origin of antiphospholipid antibodies

抗磷脂综合征(APS)是一种全身性自身免疫性疾病，以静脉或动脉血栓形成或反复妊娠并发症的发生为特征，并持续存在抗磷脂抗体(APL)。APL导致APS临床表现的发生是公认的。虽然目前已经发现了几条导致APS的信号通路，但APS的确切发病机制仍存在争议。此外，目前还不清楚APL是如何发展的。在这种情况下，出现了一个问题，为什么APL在一些人中自发发生，而另一些人则发展为慢性APL滴度。典型的临床表现仅见于后一组患者。一种常见的假说是，细菌和病毒抗原与APL自身抗原结构相似，导致感染相关的自身反应性APL(分子拟态)的发展。描述了适当的结构相似性。一些作者认为APL属于b1b细胞产生的天然抗体。这一假设可以解释一个有趣的小鼠模型，在该模型中，以APL为抗原免疫后仅一周就能检测到APL IgG产生的增加。在用(不合适的)抗原免疫后，如此快速的免疫球蛋白产生只能通过激活预先形成的B1细胞克隆来解释。拟议的项目的目的是调查致病的APL是如何产生的。特别是，应该检查APL属于天然抗体谱系的假设是否能够得到证实。此外，应检查致病性和非致病性APL是从相同的B细胞克隆还是从不同的B细胞克隆释放的。如果能够区分B淋巴细胞，这将是一个新的诊断靶点。否则，我们将关注导致APL分泌的潜在机制。为此，建立了一种可特异性诱导APL分泌的小鼠模型。初步实验已经确定TLR7是一个潜在的候选分子，它似乎对APL的释放至关重要。因此，特异性抑制TLR7可能是抑制APL释放的一种新的治疗途径。

The antiphospholipid syndrome (APS) is a systemic autoimmune disease characterized by the occurrence of either venous or arterial thrombosis or recurrent pregnancy complications combined with the persistent presence of antiphospholipid antibodies (aPL). It is well accepted that aPL cause the development of the clinical manifestations of APS. Although several signaling pathways leading to APS have been identified, the precise pathogenesis of APS is still a matter of debate. Moreover it remains unclear how aPL develop. In this context the question arises why aPL occure spontaneously in some individuals while others develop a chronic aPL titer. The typical clinical manifestations are only detectable in the latter group of patients. A common hypothesis is that bacterial and viral antigens have structural similarities to the autoantigens of the aPL, resulting in the development of infectious-associated autoreactive aPL (molecular mimicry). Appropriate structural similarities have been described. Some authors suggested that aPL belong to a repertoire of natural antibodies that are produced by b1 b-cells. This assumption could explain an interesting mouse model in which an increased aPL IgG production could be detected only one week after immunization with aPL as antigen. Such a rapid IgG production after immunization with an (unsuitable) antigen can only be explained by the activation of preformed B1 cell clones.The aim of the proposed project is to investigate how pathogenic aPLs are generated. In particular, it should be examined whether the hypothesis that aPL belong to the natural antibody repertoire can be confirmed. Furthermore, it should be examined whether pathogenic and non-pathogenic aPL are released from the same or from different B cell clones. If the B lymphocytes can be distinguished, this would represent a new diagnostic target. Otherwise, we will focus on the underlying mechanisms leading to aPL secretion. For this purpose, a mouse model is established in which the secretion of aPL can be specifically induced. Preliminary experiments have already identified TLR7 as a potential candidate molecule, which appears to be essential for the release of aPL. Thus, the specific inhibition of TLR7 could represent a new therapeutic approach to suppress the release of aPL.