2007 Fiscal Year Final Research Report Summary
Research on Genetic Reversion in Primary Immunondefiriency
| Project/Area Number |
18591186
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Pediatrics
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| Research Institution | Kanazawa University |
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Principal Investigator |
WADA Taizo Kanazawa University, Kanazawa University Hospital, Assistant Professor (30313646)
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| Project Period (FY) |
2006 – 2007
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| Keywords | primary immunodeficiency / mutation / gene reversion / Wiskott-Aldrich syndrome / X-linked severe combined immunodeficiency |
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| Research Abstract |
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
… More
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. Less
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[Journal Article] Somatic revertant mosaicism in a patient with leukocyte adhesion deficiency type 12007
Author(s)
Tone, Y., Wada, T.*, Shibata, F., Toma, T., Hashida, Y., Kasahara, Y., Koizumi, S., Yachie, A
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Journal Title
Blood 109
Pages: 1182-1184
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Reactive peripheral blood plasmacytosis in a patient with acute hepatitis A2007
Author(s)
Wada, T.*, Maeba, H., Ikawa, Y., Hashida, Y., Okumura, A., Shibata, F., Tone, Y., Inoue, M., Koizumi, S., Takatori, H., Sakai, Y., Kaneko, S., Yachie, A
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Journal Title
Int J Hematol 85
Pages: 191-194
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Skin infiltration of CD56bright CD16- natural killer cells in a case of X-SCID with Omenn syndrome- like manifestations2007
Author(s)
Shibata, F., Toma, T., Wada, T., Inoue, M., Tone, Y., Ohta, K., Kasahara, Y., Sano, F., Kimura, M., Ikeno, M., Koizumi, S., Yachie, A
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Journal Title
Eur J Haematol 79
Pages: 81-85
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Immunophenotypic analysis of Epstein-Barr virus (EBV)-infected CD8+ T cells in a patient with EBV-associated hemophagocytic lymphohistiocytosis2007
Author(s)
Wada, T.*, Kurokawa, T., Toma, T., Shibata, F., Tone, Y., Hashida, Y., Kaya, H., Yoshida, Y., Yachie, A
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Journal Title
Eur J Haematol 79
Pages: 72-75
Description
「研究成果報告書概要(欧文)」より
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[Journal Article] Clonotypic analysis of T cell reconstitution after hematopoietic Stem cell transplantation (HSCT) in patients with severe combined immunodeficiency2007
Author(s)
Okamoto, H., Arii, C., Shibata, F., Toma, T., Wada, T., Inoue, M., Tone, Y., Kasahara, Y., Koizumi, S.,Kamachi, Y., Ishida, Y., Inagaki, J., Kato, M., Morio, T., Yachie, A
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Journal Title
Clin Exp Immunol 148
Pages: 450-460
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Detection of revertant T cells in atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome2008
Author(s)
Wada, T., Toma, T., Tone, Y., Kasahara, Y., Koizumi, S., Yasui, M., Inoue, M., Kawa, K., Yachie, A
Organizer
1st Meeting of the Japanese Society for Immunodeficiencies. Jan
Place of Presentation
Tokyo
Year and Date
20080100
Description
「研究成果報告書概要(欧文)」より
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[Presentation] A case of atypical X-linked severe combined immunodeficiency mimicking Omenn syndrome with autologous T and NK cells2007
Author(s)
Wada, T., Toma, T., Yokoyama, T., Kasahara, Y., Koizumi, S., Yachie, A., Yasui, M., Inoue, M., Kawa. K
Organizer
35th Meeting of the Japan Society for Clinical Immunology
Place of Presentation
Osaka
Year and Date
20070800
Description
「研究成果報告書概要(欧文)」より
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[Presentation] A case of leukocyte adhesion deficiency type 1 with revertant T-cell mosaicism2006
Author(s)
Tone, Y., Wada, T., Shibata, F., Kanegane, C., Toma, T., Kasahara, Y., Koizumi, S., Yachie, A
Organizer
56th Meeting of the Japanese Society for Allergology
Place of Presentation
Tokyo
Year and Date
20061100
Description
「研究成果報告書概要(欧文)」より
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[Presentation] Somatic revertant mosaicism in a patient with leukocyte Adhesion deficiency type 12006
Author(s)
Wada, T., Tone, Y., Shibata, F., Toma, T., Ohta, K., Kasahara, Y., Koizumi, S., Yachie, A
Organizer
12th Meetning of the European Society for Immunodeficiencies (ESID)
Place of Presentation
Budapest, Hungary.
Year and Date
20061000
Description
「研究成果報告書概要(欧文)」より
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[Presentation] A case of leukocyte adhesion deficiency type 1 with CD 18+ T cells caused by gene reversion2006
Author(s)
Wada, T., Tone, Y., Shibata, F., Toma, T., Kasahara, Y., Koizumi, S., Yachie, A
Organizer
45th Meeting of the Hokuriku Clinical Immunology Conference
Place of Presentation
Kanazawa
Year and Date
20060700
Description
「研究成果報告書概要(欧文)」より
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