| Project/Area Number |
12557049
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 展開研究 |
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| Research Field |
内科学一般
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| Research Institution | Keio University |
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Principal Investigator |
KUWANA Masataka Institute for Advanced Medical Research, Keio University, School of Medicine, Assistant Professor, 医学部, 講師 (50245479)
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| Co-Investigator(Kenkyū-buntansha) |
KAWAKAMI Yutaka Institute for Advanced Medical Research, Keio University, School of Medicine, Professor, 医学部, 教授 (50161287)
IKEDA Yasuo Department of Internal Medicine, Keio University, School of Medicine, Professor, 医学部, 教授 (00110883)
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| Project Period (FY) |
2000 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥12,300,000 (Direct Cost: ¥12,300,000)
Fiscal Year 2002: ¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2001: ¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2000: ¥5,400,000 (Direct Cost: ¥5,400,000)
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| Keywords | Autoantibody / T cell / Thrombosis / Phospholipid / Antiphospholipid antibody / Immuno-therapy / Autoimmune disease / エピトープ / 自己反応性T細胞 / 抗原提示細胞 / 習慣性流産 / T細胞リセプター |
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| Research Abstract |
Antiphospholipid syndrome (APS) is characterized by recurrent thrombosis and intrauterine fetal loss in association with antiphospholipid antibodies. β_2-glycoprotein I (β_2GPI), a plasma glycoprotein that binds various kinds of negatively charged substances including phospholipids, is known to be the most common antigenic target for antiphopholipid antibodies associated with the clinical features of APS. Accumulating evidences in APS patients as well as in experimental APS indicate an important role of β_2GPI-specific CD4^+ T cells in anti-β_2GPI antibody production. In this research project, we have identified and characterized autoreactive CD4^+ T cells to β2GPI that promote antiphospholipid antibody production in APS patients. β_2GPI-specific CD4^+ T cells preferentially recognize the antigenic peptide containing the major phospholipid-binding site in the context of DRB4^*0103 (DR53). T-cell receptor β chains of β_2GPI-specific T cells are highly restricted and mainly utilize rearranged Vβ_7 or Vβ_8 gene segments. T-cell helper activity that stimulates B cells to produce anti-β_2GPI antibodies is mediated through IL-6 and CD40-CD40 ligand engagement. β_2GPI-specific T cells respond to reduced β_2GPI and recombinant β_2GPI fragments produced in bacteria, but not to native β_2GPI, indicating that the epitopes recognized by β_2GPI-specific T cells are apparently cryptic. Activation of β2GPI-specific T cells resulting in production of pathogenic anti-β2GPI antibodies can be induced by the exposure to cryptic peptides of β_2GPI. Finally, β_2GPI-specific T cell is a reasonable target of potential therapeutic strategies that selectively suppress pathogenic antiphospholipid antibody production in APS patients.
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