Elucidation of novel pathogenic mechanism for skin diseases related to misfolded HLA

• Project/Area Number: 15K15419
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Dermatology
• Research Institution: Osaka University
• Principal Investigator: Noriko Arase 大阪大学, 医学系研究科, 助教 (30360481)
• Co-Investigator(Renkei-kenkyūsha): KATAYAMA Ichiro 大阪大学, 大学院医学系研究科, 教授 (80191980) ; AZUKIZAWA Hiroaki 奈良県立医科大学, 大学院医学研究科, 准教授 (10379240) ; ARASE Hisashi 大阪大学, 微生物病研究所, 教授 (10261900)
• Project Period (FY): 2015-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2015: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: β2GPI / HLA Class II / ulcer / autoantibody / ANCA関連血管炎 / 皮膚潰瘍 / 抗リン脂質抗体症候群 / HLAクラスII / 自己抗体 / ミスフォールド蛋白 / 自己免疫性皮膚疾患

Outline of Final Research Achievements

Our research revealed that cellular misfolded proteins associated with HLA Class II, and the autoantibodies against these complexes seems to have pathogenic roles in certain autoimmune diseases.
Chronic ulcers are sometimes idiopathic and intractable. When we analyzed chronic ulcer patients who were not diagnosed as antiphospholipid syndrome, 27% of the patients possessed anti-β2GPI/HLA-DR complex Abs. Furthermore, β2GPI/HLA-DR complexes were observed in the skin region prior to ulceration. These results shows that anti-β2GPI/HLA-DR complex Abs plays an important role in intractable chronic ulcers. Antibodies against misfoleded HLA Class I/HLA Class II complex are observed in a certain skin disease, and these antibodies are considered to be found in other skin diseases.

