Analysis of Pathogenic Autoreactive T cells in Patients with Antiphospholipid Syndrome and its Application for Developing Specific Immune Therapies

抗磷脂综合征患者致病性自身反应性 T 细胞分析及其在开发特异性免疫疗法中的应用

基本信息

批准号：
12557049
负责人：
KUWANA Masataka
金额：
$ 7.87万
依托单位：
Keio University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2002
项目状态：
已结题

项目摘要

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.

抗磷脂综合征 (APS) 的特征是与抗磷脂抗体相关的复发性血栓形成和宫内胎儿丢失，β_2-糖蛋白 I (β_2GPI) 是一种结合多种带负电物质（包括磷脂）的血浆糖蛋白，已知是最常见的抗原。与 APS 临床特征相关的抗磷脂抗体的靶点在 APS 患者以及实验性 APS 中不断积累的证据表明，抗磷脂抗体具有重要作用。 β_2GPI 特异性 CD4^+ T 细胞在抗 β_2GPI 抗体生成中的作用在本研究项目中，我们鉴定并鉴定了与 β2GPI 发生自身反应的 CD4^+ T 细胞，这些细胞可促进 APS 患者中抗磷脂抗体的生成。优先识别包含 DRB4^*0103 (DR53) 背景下的主要磷脂结合位点的抗原肽。 β_2GPI 特异性 T 细胞受到高度限制，主要利用重排的 Vβ_7 或 Vβ_8 基因片段刺激 B 细胞产生抗 β_2GPI 抗体，这是通过 IL-6 和 CD40-CD40 配体接合介导的。 T 细胞对细菌中产生的还原 β_2GPI 和重组 β_2GPI 片段有反应，但对天然 β_2GPI 没有反应，这表明β_2GPI 特异性 T 细胞识别的表位显然是隐性的。暴露于 β_2GPI 的隐性肽可以诱导 β2GPI 特异性 T 细胞的激活，从而产生抗 β2GPI 致病性抗体。最后，β_2GPI 特异性 T 细胞是一种合理的选择。选择性抑制 APS 患者致病性抗磷脂抗体产生的潜在治疗策略的目标。