Pathogenic role of anti-β2-glycoprotein I antibodies in antiphospholipid associated fetal loss:: characterisation of β2-glycoprotein I binding to trophoblast cells and functional effects of anti-β2-glycoprotein I antibodies in vitro
Pathogenic role of anti-β2-glycoprotein I antibodies in antiphospholipid associated fetal loss:: characterisation of β2-glycoprotein I binding to trophoblast cells and functional effects of anti-β2-glycoprotein I antibodies in vitro
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DOI：
10.1136/ard.2004.021444
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发表时间：
2005-03-01
影响因子：
27.4
通讯作者：
Meroni, PL
中科院分区：
文献类型：
--
作者：
Di Simone, N;Raschi, E;Meroni, PL
背景资料：与β 2-糖蛋白I反应的抗磷脂抗体目的：探讨β 2GPI磷脂结合位点的特异性突变是否影响其与滋养层细胞的结合，进而影响抗β 2GPI抗体的功能效应。通过人单克隆IgM或多克隆IgG抗-β 2GPI抗体与滋养层单层的结合来评价β 2GPI对滋养层的粘附，所述滋养层单层培养于（1）完全培养基中;（2）无血清培养基中;（3）在纯化的人β 2GPI存在下血清饥饿后;或（4）在氨基酸环Cys（281）-Lys-Asn-Lys-Glu-Lys-Lys-Cys（288）中具有单个或多个突变的β 2GPI存在下。结果：β 2GPI与滋养层细胞的粘附及特异性抗体的识别与磷脂结合位点的突变数成反比。抗-β 2GPI抗体降低促性腺激素释放，激素依赖性hCG mRNA的表达，和蛋白质合成在β 2GPI的存在下，而加入突变体或缺乏β 2GPI没有effect.Conclusions：β 2GPI结合滋养层细胞在体外通过其第五域，如报告的内皮细胞，并可以识别的抗-β 2GPI抗体;抗体结合下调滋养层hCG的合成和分泌。这种机制可能有助于与抗磷脂综合征相关的胎儿丢失妇女的胎盘形成缺陷。
Background: Antiphospholipid antibodies reacting with beta2-glycoprotein I (beta2GPI) have been associated with recurrent fetal loss and pregnancy complications.Objective: To investigate whether specific mutations in the phospholipid binding site of b2GPI might affect its binding to trophoblast and in turn the anti-beta2GPI antibody induced functional effects.Methods: beta2GPI adhesion to trophoblast was evaluated as human monoclonal IgM or polyclonal IgG anti-beta2GPI antibody binding to trophoblast monolayers cultured (1) in complete medium; ( 2) in serum-free medium; ( 3) after serum starvation in the presence of purified human beta2GPI; or ( 4) in the presence of beta2GPI with single or multiple mutations in the amino acid loop Cys(281)-Lys-Asn-Lys-Glu-Lys-Lys-Cys(288). The effect of anti-beta2GPI binding to trophoblast was evaluated as chorionic gonadotropin (hCG) mRNA expression, and protein release by RT-PCR and radioimmunoassay, respectively.Results: beta2GPI adhesion to trophoblast and its consequent recognition by the specific antibodies were inversely proportional to the mutation number in the phospholipid binding site. Anti-beta2GPI antibodies reduced gonadotropin release, hormone dependent hCG mRNA expression, and protein synthesis in the presence of beta2GPI, while the addition of the mutants or the absence of beta2GPI had no effect.Conclusions: beta2GPI binds to trophoblast in vitro through its fifth domain, as reported for endothelial cells, and can be recognised by anti-beta2GPI antibodies; the antibody binding downregulates trophoblast hCG synthesis and secretion. Such a mechanism might contribute to defective placentation in women with fetal loss associated with the antiphospholipid syndrome.