Bacterial induction of autoantibodies to β2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome
Bacterial induction of autoantibodies to β2-glycoprotein-I accounts for the infectious etiology of antiphospholipid syndrome
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DOI：
10.1172/jci200212337
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发表时间：
2002-03-01
影响因子：
15.9
通讯作者：
Shoenfeld, Y
中科院分区：
文献类型：
--
作者：
Blank, M;Krause, I;Shoenfeld, Y
抗磷脂综合征（APS）的特征在于存在针对β 2-糖蛋白-I（β 2GPI）的致病性自身抗体。引起抗β 2GPI产生的因素尚未确定，但已报告与感染因子相关。最近，我们确定了一个六肽（TLRVYK），是由致病性抗β 2GPI单克隆抗体特异性识别。在本研究中，我们评估了APS相关的致病潜力的微生物病原体携带序列相关的六肽。研究了用一组微生物制剂免疫的小鼠产生抗β 2GPI自身抗体的情况。从免疫的小鼠中亲和纯化对TLRVYK肽特异性的IgG，并在妊娠第0天被动静脉内输注到幼稚小鼠中。在妊娠第15天评价输注小鼠的APS参数。免疫后，在用流感嗜血杆菌、淋病奈瑟菌或破伤风类毒素免疫的小鼠中观察到抗肽[TLRVYK]抗β 2GPI Ab的高滴度。通过竞争和免疫印迹测定证实了与相应靶分子结合的特异性。输注亲和纯化的抗肽Ab的幼稚小鼠具有显著的血小板减少症、延长的活化部分凝血活酶时间和升高的胎儿丢失百分比，与用致病性抗β 2GPI mAb免疫的对照组小鼠相似。我们的研究建立了实验性APS的分子模拟机制，证明与β 2 GPI同源的细菌肽诱导致病性抗β 2 GPI Ab沿着APS表现。
The antiphospholipid syndrome (APS) is characterized by the presence of pathogenic autoantibodies against beta2-glycoprotein-I (beta2GPI). The factors causing production of anti-beta2GPI remain unidentified, but an association with infectious agents has been reported. Recently, we identified a hexapeptide (TLRVYK) that is recognized specifically by a pathogenic anti-beta2GPI mAb. In the present study we evaluated the APS-related pathogenic potential of microbial pathogens carrying sequences related to this hexapeptide. Mice immunized with a panel of microbial preparations were studied for the development of anti-beta2GPI autoantibodies. IgG specific to the TLRVYK peptide were affinity purified from the immunized mice and passively infused intravenously into naive mice at day 0 of pregnancy. APS parameters were evaluated in the infused mice on day 15 of pregnancy. Following immunization, high titers of antipeptide [TLRVYK] anti-beta2GPI Ab's were observed in mice immunized with Haemophilus influenzae, Neisseria gonorrhoeae, or tetanus toxoid. The specificity of binding to the corresponding target molecules was confirmed by competition and immunoblot assays. Naive mice infused with the affinity-purified antipeptide Ab's had significant thrombocytopenia, prolonged activated partial thromboplastin time and elevated percentage of fetal loss, similar to a control group of mice immunized with a pathogenic anti-beta2GPI m Ab. Our study establishes a mechanism of molecular mimicry in experimental APS, demonstrating that bacterial peptides homologous with beta2GPI induce pathogenic anti-beta2GPI Ab's along with APS manifestations.