Study for pathological significance of autoantibodies and establishment of therapy in myositis-associated intractable acute interstitial pneumonia

• Project/Area Number: 25293222
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Partial Multi-year Fund
• Section: 一般
• Research Field: Collagenous pathology/Allergology
• Research Institution: Kyoto University
• Principal Investigator: MIMORI Tsuneyo 京都大学, 医学(系)研究科(研究院), 教授 (10157589)
• Co-Investigator(Renkei-kenkyūsha): FUJII Takao 和歌山大学, 医学部, 教授 (70255462) ; OMURA Koichiro 京都大学, 大学院医学研究科, 准教授 (40432372) ; YOSHIFUJI Hajime 京都大学, 大学院医学研究科, 助教 (20422975) ; YUKAWA Naoichiro 和歌山大学, 医学部, 講師 (90422972) ; IMURA Yoshitaka 京都大学, 大学院医学研究科, 助教 (60456895) ; NAKASHIMA Ran 京都大学, 大学院医学研究科, 助教 (10599525) ; TERAO Chikashi 京都大学, 大学院医学研究科, 助教 (60610459)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Project Status: Completed (Fiscal Year 2015)
• Budget Amount: ¥18,460,000 (Direct Cost: ¥14,200,000、Indirect Cost: ¥4,260,000); Fiscal Year 2015: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2014: ¥5,330,000 (Direct Cost: ¥4,100,000、Indirect Cost: ¥1,230,000); Fiscal Year 2013: ¥7,800,000 (Direct Cost: ¥6,000,000、Indirect Cost: ¥1,800,000)
• Keywords: MDA5 / IFIH1 / 自己抗体 / 皮膚筋炎 / 無筋症性皮膚筋炎 / 間質性肺炎 / 膠原病難治性病態 / 免疫抑制療法 / モデルマウス / 治療 / 難治性病態

Outline of Final Research Achievements

Anti-MDA5 autoantibody is specifically detected in patients with clinically amyopathic dermatomyositis accompanied with lethal acute interstitial pneumonia. In order to demonstrate the direct pathogenic role of anti-MDA5, we tried to administrate patient's IgG to SKG mice, but no significant change was found compared with normal IgG. We found a new autoantibody that is associated with anti-MDA5-positive patients, and the target autoantigen was identified as a nuclear molecule involved in DNA repair, mRNA splicing and natural immunity against RNA viral infection. The intensive immunosuppressive therapy (high-dose glucocorticoids, tacrolimus and intravenous cyclophosphamide pulse) appeared to improve a life prognosis of anti-MDA5-positive patients when compared with the historical control of conventional step-up therapy.

