The altered immune response caused by CCDC22 mutation and its association with EBV-HLH development and severity.

• Project/Area Number: 20K17405
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Wakayama Medical University
• Principal Investigator: Yamashita Yusuke 和歌山県立医科大学, 医学部, 助教 (50794153)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000); Fiscal Year 2021: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2020: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: CCDC22 / EBV-HLH / NFκB

Outline of Research at the Start

EBウイルス関連血球貪食症候群（EBV-HLH）は, EBV感染が引き金となって過剰な炎症が生じ, 汎血球減少と臓器障害を呈する全身性炎症性疾患である. 発症には, EBV感染細胞に対する宿主の病的免疫応答が関わっているが, その詳細は不明である. 申請者はEBV-HLH患者にNFκB経路を制御するCCDC22の新規遺伝子変異を同定した. CCDC22変異によるNFκB制御の変調がEBV-HLHの病態に関与していると予想され, CCDC22の機能解析を行い, CCDC22変異のEBV-HLHにおける役割を検討する.

Outline of Final Research Achievements

We conducted a functional analysis of the CCDC22V38M mutation, which was identified in a patient with severe EBV-HLH. NFκB activity was unaffected by forced expression of CCDC22 in HEK293T cells. However, the V38M mutation altered its intracellular localization. Knockdown of CCDC22 in Neuro2a cells resulted in impaired neuronal differentiation. CCDC22V38M mice did not significantly differ from wild type in their natural course. RNAseq of MEFs revealed alterations in the expressions of cytokine- and chemokine-related gene. Although this study does not establish a direct link between the CCDC22V38M mutation and the development of HLH, it suggests that CCDC22 plays an important role in the functioning of the nervous and immune systems.

Academic Significance and Societal Importance of the Research Achievements

本研究では、難治性疾患であるEBV-HLHの重症例より同定したCCDC22新規遺伝子変異の解析を行った。本研究ではCCDC22の免疫系への関与が示唆される新知見が得られた。CCDC22については、NFκBの調節因子であることや、タンパクの細胞内輸送に関わることなど報告されているものの、まだ機能は十分に解明されていない。本研究成果を足がかりにCCDC22の機能解析が進めば、免疫系の新たな調節機構の解明や、EBV-HLHの病態解明に貢献できる可能性がある。

