Antiphospholipid syndrome : Elucidation of molecular mechanism to give insights into new therapeutic approach

人们普遍认为，抗磷脂综合征（APS）的主要事件是补体系统的激活。我们对血浆蛋白进行了蛋白质组学分析，这些蛋白与带负电荷的磷脂、心磷脂（CL）或磷脂酰丝氨酸（PS）结合，因此可能参与了发病机制。从包埋CL或PS的Octyl-Sepharose柱中回收的血浆蛋白通过双向电泳分离。通过肽质量指纹图谱鉴定因子H、因子H相关蛋白1、IHRP、补体4、补体C1q和β 2糖蛋白I。一组APS患者被证明有抗因子H抗体，但抗因子H与血栓或产科并发症的密切联系并没有明确证明。目前正在研究这些蛋白在APS患者的抗磷脂IgG存在下诱导兔网织红细胞溶血的能力。流产是APS患者的并发症之一。从这个角度来看，植入可能是抗磷脂抗体的靶点。基质金属蛋白酶（MMPs）参与胚胎着床过程，如滋养细胞侵袭和脱体细胞化。因此，通过原位酶谱分析了MMP生物活性的时空分布，结果表明，与植入后期相比，这些活性在性交后小鼠子宫中明显增加。活性归因于proMMP9，它从子宫浆膜移动到子宫内膜，但与mRNA上调无关。该活性与浸润的中性粒细胞共定位，中性粒细胞减少的小鼠不表现出MMP9的表达。切除雄性小鼠的精囊后，雌性小鼠的MMP9在性交后的增加被消除。这些结果表明，着床前子宫中主要的MMP活性源于精浆吸引的携带prommp9的中性粒细胞。考虑到我们的结果以及之前关于缺乏mmp9的雌性小鼠生育能力降低的报道，我们推测中性粒细胞浸润参与了支持妊娠所需的细胞外基质降解。少

It is generally accepted that the primary event of antiphohpholipid syndrome (APS) is the activation of the complement system. We carried out a proteomic analysis of the plasma proteins that are binding to negatively charged phospholipids, cardiolipin (CL) or phosphatidylserine (PS), and are thus potentially involved in the pathogenesis. The plasma proteins recovered from an Octyl-Sepharose column, in which CL or PS was embedded, were separated by two-dimensional electrophoresis. By peptide mass fingerprinting, factor H, factor H-related protein-1, IHRP, Complement 4, complement C1q and beta2 glycoprotein I were identified. A group of APS patients was demonstrated to have anti-factor H antibodies, but a close link of anti-factor H to the thrombotic or obstetric complications was not clearly demonstrated. These proteins are now being studied for their capability of inducing hemolysis of rabbit reticulocytes in the presence of antiphospholipid IgG from the APS patients.Miscarriage is one … More of the complications found in APS patients. From this point of view, implantation may be a target of antiphospholipid antibodies. Matrix metalloproteinases (MMPs) have been implicated in embryonal implantation processes such as trophoblast invasion and decidualization. Therefore, temporal and spatial distributions of MMP bioactivities were analyzed by in situ zymography, which indicated these activities to be markedly increased in the post-coital mouse uterus as compared with the later implantation stage. Activity was ascribed to proMMP9, which moved from the uterine serosa to the endometrium but was not associated with mRNA upregulation. The activity was co-localized with infiltrating neutrophils, and neutropenic mice did not exhibit MMP9 expression. Removing the seminal vesicles from male mice abolished the post-coital increase in MMP9 in the female. These results indicate the major MMP activity in the preimplantation uterus to originate in proMMP9-bearing neutrophils attracted by seminal plasma. Considering our results together with those of previous reports of reduced fertility in Mmp9-deficient female mice, we speculate that neutrophil infiltration participates in the extracellular matrix degradation needed to support pregnancy. Less