshioka,Noriko Arase,Tateki Kubo,Hajime Nakano,Manabu Fujimoto]
  • Journal Title: The Journal of dermatology Volume: - Pages: in press
  • DOI: 10.1111/1346-8138.16346
  • Peer Reviewed
• [Journal Article] Abrogation of self-tolerance by misfolded self-antigens complexed with MHC class II molecules. (2022)
  • Author(s): [Hui Jin,Kazuki Kishida,Noriko Arase,Sumiko Matsuoka,Wataru Nakai,Masako Kohyama,Tadahiro Suenaga,Ken Yamamoto,Takehiko Sasazuki,Hisashi Arase]
  • Journal Title: Science advances Volume: 8 Pages: eabj9867
  • DOI: 10.1126/sciadv.abj9867
  • Peer Reviewed / Open Access
• [Journal Article] Serum autoantibodies against the extracellular region of α6β4 integrin in a patient with dipeptidyl peptidase-4 inhibitor-induced bullous pemphigoid. (2022)
  • Author(s): [Chigusa Yamashita,Noriko Arase,Shuhei Higuchi,Hisashi Arase,Junichi Takagi,Satoshi Nojima,Atsushi Tanemura,Manabu Fujimoto]
  • Journal Title: JAAD case reports Volume: 20 Pages: 65~68
  • DOI: 10.1016/j.jdcr.2021.12.021
  • Peer Reviewed / Open Access
• [Journal Article] Corrigendum to "Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies" [J. Autoimmun. 126 (2022) 102774]. (2022)
  • Author(s): [Noriko Arase,Hideaki Tsuji,Hyota Takamatsu,Hui Jin,Hachiro Konaka,Yasuhito Hamaguchi,Kyoko Tonomura,Yorihisa Kotobuki,Ikuko Ueda-Hayakawa,Sumiko Matsuoka,Toru Hirano,Hideki Yorifuji,Hiroyuki Murota,Koichiro Ohmura,Ran Nakashima,Tomoharu Sato,Atsushi Kumanogoh,Ichiro Katayama,Hisashi Arase,Manabu Fujimoto]
  • Journal Title: Journal of autoimmunity Volume: 127 Pages: 102797
  • DOI: 10.1016/j.jaut.2022.102797
  • Peer Reviewed / Open Access
• [Journal Article] A Case of Pretibial Epidermolysis Bullosa with Novel Mutations of the COL7A1 Gene. (2022)
  • Author(s): [Yuri Shimizu,Yorihisa Kotobuki,Noriko Arase,Hisashi Arase,Ichiro Katayama,Manabu Fujimoto]
  • Journal Title: Annals of dermatology Volume: 34 Pages: 81~83
  • DOI: 10.5021/ad.2022.34.1.81
  • Peer Reviewed
• [Journal Article] Cell surface-expressed Ro52/IgG/HLA-DR complex is targeted by autoantibodies in patients with inflammatory myopathies. (2022)
  • Author(s): [Noriko Arase,Hideaki Tsuji,Hyota Takamatsu,Hui Jin,Hachiro Konaka,Yasuhito Hamaguchi,Kyoko Tonomura,Yorihisa Kotobuki,Ikuko Ueda-Hayakawa,Sumiko Matsuoka,Toru Hirano,Hideki Yorifuji,Hiroyuki Murota,Koichiro Ohmura,Ran Nakashima,Tomoharu Sato,Atsushi Kumanogoh,Ichiro Katayama,Hisashi Arase,Manabu Fujimoto]
  • Journal Title: Journal of autoimmunity Volume: 126 Pages: 102774
  • DOI: 10.1016/j.jaut.2021.102774
  • Peer Reviewed / Open Access
• [Journal Article] Myxovirus resistance protein 1-expressing fatal myocarditis in a patient with anti-MDA5 antibody-positive dermatomyositis. (2021)
  • Author(s): [Rika Sakamoto,Yorihisa Kotobuki,Saki Iga,Satoshi Nojima,Rikako Deno,Yuma Hanaoka,Kyoko Tonomura,Eiji Kiyohara,Yukinobu Nakagawa,Ikuko Ueda-Hayakawa,Noriko Arase,Manabu Fujimoto]
  • Journal Title: Rheumatology (Oxford, England) Volume: 60 Pages: e450~e452
  • DOI: 10.1093/rheumatology/keab637
  • Peer Reviewed / Open Access
• [Journal Article] A pediatric case of cellulitis caused by Stenotrophomonas maltophilia with microvascular thrombosis and diffuse subcutaneous hemorrhage (2021)
  • Author(s): [Emi Inoue,Noriko Arase,Takako Miyamura,Tomohiro Wataya,Yusuke Tanaka,Nobuo Kashiwagi,Hiroshi Sakai,Satoshi Nojima,Manabu Fujimoto]
