origin of antiphospholipid antibodies

抗磷脂抗体的起源

• 批准号: 390959600
• 负责人: Privatdozentin Dr. Nadine Müller-Calleja
• 金额: --
• 依托单位: Institut für Klinische Chemie und Laboratoriumsmedizin
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2017
• 资助国家: 德国
• 起止时间: 2016-12-31 至 2018-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/390959600?language=en
• 关键词: origin; antiphospholipid; antibodies

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.

抗磷脂综合征（APS）是一种系统性自身免疫性疾病，其特征是静脉或动脉血栓形成或反复妊娠并发症的发生，并伴有抗磷脂抗体（aPL）的持续存在。aPL引起APS临床表现的发展已被广泛接受。虽然已经确定了导致APS的几种信号通路，但APS的确切发病机制仍然存在争议。此外，目前尚不清楚aPL如何发展。在这种情况下，问题出现了，为什么aPL自发发生在一些人，而其他人发展慢性aPL滴度。典型的临床表现仅在后一组患者中可检测到。一种常见的假设是，细菌和病毒抗原与aPL的自身抗原具有结构相似性，从而导致感染相关的自身反应性aPL（分子模仿）的发展。已经描述了适当的结构相似性。一些作者认为aPL属于由b1 b细胞产生的天然抗体库。这一假设可以解释一个有趣的小鼠模型，在以aPL为抗原免疫后仅一周就可以检测到aPL IgG产生增加。用（不合适的）抗原免疫后如此快速地产生IgG只能通过激活预先形成的B1细胞克隆来解释。拟建项目的目的是研究致病性原料药是如何产生的。特别是，应该检查aPL属于天然抗体库的假设是否可以证实。此外，还应检查病原性和非病原性aPL是否从相同或不同的B细胞克隆中释放。如果B淋巴细胞可以被区分，这将代表一个新的诊断目标。否则，我们将重点关注导致aPL分泌的潜在机制。为此，我们建立了特异性诱导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。