Analysis of abnormal methylation of cytokines involved in the pathogenesis of autoimmune pancreatitis and its application to pathological diagnosis

• Project/Area Number: 20K07405
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49020:Human pathology-related
• Research Institution: Shinshu University
• Principal Investigator: Uehara Takeshi 信州大学, 学術研究院医学系, 准教授 (80402121)
• Co-Investigator(Kenkyū-buntansha): 松田 和之 信州大学, 学術研究院保健学系, 教授 (00647084) ; 増本 純也 愛媛大学, プロテオサイエンスセンター, 教授 (20334914)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2021: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2020: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
• Keywords: 自己免疫性膵炎 / サイトカイン / メチル化アレイ解析 / メチル化 / IgG4 / メチル化特異的定量PCR法 / IgG4関連疾患

Outline of Research at the Start

本研究計画では「AIP におけるIgG4 産生および線維化は被障害臓器の組織に起因するエピゲネティックな修飾に影響を受けている」という仮説を検証する。
1. 選択症例から保存病理検体、血清材料を集め、IgG4 産生および線維化の原因となるようなエピゲネティック異常が生じているかサイトカインに関与する因子を中心に解析を行い、原因候補を特定し、IgG4 産生および線維化に関与する因子の異常の同定を目指す。
2. 特定されたIgG4 産生および線維化に関与するサイトカイン異常が、実際にIgG4 産生や線維化に関わるサイトカインにどのように関与するのか解明し、制御方法の樹立を目指す。

Outline of Final Research Achievements

We performed whole-genome methylation profiling using the Infinium
MethylationEPIC Kit (Illumina, USA) to identify methylation abnormalities of cytokines and cytokine-related factors in autoimmune pancreatitis (AIP). Methylation array analysis was performed on the inflammatory area of AIP, the obstructive pancreatitis area of pancreatic cancer, and the respective lymph nodes. No systematic methylation abnormalities were found in the heat map analysis. On the other hand, during the analysis, we found methylation aberrations in cytokine-related factors that may regulate overall inflammation, factors that may regulate AIP and may lead to prevention of AIP development. We plan to continue analysis of candidate genes.

Academic Significance and Societal Importance of the Research Achievements

自己免疫性膵炎(AIP)発症メカニズムについては、いまだ不明な点が多い。AIPにおいて様々なサイトカインが病態形成に関与していることが知られている。そこでAIPで生じる線維化や高IgG4血症を生じさせるサイトカイン異常がメチル化異常によって誘発されているという仮説を立て、病理学的、分子生物学的視点から検証した。アレイ解析でそれらに系統的な特異なメチル化異常は見いだせなかった。一方で解析の中で、炎症全体を制御するサイトカイン関連因子にメチル化異常が生じていた。AIPを制御する可能性のある因子を見出したことは、AIP発症を防ぐことにつながる可能性があり、学術的意義および社会的意義がある。