Research Products

• [Journal Article] Myeloperoxidase/HLA Class II Complexes Recognized by Autoantibodies in Microscopic Polyangiitis (2017)
  • Author(s): Hiwa Ryosuke、Ohmura Koichiro、Arase Noriko、Jin Hui、Hirayasu Kouyuki、Kohyama Masako、Suenaga Tadahiro、Saito Fumiji、Terao Chikashi、Atsumi Tatsuya、Iwatani Hirotsugu、Mimori Tsuneyo、Arase Hisashi
  • Journal Title: Arthritis Rheumatol. Volume: 69 Issue: 10 Pages: 2069-2080
  • DOI: 10.1002/art.40170
  • Peer Reviewed
• [Journal Article] Novel autoantibody against the β2-glycoprotein I/HLA-DR complex in patients with refractory cutaneous ulcers (2017)
  • Author(s): Arase N, Tanimura K, Jin H, Yamaoka T, Kishibe M, Nishioka M, Kiyohara E, Tani M, Matsuoka S, Ohmura K, Takasugi K, Yamamoto T, Murota H, Arase H, Katayama I.
  • Journal Title: Br J Dermatol. Volume: 印刷中 Issue: 1 Pages: 272-275
  • DOI: 10.1111/bjd.15571
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] The effect of rhododendrol inhibition of NF-κB on melanocytes in the presence of tyrosinase. (2016)
  • Author(s): Arase N, Yang L, Tanemura A, Yang F, Suenaga T, Arase H, Katayama I.
  • Journal Title: J Dermatol Sci. Volume: 83 Issue: 2 Pages: 157-159
  • DOI: 10.1016/j.jdermsci.2016.05.002
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] LILRA2 is an innate immune sensor for microbially cleaved immunoglobulins. (2016)
  • Author(s): Hirayasu K, Saito F, Suenaga T, Shida K, Arase N, Oikawa K, Yamaoka T, Murota H, Chibana H, Nagai H, Nakamura Y, Katayama I, Colonna M, Arase H.
  • Journal Title: Nature Microbiology Volume: - Issue: 6 Pages: 1-7
  • DOI: 10.1038/nmicrobiol.2016.54
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] ミスフォールドタンパク質/主要組織適合抗原複合体と自己免疫疾患(総説) (2016)
  • Author(s): 荒瀬規子、荒瀬尚
  • Journal Title: 日本臨床 Volume: 74(2) Pages: 359-368
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Possible involvement of CCR4+CD8+ T cells and elevated serum CCL22 and CCL17 in Patients with Rhododenol-induced Leukoderma. (2015)
  • Author(s): Nishioka M, Tanemura A, Yang L, Tanaka A, Arase N, Katayama I
  • Journal Title: J Dermatol Sci. Volume: 77 Issue: 3 Pages: 188-190
  • DOI: 10.1016/j.jdermsci.2015.02.014
  • Peer Reviewed / Open Access
• [Journal Article] β2-glycoprotein I/ HLA class II complexes are novel autoantigens in antiphospholipid syndrome. (2015)
  • Author(s): Tanimura K, Jin H, Suenaga T, Morikami S, Arase N, Kishida K, Hirayasu K, Kohyama M, Ebina Y, Yasuda S, Horita T, Takasugi K, Ohmura K, Yamamoto K, Katayama I, Sasazuki T, Lanier LL, Atsumi T, Yamada H, Arase H.
  • Journal Title: Blood Volume: 125 Issue: 18 Pages: 2835-2844
  • DOI: 10.1182/blood-2014-08-593624
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Cellular misfolded proteins rescued from degradation by MHC class II molecules are possible targets for autoimmune diseases. (2015)
  • Author(s): Arase N, Arase H.
  • Journal Title: J Biochem. Volume: 158 Issue: 5 Pages: 367-372
  • DOI: 10.1093/jb/mvv093
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Presentation] Recognition of SS-A/IgG/HLA-DR complex by autoantibodies in Sjögren’s syndrome. (2017)
  • Author(s): Noriko Arase, Hui Jin, Ichiro Katayama, Hisashi Arase
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Recognition of SS-A/IgG/HLA-DR complex by autoantibodies in Sjögren’s syndrome. (2017)
  • Author(s): Noriko Arase, Hui Jin, Yutaro Hayashi, Hiroyuki Murota, Hisashi Arase, Ichiro Katayama
  • Organizer: The 42nd Annual Meeting of The Japanese Society for Investigative Dermatology
• [Presentation] Antiphospholipid antibody recognizes β2GPI complexed with HLA class II molecules via its domain V (2017)
  • Author(s): Yuki Sasagawa, Kenji Tanimura, Hui Jin, Noriko Arase, Tadahiro Suenaga, Masako Koyama, Kouyuki Hirayasu, Satoko Morikami, Yasuhiko Ebina, Tatsuya Atsumi, Hideto Yamada, Hisashi Arase,
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Prothrombin complexed with HLA class II molecules is an autoantibody target in antiphospholipid syndrome (2017)
  • Author(s): Satoko Morikami, Yuki Sasagawa, Kenji Tanimura, Noriko Arase, Kouyuki Hirayasu, Tadahiro Suenaga,Masako Koyama, Tatsuya Atsumi, Hideto Yamada, Hisashi Arase,
  • Organizer: The 46th Annual Meeting of The Japanese Society for Immunology
• [Presentation] Absent Glycoprotein Non-metastatic B / Osteoactivin (GPNMB) expression by the lesional basal keratinocytes in vitiligo. (2017)