Research Products

• [Journal Article] Two cases of autoimmune and secondary pulmonary alveolar proteinosis during immunosuppressive therapy in dermatomyositis with interstitial lung disease. (2016)
  • Author(s): Imura Y, Yukawa N, Handa T, Nakashima R, Murakami K, Yoshifuji H, Ohmura K, Ishii H, Nakata K, Mimori T:
  • Journal Title: Mod Rheumatol. [Epub ahead of print] Volume: 00 Pages: 1-6
  • Peer Reviewed
• [Journal Article] Clinical significance and new detection system of autoantibodies in myositis with interstitial lung disease. (2016)
  • Author(s): Nakashima, Hosono Y, Mimori T
  • Journal Title: Lupus (in press) Volume: 00 Pages: 00-00
  • Peer Reviewed / Acknowledgement Compliant
• [Journal Article] Clinical Utility of an Enzyme-linked Immunosorbent Assay for Detecting Anti-Melanoma Differentiation-Associated Gene 5 Antibodies. (2016)
  • Author(s): Sato S, Murakami A, Kuwajima A, Takehara K, Mimori T, Kawakami A, Mishima M, Suda T, Seishima M, Fujimoto M, Kuwana M
  • Journal Title: PLoS One (in press) Volume: 00 Pages: 00-00
  • Peer Reviewed / Open Access
• [Journal Article] DNA mismatch repair enzymes: Genetic defects and autoimmunity. (2015)
  • Author(s): Muro Y, Sugiura K, Mimori T, Akiyama M.
  • Journal Title: Clin Chim Acta. Volume: 442C Pages: 102-109
  • DOI: 10.1016/j.cca.2015.01.014
  • Peer Reviewed
• [Journal Article] Prognostic Significance of Anti-Aminoacyl-tRNA Synthetase Antibodies in Polymyositis/Dermatomyositis-Associated Interstitial Lung Disease: A Retrospective Case Control Study. (2015)
  • Author(s): Hozumi H, Enomoto N, Kono M, Fujisawa T, Inui N, Nakamura Y, Sumikawa H, Johkoh T, Nakashima R, Imura Y, Mimori T, Suda T
  • Journal Title: PLoS One Volume: 19;10(3) Issue: 3 Pages: e0120313-e0120313
  • DOI: 10.1371/journal.pone.0120313
  • Peer Reviewed / Open Access
• [Journal Article] Anti-PM/Scl antibodies are found in Japanese patients with various systemic autoimmune conditions besides myositis and scleroderma (2014)
  • Author(s): Muro Y, Hosono Y, Sugiura K, Ogawa Y, Mimori T, Akiyama M.
  • Journal Title: Arthritis Res Ther Volume: 17 Issue: 1 Pages: 573-573
  • DOI: 10.1186/s13075-015-0573-x
  • NAID: 120005753819
  • Peer Reviewed / Open Access
• [Journal Article] Two patients in the same family with anti-ARS antibody-associated myositis" to Rheumatology. (2014)
  • Author(s): Ozaki T, Yamashita H, Hosono Y, Nakashima R, Mimori T, Takahashi Y, Kaneko H, Kano T, Mimori A
  • Journal Title: Mod Rheumatol Volume: 24(4) Issue: 4 Pages: 699-700
  • DOI: 10.3109/14397595.2013.844299
  • Peer Reviewed
• [Journal Article] GM-CSF but not IL-17 is critical for the development of severe interstitial lung disease in SKG mice. (2014)
  • Author(s): Shiomi A, Usui T, Ishikawa Y, Shimizu M, Murakami K, Mimori T
  • Journal Title: J Immunol Volume: 193(2) Issue: 2 Pages: 849-859
  • DOI: 10.4049/jimmunol.1303255
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Amyopathic Dermatomyositis Complicated with Eosinophilic Pneumonia (2014)
  • Author(s): Iijima Y, Furusawa H, Tateishi T, Tsuchiya K, Fujie T, Tamaoka M, Sakashita H, Miyazaki Y, Sumi Y, Hosono Y, Nakashima R, Mimori T, Inase N
  • Journal Title: Internal Medicine Volume: 53 Issue: 14 Pages: 1539-1544
  • DOI: 10.2169/internalmedicine.53.0738
  • NAID: 130004466386
  • ISSN: 0918-2918, 1349-7235
  • Peer Reviewed / Open Access
• [Journal Article] Functional engraftment of human peripheral T and B cells and sustained production of autoantibodies in NOD/LtSzscid/ IL-2Rγ-/- mice. (2014)
  • Author(s): Ishikawa Y, Usui T, Shiomi A, Shimizu M, Murakami K, Mimori T
  • Journal Title: Eur J Immunol. Volume: 44(11) Issue: 11 Pages: 3453-3463
  • DOI: 10.1002/eji.201444729
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Autoantibodies to DNA mismatch repair enzymes in polymyositis/dermatomyositis and other autoimmune diseases: a possible marker of favorable prognosis (2014)
  • Author(s): Muro Y, Nakashima R, Hosono Y, Sugiura K, Mimori T, Akiyama M
  • Journal Title: Arthritis Rheumatol Volume: 66 Issue: 12 Pages: 3457-3462
  • DOI: 10.1002/art.38866
  • Peer Reviewed
• [Journal Article] The multicenter study of a new assay for simultaneous detection of multiple anti-aminoacyl-tRNA synthetases in myositis and interstitial pneumonia. (2014)
  • Author(s): Nakashima R, Imura Y, Hosono Y, Seto M, Murakami A, Watanabe K, Handa T, Mishima M, Hirakata M, Takeuchi T, Fujio K, Yamamoto K, Kohsaka H, Takasaki Y, Enomoto N, Suda T, Chida K, Hisata S, Nukiwa T, Mimori T
  • Journal Title: PLoS ONE Volume: 9 Issue: 1 Pages: e85062-e85062
  • DOI: 10.1371/journal.pone.0085062
  • Peer Reviewed
• [Journal Article] Two patients in the same family with anti-ARS antibody-associated myositis. (2014)
