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（AP）的特征是复发性血栓形成和宫内胎儿丧失与抗磷脂抗体相关。 β_2-糖蛋白I（β_2GPI）是一种结合各种带负电荷的物质在内的血浆糖蛋白，包括磷脂，是与APS临床特征相关的抗嗜磷脂抗体的最常见抗原性抗原靶标。 APS患者以及实验AP中积累的证据表明β_2GPI特异性CD4^+ T细胞在抗-β_2GPI抗体产生中的重要作用。在该研究项目中，我们已经确定并表征了自动反应性CD4^+ T细胞，以β2GPI促进APS患者的抗磷脂抗体产生。 β_2GPI特异性CD4^+ T细胞优先识别在DRB4^*0103（DR53）的背景下含有主要磷脂结合位点的抗原肽。 β_2GPI特异性T细胞的T细胞受体β链受到高度限制，主要使用重新排列的Vβ_7或Vβ_8基因段。刺激B细胞产生抗β_2GPI抗体的T细胞辅助活性通过IL-6和CD40-CD40配体参与介导。 β_2GPI特异性T细胞对细菌中产生的β_2GPI和重组β_2GPI片段的响应响应，但对天然β_2GPI不反应，这表明β_2GPI特异性T细胞识别的表位显然是隐形的。通过暴露于β_2GPI的加密肽来诱导β2GPI特异性T细胞的激活，导致致病性抗β2GPI抗体产生。最后，β_2GPI特异性T细胞是潜在治疗策略的合理靶标，可有选择地抑制APS患者的致病性抗磷脂抗体产生。