  • Author(s): Takahashi Aya, Yang Fei, Yang Lingli, Arase Noriko, Tanemura Atsushi, Kaneda Mari, Arunasiri Iddamalgoda, Inoue Shintaro, Katayama Ichiro
  • Organizer: The 42nd Annual Meeting of The Japanese Society for Investigative Dermatology
• [Presentation] 初診時、薬剤性水疱性扁平苔癬と診断した高齢者前脛骨型表皮水疱症 (2017)
  • Author(s): 清水友理、壽 順久、荒瀬規子、片山一朗
  • Organizer: 第47回皮膚アレルギー・接触皮膚炎学会学術大会
• [Presentation] Immunological analysis of the patients with vitiligo vulgaris and rhododendrol-induced leukoderma. (2016)
  • Author(s): Arase N, Tanemura A, Yang L, Jin H, Nishioka M, Yang F, Aoyama Y, Suenaga T, Arase H, Katayama I.
  • Organizer: 第41回日本研究皮膚科学会総会
  • Place of Presentation: 仙台市
  • Year and Date: 2016-12-09
• [Presentation] Novel Autoantibody against neo-self β2-glycoprotein I/HLA-DR Complex. (2016)
  • Author(s): Arase N, Jin H, Tanimura K, Matsuoka S, Ohmura K, Murota H, Katayama I, Arase H
  • Organizer: 日本免疫学会総会
  • Place of Presentation: 宜野湾市
  • Year and Date: 2016-12-05
• [Presentation] ロドデノール白斑発症機構の解析 (2016)
  • Author(s): 荒瀬規子 種村篤 楊伶俐 楊飛 西岡めぐみ 高橋彩 片山一朗
  • Organizer: 第27回日本色素細胞学会
  • Place of Presentation: 岐阜市
  • Year and Date: 2016-11-12
  • Invited
• [Presentation] Novel Autoantibody against the β2GP1/HLA-DR Complex in Patients with Refractory Cutaneous Ulcerations. (2016)
  • Author(s): Arase N, Jin H, Tanimura K, Matsuoka S, Yamaoka T, Nishioka M, Kiyohara E, Tani M, Ohmura K, Murota H, Arase H, Katayama I
  • Organizer: 15th International Congress on Antiphospholipid Antibodies
  • Place of Presentation: Girne, Northern Cyprus
  • Year and Date: 2016-09-21
  • Int'l Joint Research
• [Presentation] ロドデノールによる白斑症状の免疫学的機序に関する研究 (2016)
  • Author(s): 荒瀬規子
  • Organizer: 第115回皮膚科学会総会
  • Place of Presentation: 京都市
  • Year and Date: 2016-06-03
• [Presentation] メラノーマに対するHVJ-Eの抗腫瘍効果: ライブイメージングで見えたそのメカニズム (2016)
  • Author(s): 楊 怜悧、荒瀬規子、山岡俊文、揚 飛、金田眞理、種村 篤、室田浩之、片山一朗
  • Organizer: 第405回日本皮膚科学会北海道地方会
  • Place of Presentation: 札幌
  • Year and Date: 2016-03-19
• [Presentation] Presence of anti-β2GP1/HLA-DR complex autoantibodies in the non-APS patients with recurrent limb ulcerations. (2015)
  • Author(s): Noriko Arase, Kenji Tanimura, Jin Hui, Sumiko Matsuoka, Toshifumi Yamaoka, Megumi Nishioka, Eiji Kiyohara, Mamori Tani, Koichiro Ohmura, Hiroyuki Murota, Hisashi Arase, Ichiro Katayama
  • Organizer: 日本研究皮膚科学会 第40回学術大会・総会
  • Place of Presentation: 岡山
  • Year and Date: 2015-12-11
• [Presentation] MHC class II molecules expose autoantibody epitopes on autoantigens. (2015)
  • Author(s): Hiwa Ryosuke, Ohmura Koichiro, Arase Noriko, Jin Hui, Hirayasu Kouyuki, Kohyama Masako, Suenaga Tadahiro, Saito Fumiji, Iwatani Hirotsugu, Atsumi Tatsuya, Terao Chikashi, Mimori Tsuneyo, Arase Hisashi
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] DIR is an innate immune sensor for microbially cleaved immunoglobulins. (2015)
  • Author(s): Kouyuki Hirayasu, Fumiji Saito, Tadahiro Suenaga, Kyoko Shida, Noriko Arase, Keita Oikawa, Toshifumi Yamaoka, Hiroyuki Murota, Hiroji Chibana, Ichiro Nakagawa, Tomoko Kubori, Hiroki Nagai, Yuji Nakamaru, Ichiro Katayama, Marco Colonna, Hisashi Arase.
  • Organizer: 第44回日本免疫学会学術集会
  • Place of Presentation: 札幌
  • Year and Date: 2015-11-18
• [Presentation] Novel autoantibody against the β2GP1/HLA-DR complex in patients with refractory cutaneous ulcerations. (2015)
  • Author(s): Noriko Arase, Hui Jin, Kenji Tanimura, Toshifumi Yamaoka, Eiji Kiyohara, Koichiro Ohmura, Hiroyuki Murota, Hisashi Arase, Ichro Katayama
  • Organizer: 14th International Workshop on Langerhans Cells
  • Place of Presentation: 京都
  • Year and Date: 2015-11-05
  • Int'l Joint Research
• [Presentation] MPO/HLA class II複合体は顕微鏡的多発血管炎における自己抗体の標的である (2015)
  • Author(s): 日和良介、大村浩一郎、荒瀬規子、金暉、平安恒幸、香山雅子、末永忠広、齋藤史路、岩谷博次、渥美達也、寺尾知可史、三森経世、荒瀬尚
  • Organizer: 第43回日本臨床免疫学会総会
  • Place of Presentation: 神戸
  • Year and Date: 2015-10-22
• [Presentation] 難治性ロドデノール誘発性脱色素斑患者9例の臨床的検討 (2015)
  • Author(s): 髙橋 彩、楊 飛、楊 伶俐、永田由子、西岡めぐみ、荒瀬規子、種村 篤、片山一朗
  • Organizer: 第67回 日本皮膚科学会西部支部学術大会
  • Place of Presentation: 長崎
  • Year and Date: 2015-10-17
• [Presentation] ミスフォールドタンパク質ーHLAクラスII複合体と自己免疫疾患ー原因不明難治性皮膚潰瘍症例でのb2GPI HLA-DR複合体抗体の検討ー (2015)
  • Author(s): 荒瀬規子、Hui Jin、谷村憲司、山岡俊文、室田浩之、荒瀬尚、片山一朗
  • Organizer: 第22回分子皮膚科学フォーラム
  • Place of Presentation: 高知
  • Year and Date: 2015-04-17
• [Book] WHAT’S NEW in 皮膚科学 (2016)
  • Author(s): 荒瀬規子、片山一朗
  • Total Pages: 236
  • Publisher: メディカルレビュー社
• [Book] WHAT'S NEW in 皮膚科学 2016-2017 (2016)
  • Author(s): 荒瀬規子 片山一朗
  • Total Pages: 236
  • Publisher: メディカルレビュー社