Research of clinical significance and molecular mechanisms of somatic revertant mosaicism in primary immunodeficiency.

• Project/Area Number: 20591247
• 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: WADA Taizo Kanazawa University, 附属病院, 講師 (30313646)
• Project Period (FY): 2008 – 2010
• Project Status: Completed (Fiscal Year 2010)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2010: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2009: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2008: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 免疫学 / 遺伝子 / 原発性免疫不全症 / 復帰変異 / 体細胞モザイク / 遺伝子変異 / reversion / X連鎖重症複合免疫不全症

Research Abstract

Somatic revertant mosaicism has been described in an increasing number of primary immunodeficiency. Revertant cells with a selective advantage in vivo have been associated with attenuated clinical phenotype in some cases. In this research, we report an atypical case of X-linked severe combined immunodeficiency presenting with Omenn syndrome-like syndrome due to revertant mosaicism. We show the underlying mechanism and the importance of revertant mosaicism as a possible cause for variable phenotypic expression. The study of this fascinating phenomenon also continues to provide unique opportunities to evaluate the biological effects of restored gene expression and deserves close investigation.

Research Products

• [Journal Article] Analysis of mutations and recombination activity in RAG-deficient patients. (2011)
  • Author(s): Asai E, Wada T, Sakakibara Y, Toga A, Toma T, Shimizu T, Nampoothirihiri S, Imai K, Nonoyama S, Morio T, Muramatsu H, Kamachi Y, Ohara O, Yachie A.
  • Journal Title: Clin Immuuents. 138 Pages: 172-177
  • NAID: 120002772030
  • Peer Reviewed
• [Journal Article] Delayed Wound Healing in Leukocyte Adhesion Deficiency Type 1. (2011)
  • Author(s): Wada T, Tone Y, Shibata F, Toma T, Yachie A.
  • Journal Title: J Pediatr. 158 Pages: 342-342
  • NAID: 120002463528
  • Peer Reviewed
• [Journal Article] Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. (2011)
  • Author(s): Radhakrishnan N, Yadav SP, Sachdeva A, Pruthi PK, Sawhney S, Piplani T, Wada T, Yachie A.
  • Journal Title: J Pediatr Hematol Oncol. 33 Pages: 74-78
  • Peer Reviewed
• [Journal Article] Human heme oxygenase-1 deficiency presenting with hemolysis, nephritis, and asplenia. (2011)
  • Author(s): Radhakrishnan N, Yadav SP, Wada T, et al
  • Journal Title: J Pediatr Hematol Oncol Volume: 33 Pages: 74-78
  • Peer Reviewed
• [Journal Article] Delayed wound healing in leukocyte adhesion deficiency type 1. (2011)
  • Author(s): Wada T, Tone Y, Shibata F, et al.
  • Journal Title: J Pediatr Volume: 158 Pages: 342-342
  • NAID: 120002463528
  • Peer Reviewed
• [Journal Article] Analysis of mutations and recombination activity in RAG-deficient patients. (2011)
  • Author(s): Asai E, Wada T, Sakakibara Y, et al.
  • Journal Title: Clin Immunol Volume: 138 Pages: 172-177
  • NAID: 120002772030
  • Peer Reviewed
• [Journal Article] Colchicine responsive chronic recurrent multifocal osteomyelitis with MEFV mutations : A variant of familial Mediterranean fever? (2010)
  • Author(s): Shimizu M, Tone Y, Toga A, Yokoyama T, Wada T, Toma T, Yachie A.
  • Journal Title: Rheumatol. 49 Pages: 2221-2223
  • NAID: 120002772031
  • Peer Reviewed
• [Journal Article] Differential resistance to antiviral drugs in an immunocompromised patient with cytomegalovirus encephalitis. (2010)
  • Author(s): Wada T, Mase S, Shibata F, Shimizu M, Toma T, Yachie A.
