自己抗体による強皮症発症機構の解明

• Project/Area Number: 21K08344
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 53050:Dermatology-related
• Research Institution: Osaka University
• Principal Investigator: 荒瀬 規子 大阪大学, 大学院医学系研究科, 助教 (30360481)
• Project Period (FY): 2021-04-01 – 2025-03-31
• Project Status: Granted (Fiscal Year 2023)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2023: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000); Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2021: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 全身性強皮症 / B細胞 / 自己抗体 / 強皮症 / 皮膚筋炎 / 抗MDA5抗体 / 抗ARS抗体症候群 / 間質性肺炎 / 筋症状 / Ro52/IgG/HLAクラスII複合体 / ミスフォールド蛋白 / HLA

Outline of Research at the Start

私たちは以前よりいくつかの自己免疫疾患でミスフォールド蛋白とHLAクラスII分子の複合体が自己抗体の標的となり、疾患発症にも関わる可能性を見出してきた。私たちは今回、新規の強皮症サブタイプ特異的自己抗体を見出した。この標的自己抗原をクローニングし、機能解析を行う。さらに、この自己抗原や今まで知られている核内抗原がミスフォールド蛋白／HLAクラスII複合体を形成し強皮症発症に関連するかを各種動物モデルを用いて検討する。

Outline of Annual Research Achievements

全身性強皮症は皮膚硬化を主症状とし、併存症には間質性肺炎等が生じる難治性自己免疫疾患である。他の膠原病同様、発症機構は不明で治療は対処療法に限られている。最近抗CD20抗体の全身性強皮症への有効性が確認され、今までの治療に加えて本疾患対する治療の新たな選択肢が増えつつある。一方で、抗CD20抗体の全身性強皮症に対する作用機構には未だに不明な点があるため今後も解析していく必要性が残されていると考えられる。
強皮症では疾患サブタイプに特異的な抗核抗体が認められ全身性強皮症の臨床症状もこれらの自己抗体により概ね規定されている。これらの抗核抗体は核内抗体であるため抗体の作用には不明な点が多かったが、最近これらの抗体の細胞機能に対する直接作用も報告され、抗核抗体の新たな役割の存在の可能性が考えられている。
一方、我々は全身性強皮症患者において、抗核抗体以外の細胞表面分子に対する自己抗体を見出し、全身性強皮症患者からそれらのモノクロナール抗体を作成することに成功した。この自己抗体の抗体価は全身性強皮症の疾患活動性とも関連することが新たに判明した。この結果はこれらの自己抗体の重要性を示唆していると考えられる。
令和５年度はこれらのモノクロナール抗体の性質の解析を行い、in vitroでこれらの強皮症モノクロナール抗体がモノサイトの機能に影響する新たな機能を見出した。現在このようなモノクロナール抗体の新たな作用機序をさらに深く解析している。一方、これらの抗体のin vivoでの作用を解析しようとしている。

Current Status of Research Progress

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

Reason

全身性強皮症の患者から新たなモノクロナール抗体を樹立し、それらのモノクロナール抗体の新たな機能を見出した。これらの抗体は、その抗体価が疾患活動性とも関連することから、全身性強皮症で重要な役割を担っていることが考えられた。

Strategy for Future Research Activity

これらのモノクロナール抗体が新たな機能を有することが判明したため、今後in vivoへの投与を行うことで生体への影響を観察していく予定である。さらに今回判明した本抗体の機能解析を進めると共に、これらの抗体の新たな機能や分子機構を解析し、病態への影響を解析していく予定である。

