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（APS）的特点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荷物质（包括磷脂）的血浆糖蛋白，已知是与APS临床特征相关的抗磷脂抗体最常见的抗原靶点。在APS患者和实验APS中积累的证据表明，β _2gpi特异性CD4^+ T细胞在抗β _2gpi抗体的产生中起重要作用。在本研究项目中，我们已经鉴定并表征了APS患者中促进抗磷脂抗体产生的自身反应性CD4^+ T细胞β2GPI。β _2gpi特异性CD4^+ T细胞优先识别DRB4^*0103 （DR53）中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抗体的t细胞辅助活性是通过IL-6和CD40-CD40配体结合介导的。β_2GPI特异性T细胞对细菌中产生的减少的β_2GPI和重组的β_2GPI片段有反应，但对天然的β_2GPI没有反应，这表明β_2GPI特异性T细胞识别的表位明显是隐性的。暴露于β 2gpi的隐肽可以诱导β 2gpi特异性T细胞的激活，从而产生致病性抗β 2gpi抗体。最后，β _2gpi特异性T细胞是选择性抑制APS患者致病性抗磷脂抗体产生的潜在治疗策略的合理靶点。

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.