  • Journal Title: J Clin Virol. 49 Pages: 223-224
  • NAID: 120002463527
  • Peer Reviewed
• [Journal Article] Distinct cytokine profiles of systemic 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, Ohta K, Kasahara Y, Yachie A.
  • Journal Title: Rheumatol. 49 Pages: 1645-1653
  • Peer Reviewed
• [Journal Article] Bicipital synovial cyst in systemic-onset juvenile idiopathic arthritis. (2010)
  • Author(s): Shimizu M, Yokoyama T, Wada T, Yachie A.
  • Journal Title: J Pediatr. 157 Pages: 168-168
  • Peer Reviewed
• [Journal Article] Clinical significance of CD5 downregulation in Epstein-Barr virus (EBV)-infected CD8+ T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis. (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. 201 Pages: 1923-1932
  • Peer Reviewed
• [Journal Article] Clinical significance of CD5 downregulation in Epstein-Barr virus(EBV)-infected CD8^<+> T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis. (2010)
  • Author(s): Toga A, Wada T, Sakakibara Y, et al.
  • Journal Title: J Infect Dis Volume: 201 Pages: 1923-1932
  • Peer Reviewed
• [Journal Article] Bicipital synovial cyst in systemic-onset juvenile idiopathic arthritis. (2010)
  • Author(s): Shimizu M, Yokoyama T, Wada T, et al.
  • Journal Title: J Pediatr Volume: 157 Pages: 168-168
  • Peer Reviewed
• [Journal Article] Distinct cytokine profiles of systemic 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, Wada T, et al.
  • Journal Title: Rheumatol Volume: 49 Pages: 1645-1653
  • Peer Reviewed
• [Journal Article] Differential resistance to antiviral drugs in an immunocompromised patient with cytomegalovirus encephalitis. (2010)
  • Author(s): Wada T, Mase S, Shibata F, et al.
  • Journal Title: J CIin Virol Volume: 49 Pages: 223-224
  • NAID: 120002463527
  • Peer Reviewed
• [Journal Article] Colchicine responsive chronic recurrent multifocal osteomyelitis with MEFV mutations : Avariant of familial Mediterranean fever? (2010)
  • Author(s): Shimizu M, Tone Y, Wada T, et al.
  • Journal Title: Rheumatol Volume: 49 Pages: 2221-2223
  • 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, Asai E, Toga A, Sakakibara Y, Shibata F, Tone Y, Shimizu M, Toma T, Yachie A.
  • Journal Title: Int J Hematol. 90 Pages: 611-615
  • NAID: 10026110032
  • Peer Reviewed
• [Journal Article] Analysis of T-cell receptor V β diversity in peripheral CD4+ and CD8+ T lymphocytes in patients with autoimmune thyroid diseases. (2009)
  • Author(s): Okajima M, Wada T, Nishida M, Yokoyama T, Nakayama Y, Hashida Y, Shibata F, Tone Y, Ishizaki A, Shimizu M, Saito T, Ohta K, Toma T, Yachie A.
  • Journal Title: Clin Exp Immunol. 155 Pages: 166-172
  • 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, et al.
  • Journal Title: Int J Hematol. 90 Pages: 611-615
  • NAID: 10026110032
  • Peer Reviewed
• [Journal Article] Analysis of T-cell receptor Vβ diversity in peripheral CD4^+ and CD8^+ T lymphocytes in patients with autoimmune thyroid diseases. (2009)
  • Author(s): Okajiraa M, Wada T, Nishida M, et al.
  • Journal Title: Clin Exp Immunol. 155 Pages: 166-172
  • Peer Reviewed
• [Journal Article] Somatic mosaicism in primary immune deficiencies. (2008)
  • Author(s): Wada T, Candotti F.
  • Journal Title: Curr Opin Allergy Clin Immunol. 8 Pages: 510-514
• [Journal Article] Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome. (2008)
  • Author(s): Wada T, Yasui M, Toma T, Nakayama Y, Nishida M, Shimizu M, Okajima M, Kasahara Y, Koizumi S, Inoue M, Kawa K, Yachie A.
