Establishment of novel diagnostic parameters for the early therapeutic intervention of EBV-associated lymphoproliferative diseases.

2011 Fiscal Year Final Research Report

• Project/Area Number: 21591353
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Pediatrics
• Research Institution: Kanazawa University
• Principal Investigator: YACHIE Akihiro 金沢大学, 医学系, 教授 (40210281)
• Project Period (FY): 2009 – 2011
• Keywords: EBウイルス / CAEBV / EBV-HLH / CD5 / フローサイトメトリー

Research Abstract

EBV-HLH is characterized by extreme cytokinemia and cytopenia, frequently leading to aggressive deterioration and fatal outcome. It is of paramount importance to make correct diagnosis and start therapeutic intervention as soon as possible, as the delay in the treatment may result in irreversible damage to vital organs within several hours. We now understand that the essential pathogenesis of EBV-HLH is selective activation and expansion of an ectopically EBV-infected CD8^+T cell clone. Thus the definitive diagnosis of EBV-HLH can be made by identifying the target of EBV infection and by proving the clonality of the EBV-infected cells.
In this study, we analyzed the profiles of surface antigen expression of the infected CD8^+T cells and serum cytokines. With these results, we tried to establish a simplified method to establish parameters for the early diagnosis of EBV-HLH. As was expected, EBV infection in most cases of EBV-HLH was confined to a single clone of CD8+T cells, expressing a particular TCR Vβ. CDR3 size distribution analysis indicates that these cells are of a single clone. The abnormal clones exhibited high levels of HLA-DR and decreased levels of CD5. Therefore, EBV-infected cells were identifiable as HLA-DR^++CD5^-cell population within CD8^+T cells. Further analysis revealed that similar cell population was observed in patients with FHL2 during acute viral infection, including EBV.

Research Products

• [Journal Article] Characterization of Epstein-Barr virus(EBV)-infected cells in EBV-associated hemophagocytic lympho-histiocytosis in two patients with X-linked lymphoproliferative syndrome type 1 and type 2 (2012)
  • Author(s): Yang X, Wada T, Imadome K, Nishida N, Mukai T, Fujiwara M, Kawashima H, KatoF, Fujiwara S, Yachie A, Zhao X, Miyawaki T, Kanegane H
  • Journal Title: Herpesviridae Volume: 3 Pages: 1
  • Peer Reviewed
• [Journal Article] Distinct cytokine profiles of systemic-onset juvenile idiopathic arthritis-associated macrophage activation syndrome with particular emphasis on the role of interleukin-18 in its pathogenesis (2010)
  • Author(s): Shimizu M, Yokoyama T, Yamada K, Kaneda H, Wada H, Wada T, Toma T, OhtaK, Kasahara Y, Yachie A
  • Journal Title: Rheumatology Volume: 49 Pages: 1645-53
  • Peer Reviewed
• [Journal Article] Clinical significance of cloned expansion and CD5 down-regulation in Epstein-Barr Virus(EBV)-infected CD8^+T lymphocytes in EBV-associated hemophagocytic lympho-histiocytosis (2010)
  • Author(s): Toga A, Wada T, Sakakibara Y, Mase S, Araki R, Tone Y, Toma T, Kurokawa T, Yanagisawa R, Tamura K, Nishida N, Taneichi H, Kanegane H, Yachie A.
  • Journal Title: J Infect Dis Volume: 201 Pages: 1923-32
  • Peer Reviewed
• [Journal Article] Flow cytometric analysis of skin blister fluid induced by mosquito bites in a patient with chronic active Epstein-Barr virus infection (2009)
  • Author(s): Wada T, Yokoyama T, Nakagawa H, AsaiE, Toga A, Sakakibara Y, Shibata F, Tone Y, Shimizu M, Toma T, Yachie A
  • Journal Title: Int J Hematol Volume: 90 Pages: 611-5
  • Peer Reviewed
• [Presentation] Characterization of EBV-infected CD8^+T cells in EBV-associated hemophagocytic lymphohistiocytosis (2010)
  • Author(s): Wada T, Toga A, Sakakibara Y, Toma T, Yanagisawa R, Kanegane H, Yachie A
  • Organizer: 第72回日本血液学会学術集会
  • Place of Presentation: パシフィコ横浜(神奈川県)
  • Year and Date: 20100924-26
• [Presentation] Clinical significance of CD5 downregulation in Epstein Barr virus(EBV)-infected CD8^+T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis (2010)
  • Author(s): Wada T, Toga A, Sakakibara Y, Toma T, Yanagisawa R, Kanegane H, Yachie A
  • Organizer: 14^th International Congress of Immunology
  • Place of Presentation: 神戸ポートピアホテル、神戸国際展示場(兵庫県)
  • Year and Date: 20100822-27
• [Presentation] Increased subpopulation of CD8^+T cells with CD5 down-regulation in familial hemophagocytic lymphohistiocytosis type 2 (2010)
  • Author(s): Wada T, Sakakibara Y, Shimizu M, Nishimura R, Toma T, Ueno Y, Horita S, Yasumi T, Ohara O, Yachie A
  • Organizer: XIVth Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Istanbul Lutfi Kirdar Convention and Exhibition Centre(Turkey)
  • Year and Date: 20100606-09
• [Presentation] The diagnostic significance of interleukin-18 in patients with systemic juvenile idiopathic arthritis predisposing to macrophage activation syndrome (2009)
  • Author(s): Shimizu M, Yokoyama T, Kaneda H, WadaT, Toma T, Ohta K, Kasahara Y, Yachie A.
  • Organizer: The 9^th World Congress on Inflammation
  • Place of Presentation: Keio PlazaHotel(東京都)
  • Year and Date: 20090706-10