Research Products

• [Journal Article] Allosteric Inhibition of c-Abl to Induce Unfolded Protein Response and Cell Death in Multiple Myeloma (2022)
  • Author(s): Kosako Hideki、Yamashita Yusuke、Morita Shuhei、Iwabuchi Sadahiro、Hashimoto Shinichi、Matsuoka Taka-Aki、Sonoki Takashi、Tamura Shinobu
  • Journal Title: International Journal of Molecular Sciences Volume: 23 Issue: 24 Pages: 16162-16162
  • DOI: 10.3390/ijms232416162
  • Peer Reviewed / Open Access
• [Journal Article] Intestinal Mucosa-Associated Lymphoid Tissue Lymphoma Transforming into Diffuse Large B-Cell Lymphoma in a Young Adult Patient with Neurofibromatosis Type 1: A Case Report (2022)
  • Author(s): Kosako Hideki、Yamashita Yusuke、Tanaka Ken、Mishima Hiroyuki、Iwamoto Ryuta、Kinoshita Akira、Murata Shin-ichi、Ohshima Koichi、Yoshiura Koh-ichiro、Sonoki Takashi、Tamura Shinobu
  • Journal Title: Medicina Volume: 58 Issue: 12 Pages: 1830-1830
  • DOI: 10.3390/medicina58121830
  • Peer Reviewed / Open Access
• [Journal Article] Sudden Cardiac Death in a Patient with Thrombotic Thrombocytopenic Purpura: A Case Report (2022)
  • Author(s): Yoshida Kikuaki、Murata Shogo、Morimoto Masaya、Mushino Toshiki、Tanaka Ken、Yamashita Yusuke、Hosoi Hiroki、Nishikawa Akinori、Tamura Shinobu、Hatakeyama Kinta、Matsumoto Masanori、Sonoki Takashi
  • Journal Title: Hematology Reports Volume: 14 Issue: 2 Pages: 203-209
  • DOI: 10.3390/hematolrep14020027
  • Peer Reviewed / Open Access
• [Journal Article] Risk Factors for Therapeutic Intervention of Remdesivir in Mild to Moderate COVID-19?A Single-Center Retrospective Study of the COVID-19 Fourth Pandemic Period in Wakayama, Japan (2022)
  • Author(s): Tamura Shinobu、Kaki Takahiro、Niwa Mayako、Yamano Yukiko、Kawai Shintaro、Yamashita Yusuke、Tanaka Harumi、Saito Yoshinobu、Kajimoto Yoshinori、Koizumi Yusuke、Yamaue Hiroki、Nakao Naoyuki、Nojiri Takako、Hironishi Masaya
  • Journal Title: Medicina Volume: 58 Issue: 1 Pages: 118-118
  • DOI: 10.3390/medicina58010118
  • Peer Reviewed / Open Access
• [Journal Article] Progressive Massive Splenomegaly in an Adult Patient with Kabuki Syndrome Complicated with Immune Thrombocytopenic Purpura (2021)
  • Author(s): Mushino Toshiki、Hiroi Takayuki、Yamashita Yusuke、Suzaki Norihiko、Mishima Hiroyuki、Ueno Masaki、Kinoshita Akira、Minami Koichi、Imai Kohsuke、Yoshiura Ko-ichiro、Sonoki Takashi、Tamura Shinobu
  • Journal Title: Internal Medicine Volume: 60 Issue: 12 Pages: 1927-1933
  • DOI: 10.2169/internalmedicine.6694-20
  • NAID: 130008052635
  • ISSN: 0918-2918, 1349-7235
  • Year and Date: 2021-06-15
  • Peer Reviewed / Open Access
• [Journal Article] Erdheim-Chester disease diagnosed with right atrium tumors (2021)
  • Author(s): Takeda S, Murata S, Tane M, Yoshida K, Iwamoto R, Warigaya K, Sakaki A, Yokoya Y, Tanaka K, Tochino Y, Yamashita Y, Hosoi H, Mushino T, Nishikawa A, Tamura S, Sonoki T.
  • Journal Title: Rinsho Ketsueki Volume: 62 Pages: 91-93
  • NAID: 130007995472
  • Peer Reviewed
• [Journal Article] A Patient with Kabuki Syndrome Mutation Presenting with Very Severe Aplastic Anemia (2021)
  • Author(s): Tamura Shinobu、Kosako Hideki、Furuya Yoshiaki、Yamashita Yusuke、Mushino Toshiki、Mishima Hiroyuki、Kinoshita Akira、Nishikawa Akinori、Yoshiura Ko-Ichiro、Sonoki Takashi
  • Journal Title: Acta Haematologica Volume: 145 Issue: 1 Pages: 89-96
  • DOI: 10.1159/000518227
  • Peer Reviewed
• [Journal Article] Intracranial Hemorrhage in a Patient with TAFRO Syndrome Treated with Cyclosporine A and Rituximab (2021)
  • Author(s): Akagi Yuina、Kato Takashi、Yamashita Yusuke、Hosoi Hiroki、Murata Shogo、Yamamoto Shuto、Warigaya Kenji、Nakao Taisei、Murata Shinichi、Sonoki Takashi、Tamura Shinobu
  • Journal Title: Medicina Volume: 57 Issue: 9 Pages: 971-971
  • DOI: 10.3390/medicina57090971
  • Peer Reviewed / Open Access
• [Journal Article] Heterozygous missense variant of the proteasome subunit β-type 9 causes neonatal-onset autoinflammation and immunodeficiency (2021)
  • Author(s): Kanazawa N, Hemmi H, Kinjo N, Ohnishi H, Hamazaki J, M.H, K.A, M.T, H.S, K.N, K.S, H.Y, I.K, N.R, T.M, Y.Y, T.S, O.T, O.T, K.T, S.I, F.Y, W.N, I.Y, K.K, O.S, T.T, N.K, M.S, Y.K, Kaisho T
  • Journal Title: Nature Communications Volume: 12 Issue: 1 Pages: 0-0
  • DOI: 10.1038/s41467-021-27085-y
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Pegcetacoplan for refractory paroxysmal nocturnal haemoglobinuria associated with the C5 genetic variant (2021)
  • Author(s): Tamura Shinobu、Hori Yoshikazu、Hiroi Takayuki、Morimoto Masaya、Yamashita Yusuke、Mushino Toshiki、Sonoki Takashi
  • Journal Title: British Journal of Haematology Volume: 196 Issue: 6
  • DOI: 10.1111/bjh.17963
  • Peer Reviewed / Open Access
• [Journal Article] Targeting Adaptive IRE1α Signaling and PLK2 in Multiple Myeloma: Possible Anti-Tumor Mechanisms of KIRA8 and Nilotinib. (2020)
  • Author(s): Yamashita Y, Morita S, Hosoi H, Kobata H, Kishimoto S, Ishibashi T, Mishima H, Kinoshita A, Backes BJ, Yoshiura KI, Papa FR, Sonoki T, Tamura S
  • Journal Title: Int J Mol Sci. Volume: Aug 31;21(17) Issue: 17 Pages: 6314-6314
  • DOI: 10.3390/ijms21176314
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Paroxysmal nocturnal hemoglobinuria treated with eculizumab in Wakayama, Japan: a retrospective analysis (2020)
  • Author(s): 田村 志宣、花岡 伸佳、園木 孝志、古家 美昭、堀 善和、弘井 孝幸、山下 友佑、大岩 健洋、村田 祥吾、蒸野 寿紀、西川 彰則
  • Journal Title: Rinsho Ketsueki Volume: 61 Issue: 6 Pages: 605-611
  • DOI: 10.11406/rinketsu.61.605
  • NAID: 130007869147
  • ISSN: 0485-1439, 1882-0824
  • Peer Reviewed
• [Journal Article] Two Episodes of Transfusion-related Acute Lung Injury (TRALI) Occurring within a Short Period (2020)
  • Author(s): Akagi Yuina、Murata Shogo、Yamashita Yusuke、Tanaka Ken、Hiroi Takayuki、Mushino Toshiki、Hosoi Hiroki、Nishikawa Akinori、Tamura Shinobu、Sonoki Takashi
  • Journal Title: Internal Medicine Volume: 59 Issue: 20 Pages: 2577-2581
  • DOI: 10.2169/internalmedicine.4700-20
  • NAID: 130007926297
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Brentuximab vedotin for refractory anaplastic lymphoma kinase-negative anaplastic large cell lymphoma in leukemic phase with <em>RUNX3</em> overexpression (2020)
  • Author(s): Yamashita Yusuke、Hori Yoshikazu、Kosako Hideki、Oiwa Takehiro、Warigaya Kenji、Mushino Toshiki、Murata Shogo、Fujimoto Masakazu、Nishikawa Akinori、Murata Shin-ichi、Sonoki Takashi、Tamura Shinobu
  • Journal Title: Hematology Reports Volume: 12 Issue: 1 Pages: 8368-8368
  • DOI: 10.4081/hr.2020.8368
  • Peer Reviewed / Open Access / Int'l Joint Research