  • Journal Title: Blood. 112 Pages: 1872-1875
  • Peer Reviewed
• [Journal Article] 原発性免疫不全症における遺伝子変異のreversion(復帰) (2008)
  • Author(s): 和田泰三
  • Journal Title: 金沢大学十全医学会雑誌 117 Pages: 139-142
  • NAID: 10026960746
• [Journal Article] Detection of T lpiphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined imnunodeficiency mimicking Omenn syndrome. (2008)
  • Author(s): Wada T, Yasui M, Toma T, et al.
  • Journal Title: Blood. 112 Pages: 1872-1875
  • Peer Reviewed
• [Presentation] Intermittent X-linked thrombocytopeniaの1例 (2011)
  • Author(s): 和田泰三, 榊原康久, 東馬智子, 新井田要, 谷内江昭宏, 平松正行, 堀澤徹, 岡田直樹, 伊藤順庸, 中村常之, 犀川太
  • Organizer: 第4回日本日本免疫不全研究会
  • Place of Presentation: 九州大学医学部百年講堂,福岡県
  • Year and Date: 2011-01-22
• [Presentation] EBV関連血球貪食性リンパ組織球症におけるEBV感染細胞の特徴 (2010)
  • Author(s): 和田泰三, 栂暁子, 榊原康久, 東馬智子, 谷内江昭宏, 柳沢龍, 金兼弘和
  • Organizer: 第20回EBウイルス感染症研究会
  • Place of Presentation: ベルサール八重洲,東京都
  • Year and Date: 2010-03-06
• [Presentation] Revertant somatic mosaicism in primary immunodeficiency. (2010)
  • Author(s): 和田泰三
  • Organizer: The 2nd Symposium for PID in Asia
  • Place of Presentation: Kazusa DNA Academia(千葉県)
  • Year and Date: 2010-02-05
• [Presentation] 蚊アレルギー/蚊刺過敏症における水疱内細胞成分の解析 (2010)
  • Author(s): 和田泰三, 榊原康久, 栂暁子, 横山忠史, 清水正樹, 東馬智子, 谷内江昭宏
  • Organizer: 第42回日本小児感染症学会
  • Place of Presentation: 仙台国際センター,宮城県
• [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 Center,トルコ
• [Presentation] Analysis of mutations and recombination activity in patients with RAG1/2 deficiency. (2010)
  • Author(s): Asai E, Wada T, Sakakibara Y, Toma T,Shimizu T, Imai K, Nonoyama S, Morio T, Kamachi Y, Ohara O, Yachie A
  • Organizer: XIVth Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Istanbul Lutfi Kirdar Convention Center,トルコ
• [Presentation] EBV関連血球貪食性リンパ組織球症におけるEBV感染CD8陽性T細胞の特徴 (2010)
  • Author(s): 和田泰三, 栂暁子, 榊原康久, 東馬智子, 柳沢龍, 金兼弘和, 谷内江昭宏
  • 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
• [Presentation] Clinical significance of CD5 downregulation in Epstein-Barr virus (EBV)-infected CD8^+ T lymphocytes in EBV-associated hemophagocytic lymphohistiocytosis. (2010)
  • Author(s): 和田泰三, 栂暁子, 榊原康久, 東馬智子, 柳沢龍, 金兼弘和, 谷内江昭宏
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸国際展示場,兵庫県
• [Presentation] Revertant Somatic Mosaicism in Primary Immunodeficiency. (2010)
  • Author(s): 和田泰三
  • Organizer: The 2nd Symposium for PID in Asia
  • Place of Presentation: かずさアカデミアホール,千葉県
• [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, Taga A, Sakakibara Y, et al.
