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

一般认为，抗磷脂综合征(APS)的首要事件是补体系统的激活。我们对与带负电荷的磷脂、心磷脂(CL)或磷脂酰丝氨酸(PS)结合的血浆蛋白进行了蛋白质组学分析，因此可能参与了发病机制。从包埋CL或PS的辛基-琼脂糖柱中回收血浆蛋白，用双向电泳法进行分离。通过肽质量指纹图谱分析，鉴定出H因子、H因子相关蛋白-1、IHRP、补体4、补体C1q和β2糖蛋白I。一组APS患者被证实存在抗H因子抗体，但抗H因子与血栓形成或产科并发症的密切联系并不清楚。这些蛋白目前正在研究它们在抗磷脂抗体存在的情况下诱导兔网织红细胞溶血的能力。失孕是一个…APS患者的并发症较多。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)参与了滋养层侵袭和蜕膜形成等胚胎着床过程。因此，用原位酶谱分析了小鼠子宫中基质金属蛋白酶活性的时空分布，结果表明，与着床后期相比，性交后小鼠子宫中的活性显著增加。活性归因于原MMP9，它从子宫浆膜转移到子宫内膜，但与mRNA上调无关。该活性与浸润性中性粒细胞共同定位，中性粒细胞减少的小鼠不表现出MMP9的表达。去除雄性小鼠的精囊可以消除雌性小鼠性交后MMP9的增加。这些结果表明，植入前子宫中的基质金属蛋白酶活性主要来源于精浆所吸引的含有基质金属蛋白酶原9的中性粒细胞。考虑到我们的结果以及之前关于Mmp9基因缺陷雌性小鼠生育力下降的报道，我们推测中性粒细胞渗透参与了支持怀孕所需的细胞外基质降解。较少

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