Research Products

• [Journal Article] A case of anti-melanoma differentiation antigen 5 antibody-positive dermatomyositis in which monitoring of Ro52/IgG/HLA-DR complex antibody titer was useful to exclude interstitial pneumonia (2024)
  • Author(s): Hatano Yoko, Tonomura Kyoko, Yamashita Chigusa, Arase Noriko, Ishitsuka Yosuke, Ueda-Hayakawa Ikuko, Tanemura Atsushi, Kimura Yuka, Kataoka Yoko, Fujimoto Manabu
  • Journal Title: J. Cutan. Immunol. Allergy Volume: 7
  • DOI: 10.3389/jcia.2024.12630
  • Peer Reviewed / Open Access
• [Journal Article] Efficacy and safety of nemolizumab and topical corticosteroids for prurigo nodularis: Results from a randomised, double-blind, placebo-controlled, phase II/III clinical study in patients aged ≧13 years (2024)
  • Author(s): Yokozeki H, Murota H, Matsumura T, Komazaki H; Nemolizumab-JP11 Study Group.
  • Journal Title: Br J Dermatol Volume: Online ahead of print. Issue: 2 Pages: 200-208
  • DOI: 10.1093/bjd/ljae131
  • Peer Reviewed
• [Journal Article] Analysis of gut microbiome, host genetics, and plasma metabolites reveals gut microbiome-host interactions in the Japanese population (2023)
  • Author(s): Tomofuji Yoshihiko、Kishikawa Toshihiro、Sonehara Kyuto et al.
  • Journal Title: Cell Reports Volume: 42 Issue: 11 Pages: 113324-113324
  • DOI: 10.1016/j.celrep.2023.113324
  • Peer Reviewed / Open Access
• [Journal Article] Anti-α6β4 integrin autoantibodies inhibit the binding of laminins to α6β4 integrin in patients with pemphigoid and affect the gastrointestinal tract (2023)
  • Author(s): Arase N, Sasaoka Y, Narita J, Kiyohara E, Hashimoto K, Shinzaki S, Nojima S, Takagi J, Fujimoto M.
  • Journal Title: J Eur Acad Dermatol Venereol Volume: 38(2) Issue: 2 Pages: 404-412
  • DOI: 10.1111/jdv.19582
  • Peer Reviewed
• [Journal Article] Dermatofibrosarcoma protuberans of the cheek without surface alteration (2023)
  • Author(s): Kaneda E, Yamashita C, Tonomura K, Kiyohara E, Ishitsuka Y, Arase N, Seike S, Kubo T, Fujimoto M, Tanemura A.
  • Journal Title: Eur J Dermatol Volume: 33(3) Issue: 3 Pages: 306-307
  • DOI: 10.1684/ejd.2023.4457
  • Peer Reviewed
• [Journal Article] 59.Age distribution and prevalence in different age groups of four myositis-specific autoantibodies, including anti-ARS, anti-MDA5, anti-Mi-2, and anti-TIF1γ antibodies (2023)
  • Author(s): Ueda-Hayakawa I, Tonomura K, Maekawa A, Kaneda E, Arase N, M Fujimoto M
  • Journal Title: J Dermatol. Volume: - Issue: 8 Pages: 1058-1062
  • DOI: 10.1111/1346-8138.16772
  • Peer Reviewed
• [Journal Article] 58.A case of erosive pustular dermatosis of the scalp following bullous pemphigoid in a hematopoietic stem cell transplant recipient (2023)
  • Author(s): Yamashita C, Arase N, Fukushima K, Ueda-Hayakawa I, Tonomura K, Tanemura A, Sakai H, Fujimoto M
  • Journal Title: J Dermatol. Volume: - Issue: 7
  • DOI: 10.1111/1346-8138.16743
  • Peer Reviewed
• [Journal Article] Aggressive Squamous Cell Carcinoma in a Case of Epidermodysplasia Verruciformis Carrying a TMC6 Splice-site Mutation (2023)
  • Author(s): Yokoi Kazunori、Arase Noriko、Shimbo Takashi、Fujimoto Manabu、Tanemura Atsushi
  • Journal Title: Acta Dermato-Venereologica Volume: 103 Pages: 4550-4550
  • DOI: 10.2340/actadv.v103.4550
  • Peer Reviewed / Open Access
• [Journal Article] Mitigating Drug Target Drug Complexes in Patients With Paroxysmal Nocturnal Hemoglobinuria Who Switch C5 Inhibitors (2023)
  • Author(s): Nishimura Jun‐ichi、Soubret Antoine、Arase Noriko、et al.
  • Journal Title: Clinical Pharmacology & Therapeutics Volume: 113 Issue: 4 Pages: 904-915
  • DOI: 10.1002/cpt.2851
  • Peer Reviewed / Open Access / Int'l Joint Research
• [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-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: - Issue: 7
  • 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 Issue: 9
  • DOI: 10.1126/sciadv.abj9867
  • 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 Issue: 1 Pages: 81-83
  • DOI: 10.5021/ad.2022.34.1.81