Research Products

• [Journal Article] Usual Interstitial Pneumonia Pattern Interstitial Lung Disease Developed in a Patient with IgG4-related Chronic Sclerosing Sialadenitis (2022)
  • Author(s): Yamamoto Hiroshi、Komatsu Masamichi、Sonehara Kei、Ikuyama Yuichi、Urushihata Kazuhisa、Tateishi Kazunari、Kitaguchi Yoshiaki、Ushuiki Atsuhito、Asaka Shiho、Uehara Takeshi、Kawakami Satoshi、Mori Kentaro、Hamanaka Kazutoshi、Nishie Kenichi、Hebisawa Akira、Hanaoka Masayuki
  • Journal Title: Internal Medicine Volume: 61 Issue: 17 Pages: 2637-2642
  • DOI: 10.2169/internalmedicine.8937-21
  • NAID: 130008158383
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2022-09-01
  • Peer Reviewed / Open Access
• [Journal Article] IgG4 expression and IgG4/IgG ratio in the tumour invasion front predict long-term outcomes for patients with intrahepatic cholangiocarcinoma. (2022)
  • Author(s): Yoshizawa T, Uehara T, Iwaya M, Asaka S, Nakajima T, Kinugawa Y, Shimizu A, Kubota K, Notake T, Masuo H, Sakai H, Hosoda K, Hayashi H, Nagaya T, Ota H, Soejima Y.
  • Journal Title: Pathology, Online ahead of print. Volume: 55 Issue: 4 Pages: 508-513
  • DOI: 10.1016/j.pathol.2022.11.007
  • Peer Reviewed
• [Journal Article] Prognostic implication of IgG4 and IgG1-positive cell infiltration in the lung in patients with idiopathic interstitial pneumonia (2022)
  • Author(s): Komatsu Masamichi、Yamamoto Hiroshi、Uehara Takeshi、、Terasaki Yasuhiro、Kunugi Shinobu、Ushiki Atsuhito、Yasuo Masanori、Suda Takafumi、Hanaoka Masayuki
  • Journal Title: Scientific Reports Volume: 12 Issue: 1 Pages: 9303-9303
  • DOI: 10.1038/s41598-022-13333-8
  • Peer Reviewed / Open Access
• [Journal Article] Immunoglobulin G4‐related orbital disease in an 8‐year‐old girl (2022)
  • Author(s): Hoshiyama Sayako、Maruyama Yuta、Iwaya Mai、Uehara Takeshi、Nakazawa Yozo
  • Journal Title: Pediatrics International Volume: 64 Issue: 1
  • DOI: 10.1111/ped.15014
  • Peer Reviewed
• [Journal Article] Concordance of the histological diagnosis of type 1 autoimmune pancreatitis and its distinction from pancreatic ductal adenocarcinoma with endoscopic ultrasound-guided fine needle biopsy specimens: an interobserver agreement study. (2022)
  • Author(s): Notohara K, Kamisawa T, Kanno A, et al.
  • Journal Title: Virchows Arch. Volume: 480 Issue: 3 Pages: 565-575
  • DOI: 10.1007/s00428-021-03236-w
  • Peer Reviewed
• [Journal Article] Cut-off values of serum IgG4 among three reagents, including a novel IgG4 reagent: a multicenter study (2021)
  • Author(s): Usami Yoko、Sugano Mitsutoshi、Uehara Takeshi、Koinuma Masayoshi、Ishimine Nau、Kawasaki Kenji、Yamauchi Kazuyoshi、Hamano Hideaki、Honda Takayuki
  • Journal Title: Scientific Reports Volume: 11 Issue: 1 Pages: 1-7
  • DOI: 10.1038/s41598-021-86024-5
  • Peer Reviewed / Open Access
• [Journal Article] Diagnosing Biliary Strictures (2021)
  • Author(s): Hori Yasuki、Chari Suresh T.、Tsuji Yoshihisa、Takahashi Naoki、Inoue Dai、Hart Phil A.、Uehara Takeshi、Horibe Masayasu、Yamamoto Satoshi、Satou Akira、Zhang Lizhi、Notohara Kenji、Naitoh Itaru、Nakazawa Takahiro
  • Journal Title: Mayo Clinic Proceedings: Innovations, Quality & Outcomes Volume: 5 Issue: 3 Pages: 535-541