  • Organizer: 14th International Congress of Immunology
  • Place of Presentation: 神戸国際展示場(兵庫県)
• [Presentation] Increased subpopulation of CD8+ T cells with CD5 down-regulation infamilial hemophagocytic lymphohistiocytosis type 2. (2010)
  • Author(s): Wada T, Sakakibara Y, Shimizu M, et al.
  • Organizer: XIVth Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Istanbul Lutfi Kirdar Convention Center (トルコ)
• [Presentation] 原発性免疫不全症における遺伝子変異のreversion(復帰) (2009)
  • Author(s): 和田泰三
  • Organizer: 十全医学会総会・学術集会
  • Place of Presentation: 金沢大学医学部記念館,石川県
  • Year and Date: 2009-07-25
• [Presentation] 原発性免疫不全症に遺伝子変異のreversion(復帰) (2009)
  • Author(s): 和田泰三
  • Organizer: 十全医学会総会・学術集会
  • Place of Presentation: 金沢大学医学部記念館(石川県)
  • Year and Date: 2009-07-25
• [Presentation] 蚊刺による水疱の細胞成分を解析した慢性活動性EBウイルス感染症の1例 (2009)
  • Author(s): 和田泰三, 中川裕康, 橋田暢子, 柴田文恵, 刀祢裕美, 清水正樹, 東馬智子, 笠原善仁, 谷内江昭宏
  • Organizer: 第19回EBウイルス感染症研究会
  • Place of Presentation: ベルサール八重洲,東京都
  • Year and Date: 2009-03-07
• [Presentation] Detection of revertant T lymphocytes in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn sydrome. (2008)
  • Author(s): Wada. T, Yasui M, Toma T, et al.
  • Organizer: 第13回欧州免疫不全学会(ESID)
  • Place of Presentation: 第13回欧州免疫不全学会(ESID)
  • Year and Date: 2008-10-16
• [Presentation] 慢性活動性EBウイルス感染症男児例における蚊刺後の水疱内細胞成分の解析 (2008)
  • Author(s): 和田泰三, 柴田文恵, 中川裕康, 橋田暢子, 刀祢裕美, 清水正樹, 東馬智子, 笠原善仁, 谷内江昭宏
  • Organizer: 第16回北陸ウイルス研究会
  • Place of Presentation: 金沢都ホテル,石川県
  • Year and Date: 2008-09-13
• [Presentation] EBウイルス関連血球貪食症候群におけるEBV感染細胞とCD5 発現の解析 (2008)
  • Author(s): 和田泰三
  • Organizer: 第4回小児皮膚免疫アレルギー
  • Place of Presentation: ホテル日航金沢,石川県
  • Year and Date: 2008-06-18
• [Presentation] Omenn症候群様症状を呈した非典型的X-SCIDにみられた遺伝子変異の復帰 (2008)
  • Author(s): 和田泰三, 東馬智子, 刀祢裕美ら
  • Organizer: 第111回日本小児科学会学術集会
  • Place of Presentation: 第111回日本小児科学会学術集会
  • Year and Date: 2008-04-25
• [Presentation] Detection of T lymphocytes with a second-site mutation in skin lesions of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome. (2008)
  • Author(s): Wada T, Yasui M, Toma T, Nakayama Y, Nishida M, Shimizu M, Okajima M, Kasahara Y, Koizumi S, Inoue M, Kawa K, Yachie A
  • Organizer: XIIIth Meeting of the European Society for Immunodeficiencies
  • Place of Presentation: Theater aan de Parade,オランダ
• [Presentation] Omenn 症候群様症状を呈した非典型的X-SCIDにみられた遺伝子変異の復帰 (2008)
  • Author(s): 和田泰三, 東馬智子, 刀祢裕美, 笠原善仁, 小泉晶一, 谷内江昭宏, 安井昌博, 井上雅美, 河敬世
  • Organizer: 第111回日本小児科学会学術集会
  • Place of Presentation: 東京国際フォーラム,東京都