  • Peer Reviewed / Open Access
• [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: 102774-102774
  • DOI: 10.1016/j.jaut.2021.102774
  • 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): Yamashita Chigusa、Arase Noriko、Higuchi Shuhei、Arase Hisashi、Takagi Junichi、Nojima Satoshi、Tanemura Atsushi、Fujimoto Manabu
  • 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: 102797-102797
  • DOI: 10.1016/j.jaut.2022.102797
  • 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 Issue: 12 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 Issue: 6 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): Liu Y, Ohshima S, Arase H, et al.
  • Journal Title: Cell Volume: Jun 24;184(13) Issue: 13 Pages: 3452-3466
  • DOI: 10.1016/j.cell.2021.05.032
  • Peer Reviewed / Open Access
• [Journal Article] Anti?Double‐Stranded DNA Antibodies Recognize DNA Presented on HLA Class II Molecules of Systemic Lupus Erythematosus Risk Alleles (2021)
  • Author(s): Tsuji Hideaki、Ohmura Koichiro、Jin Hui、Naito Ryota、Arase Noriko、Kohyama Masako、Suenaga Tadahiro、Sakakibara Shuhei、Kochi Yuta、Okada Yukinori、Yamamoto Kazuhiko、Kikutani Hitoshi、Morinobu Akio、Mimori Tsuneyo、Arase Hisashi
  • Journal Title: Arthritis & Rheumatology Volume: 74 Issue: 1 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: JOURNAL OF DERMATOLOGY Volume: in press Issue: 6
  • 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): Kume M, Arase N, Okiyama N, Koguchi-Yoshioka H, Tada T, Saruban H, Fujimoto M.
  • Journal Title: Rheumatology (Oxford) Volume: 60(4) Issue: 4 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): Kishikawa Toshihiro、Arase Noriko、Tsuji Shigeyoshi、Maeda Yuichi、Nii Takuro、Hirata Jun、Suzuki Ken、Yamamoto Kenichi、Masuda Tatsuo、Ogawa Kotaro、Ohshima Shiro、Inohara Hidenori、Kumanogoh Atsushi、Fujimoto Manabu、Okada Yukinori
  • Journal Title: Journal of Dermatological Science Volume: 102 Issue: 2 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 Issue: 3 Pages: 71-72
  • DOI: 10.1002/cia2.12159
  • 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-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 Issue: 1
  • 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 Issue: 1
  • DOI: 10.1111/dth.14714
  • Peer Reviewed / Open Access
• [Journal Article] Increased levels of plasma nucleotides in patients with rheumatoid arthritis (2020)
  • Author(s): Kishikawa T、Maeda Y、Nii T、Arase N、Hirata J、Suzuki K、Yamamoto K、Masuda T、Ogawa K、Tsuji S、Matsushita M、Matsuoka H、Yoshimura M、Tsunoda S、Ohshima S、Narazaki M、Ogata A、Saeki Y、Inohara H、Kumanogoh A、Takeda K、Okada Y
  • Journal Title: International Immunology Volume: 33 Issue: 2 Pages: 119-124
  • DOI: 10.1093/intimm/dxaa059
  • Peer Reviewed / Open Access
• [Presentation] ミスフォールド蛋白/HLAクラスII複合体と膠原病 -炎症性筋疾患における抗Ro52/IgG/HLA-DR抗体の意義- (2023)
  • Author(s): 荒瀬規子、荒瀬 尚、藤本 学
  • Organizer: 第122回日本皮膚科学会総会
  • Invited
• [Presentation] Cellular misfolded protein/MHC class II complexes are possible autoantibody targets for autoimmune diseases Significance of anti-Ro52/IgG/HLA-DR autoantibodies in dermatomyositis (2023)
  • Author(s): Noriko Arase, Hisashi Arase, Manabu Fujimoto
  • Organizer: 第５回International Conference on Cutaneous Lupus Erythematosus
  • Int'l Joint Research / Invited
• [Presentation] 抗MDA5抗体陽性皮膚筋炎の加療中に皮膚腺病を発症した１例 (2023)
  • Author(s): 秦野暢子、外村香子、浅田充夫、山下千佳紗、石塚洋典、荒瀬規子、植田郁子、種村 篤、藤本 学、平田陽彦、五十嵐謙人、山本 剛、木村優香、片岡葉子
  • Organizer: 日本皮膚科学会 第496回大阪地方会
• [Presentation] 造血幹細胞移植後に生じたerosive pustular dermatosis of the scalpの1例 (2022)
  • Author(s): 山下千佳紗、荒瀬規子、坂井浩志、藤本 学
  • Organizer: 日本皮膚科学会 第115回近畿皮膚科集談会
• [Presentation] TMC6に変異を認め進行有棘細胞癌を生じた疣贅状表皮発育異常症の1例 (2022)
  • Author(s): 藤本 萌、横井一範、黒神 祐、外村香子、荒瀬規子、種村 篤、藤本 学、新保敬史、玉井克人
  • Organizer: 第73回皮膚科学会中部支部
• [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
• [Presentation] COVID-19ワクチン接種後に生じたlichen planus pemphigoidesの1例 (2021)
  • Author(s): 黒崎友木穂、石塚洋典、荒瀬規子、藤本 学、加藤保宏
  • Organizer: 日本皮膚科学会 第488回大阪地方会
• [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: 9784521748627