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About 1–3% of all couples are confronted with recurrent miscarriage, which is internationally defined as ≥3 consecutive miscarriages before 20 weeks of gestation (Coulam, 1991). Recurrent miscarriage is a heterogeneous disorder. Possible etiologic factors include uterine anomalies, endocrine disorders, acquired thrombophilia (anti-phospholipid syndrome), hereditary thrombophilia, or balanced translocations in the maternal or paternal DNA (Branch et al., 2010; Larsen et al., 2013). However, in many couples no causal factor can be identified (Branch et al., 2010; Rai and Regan, 2006). During pregnancy the maternal immune system has to tolerate the persistence of the semi-allogeneic fetal cells. The extravillous trophoblasts, which is in direct contact with maternal cells, expresses only HLA-C and the non-classical HLA-E, -F and -G. Chimeric fetal cells in the peripheral circulation express all classical HLA class I and II antigens. Approximately 30% of healthy women develop HLA antibodies during pregnancy, the presence of these antibodies increases after 28 weeks of pregnancy and antibodies can still be present at time of a new conception (Regan et al., 1991; van Kampen et al., 2001). Therefore, the incidence of HLA antibodies in the first trimester is higher in multiparous women than in nulliparous women (van Kampen et al., 2001). Binding of antibodies to paternal HLA antigens of the fetus might lead to complement fixation and antibody mediated rejection of the fetus. In women with recurrent miscarriage an increased deposition of C4d, a marker of classical complement activation, was found at the maternal-fetal interface (Meuleman et al., 2015). In spontaneous preterm birth C4d in fetal umbilical cord endothelium was associated with circulating maternal anti-HLA class I antibodies (Lee et al., 2011). A recent meta-analysis showed no significant association between HLA antibodies and the occurrence of recurrent miscarriage (Lashley et al., 2013), however the included studies showed a high level of clinical and statistical heterogeneity. Interestingly, the role of HLA-C specific antibodies has not been studied yet, while from transplantation settings we know that a proportion of alloantibodies cause rejection, amongst others depending on their ability to activate complement (Loupy et al., 2013). We hypothesize that antibody mediated reactivity plays a role in unexplained recurrent miscarriage. Therefore, the incidence of HLA antibodies, especially those directed against the only polymorphic classical HLA I antigen expressed on trophoblast (HLA-C), is compared between women with recurrent miscarriage and women with uneventful pregnancy. In conclusion, in this study which included a homogenous well-defined group of women with recurrent miscarriage, a higher incidence of HLA antibodies was observed compared to women with an uneventful pregnancy. Especially, the presence of complement fixing HLA-C antibodies in relation to the selective expression of HLA-C on trophoblast tissue might explain the aetiology in a proportion of the women with recurrent miscarriage. |
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