  • DOI: 10.1016/j.mayocpiqo.2021.03.005
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] IL-6 expression helps distinguish Castleman’s disease from IgG4-related disease in the lung (2021)
  • Author(s): Kinugawa Yasuhiro、Uehara Takeshi、Iwaya Mai、Asaka Shiho、Kobayashi Shota、Nakajima Tomoyuki、Komatsu Masamichi、Yasuo Masanori、Yamamoto Hiroshi、Ota Hiroyoshi
  • Journal Title: BMC Pulmonary Medicine Volume: 21 Issue: 1 Pages: 1-6
  • DOI: 10.1186/s12890-021-01603-6
  • Peer Reviewed / Open Access
• [Journal Article] A comparison of the features of fluorine-18 fluorodeoxyglucose-positron emission tomography (FDG-PET) between IgG4-related disease with bilateral hilar lymphadenopathy and sarcoidosis (2020)
  • Author(s): Ozawa Y, Yamamoto H, Yasuo M, Komatsu M, Ushiki A, Hamano H, Uehara T, Kawakami S, Fujita A, Fujinaga Y, Oguchi K, Kawa S, Hanaoka M
  • Journal Title: Nagoya Journal of Medical Science Volume: 82 Issue: 1 Pages: 101-111
  • DOI: 10.18999/nagjms.82.1.101
  • NAID: 120006797878
  • ISSN: 2186-3326
  • URL: https://nagoya.repo.nii.ac.jp/records/29358
  • Peer Reviewed
• [Journal Article] Guidance for diagnosing autoimmune pancreatitis with biopsy tissues (2020)
  • Author(s): Notohara K, Kamisawa T, Fukushima N, Furukawa T, Tajiri T, Yamaguchi H, Aishima S, Fukumura Y, Hirabayashi K, Iwasaki E, Kanno A, Kasashima S, Kawashima A, Kojima M, Kubota K, Kuraishi Y, Mitsuhashi T, Naito Y, Naitoh I, Nakase H, Nishino T, Ohike N, Sakagami J, Shimizu K, Shiokawa M, Uehara T, et al.
  • Journal Title: Pathol Int Volume: 70 Issue: 10 Pages: 699-711
  • DOI: 10.1111/pin.12994
  • Peer Reviewed
• [Journal Article] Corticosteroids prevent the progression of autoimmune pancreatitis to chronic pancreatitis (2020)
  • Author(s): Kuraishi Y, Uehara T, Watanabe T, Ashihara N, Ozawa M, Kanai K, Kawa S: Corticosteroids prevent the progression of autoimmune pancreatitis to chronic pancreatitis.
  • Journal Title: Pancreatology Volume: 20 Issue: 6 Pages: 1062-1068
  • DOI: 10.1016/j.pan.2020.07.408
  • Peer Reviewed
• [Journal Article] Immunostaining With Immunoglobulin G Subclass Antibody Cocktail for Diagnosis of Type 1 Autoimmune Pancreatitis (2020)
  • Author(s): Nakata R, Uehara T, Iwaya M, Asaka S, Kobayashi S, Sugano M, Higuchi K, Kusama Y, Nakazawa K, Nakaguro M, Kobayashi M, Tateishi A, Makino M, Kawaguchi K, Maejima T, Ishii K, Sano K, Shimojo H, Hori A, Otsuki T, Hamano H, Kawa S, Ota H
  • Journal Title: Int J Surg Pathol Volume: 28 Issue: 8 Pages: 844-849
  • DOI: 10.1177/1066896920924781
  • Peer Reviewed
• [Journal Article] Utility of gastric biopsy in diagnosing IgG4-related gastrointestinal disease (2020)
  • Author(s): Uchino K, Notohara K, Uehara T, Kuraishi Y, Itakura J, Matsukawa A
  • Journal Title: Pathol Int Volume: 71 Issue: 2 Pages: 124-134
  • DOI: 10.1111/pin.13059
  • NAID: 120007182892
  • Peer Reviewed
• [Presentation] EUS-FNB検体による1型自己免疫性膵炎の生検診断についての診断者間一致の検討 (2022)
  • Author(s): 能登原 憲司, 神澤 輝実, 古川 徹, 福嶋 敬宜, 上原 剛, 笠島 里美, 池浦 司, 川 茂幸, 岡崎 和一
  • Organizer: 第111回日本病理学会総会
• [Presentation] 肝内胆管癌におけるIgG4の発現と予後 (2022)
  • Author(s): 吉澤 隆裕, 清水 明, 上原 剛, 窪田 晃治, 野竹 剛, 増尾 仁志, 坂井 紘紀, 細田 清孝, 林 輝, 副島 雄二
  • Organizer: 日本消化器外科学会総会 77回