原発性免疫不全症における原因遺伝子の復帰に関する研究

Material type: 文書・図像類

Author: 和田, 泰三ほか

Publisher: 金沢大学附属病院小児科

Publication date: 2008-04

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Note (General)：: 原発性免疫不全症において、遺伝子変異の復帰(gene reversion)を認めた症例を新たに2例見出した。白血球接着異常症(LAD-1)の乳児例は世界初の報告であり(Blood 2007)、X連鎖重症複合免疫不全症(XSCID)の乳児例は世界第2例目となる(投稿中)。前者では、患児の1つのCD8陽...

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Material Type: 文書・図像類
Title: 原発性免疫不全症における原因遺伝子の復帰に関する研究
Author/Editor: 和田, 泰三
Wada, Taizo
Author Heading: 和田, 泰三
Wada, Taizo
Publication, Distribution, etc.: 金沢大学附属病院小児科
Publication Date: 2008-04
Publication Date (W3CDTF): 2008-04
Alternative Title: Research on Genetic Reversion in Primary Immunondefiriency
Periodical title: 平成19(2007)年度科学研究費補助金基盤研究(C) 研究成果報告書 = 2007 Fiscal Year Final Research Report
No. or year of volume/issue: 2006-2007
Volume: 2006-2007
Pages: 7p.-
Text Language Code: jpn
Subject Heading: 原発性免疫不全症
遺伝子変異
復帰
Wiskott-Aldrich症候群
X連鎖重症複合免疫不全症
primary immunodeficiency
mutation
gene reversion
Wiskott-Aldrich syndrome
X-linked severe combined immunodeficiency
Target Audience: 一般
Note (General): 原発性免疫不全症において、遺伝子変異の復帰(gene reversion)を認めた症例を新たに2例見出した。白血球接着異常症(LAD-1)の乳児例は世界初の報告であり(Blood 2007)、X連鎖重症複合免疫不全症(XSCID)の乳児例は世界第2例目となる(投稿中)。前者では、患児の1つのCD8陽性T細胞において父親由来のスプライス変異が正常に戻るreversionが起きたと考えられた。本研究により、reversionはprogenitorレベルだけではなくある程度成熟した細胞でも起こり得ること、CD18陽性T細胞はCD18陰性T細胞に対して増殖優位性を有すること、reversion症例では必ずしも臨床症状の改善や修飾がみられないことなど、種々の重要な知見を得ることができた。一方、後者では、元の変異を代償する第二変異によるreversionがT細胞に検出された。Reversionを有するCD8陽性T細胞が主として皮膚にクローン性に増殖しており、通常XSCIDでは見られない皮疹と関連している可能性が示唆され、reversionは原発性免疫不全症の病態を修飾する重要な因子となる得ること等の重要な知見を得ることができた。in vitroの実験として計画しているWiskott-Aldrich症候群をモデルとした復帰変異の誘導実験に関しては、WASP遺伝子と薬剤耐性遺伝子の融合遺伝子を発現するレトロウイルスベクターの構築が終了し、感染性ウイルスを産生する段階にあり、基礎実験を継続している。今後の発展が期待される。
We have identified two novel cases of genetic reversion in primary immunodeficiency including leukocyte adhesion deficiency type 1 (LAD-1) and X-linked severe combined immunodeficiency (XSCID).1) LAD-1 is an autosomal recessive disorder caused by mutations in the ITGB2 (CD18) gene, and characterized by recurrent severe infections, impaired pus formation, and defective wound healing. We describe an unusual case of severe phenotypic LAD-1 presenting somatic mosaicism. The patient is a compound heterozygote bearing two different frameshift mutations which abrogate protein expression. CD 18 expression was, however, detected in a small proportion of T cells, but was undetectable in granulocytes, monocytes, B cells, and NK cells. The T cells were not of maternal origin, lacked the paternal mutation, and showed a selective advantage in vivo. Molecular analysis using sorted CD18+ cells revealed them to be derived from a single CD84 T cell carrying T-cell receptor VB22. These findings suggest t hat spontaneous in vivo reversion was responsible for the somatic mosaicism in our patient. (Blood 2007)2) XSCID is caused by mutations of the common gamma chain (γc) of cytokine receptors and usually characterized by the absence of T and natural killer (NK) cells and the presence of B Cells. Here, we report an atypical case of XSCID presenting with autologous T and NK cells and Omenn syndrome-like manifestations including erythroderma, lymphadenopathy, hepatosplenomegaly, eosinophilia, low serum IgG, elevated serum IgE, and the presence of activated T cells. The patient carried a splice-site mutation (IVS 1+5G>A) that caused most of the mRNA to be incorrectly spliced but produced normally spliced transcript in lesser amount, leading to residual γc expression and development of T and NK cells. The skin biopsy specimen showed massive infiltration of revertant T cells. Those T cells were found to have a second-site mutation that was located at position +1 of the cryptic donor site activated by the IVS1+5G>A, and to result in complete restoration of correct splicing. These findings suggest that the clinical spectrum of XSCID is quite broad and includes atypical cases mimicking Omenn syndrome, and highlight the importance of revertant mosaicism as a possible cause for variable phenotypic expression. (manuscript in submission)In addition to the clinical researches, we have constructed retroviral vectors expressing reversion mutations. These vectors will be used to evaluate conditions of induction of gene reversion in vitro in future experiments.
研究課題/領域番号:18591186, 研究期間(年度):2006-2007
出典：「原発性免疫不全症における原因遺伝子の復帰に関する研究」研究成果報告書　課題番号18591186 (KAKEN：科学研究費助成事業データベース（国立情報学研究所）)　　　本文データは著者版報告書より作成
DOI: 10.24517/00050619
Source: https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=44277&item_no=1&attribute_id=26&file_no=1
https://kanazawa-u.repo.nii.ac.jp/?action=repository_action_common_download&item_id=44277&item_no=1&attribute_id=26&file_no=1
Access Restrictions: 限定公開
Rights (production): CC BY-NC-ND
Related Material: https://kaken.nii.ac.jp/search/?qm=30313646
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18591186/
https://kaken.nii.ac.jp/report/KAKENHI-PROJECT-18591186/185911862007kenkyu_seika_hokoku_gaiyo/
Data Provider (Database): 国立情報学研究所 : 学術機関リポジトリデータベース（IRDB）（機関リポジトリ）
https://irdb.nii.ac.jp
Original Data Provider (Database): 金沢大学 : 金沢大学学術情報リポジトリKURA