  • Author(s): Ozaki T, Yamashita H, Hosono Y, Nakashima R, Mimori T, Takahashi Y, Kaneko H, Kano T, Mimori A
  • Journal Title: Mod Rheumatol. [Epub ahead of print] Volume: 未定
  • Peer Reviewed
• [Journal Article] Skin ulcer is a predictive and prognostic factor of acute or subacute interstitial lung disease in dermatomyositis. (2013)
  • Author(s): Ishigaki K, et al.
  • Journal Title: Rheumatology International Volume: 33 Issue: 9 Pages: 2381-2389
  • DOI: 10.1007/s00296-013-2735-y
  • Peer Reviewed
• [Journal Article] The prognostic value of HRCT in myositis-associated interstitial lung disease. (2013)
  • Author(s): Tanizawa K, Handa T, Nakashima R, Kubo T, Hosono Y, Aihara K, Ikezoe K, Watanabe K, Taguchi Y, Hatta K, Oga T, Chin K, Nagai S, Mimori T, Mishima M
  • Journal Title: Respir Med. Volume: 107 Issue: 5 Pages: 745-752
  • DOI: 10.1016/j.rmed.2013.01.014
  • Peer Reviewed
• [Journal Article] 抗MDA5 (melanoma differentiation-associated gene 5)抗体と皮膚筋炎・急速進行性間質性肺炎 (2013)
  • Author(s): 中嶋蘭、三森経世
  • Journal Title: 日本臨床免疫学会会誌 Volume: 36 Pages: 71-76
  • NAID: 10031171396
• [Presentation] The Clinical Features of Recurrent Interstitial Lung Disease in Dermatomyositis Patients with Anti- Melanoma Differentiation-Associated Gene 5 Antibody. (2015)
  • Author(s): Hosono Y, Nakashima R, Mimori T et al,
  • Organizer: American College of Rheumatology 2015
  • Place of Presentation: San Francisco, USA
  • Year and Date: 2015-11-06
  • Int'l Joint Research
• [Presentation] Clinical Significance and New Detection System of Autoantibodies in Myositis with Interstitial Lung Disease. (2015)
  • Author(s): Mimori T
  • Organizer: 12th Dresden Symposium on Autoantibodies
  • Place of Presentation: Dresden, Germany
  • Year and Date: 2015-09-22
  • Int'l Joint Research / Invited
• [Presentation] Risk factors for life prognosis of interstitial lung disease in dermatomyositis patients with anti-melanoma differentiation-associated gene 5 antibody. (2015)
  • Author(s): Hosono Y, Nakashima R, Mimori T
  • Organizer: 12th Dresden Symposium on Autoantibodies
  • Place of Presentation: Dresden, Germany
  • Year and Date: 2015-09-22
  • Int'l Joint Research
• [Presentation] シンポジウム：自己免疫疾患の新規標的分子と治療戦略．GM-CSFと自己免疫疾患：関節炎合併間質性肺炎モデルを中心に (2015)
  • Author(s): 塩見葵、臼井崇、三森経世
  • Organizer: 第36回日本炎症・再生医学会
  • Place of Presentation: 東京
  • Year and Date: 2015-07-21
  • Invited
• [Presentation] 多発性筋炎・皮膚筋炎患者の筋炎特異的自己抗体、筋炎関連抗体と臨床的特徴の検討 (2015)
  • Author(s): 西岡亜紀、三森経世ほか
  • Organizer: 第59回日本リウマチ学会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23
• [Presentation] 抗ARS抗体陽性間質性肺炎に対する免疫抑制薬の早期併用の有用性 (2015)
  • Author(s): 細野祐司、三森経世ほか
  • Organizer: 第59回日本リウマチ学会
  • Place of Presentation: 東京
  • Year and Date: 2015-04-23
• [Presentation] The early use of cyclosporine is beneficial for long-term prognosis in patients of polymyositis/ dermatomyositis-associated interstitial lung disease with anti-synthetase antibodies. (2014)
  • Author(s): Hosono Y, Nakashima R, Mimori T, et al
  • Organizer: American College of Rheumatology (ACR2014)
  • Place of Presentation: Boston, USA, Nov. 17, 2014.
  • Year and Date: 2014-11-15 – 2014-11-19
• [Presentation] 膠原病と自己抗体－間質性肺炎合併皮膚筋炎における自己抗体の意義－ (2014)
  • Author(s): 三森経世
  • Organizer: 第445回日本皮膚科学会大阪地方会
  • Place of Presentation: 大阪
  • Year and Date: 2014-10-04
  • Invited
• [Presentation] 膠原病診療における自己抗体の臨床活用法 (2014)
  • Author(s): 三森経世
  • Organizer: 第2回日本肺高血圧学会・第3回日本肺循環学会合同集会
  • Place of Presentation: 東京
  • Year and Date: 2014-10-03 – 2014-10-05
  • Invited
• [Presentation] Change of anti-MDA5 antibody titer is the useful marker for predicting of resistance to therapy in dermatomyositis with interstitial pneumonia. (2014)
  • Author(s): Hosono Y, Nakashima R, Mimori T, et al
  • Organizer: 12th International Workshop on Autoimmunity and Autoantibodies
  • Place of Presentation: San Paulo, Brazil
  • Year and Date: 2014-08-28 – 2014-08-30
• [Presentation] 筋炎における難治性間質性肺炎の治療（シンポジウム「膠原病の新規治療」） (2014)
  • Author(s): 細野祐司、中嶋蘭、三森経世
  • Organizer: 第58回日本リウマチ学会
  • Place of Presentation: 東京
  • Year and Date: 2014-04-24 – 2014-04-26
• [Presentation] 筋炎における難治性間質性肺炎の治療 (2014)
  • Author(s): 細野祐司、中嶋蘭、三森経世
  • Organizer: 第58回日本リウマチ学会（シンポジウム）
  • Place of Presentation: 東京
• [Presentation] The onset of myositis with myositis-specific autoantibodies (MSAs) are associated with the seasons. (2013)
  • Author(s): Hosono Y, Nakashima R, Imura Y, Yukawa N, Yoshifuji H, Hashimoto M, Ohmura K, Fujii T, Mimori T
  • Organizer: EULAR2013 (European League Against Rheumatism)
  • Place of Presentation: Madrid, Spain
• [Presentation] 膠原病における自己抗体の基礎から臨床まで (2013)
  • Author(s): 三森経世
  • Organizer: 第57回日本リウマチ学会（教育講演）
  • Place of Presentation: 京都
  • Invited