Dataset Information

The maternal immune response to fetal platelet GPIb? causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies.

ABSTRACT: Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet ?IIb?3 integrin and GPIb? are the major antibody targets in immune thrombocytopenia, the reported incidence of anti-GPIb?-mediated FNIT is rare. Here, we developed mouse models of FNIT mediated by antibodies specific for GPIb? and ?3 integrin and compared their pathogenesis. We found, unexpectedly, that miscarriage occurred in the majority of pregnancies in our model of anti-GPIb?-mediated FNIT, which was far more frequent than in anti-?3-mediated FNIT. Dams with anti-GPIb? antibodies exhibited extensive fibrin deposition and apoptosis/necrosis in their placentas, which severely impaired placental function. Furthermore, anti-GPIb? (but not anti-?3) antiserum activated platelets and enhanced fibrin formation in vitro and thrombus formation in vivo. Importantly, treatment with either intravenous IgG or a monoclonal antibody specific for the neonatal Fc receptor efficiently prevented anti-GPIb?-mediated FNIT. Thus, the maternal immune response to fetal GPIb? causes what we believe to be a previously unidentified, nonclassical FNIT (i.e., spontaneous miscarriage but not neonatal bleeding) in mice. These results suggest that a similar pathology may have masked the severity and frequency of human anti-GPIb?-mediated FNIT, but also point to possible therapeutic interventions.

SUBMITTER: Li C

PROVIDER: S-EPMC3204841 | biostudies-other | 2011 Nov

REPOSITORIES: biostudies-other

ACCESS DATA

Publications

The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies.

Li Conglei C Piran Siavash S Chen Pingguo P Lang Sean S Zarpellon Alessandro A Jin Joseph W JW Zhu Guangheng G Reheman Adili A van der Wal Dianne E DE Simpson Elisa K EK Ni Ran R Gross Peter L PL Ware Jerry J Ruggeri Zaverio M ZM Freedman John J Ni Heyu H

The Journal of clinical investigation 20111024 11

Fetal and neonatal immune thrombocytopenia (FNIT) is a severe bleeding disorder caused by maternal antibody-mediated destruction of fetal/neonatal platelets. It is the most common cause of severe thrombocytopenia in neonates, but the frequency of FNIT-related miscarriage is unknown, and the mechanism(s) underlying fetal mortality have not been explored. Furthermore, although platelet αIIbβ3 integrin and GPIbα are the major antibody targets in immune thrombocytopenia, the reported incidence of an ...[more]

PMID: 22019589

Similar Datasets

Project description:BackgroundFetal cells (microchimerism) are acquired by women during pregnancy. Fetal microchimerism persists decades later and includes cells with pluripotent capacity. Persistent microchimerism has the capacity for both beneficial and detrimental maternal health consequences. Both miscarriage and termination of pregnancy can result in fetal microchimerism. We sought to determine whether cellular fetal microchimerism is acquired during management of pregnancy loss and further explored factors that could influence fetal cell transfer, including viability of fetal tissue, surgical versus medical management and gestational age.MethodsPregnant women (n= 150 samples from 75 women) with singleton pregnancies undergoing a TOP (n= 63) or treatment for embryonic or fetal demise (miscarriage, n= 12) were enrolled. Mononuclear cells were isolated from blood samples drawn before, and 30 min after, treatment. Fetal cellular microchimerism concentrations were determined using quantitative PCR for a Y chromosome-specific sequence, expressed as genome equivalents of fetal DNA per 100 000 maternal cell equivalents (gEq/10(5)). Detection rate ratios were determined according to clinical characteristics.ResultsCellular fetal microchimerism was found more often in post- compared with pretreatment samples, 24 versus 5% (P= 0.004) and at higher concentrations, 0-36 versus 0-0.7 gEq/10(5) (P< 0.001). Likelihood of microchimerism was higher in surgical than medical management, detection rate ratio 24.7 (P= 0.02). The detection rate ratio for TOP versus miscarriage was 16.7 for known male fetuses (P= 0.02). Microchimerism did not vary with gestational age.ConclusionsSignificant fetal cell transfer occurs during miscarriage and TOP. Exploratory analyses support relationships between obstetric clinical factors and acquisition of fetal cellular microchimerism; however, our limited sample size precludes definitive analysis of these relationships, and confirmation is needed. In addition, the long-term persistence and potential consequences of fetal microchimerism on maternal health merit further investigation.

Project description:Transplacental antibody transfer from mother to fetus provides protection from infection in the first weeks of life, and the four different subclasses of IgG (IgG1, IgG2, IgG3, and IgG4) have diverse roles in protection against infection. In this study, we evaluated concentrations and transplacental transfer ratios of the IgG subclasses in a healthy UK-based cohort of mother-cord pairs, and investigated associations with maternal, obstetric, and fetal factors. In agreement with previous studies, we found a strong association between maternal and cord IgG for all subclasses. We report a transfer efficiency hierarchy of IgG1>IgG3>IgG4=IgG2 in our study population, and our review of the literature demonstrates that there is no consensus in the hierarchy of subclass transfer, despite the commonly made statement that the order is IgG1>IgG4>IgG3>IgG2. We report additional data regarding negative associations between elevated maternal IgG concentrations and maternal/cord transfer ratios, finding an effect on IgG1, IgG2, and IgG3 subclasses. Levels of IgG subclasses were the same between venous and arterial blood samples from the umbilical cord, but there was a significantly higher level of total IgG in arterial blood. We found no correlation between placental FcRn protein levels and IgG transfer in our cohort, suggesting that IgG is the main determinant of observed differences in transplacental transfer ratios at term. Neonatal IgG1 and IgG4 levels were increased with later gestation at delivery, independent of any increase in transplacental transfer, indicating that the benefit of later gestation is through accumulation of these subclasses in the fetus. Neonatal IgG2 levels and transfer ratios were reduced in rhesus-negative pregnancies, suggesting that administered anti-D antibodies may compete for transplacental transfer of this subclass. Maternal influenza vaccination resulted in elevated maternal and neonatal levels of IgG4, whereas maternal Tdap vaccination had no impact on neonatal levels of the subclasses, nor transfer. However, within Tdap vaccinated pregnancies, later gestation at Tdap vaccination was associated with higher transplacental transfer. Our study provides information regarding levels and transfer of IgG subclasses in healthy term pregnancies and demonstrates the importance of recording detailed clinical information in studies of antibody transfer, including parity, ethnicity, and timing of maternal vaccine delivery.

Dataset Information

The maternal immune response to fetal platelet GPIb? causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies.

Publications

The maternal immune response to fetal platelet GPIbα causes frequent miscarriage in mice that can be prevented by intravenous IgG and anti-FcRn therapies.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets