origin of antiphospholipid antibodies

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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.