  • Journal Title: Journal of Cutaneous Immunology and Allergy Volume: 4 Pages: 181~183
  • DOI: 10.1002/cia2.12197
  • Peer Reviewed / Open Access
• [Journal Article] An infectivity-enhancing site on the SARS-CoV-2 spike protein targeted by antibodies (2021)
  • Author(s): [Yafei Liu,Wai Tuck Soh,Jun ichi Kishikawa,Mika Hirose,Emi E. Nakayama,Songling Li,Miwa Sasai,Tatsuya Suzuki,Asa Tada,Akemi Arakawa,Sumiko Matsuoka,Kanako Akamatsu,Makoto Matsuda,Chikako Ono,Shiho Torii,Kazuki Kishida,Hui Jin,Wataru Nakai,Noriko Arase, et.al]
  • Journal Title: Cell Volume: 184 Pages: 3452~3466
  • DOI: 10.1016/j.cell.2021.05.032
  • Peer Reviewed / Open Access
• [Journal Article] Anti‐dsDNA antibodies recognize DNA presented on HLA class II molecules of systemic lupus erythematosus risk alleles (2021)
  • Author(s): [Hideaki Tsuji,Koichiro Ohmura,Hui Jin,Ryota Naito,Noriko Arase,Masako Kohyama,Tadahiro Suenaga,Shuhei Sakakibara,Yuta Kochi,Yukinori Okada,Kazuhiko Yamamoto,Hitoshi Kikutani,Akio Morinobu,Tsuneyo Mimori,Hisashi Arase]
  • Journal Title: Arthritis & Rheumatology Volume: 74 Pages: 105~111
  • DOI: 10.1002/art.41897
  • 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: The Journal of dermatology Volume: 48 Pages: e263~e264
  • DOI: 10.1111/1346-8138.15855
  • Peer Reviewed
• [Journal Article] Unilateral heliotrope rash: a warning sign for anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis. (2021)
  • Author(s): [Miki Kume,Noriko Arase,Naoko Okiyama,Hanako Koguchi-Yoshioka,Tomomi Tada,Hiroko Saruban,Manabu Fujimoto]
  • Journal Title: Rheumatology (Oxford, England) Volume: 60 Pages: e134~e135
  • DOI: 10.1093/rheumatology/keaa574
  • Peer Reviewed / Open Access
• [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] A NOVEL AUTOANTIBODY AGAINST beta 2-GLYCOPROTEIN I/HLA CLASS II COMPLEXES IS A MAJOR RISK FACTOR FOR RECURRENT PREGNANCY LOSS (2021)
  • Author(s): [Kenji Tanimura,Shigeru Saito,Mikiya Nakatsuka,Takeshi Nagamatsu,Tomoyuki Fujii,Atsushi Fukui,Yuki Sasagawa,Masashi Deguchi,Noriko Arase,Hisashi Arase,Hideto Yamada]
  • Journal Title: PLACENTA Volume: 103 Pages: 253~254
  • Peer Reviewed
• [Journal Article] Use of a combination of oral psoralen, ultraviolet A and interferon-γ 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: The Journal of dermatology Volume: 48 Pages: e17~e18
  • DOI: 10.1111/1346-8138.15628
  • 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 / Open Access
• [Presentation] DPP-4阻害薬服用中に発症した抗α6β4インテグリン抗体陽性水疱性類天疱瘡の1例 (2021)
  • Author(s): 山下千佳紗、荒瀬規子、種村篤、野島聡、藤本学
  • Organizer: 第51回日本皮膚免疫アレルギー学会総会学術大会
• [Presentation] An infectivity-enhancing site on the SARS-Cov-2 spike protein targeted by antibodies (2021)
  • Author(s): Yafei Liu, Wataru Nakai, Noriko Arase, Masako Kohyama, Hisashi Arase
  • Organizer: The 50th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Plasma metabolome-wide analysis in Japanese identifies potential biomarkers of psoriasis and clinical subtypes (2021)
  • Author(s): Yukinori Okada, Toshihiro Kishikawa, Noriko Arase, Shigeyoshi Tsuji, Yuichi Maeda, Takuro Nii, Jun Hirata, Ken Suzuki, Kenichi Yamamoto, Shiro Ohshima, Hidenori Inohara, Atsushi Kumanogoh, Manabu Fujimoto
  • Organizer: The 46th Annual Meeting of the Japanese Society for Investigative Dermatology
• [Book] 皮膚科 ベストセレクション 皮膚科 膠原病 (2021)
  • Author(s): 荒瀬規子、荒瀬尚
  • Total Pages: 515
  • Publisher: 中山書店
  • ISBN: 978-4-521-74862-7