Horbach D A, van Oort E, Tempelman M J, Derksen R H, de Groot P G
Department of Haematology, University Hospital Utrecht, The Netherlands.
Thromb Haemost. 1998 Nov;80(5):791-7.
The presence of antiphospholipid antibodies (aPL) is strongly correlated with venous and arterial thrombosis, fetal loss and thrombocytopenia. This relation is called the antiphospholipid syndrome (APS). It is well recognized that thrombosis related aPL are not directed against phospholipids alone, but to phospholipid bound plasma proteins like beta2-glycoprotein I (beta2GPI). aPL that need beta2GPI for the binding to negatively charged phospholipids are called anti-beta2GPI-antibodies. Recently, a mutation in the gene encoding beta2GPI has been described, which results in an amino acid substitution Trp316 into Ser316. This Ser316-beta2GPI did not bind to negatively charged phospholipids. Because only phospholipid bound beta2GPI is recognized by human anti-beta2GPI-antibodies, it might be argued that individuals carrying the Trp316Ser mutation are protected against the development of anti-beta2GPI-antibodies. To investigate this hypothesis, the prevalence of the Trp316Ser mutation was measured in 170 systemic lupus erythematosus (SLE) patients and in 18 patients with the primary antiphospholipid syndrome (PAPS) and the mutation was correlated with the presence of anti-beta2GPI-antibodies. In the total patient group 1 homozygous patient and 21 heterozygous patients were found. The allele frequency of the mutation in SLE patients with anti-beta2GPI-antibodies (0.063) was comparable to that found in SLE patients without anti-beta2GPI-antibodies (0.062). These results indicate that the heterozygous presence of Trp316Ser mutation does not prevent an individual from developing anti-beta2GPI-antibodies. We showed that this can be explained by the concentration of Trp316-beta2GPI in heterozygous patients, which is far above the minimal beta2GPI level necessary for optimal phospholipid binding. In our single patient homozygous for the Trp316Ser mutation no binding beta2GPI to the phospholipid surface was detected and no anti-beta2GPI-antibodies were present in the plasma of this patient. In conclusion, heterozygous Trp316Ser beta2GPI persons are not protected against the development of anti-beta2GPI-antibodies. To confirm that homozygotes do not develop anti-beta2GPI-antibodies a very large population is needed, due to the relatively low prevalence of the mutation.
抗磷脂抗体（aPL）的存在与静脉和动脉血栓形成、胎儿丢失及血小板减少密切相关。这种关系被称为抗磷脂综合征（APS）。众所周知，与血栓形成相关的aPL并非仅针对磷脂，而是针对与磷脂结合的血浆蛋白，如β2糖蛋白I（β2GPI）。需要β2GPI才能与带负电荷的磷脂结合的aPL被称为抗β2GPI抗体。最近，有人描述了编码β2GPI的基因发生突变，导致氨基酸Trp316被替换为Ser316。这种Ser316-β2GPI不能与带负电荷的磷脂结合。由于人类抗β2GPI抗体仅识别与磷脂结合的β2GPI，因此可以认为携带Trp316Ser突变的个体可免受抗β2GPI抗体的产生。为了验证这一假设，对170例系统性红斑狼疮（SLE）患者和18例原发性抗磷脂综合征（PAPS）患者进行了Trp316Ser突变的发生率检测，并将该突变与抗β2GPI抗体的存在进行关联分析。在整个患者组中，发现1例纯合子患者和21例杂合子患者。有抗β2GPI抗体的SLE患者中该突变的等位基因频率（0.063）与无抗β2GPI抗体的SLE患者中发现的频率（0.062）相当。这些结果表明，Trp316Ser突变的杂合状态并不能阻止个体产生抗β2GPI抗体。我们发现这可以用杂合子患者中Trp316-β2GPI的浓度来解释，该浓度远高于最佳磷脂结合所需的最低β2GPI水平。在我们的1例Trp316Ser突变纯合子患者中，未检测到β2GPI与磷脂表面的结合，且该患者血浆中也不存在抗β2GPI抗体。总之，Trp316Serβ2GPI杂合子个体不能免受抗β2GPI抗体的产生。由于该突变的发生率相对较低，因此需要非常大的人群来证实纯合子不会产生抗β2GPI抗体。
